Generex Pipeline Review by Rich Steffens

Antigen Express Makes Progress in Targeting Early Stage Breast Cancer Patients Who Don't Benefit From Roche's Herceptin

2012-01-07T19:25:00.000-08:00

As we look forward to cancer research developments in 2012, let's first take a quick look back to 2005. In that year, Genentech, which was acquired for $46.8B in 2009 by Roche (RHHBY.PK), presented findings for their now blockbuster cancer fighting drug Herceptin to a packed room at ASCO's Annual Meeting. Herceptin was found to reduce the risk of recurrence 46% in women with early stage over expressing HER2 breast cancer, according to results reported for the first time from the large scale international HERA study.

Results from HERA showed that Herceptin significantly improved disease free survival at two years, from 77.4% in the observation group to 85.8%. Lisa Hutchinson, the Editor of Nature ReviewsClinical Oncology, wrote at the time that the Herceptin report "received rapturous applause and a standing ovation" from physicians and other attendees at the ASCO session.

Herceptin is a humanized monoclonal antibody that binds to a specific epitope of the HER2 protein on the breast cancer cell surface. Herceptin is a HER2+ breast cancer therapy designed to treat aggressive HER positive metastatic and adjuvant breast cancer. Adjuvant therapy is used after primary treatments, such as surgery or radiation for early stage invasive breast cancer. This additional treatment may reduce the risk that cancer will return.

The IHC test gives a score of 0 to 3+ that indicates the amount of HER2 receptor protein in tumors. Women with IHC positive scores tend to respond favorably to Herceptin. Samples with strong HER2 overexpression, IHC 3+, indicate eligibility for Herceptin therapy. This population makes up approximately 25% of HER2/neu breast cancer patients.

In the first six months of 2011, Roche reported worldwide sales of Herceptin at $3.5B. Approximately 70% of Herceptin's global sales come from adjuvant therapy for women with early-stage HER2 breast cancer following surgery. Immunological agents in development that target patients that exhibit lower expression of the HER-2/neu protein can fill an unmet medical need, and potentially earn far greater sales than Herceptin if they move on to win FDA approval.

During December's San Antonio Breast Cancer Symposium, cancer immunotherapy took another significant step in that direction when interim Phase II results were revealed for Antigen Express' AE37 HER2/neu peptide breast cancer vaccine. Antigen Express is a wholly owned subsidiary for Generex (GNBT.OB) Biotechnology. Here are highlights from the SABCS presentation:

+ Disease-free survival in the low HER2 expressing patients, or the larger percentage of breast cancer patients who are not eligible for Herceptin, was 88.6% in the treated group, n=53, versus 71.9% in the control arm, n=78, at a median follow-up of 22 months.

+ The AE37 vaccine elicits statistically significant peptide specific in-vivo and ex-vivo immune responses, which are maintained for 12 months after completion ofthe vaccine series, while there have been no proliferative changes for control patients.

+ Vaccine patients had statistically significant increases in DTH reactions, while controls had no response.

+ 99% of local and systemic toxicities were grade 2 or less. There have been no grade 4-5 local or systemic toxicities.

+ AE37 represents the only HER2-based peptide vaccine currently being studied in a randomized trial, and its use is not restricted to patients with a particular type of HLA peptide.

There are currently over 250 patients enrolled in the well designed Phase 2 study, the largest breast cancer adjuvant vaccine trial conducted to date. As a result of these findings, Antigen Express announced that they are "assessing the data for potential opportunity to move forward with a Phase 3 clinical development program following an End-of-Phase 2 meeting with the FDA for AE37, which Antigen Express believes, if confirmed, could occur in the first half of 2012". The company will seek a special protocol assessment SPA approval from the FDA. The current ongoing, controlled, randomized, and single-blinded Phase 2 clinical study will continue as planned to enroll a total of 300 women. Further Phase II results, providing a catalyst moment for GNBT's stock, are due within 2012.

Antigen Express is seeking a large Pharma partner to help fund the pivotal Phase 3 clinical development program in women with breast cancer that express low to moderate levels of HER2. A randomized, controlled, double blind study in 1000 HER 1+ 2+ node positive and high risk node negative patients across the US, Europe and Asia is projected to start later in 2012, once a large Pharma partner is in place.

The AE37 cancer vaccine has also been studied in a completed Phase 1 trial with prostate cancer patients demonstrating appropriate dosing and immune activation similar to that seen in the breast cancer trials. Antigen Express is gearing up to move AE37 more rapidly into larger Phase II clinical trial in men with newly diagnosed HER2 positive prostate cancer, which are currently being designed with leading oncologists in prostate cancer. HER-2/neu is over expressed in 11% of ovarian cancers, 39% of prostate cancers, 7 – 34% of gastric cancers, 10 – 82% of pancreatic adenocarcinomas, and is expressed at some level in the majority of epithelial-derived cancers. The potential market for a HER2-based peptide vaccine, such as AE37, is much larger than women with early stage breast cancer or men with newly diagnosed HER2 positive prostate cancer.

Beyond these known developments, a November 2011 patent application reveals plans to further research into combination therapy of AE37 with Herceptin by the Henry M. Jackson Foundation for the Advancement of Military Medicine. The patent details a Phase I study protocol that currently includes 102 disease-free breast cancer patients that over express HER2, IHC 3+, further expanding AE37's potential market grasp. In the patent, the researchers of the study, who are independent of Generex and Antigen Express, state in regards to the study's outcomes that "the in vivo DTH data strongly suggest that AE37 in combination with Herceptin should be more effective at reducing breast cancer recurrence and increasing disease-free survival time than Herceptin alone".

Investing in small biotechs comes with great risk, and each investor is responsible to themsleves to conduct their own due diligence. Generex had previously outlined plans to conduct a reverse stock split of GNBT shares sometime in the near future, only in conjunction with a move to a major exchange, to spin out Antigen Express, while retaining controlling interest, and the spin-out will be accomplished by the issuance of one or more dividends of Antigen Express stock to Generex stockholders. The company has not publicly altered these intentions, and shareholders are awaiting an update on these key areas.

What we may be witnessing is a new era in therapeutic cancer vaccines where the earlier setbacks seen in the overall industry make way to success stories, as Herceptin's success has done for the monoclonal antibody market, as I wrote to an industry leader last year. "I do believe that the cancer vaccine market will follow after the monoclonal antibody market. Once there is a clear cut success story, then all the big pharmas will race to secure their own cancer vaccines to bring to market," expressed Col George E Peoples MD, FACS, Director, Cancer Vaccine Development Program, in a response email. I am increasingly hopeful that Antigen Express' AE37 will prove to be the revoltuionary vaccine that leads the way.

An Update of a Phase II Trial of the HER2 Peptide AE37 Vaccine in Breast Cancer Patients To Prevent Recurrence

2012-01-02T17:39:00.000-08:00

The following is the full abstract detailing interim results of the AE37 HER2/neu peptide vaccine that was presented at the San Antonio Breast Cancer Symposium in December:

Hale DF, Perez S, Sears AK, Clifton GT, Vreeland TJ, Holmes JP, Ardavanis A, Pistamaltzian N, Rellias G, Ponniah S, Papamichail M, Peoples GE, Mittendorf EA. Brooke Army Medical Center, Ft. Sam Houston, TX; Saint Savas Cancer Hospital, Athens, Greece; Naval Medical Center San Diego, San Diego, CA; Uniformed Services University of the Health Sciences, USMCI, Bethesda, MD; UT M.D. Anderson Cancer Center, Houston, TX

Introduction

AE37 is the Ii-Key hybrid of the HER2-derived peptide AE36 (HER2:776-790). A phase I trial administering AE37 with the immunoadjuvant GM-CSF demonstrated the vaccine to be safe and capable of stimulating CD4+helper T-cells with HER2-specific anti-tumor activity. Here we present an update of our prospective, randomized, single-blinded, phase II trial of the AE37 vaccine for the prevention of breast cancer recurrence in disease-free, high risk patients.

Methods

After completion of standard therapy, disease-free, node positive or high risk node negative breast cancer patients were randomized to receive either AE37+GM-CSF (vaccine) or GM-CSF alone (control) in six monthly intradermal inoculations. Patients were enrolled with any level of HER2 expression, (IHC 1+ 2+ or 3+). Specific immunologic responses to both AE36 and AE37 were evaluated in all patients at pre-determined intervals: before (RO), mid-series (R3), upon completion (R6), and at six (RC6) and 12 (RC12) months after completion of the vaccine series. In vitro responses were measured using the [3H]-thymidine incorporation assay and in vivo responses using delayed-type hypersensitivity (DTH) reactions. The trial's primary endpoint is disease recurrence.

Results

To date, 215 patients have enrolled (vaccine=92, control=123). 99% of local and systemic toxicities were ≤grade 2 or less. There were no grade 4-5 local or systemic toxicities and no difference between toxicity profiles of vaccine and control groups. Vaccine patients exhibited a statistically significant increase from baseline in AE36 and AE37 proliferative responses at each time point, including maintenance of this response up to 12 months post-vaccination (AE36 (cpm):

R0=0, R3=1335, R6=1242, RC6=1586, RC12=1360; AE37: R0=0, R3=2859, R6=2300, RC6=3235, RC12=3279, p<0.001) while there have been no proliferative changes for control patients (AE36: R0=91, R3=95, R6=97, RC6=126, RC12=48; AE37: R0=291, R3=399, R6=319, RC6=103, RC12=0). Vaccine patients also had statistically significant increases in DTH reactions to both AE36 and AE37 (AE36 (mm): R0=0, R6=15, RC6=15, RC12=15; AE37: R0=0, R6=24, RC6=17, RC12=20 p=<0.001) while controls had no response (AE36: R0, R6, RC6, RC12=0; AE37: R0, R6, RC6, RC12=0).

With a median follow up of 17 months, breast cancer recurrences were reduced by 42% in vaccine patients compared to control patients (7.6% vs. 13.2%, p=0.15). In an analysis of patients with low HER2 expression (IHC 1 or 2+), vaccine patients experienced a 49% reduction in recurrence compared to controls (9.5% vs. 18.6%, p=0.16) with no reduction seen in HER2 over-expressing patients (6.0% vs. 7.9%, p=0.49).

Conclusions

The AE37 vaccine is safe and well tolerated with only mild toxicity, which is attributable to the GM-CSF immunoadjuvant. The AE37 vaccine elicits strong peptide specific in-vivo and ex-vivo immune responses, which are maintained for 12 months after completion of the vaccine series. While the number of recurrences are still low, the recurrence rate appears to decrease in vaccinated patients. Administration of the AE37 vaccine may reduce the risk of breast cancer recurrence with the greatest benefit in patients with low levels of HER2 expression.

The poster, which accompanies the abstract, details further information of the interim analysis. Here's some of findings,

AE37 is the Ii-Key hybrid of the HER2-derived peptide AE36 (HER2:776-790). A phase I trial administering AE37 with the immunoadjuvant GM-CSF demonstrated vaccine capable of stimulating CD4+helper T-cells with HER2-specific anti-tumor activity.
Here we present an update of our prospective, randomized, single-blinded, phase II trial of the AE37 + GM-CSF vs. GM-CSF alone for the prevention of breast
cancer recurrence in disease-free, high risk patients.

To date, 247 patients have enrolled (vaccine=103, control=144).

99% of local and systemic toxicities were grade 2 or less. There
have been no grade 4-5 local or systemic toxicities.

Vaccine patients exhibited a statistically significant increase baseline in AE36 and AE37 proliferative responses at each time point, including maintenance of this response up to 12 months post-vaccination while there have been no proliferative changes for control patients.

Vaccine patients also had statistically significant increases in DTH reactions to both AE36 and AE37 while controls had no response.

With a median follow up of 22 months disease free survival (DFS) was improved from 82% to 89.7% in the vaccinated patients compared to controls corresponding to a
43% reduction in recurrences.

In subset analyses by HER2 expression levels, DFS was improved from 71.9% to 88.6% in vaccinated patients with low HER2 expression (IHC 1+ or 2+) compared to controls
corresponding to a 46% reduction in recurrences. There was no improvement in DFS for patients with HER2 over-expressing (IHC 3+ or FISH positive) tumors comparing to controls.

The AE37 vaccine is safe and well tolerated with only mild toxicity, which is attributable to the GM-CSF immunoadjuvant. The AE37 vaccine elicits strong peptide specific in-vivo and ex-vivo immune responses, which are maintained for 12 months after completion ofthe vaccine series. While the number of recurrences are
still low the reactions the recurrence rate is decreased in vaccinated
patients. Administration of the AE37 vaccine may reduce the risk of breast cancer recurrence with the greatest benefit in patients with low levels of HER2 expression.

Recent Advances in Understanding the Immune System and the Role of T Helper Cells

2011-12-02T19:56:00.000-08:00

Utilizing a modulated immune response mediated by T helper cells, Antigen Express technology focuses on a class of lymphocytes that plays a multifaceted role in the immune system, both enhancing and suppressing immune response. In this podcast, Eric von Hofe, Ph.D., President of Antigen Express, takes a look at advancements in immunotherapy and their studies investigating the efficacy and safety of these technology platforms.

Listen to this podcast from Dr von Hofe here.

New AE37 Phase II Data to be Presented at SABCS 2011

2011-09-23T17:47:00.000-07:00

Researchers from the United States Military Cancer Institute will present new study findings from the ongoing Phase II trial of AE37 as a preventative cancer vaccine at the upcoming San Antonio Breast Cancer Symposium. The SABCS is a collaboration between the Cancer Therapy & Research Center (CTRC) at UT Health Science Center San Antonio and the American Association for Cancer Research (AACR). The symposium is the premier event for presenting and discussing the latest in breast cancer research.

The SABCS takes place between December 6th and 10th, and is held at the Henry B. Gonzalez Convention Center, San Antonio, Texas. The abstract and poster relating to AE37 will be shown during Poster Session 1, "Treatment - Therapeutic Strategies: Immunotherapy". The following is the title with listed authors from the USMCI:

P1-13-01 An Update of a Phase II Trial of the HER2 Peptide AE37 Vaccine in Breast Cancer Patients To Prevent Recurrence
Hale DF, Perez S, Sears AK, Clifton GT, Vreeland TJ, Holmes JP, Ardavanis A, Pistamaltzian N, Rellias G, Ponniah S, Papamichail M, Peoples GE, Mittendorf EA. Brooke Army Medical Center, Ft. Sam Houston, TX; Saint Savas Cancer Hospital, Athens, Greece; Naval Medical Center San Diego, San Diego, CA; Uniformed Services University of the Health Sciences, USMCI, Bethesda, MD; UT M.D. Anderson Cancer Center, Houston, TX.

The full abstract will be available during the event. Click on the title of the AE37 abstract to view the SABCS website.

AE37: A Novel T-Cell Eliciting Vaccine for HER2/neu Breast Cancer

2011-09-08T15:54:00.000-07:00

Antigen Express is a wholly owned subsidiary of Generex Biotechnology. Col George Peoples, and the United States Military Cancer Institute researchers studying Antigen Express' AE37 vaccine, have published a new article that will appear in a future edition of Expert Opinion on Biological Therapy. The title is AE37: a novel T-cell-eliciting vaccine for breast cancer.

ABSTRACT

Introduction: Immunotherapy, including vaccines targeting the human EGFR2 (HER-2/neu) protein, is an active area of investigation in combating breast cancer. Several vaccines are currently undergoing clinical trials, most of which are CD8+ T-cell-eliciting vaccines. AE37 is a promising primarily CD4+ T-cell-eliciting HER-2/neu breast cancer vaccine currently in clinical trials.

Areas covered: This article reviews preclinical investigations as well as findings from completed and ongoing Phase I and Phase II clinical trials of the AE37 vaccine.

Expert opinion: Clinical trials have shown the AE37 vaccine to be safe and capable of generating peptide-specific, durable immune responses. This has been shown in patients with any level of HER-2/neu expression. Early clinical findings suggest there may be benefit to AE37 vaccination in preventing breast cancer recurrence.

HER-2/neu, Herceptin, and Cancer Vaccines

I purchased the entire article, and will highlight certain findings. A complete re-paste of the article would infringe on certain copyright protections, so I'll do my best to report on the article. The authors begin by noting that in addition to expression in breast cancer, HER-2/neu is over expressed in 11% of ovarian cancers, 39% of prostate cancers, 7 – 34% of gastric cancers, 10 – 82% of pancreatic adenocarcinomas, and is expressed at some level in the majority of epithelial-derived cancers. Immunological agents targeting HER-2/neu include Roche's Herceptin, as well as other monoclonal antibodies that are in development.

In the adjuvant setting, or before metastatic late stage disease, Herceptin has been shown to reduce breast cancer recurrence by 50%. Currently, Herceptin is reserved for breast cancer patients who over express the HER-2/neu protein, or those that are HER2 3+. The authors note that the HER-2/neu protein is an attractive target for immunotherapy, since it is well characterized, contains multiple immunogenic epitopes, and promotes cancer cell growth. This review focuses on AE37, an example of a HER-2/neu-targeted vaccine, with comparison to Herceptin and RXi Pharmaceuticals E75, also known as NeuVax.

The authors state that vaccines targeting HER-2/neu may add additional therapeutic options for breast cancer patients with any level of HER-2/neu expression, which as previously noted is in contrast to Herceptin, and may bring even greater immunological and clinical benefit to those patients with lower levels of HER-2/neu expression. The patients that express HER2 in lower levels, or HER2 1+ and 2+, are not eligible for treatment with Herceptin. Additionally, successfully developed vaccines may allow the generation of long-term immunological protection from cancer, without the need for repeat infusions required with monoclonal antibodies. Several breast cancer vaccines are currently under investigation, though none have yet been approved by the FDA.

E75 and AE37

RXi Pharma's E75, a CD8+ T-cell-eliciting vaccine, is a HLA-A2/A3-restricted MHC class I epitope, which limits the amount of HER2/neu expressing breast cancer patients it may benefit. I'll note that AE37 is a promiscuous peptide vaccine, with no such HLA restrictions. The authors remark that immunity from the E75 vaccine wanes over time, although a booster inoculation series helps sustain an effective peptide-specific immune response. While such a CD8+ T-cell vaccine appears effective at eliciting cytolytic activity against HER2/neu tumors, the authors acknowledge that there is concern that a long memory vaccine specific immune response will require the use of a CD4+ helper T cell epitope, such as AE37.

The report continues to highlight preclinical and Phase I findings for Antigen Express' AE37 vaccine. To give some background, which is difficult to understand, let's look at the natural, or unmodified, peptide called AE36. AE36 is a HER2-derived peptide from the intracellular domain of the HER-2/neu protein, 776-790. AE37 is the Ii-Key hybrid modified peptide of HER2/neu, 776-790 (AE36). AE37 represents the natural AE36 peptide with the addition of the four amino acid Ii-Key peptide moiety from the Ii protein.

Ii-Key Hybrids, the General in this War against Cancer

Ii-Key hybrid technology is patented by Antigen Express. The first four amino acids of the Ii protein, or the Ii-Key peptide, increase the binding potency of MHC class II epitopes up to 250-fold, all while bypassing the usual intracellular antigen processing. There is much more to this, but if we take our time, we can understand some of these basics.

AE37 is thought of primarily as a CD4+ T-cell-eliciting vaccine, but the authors state that preclinical research has shown that while the Ii-Key hybrid AE37 enhanced proliferation of CD4+ T cells, it also significantly enhanced CD8+ T-cells' anti tumor activity. This is important, and groundbreaking. AE37, the Ii-Key hybrid vaccine, acts as the General (CD4+ T cells), and move the troops (CD8+ T cells) into action to kill cancer tumors. The authors didn't word this that way, but this is my silly explanation.

The authors continue to reveal that the Phase I study of AE37 with breast cancer patients yielded important findings. AE37 resulted in peptide-specific immune responses, which were significantly increased from baseline to completion of the vaccination series. Unlike with E75, the responses to AE37 were long lasting. The adjuvant used in all of the peptide vaccines (AE37, E75, and the CD8+ T cell eliciting vaccine named GP2), is GM-CSF. Certain patients were not given the immunoadjuvant GM-CSF. AE37 induced significant increases in both in vivo and in vitro immune responses in those patients who were not given the immunoadjuvant GM-CSF. AE37 is the first peptide vaccine to exhibit such potency in the absence of an adjuvant, as this General fires a strong weapon.

Adjuvants, Toxicity, and Hope

Concern existed that AE37's potent stimulation of CD4+ T cells could also stimulate regulatory T cells, called Tregs. Findings from the Phase I study have shown the opposite, that AE37 vaccination resulted in a decrease in the level of Tregs. Also boding well for AE37, was the findings that DTH reactions were more robust for AE37 as opposed to other peptide vaccines, with mild levels of toxicity to the vaccine amongst patients. Most reactions, although nearly always mild, to peptide based vaccines stem from the adjuvant, and AE37 requires the smaller amounts of adjuvant versus any others.

The HER-2/neu protein is also overexpressed in many prostate cancers, and the authors detailed findings from a Phase I study of AE37 in prostate cancer patients. DTH reactions were similarly positive. Toxicity was again very low, with long term immunity measured. Tregs cells were decreased six months after vaccination from pre-vaccination levels. The prostate cancer study found that found that patients with metastatic disease had smaller in vivo responses as opposed to patients with non-metastatic disease, and patients with low levels of HER-2/neu, 1+ and 2+, had significantly enhanced in vitro immune responses.

The findings from the prostate cancer Phase I study helped the investigators choose this element of the path being taken for the breast cancer Phase III. AE37 is currently being tested in a Phase II study for breast cancer patients with early stage disease, with a Phase III being designed with patients exhibiting lower levels of HER2/neu expression. This group is not eligible for Herceptin, and they have an unmet need with no current targeted options. AE37 may fill that unmet need, offering hope to the hopeless.

AE37's Ongoing Phase II Shows Success

The authors remark upon positive early findings from the ongoing Phase II study with breast cancer patients. As of January 2011, they had enrolled 206 patients, with 330 making the final tally. Toxicity is again very mild. Immunological responses have been significant, as well as in vivo measurements by DTH reactions, to the AE37 vaccine. Once again, there is a noted decrease in the levels of Tregs for the patients receiving AE37, with no changes in the control group. Basically, wow. A quote from the report:

Although preliminary, in the current Phase II trial we have observed an approximately 40% reduction in breast cancer recurrence at 17 months of median follow-up in patients treated with the AE37 peptide vaccine. Per trial design, patients are being followed for clinical recurrences and data regarding the efficacy of the vaccine will be reported after a median follow-up of 24 months.

The authors conclude that these clinical trials of the AE37 vaccine, administered with GM-CSF, have shown it to be safe and well-tolerated. Immune responses have been persistent, measured as long as 12 months after completion of the vaccine series. The authors state that these early findings suggest a clinical benefit of the AE37 vaccine in the prevention of breast cancer recurrence. We all look forward to learning more, as Generex gears up to spin out Antigen Express to a national exchange.

Click the word HOME to see earlier blogs, although they may make you sleepy.

Complications from My Sister's Juvenile Diabetes Hits Home

2011-07-27T19:14:00.000-07:00

My sister was diagnosed with Type 1 diabetes when she was in the ninth or tenth grade of high school. She was very active, and even after her diagnosis she served as the captain of the varsity cheerleading squad. She graduated at the top of her class. However, the complications from her disease struck her hard.

Susan battled with bulimia, and hated taking insulin injections. She did not want to be sick, and the needles made her feel her illness even more. I am talking more about a mental weakness. The thought of the needles, and the perception created while injecting insulin at school, did not fit with her attempts to appear perfect. She skipped her injections, manipulated her weight, and only took hold of properly controlling her diabetes when she approached twenty years old.

None of us are perfect, and she made mistakes. Diabetes is a consuming illness to live with, and treat. Juvenile diabetes is tougher for the young, as opposed to Type 2 diabetes, and how it effects an adult. I'm no doctor, so I'll skip explaining why I feel this is the case.

Susan grew into a wonderful and loving woman. She held high ranking jobs at Pepsi, and Disney. Fiercely independent, she moved to Oralando, and thrived. However, her body suffered the consequences of her earlier non-compliance to an insulin regimen. She lost feeling in her feet, and developed tunnel vision. Her kidneys eventually failed, and my father donated his kidney to her in 2001. That kidney has now failed, and she is back on dialysis.

I am fortunate to be a match, and I am donating my kidney to her tomorrow at noon. The surgery takes place at St Barnabas in Livingston. The complications from her diabetes has touched all of us in the family, and it is nothing short of a blessing to help her gain her health and freedom back. I do not want her sentenced to dialysis, since she is still young, and brings happiness to so many. Also, she would do anything for me.

My interest in Generex originated from a deep appreciation for the work they were doing in developing a non-invasive insulin delivery system. RapidMist and Oral-lyn will be their own blessing to juvenile diabetics like Susan, who would be more apt to follow a regimen that was free of needles, and free of the negative perceptions that come with injections.

Oral-lyn was not there to help my sister, but I am. She is always there for me. Oral-lyn will help the next generation, so many of these complications that result from non-compliance, eventually leading to kidney failure, will not occur.

Feuerstein Trips Over Generex in TheStreet

2011-06-27T17:59:00.000-07:00

"Ignorance more frequently begets confidence than does knowledge" ~ Charles Darwin

On June 24th, TheStreet's (TST) Senior Biotech Columnist Adam Feuerstein featured Generex (GNBT) Biotechnology and their buccal insulin spray, Oral-lyn, in his Biotech Stock Mailbag. Feuerstein put his spin on a press release Generex issued on June 16th, regarding the updated clinical and regulatory program planned for Oral-lyn. In the news release, Generex outlined the clinical path Oral-lyn will take before a submission for commercial approval will be made to the FDA. Generex had already announced this plan, which was made after the company received feedback from the FDA in late May, at their Annual Meeting on June 8th. The Annual Meeting was offered live via a webcast, and remains available on Generex's website .

Feuerstein began his latest blog about Generex by saying: "It's not in my nature to begin the Biotech Stock Mailbag with a congratulatory slap on my own back, so please allow me to indulge this one time as I revel in the latest failure acknowledged by Generex biotechnology. Last week, Generex finally admitted what every rational human being understood a long time ago: The company's experimental insulin spray for diabetes, known as Oral-Lyn, is not ready for regulatory approval. The ongoing phase III study of Oral-lyn, years behind schedule, is being shut down and cannot serve as the basis for a U.S. approval filing, Generex said."

Feuerstein's reporting that the current Phase III study is being "shut down" is completely false. On June 8th, Generex announced at their Annual Meeting that a "protocol approved" enrollment target of 500 patients has been met, and final results may be available by the end of the year. The company informed that the study results will play a key part in a future NDA, and in designing the next clinical steps to achieve that goal. Subsequently, in a press release issued on June 16th, Generex announced that Phase III "clinical trial 084 in patients with type 1 diabetes will be closed to allow a final data analysis to guide future clinical trial plans. Interim results demonstrated that the type 1 patients treated with Generex Oral-lyn™ maintained metabolic control (hemoglobin A1c) over the 12 month duration of the trial."

Feuerstein also stated in his article that "Generex updated the status of Oral-lyn based on information received in May from officials at the U.S. Food and Drug Administration. The agency, discussing Oral-lyn, raised a "variety of questions about preclinical, clinical, toxicology, manufacturing, and regulatory and product labeling issues related to the wide variety of formulations and prior protocol changes that were made historically."

Feuerstein omitted key parts of Generex's update. Generex, in their update, issued five sentences relating to feedback they received from the FDA, while Ffeuerstein chose to clip out only one. Here is the actual update: "Generex received written guidance from the US Food and Drug Administration (FDA) in late May in response to data submitted on Generex Oral-lyn™. There were no safety issues identified in the clinical trials, nor safety questions raised by the FDA. The FDA did not express any concerns about the RapidMist™ delivery device. There were a variety of questions about preclinical, clinical, toxicology, manufacturing, and regulatory and product labeling issues related to the wide variety of formulations and prior protocol changes that were made historically. Generex's new medical/regulatory team has already responded to the FDA, and is in the process of providing the additional information requested for complete clarification. The FDA guidance placed no limitations or restrictions on the types of patients included or trial designs of current or future clinical studies."

In my opinion, Generex's new medical and regulatory team are working fast to put Oral-lyn on a smarter track to win fuller label approval. The FDA guidance placed no limitations or restrictions on the types of patients included or trial designs of current or future clinical studies, which is a big plus for future labeling plans. Perhaps Feuerstein can explain why he avoided these details, which provide a wider and more accurate picture.

In the comment section of Feuerstein's latest blog about Generex, he stated that "Generex holds a shareholder meeting on June 8, at which a reverse stock split is approved. Management doesn't tell shareholders that another three years of clinical work on Oral-lyn will be required."

In reality, Generex's Senior Scientific Advisor, Dr Joseph Anderson, who previously served as Eli Lilly's Senior Medical Director, gave an update on Oral-lyn's regulatory and clinical standing early into the June 8th Annual Meeting. He clearly informed shareholders that the current Phase III study in Type 1 patients will not be sufficient for a NDA. Dr Anderson remarked on plans for a fuller label, beyond Type 1's, that would provide shareholders the maximum value that should be obtained with Oral-lyn.

Dr Anderson also told shareholders that until Generex completes a consensus meeting with the FDA, he would have a hard time giving guidance on when a NDA may be submitted. He estimated between 36 and 72 months. He said he believed the timeline may actually be significantly shorter, dependent upon pending FDA guidance from the consensus meeting. Dr Anderson informed that Type 1 patients represent less than 10% of people with diabetes, and they need to make include patients with Type 2 diabetes in an additional Phase III study.

Generex alerted that this consensus meeting with the FDA, to obtain agreement with the clinical plan and submission data package, is planned this year. The additional planned clinical studies include a key activity/effect study with the final formulation, and a series of small, well-designed phase 3 studies, potentially conducted as one study with multiple arms. Generex anticipates that these studies will be completed during 2013.

In the comment section which accompanies Feuerstein's blog, I noted his error in stating that Generex did not inform shareholders during the company's Annual Meeting that additional clinical work will be required to gain FDA approval for Oral-lyn. He quickly offered a snarly response, calling me a "dead ender", while avoiding my concerns. I was then blocked from being able to make any additional comments.

One day later, Feuerstein offered a new response. He said, "I stand corrected, sort of... Generex disclosed the FDA communication regarding Oral-lyn -- no imminent approval filing of Oral-lyn, more clinical trials required, taking years at an undisclosed cost -- during its June 8 shareholder meeting. The disclosure wasn't made in Generex's proxy statement or any other SEC filing prior to the shareholder meeting. Generex disclosed the new information at the meeting, presumably after many shareholders had already mailed in their proxy forms to vote on a reverse stock split, among other items. Selective disclosure? Certainly ill-timed disclosure, especially for a management team which desperately needed shareholder approval of the reverse stock split. To get the vote it needed, Generex did what it always does, kept shareholders in the dark."

His comments, in which he acknowledges being corrected on a key charge, require further correcting. Generex has been forewarning of the potential for additional clinical requirements for Oral-lyn, the most recent coming in March. On March 30th, Generex held a press conference and conference call from the NASDAQ MarketSite. While on the conference call, Dr Anderson informed shareholders that there may be a need for additional studies, beyond the ongoing one in Type 1 patients. Obviously, Generex needed to begin Type 2 late stage studies, and we have now heard that these studies are anticipated to be complete in 2013. A transcript of the press conference, and the conference call, where Dr Anderson gave his guidance regarding additional clinical studies, has been available at the SEC's EDGAR filing system since April 6th.

Feuerstein's ended his blog by saying, "I told you so". The blog contains the following disclaimer: "Full disclosure: Generex is suing TheStreet and me regarding prior published columns on Oral-lyn. That litigation is currently ongoing."

Feuerstein's "I told you so" moment may be a reference to a lawsuit Generex filed against Feuerstein, formerly a technology and commercial real estate beat writer, and TheStreet in response to two blogs Feuerstein wrote in March 2010. After the first blog, Generex demanded an apology for misleading or false comments, and TheStreet later placed a disclaimer above his first blog, noting certain inaccuracies, and saying that "TheStreet regrets the error". Generex's subsequent lawsuit had nothing to do with any of these latest developments.

On June 24th, after Feuerstein's latest blog was published, Generex's stock fell over 20%. Generex, like other small biotech companies that Feuerstein reports upon, are in precarious positions as they attempt to navigate the toughest of regulatory environments, while searching to raise large amounts of capital to fund their pipeline. In my opinion, readers of TheStreet deserve better, as do Generex's large base of over 37,000 shareholders.

Generex Takes Part at the American Diabetes Association's Scientific Sessions

2011-06-26T18:20:00.000-07:00

The American Diabetes Association's Scientific Sessions takes place from June 24 - 28. Generex is an exhibitor at ADA 2011, and an Oral-lyn abstract has been accepted to be presented at this prestigious industry event.

The image is of Generex's exhibition booth at ADA 2011, courtesy of Generex's Todd Falls. Click the image to enlarge. The abstract being presented at ADA 2011 highlights final six month data from a Phase II study with IGT subjects, or prediabetics, which may present a paradigm change in how they are treated. The following is the abstract from the event:

Treatment of Impaired Glucose Tolerance with Buccal Spray Insulin: A 6 Months Randomised Controlled Trial

Abstract No:
2224-PO

Author(s): ANDREA PALERMO, NICOLA NAPOLI, ERNESTO MADDALONI, ANGELO LAURIA, SILVIA MANFRINI, MARIA ALTOMARE, SERGIO LEOTTA, PAOLO POZZILLI
Location(s):
Rome, Italy

Abstract Body: In patients with impaired glucose tolerance (IGT), upon implementation of life style changes and metformin, a third returns to normal glucose tolerance, a third continues with IGT and the rest goes on to develop clinical type 2 diabetes. An increased risk for cardiovascular disease occurs in the latter two groups even though there is no progression to diabetes. A previous proof of concept study demonstrated that treatment with 12 puffs of buccal spray insulin was followed by a significant 29.6% decrease in mean plasma glucose at two-hours and a 26.8% decrease at three-hours.

We have designed a randomized controlled trial in patients with IGT comparing buccal spray insulin (Ora-lyn) (12 puffs per meal) plus physical exercise and diet (treatment group A, n=16, HbA1c at entry 6.06% + 0.5) vs. physical exercise and diet only (control group B, n=16, HbA1c at entry 5.9% + 0.3). HbA1c levels, metabolic parameters and insulin antibodies were measured at baseline and every 3 months up to 6 months. Primary endpoint is the reduction of HbA1c of 0.3% at 6 month treatment between the experimental and the control group. Secondary endpoints include the evaluation of antibodies against insulin (IA), changes in body weight and number of hypoglycaemic events.

Subjects treated with buccal spray insulin achieved a significant reduction of HbA1c compared to the control group (Δ HbA1c 0'- 6 month -0.34%+0,1 vs +0.07%+ 0,1 p =0,03). There was no significant difference in body weight and no hypoglycaemic or other adverse events were observed during the study period in both groups. No generation of IA was observed in subjects with IGT treated with buccal spray insulin.

These preliminary results indicate that buccal spray insulin is an effective treatment compared to diet + physical exercise in patients with IGT in reducing HbA1c without adverse effects. A larger trial is required to demonstrate the long term effects of this therapy. Here is the link.

According to data from the 2011 National Diabetes Fact Sheet, 79 million people in the U.S. have prediabetes (IGT). As obesity rates rise, so does the need to medically treat this group when the current recommendations of diet and exercise fall short. We have learned in recent weeks that the ongoing Phase III study in Type 1 patients has reached a protocol approved amount of subjects, and will be closed to new recruits. Final data may be available by the end of the year.

We now see positive Phase II results in IGT subjects, and plans to intitiate a Phase III study in Type 2 patients, anticipated to be completed by the end of 2013. A much broader label is being pursued for Oral-lyn, beyond Type 1's, whom make up only 10% of the US insulin market. With no adverse events reported in any studies, or cited as a concern in recent FDA guidance, Oral-lyn represents the next big thing that the current market does not understand.

Generex Shareholders Approve Reverse Stock Split, Antigen Express to be Spun Out

2011-06-08T18:18:00.000-07:00

Generex held their Annual Meeting of shareholders on Wednesday, June 8, 2011. The meeting was held in NYC, and I attended the event with my friends TC and JVF. At the meeting, the Board of Directors was broadened to include the CEO Mark Fletcher, Dr. James H. Anderson, and Dr. Eric von Hofe, who will join with the three current independent members. The most important item on the day's agenda was the vote for a proposal to enable the Board Of Directors to enact a future reverse stock split.

A remarkable 75% of of Generex's issued stock voted on the reverse split proposal, with 80% of votes cast in favor of the proposal. CEO Mark Fletcher stated that that "this vote is an endorsement of the new Generex management team and Board of Directors, and provides a clear mandate to proceed with the development plan unveiled by the Company on March 30, 2011". Personally, I feel the vote reflects shareholder sentiment that a reverse split and planned spin out of Antigen Express present the most optimal path towards success, more than anything else.

Credit for having the proposal passed should start with Seahawk Capital's Joseph Moscato (pictured above to the right of CEO Mark Fletcher), and include what must have been hard work by Mark Fletcher. While credit belongs with the CEO and Joe in winning such large support for a reverse stock split, much goes to Generex's retail shareholders. Mark informed that Generex has more than 37,000 stockholders, none of whom hold in excess of 5% of the outstanding stock, with than 295 million shares outstanding, while the Annual Meeting saw a huge turnout of 223,546,649 shares represented at the meeting. Generex's extraordinarily large retail shareholder base responded in force to this challenge.

With the reverse stock split proposal approved, Generex can now move forward with their stated plans to spin out their wholly owned subsidiary Antigen Express. I would advise all shareholders to listen to the Annual Meeting webcast that is available on Generex's website, since I will not repeat all of the details that Mr Fletcher outlined. Items concerning the reverse split and spin out of Antigen Express are complex, and I do not want to misrepresent any aspect. The items that are easy to understand are that the spin out will occur before Generex's reverse split, as Mr Fletcher responded to me during the question and answer period. Generex shareholders will freely win dividends in the new Antigen Express after a reverse stock split of GNBT shares is implemented.

Generex Oral-lyn

Since the Annual Meeting is available to be heard on Generex's website, I won't give a play by play of the entire proceeding. I'll just note a couple of interesting tidbits of information. The first item of interest comes from Generex's top metabolic Scientific Advisor, Dr Jospeh Anderson, who previously served as Eli Lilly's Senior Medical Director. He informed shareholders that the current Phase III study in Type 1 patients will not be "sufficient for an NDA that would provide shareholders the maximum value that should be obtained with Oral-lyn, because of the fact that the FDA approves drugs not for specific indications, but for therapeutic areas. So the drug would be approved for diabetes mellitus. Type 1 patients represent less than 10% of people with diabetes. And we want to make sure we include patients with Type 2 diabetes. So there is a necessity for an additional Phase III study that will include Type 2 patients".

This is a disappointment to Generex shareholders, who have been led to believe by the prior management team that the current Phase III in Type 1 patients would be suffice to anable a submission for that particular indication. The thought was that approval in Type 1 patients would improve the standing of Oral-lyn amongst the endocrinological community, increase shareholder value, and then open the door for treatment of Type 2 patients. However, both the investment and diabetes communities thought that plan was whimsical. It is refreshing to have Oral-lyn in the hands of a proven industry leader, such as Dr Anderson with his 25 years of experience, tell shareholders a more realistic and comprehensive plan that brings a potential submission within a 36 month time frame, while including Type 2 patients.

Dr Anderson presentation contained positive interim data regarding Oral-lyn's Phase III. One slide, which I photographed from the audience, shows early data in well controlled Type 1 patients from the Phase III study. These patients, with HbA1C levels under 7, were well under the optimal levels outlined by the American Diabetes Association. The graph Dr Anderson used was a close up of that optimal HbA1C level, so even the slight uptick seen in patients that went from levels at 6.3 to 6.8 appear as a concerning trend, yet the uptick is clinically and statistically insignificant. Imagine yourself standing at a dart board, with your nose touching the bullseye. All darts within the red circle are near perfect, but as you stand close you see variations. This is the case with this graph, which actually shows Oral-lyn keeping this group of Type 1 patients below the ADA guidelines associated with optimal control. The graph clearly shows that patients switched from sc injectable insulin to Oral-lyn remained well controlled throughout the duration of the study.

Dr Anderson gave a further review of Oral-lyn, talking about the positive benefits of the time profile of buccal insulin, a status update in India, and remarks about IGT patients, and of course the Treatment IND. Dr Anderson also made mention about the prior formulations of Oral-lyn that were studied in earlier years, and it appears that the FDA requires that some of that data needs to be updated in a pending study(ies) with the current formulation that Generex has determined to be optimal.

One item not mentioned, which I found at the ADA Annual Meeting web page, is that final results for Oral-lyn's Prevoral Phase II study with IGT patients will be revealed at the upcoming ADA Scientific Sessions.

Antigen Express

If you look to the upper right corner of the blog website, you will see videos that I uploaded from my Droid. The top video shows Antigen Express' President Dr Eric von Hofe's closing remarks during the Annual Meeting. Dr von Hofe's presentation was highly anticipated, since Generex plans a spin out of Antigen Express, their wholly owned subsidiary, in approximately 30 days. Antigen Express will be spun out as as a separate, DTC-eligible, SEC-registered company, that will be listed on a national exchange.

Dr von Hofe began his presentation by mentioning the approval of Dendreon's Provenge as ushering in the new era of immunotherapeutics. Antigen Express is developing the next generation of immunotherapeutic peptide vaccines, which have the advantage of being off the shelf, self potentiating, and are fully synthetic. The focus is on unmet medical needs, and Antigen has a promising technology platform. Dr von Hofe continued to explain the importance of activating CD4+ T helper cells, as I explained in my latest blog.

The most exciting update from Dr von Hofe had to due with a prospective partnership for AE37 in HER2/new expressing breast cancer patients. Dr von Hofe stated that the company should be in position to announce a partner later this year. He also informed that a large scale SPA Phase III for AE37 for breast cancer patients is being prepared to commence in the first quarter of 2012. The study population in the Phase III study will include 1000 node positive or high risk node negative HER2 expressing patients, with FISH scores as low as HER2 1, which are not eligible for Roche's Herceptin. A large scale study of this size can cost upwards of $100 million, so the company must be confident that they will secure a partner to help with the costs. Interim data from the ongoing Phase II study for breast cancer patients will be presented in the third quarter of this year, as well as in December at the San Antonio Breast Cancer Symposium.

Dr von Hofe also mentioned that a Phase II study for prostate cancer patients will begin later this year. All of these items illustrate the exciting near term milestones that Antigen Express will reach just as they begin trading as a separate stand alone biotech company. With Generex shareholders earning dividends in the future company, liquidity will be in the new stock, and GNBT shareholders will directly benefit from Antigen Express' success.

Transparency

During the Annual Meeting, and after the formal session, Generex's management team and Board of Directors made themselves available to all shareholders that had questions or concerns. In the past, Generex's management team would also respond to questions, but many of the answers appeared to be more of a dance, as opposed to reliable guidance. This has been the most obvious change under Mark Fletcher's regime. Shareholders that I attended the meeting with had numerous queries, and the team at Generex patiently responded to each one. We all were highly impressed.

Since the meeting, the company has announced a new CEO for Antigen Express following the spin out into a separate company. Mr Jos van der Woert, who has a long executive management history at companies such as Schering-Plough, where he last served as General Manager and Group Vice-President of Global Oncology and Virology, as well as Vice President positions at Pfizer and Bristol-Myers Squibb. Antigen Express will be well positioned and in very experienced hands.

Generex has also outlined a clinical and regulatory program for Oral-lyn. The company has planned a pharmokinetic and glucodynamic study using the final formulation of Oral-lyn. Also planned are a series of small, well-designed Phase 3 studies, which may potentially conducted as one study with multiple arms. Generex anticipates that these studies would be completed during the 2013 calender year. Generex informed that a consensus meeting with the FDA to obtain agreement with the clinical plan and submission data package is planned this year to insure timely regulatory agency review and positive marketing approval. Generex shareholders have never had such a comprehensive offering of guidance to properly understand what is required for Oral-lyn to gain FDA approval, with timelines that the company anticipates if all goes according to plan.

Mark Fletcher's tenure as CEO is in its earliest stages, yet he has brought the company a long way in reorganizing and redefining their goals. He also has redefined how the company communicates to their broad base of shareholders. I hope all shareholders are patient in giving him adequate time to complete the reorganization, as both Generex and Antigen Express appear to rapidly be heading in a promising direction.

Filling an Unmet Need: A Comparative Look at Generex and RXI Pharma's Breast Cancer Vaccines

2011-05-30T14:09:00.000-07:00

On June 5th, RXI (RXII) Pharmaceuticals will be presenting 36 month data for their E75 HER2/neu peptide vaccine, also known as NeuVax. The updated Phase II study results in adjuvant breast cancer will be announced during a panel RXI is hosting timed in conjunction with the 2011 ASCO Annual Meeting. RXI stated that the 24 month landmark analysis was first presented at the ASCO Breast Cancer Meeting in October 2010.

Subset Analysis of Nonrandomized Trials

The 24 month landmark analysis presented at ASCO's Breast Cancer Meeting was actually a cumulative finding of nonrandomized Phase I/II studies of E75, based upon a subset analysis of subjects. While the studies have enrolled 188 subjects, due to trial design, 72 patients received less than what was determined to be the optimal biologic dose. The 24 month landmark analysis revealed a recurrence rate of 6.5% in the E75 group vs. 14.5% in the control group (p=0.08).

A subset analysis of the study results, as researchers cull the data, found a grouping of patients with low HER2/neu expression, IHC 1+ and 2+, that are node positive, and whom received six month cycles of booster shots that benefited most from E75. The booster program was initiated after the ongoing studies revealed waning immunity of the E75 vaccine. The researchers found that amongst this subgroup of patients, the E75 vaccine reduced disease recurrence rate by ~ 50% compared to unvaccinated women.

Limitations of E75 in Filling an Unmet Need

Herceptin, the blockbuster cancer fighting drug from Roche (RHHBY.PK) and Genentech, is currently approved by the FDA for women with metastatic HER2-positive disease, and women with earlier stages of HER2-positive disease as adjuvant treatment (treatment after initial treatment, such as surgery) either alone or as part of a regimen with chemotherapy. The IHC test gives a score of 0 to 3+ that indicates the amount of HER2 receptor protein in tumors. Women with IHC positive scores tend to respond favorably to Herceptin. Samples with strong HER2 overexpression, IHC 3+, indicate eligibility for Herceptin therapy. This population makes up approximately 25% of HER2/neu breast cancer patients.

A new presentation available at RXI's website states that E75 will fill an unmet need, treating low HER2/neu expressing patients, who test in the IHC 1+ and 2+ range. As noted above, this is in contrast to Herceptin, which is available to patients that are >IHC 3+. The RXI presentation cites Herceptin's 2010 worlwide revenue of over $5 billion, while RXI's latest press release states that over 200,000 women in the U.S. are diagnosed with breast cancer annually, 75% of whom test IHC 1+, 2+ or 3+, with 25% those with HER2 3+ disease eligible for Herceptin, with E75 targeting the remaining 50% of HER2 1+ and 2+ positive patients. I will explain why I feel that may be a target that E75 can not hit, while explaining how another peptide based vaccine, from Generex (GNBT) Biotechnology's wholly owned subsidiary Antigen Express, can only make that claim.

Peptide Based Vaccines and Alleles

E75 is HLA-A2/A3+ restricted, since the peptide binds to this specific HLA allele. This means that patients that are HER2 1+ or 2+, and HLA-A2/A3-, may not benefit from this vaccine. HLA-A2/A3+ positive patients make up a good portion of the HER-2/neu breast cancer population, yet leaves near 30% out of the picture.

The United States Military Cancer Institute has conducted the various clinical trials of E75, as well as for two other peptide based vaccines, AE37 and GP2. AE37 is Generex's Ii-Key hybrid HER2/neu peptide vaccine. At ASCO 2009, the USMCI outlined the percentages of patients that have these various alleles. They found that out of 363 enrolled patients, 172, or 47.4%, were HLA-A2+, while 191, or 52.6%, were HLA-A2-. Additionally, of 100 patients typed for HLA class II, 31 were HLA-DR3+."

Similarly, in December 2010, at the San Antonio Breast Cancer Symposium, the USMCI noted the amount of HER2/neu patients that were HLA-DR3+ in their various peptide based vaccine studies, which was double the expected 13%. Patients that are HLA-DR3+ with low HER2 expression would also not be suitable for E75 or GP2. The researchers found that of the three peptide vaccines they are investigating, they believe Generex's AE37 may overcome weakly binding MHC II phenotypes, and may be used to treat low HER2 expressing subjects with the DR3+ allele.

Comparing the Unique Differences of E75, AE37, and GP2

Earlier this year, the USMCI researchers published a report titled Comparison of Different HER2/neu Vaccines in Adjuvant Breast Cancer Trials, which appeared in the February issue of Expert Review of Vaccines. The report compared the clinical characteristics of three different immunotherapeutic peptide vaccines designed for immunotherapy of breast cancer. The order of potency of specific HER2 immunity induced by the vaccines was: (1) AE37, followed by (2) GP2, followed by (3) E75.

The researchers explain that the three peptides studied in their trials are similar, but have unique differences. AE37 is the most individual, as it is a HLA class II-binding peptide, stimulating CD4 T-helper cells, and generating longer term specific immune responses as compared to the others. GP2 and E75 are HLA class I restricted, stimulating CD8+ T cells, while AE37 is a promiscuous peptide, which they explain as allowing AE37 broader relevancy.

AE37 Available to Both Node Positive and High Risk Node Negative Patients

The FDA awarded E75 a Special Protocol Assessment for a Phase III clinical trial in the adjuvant setting for node positive women with low-to-intermediate HER2+ status. This will be the first randomized study of E75. AE37 is currently in a randomized, multi-center Phase II trial in patients who have completed standard therapy for node-positive or high-risk node-negative breast cancer expressing at least low levels of the HER-2/neu oncogene. The ultimate goal of the AE37 study is to demonstrate that, after a follow-up period of 24 months, the relapse rate in the AE37 group of the study is less than half the relapse rate in the control group. The reported interim results of this study show that AE37 is on track to achieve that positive endpoint.

AE37 Alone Wholly Fills the Unmet Need

The results being presented on June 5th for E75 stem from a subset analysis of a nonrandomized Phase II study. The expected positive results should surely help RXI's rebounding stock. I don't think RXI would host this pending panel and announce 36 month results unless they like what they see. However, when compared to AE37, E75 comes with certain specific allele restrictions, limiting the patient population this vaccine can treat, beyond the reports from USMCI researchers that AE37 appears more potent and longer lasting.

When considering the claim that a peptide based vaccine targets the remaining 50% of HER2 positive patients (HER2 1+ and 2+) who achieve remission with current standard of care, but have no available HER2 targeted adjuvant treatment options to maintain their disease free status, I find that it is a claim that can only wholly be made for Generex's AE37.

The Journal of Immunology to Publish Study Detailing Generex Biotechnology's Research Collaboration with the Mayo Clinic in July Edition

2011-05-25T19:46:00.000-07:00

The July edition of the Journal of Immunology, a peer-reviewed research publication of the American Association of Immunologists, features an article that will detail the research collaboration between Generex's (GNBT) wholly owned subsidiary, Antigen Express, and the Mayo Clinic. The research is a continuation of scientific study between Antigen Express, lead by President Dr. Eric von Hofe, and the Mayo Clinic's Dr. Keith Knutson, a leader in the field of peptide vaccines in breast cancer. The title of the future article is "MHC Class II Epitope Nesting Modulates Dendritic Cell Function and Improves Generation of Antigen-Specific CD4 Helper T Cells". The abstract and article are not yet available for view, but the title is included in the Journal's future table of contents.

Antigen Express has been developing a series of CD4+ T Cell helper epitopes, based upon their proprietary Ii-Key hybrid technology. Ii-Key is a portion of the MHC class II associated invariant chain, which is known as Ii. Antigen Express explains that Ii-Key facilitates the direct loading of epitopes to the MHC class II molecule groove. Utilizing their technology, Antigen Express' Ii-Key/MHC class II epitope hybrids have shown clinical evidence of greatly enhancing the vaccine potency of the tethered epitope. Antigen Express' most advanced vaccine is AE37, a HER-2/neu hybrid peptide which is currently in a multi-center Phase II study.

The Mayo Clinic's Dr. Knutson has long studied adoptive T Cell therapy strategies to create cancer vaccines designed for immunotherapy of HER-2/neu breast cancer. Adoptive T Cell therapy strategies have largely focused generation of CD8+ T Cells, due to observations that most tumours express MHC class I, but not MHC class II. This gets tricky, so here is some info on CD4+ T Cells vs CD8+ T Cells. CD4+ T Cells recognize antigen-derived peptides in the context of self-MHC class II molecules, while CD8+ T Cells recognize antigen derived peptides in the context of self MHC class I molecules.

The problem Dr. Knutson had previously encountered is that CD8+ T-cells have a short lifespan. Earlier, Dr. Knutson reported that a problem with the use of adoptive T Cell therapy included the lack of CD4+ T cell help. In further work, Dr. Knutson has found that patients immunised with with CD4+ HER-2/neu helper epitopes, such as being developed by Antigen Express, are able to develop long lasting HER-2/neu specific CD8+ T Cell immunity. Specifically, Dr. Knutson found that greater than 60% of patients immunised with CD4+ HER-2/neu helper epitopes, each containing an encompassed HLA-A2 epitope, were able to develop HER-2/neu specific CD8+ T-cell immunity. The CD8+ T Cell response was maintained, in some patients, for at least one year following vaccination.

In contrast, 40% patients immunised with a single CD8+ T Cell HER-2/neu HLA-A2 9-merpeptide, RXI Pharmaceuticals' (RXII) NeuVax, or E75, developed HER-2/neu CD8 T Cell immunity that declined to undetectable levels within 5 months of the last vaccination. AE37 is the HER-2/neu CD4+ T Cell helper containing an encompassed HLA-A2 epitope that outshines E75 given alone in his study. If a main problem for Dr. Knuston's adoptive transfer research had been the lack of CD4+ T cell help, Dr. von Hofe and Antigen Express presented the solution.

Since we know the title of the upcoming research article authored by Dr. Knutson and Dr. von Hofe, with other Mayo Clinic researchers, is "MHC Class II Epitope Nesting Modulates Dendritic Cell Function and Improves Generation of Antigen-Specific CD4 Helper T Cells", we have a clue on where they are going with this research. A 2010 patent by Dr. Knutson, titled "METHODS AND MATERIALS FOR GENERATING T CELLS", explains what is invloved in generating antigen-specific CD4+ T cells. The patent outlines methods and materials for using nested MHC class II epitopes to generate CD4+ T cells. The patent states that the nested MHC class II epitopes provided can include an invariant chain, or Ii, and a MHC class II epitope. The patent is describing his work with Antigen Express, and the upcoming article will provide peer review documentation.

Antigen Express is also involved in a separate collaboration with the Mayo Clinic's Dr. Svetomir Markovic, a distinguished translational researcher with expertise in melanoma trials. That agreement focuses on advancing an immunotherapeutic vaccine for melanoma into the clinic. Generex is planning a spin out of Antigen Express, following approval of a reverse stock split of Generex's shares. Top industry scientists, like those found at the prestigious Mayo Clinic, are already excited about the potential found within Antigen Express' pipeline. I am certainly no scientist, so read my opinions and rough analysis with that in mind, but the potential for Antigen Express is obviously high.

Should Generex's planned reverse stock split proposal be approved, followed by a spin out of Antigen Express, adequate funding may finally be within Antigen Express' grasp, which will serve as the fuel to propel all of this successful research deeper into human studies. The winners in that scenario will be Generex's current and Antigen Express' future shareholders, and most importantly the cancer patients in need of better therapy. We are looking at the future when active immunotherapy will be a commercialized reality, designed by Antigen Express.

Generex to Spin Out Antigen Express to Unlock True Value

2011-04-02T20:03:00.000-07:00

“There is nothing wrong with change, if it is in the right direction” ~ Winston Churchill

Last week, I attended Generex (GNBT) Biotechnology's live webcast held at the NASDAQ Marketsite in New York City with a fellow shareholder friend. At the event, the company's CEO Mark Fletcher unveiled their strategic development plan for the company's future growth. We were also fortunate to sit in on the conference call held later that same afternoon, since the CEO and his top advisor, Mr Joseph Moscato from Seahawk Capital, invited shareholders in attendance to quietly listen in.

Five months ago, I wrote an article detailing my position that approval of the of the company's previous reverse stock split proposal, while the company's common stock was still listed on Nasdaq, would be preferable to such a proposal while the stock was trading on the bulletin board. We are now in the scenario which I once feared. However, Generex's forward moving plan has me enthused that the company is taking dynamic and prudent steps placing the pipeline in a better position to be properly funded. As shareholders learned in January, raising capital on the bulletin board is highly dilutive, even when the cash raised is a modest $3 million.

Last year, long time CEO Anna Gluskin was replaced by then Executive Vice-President and General Counsel Mark Fletcher, and shareholders have not heard from him since the last corporate update held in October. I wanted to watch his latest presentation in person, and to look him and his team in their eyes. I arrived at the webcast as a concerned shareholder, who was not quite certain that Generex's new management team was on a path that was most beneficial for its large group of shareholders.

Before the webcast began, my friend and I encountered Dr Gerald Bernstein, Generex Vice President of Medical Affairs, and Dr Eric von Hofe, President of Generex's wholly owned subsidiary Antigen Express. Drs Bernstein and von Hofe were the two main figures I hoped to talk with, in an attempt to gauge their sentiment towards the changes that have taken place at Generex. After speaking with them, I noticed their renewed confidence and enthusiasm. During the 15 or so minutes leading into the webcast, I chatted with Dr von Hofe about publicly known details surrounding the Phase II study of the AE37 HER2/neu peptide vaccine for early stage breast cancer patients, and he expressed his optimism for the new team leading Generex. As we spoke, I had no idea how vital of a role Antigen Express would take in Generex's forward moving plan.

Last summer, while at the company's Annual Meeting, I told Generex Board of Directors member John Barratt, that while I am optimistic for the company's pipeline of metabolic drugs and immunotherapeutic vaccines, I would like to see greater transparency from management. I again met Mr Barratt before the webcast. Mr Barratt is now Chairman of the Board of Directors, and he took the time to welcome us to the event. As we all walked into the room where the webcast would take place, Mr Barratt told us to get ready to see a new era of transparency for Generex. Transparency is his mandate for the new CEO, and Mr Fletcher also promised us that the company will be transparent on all matters.

By now, it is known that Generex's strategic plan includes a spin out of Antigen Express, as a separate DTC-eligible SEC registered company. According to the company, the spin out will be accomplished by the issuance of one or more dividends of Antigen Express stock to Generex stockholders. The record dates are yet to be determined. The stock dividends will enable Generex stockholders to directly participate in the promising future of Antigen Express, as well as create a large shareholder base with the potential for substantial liquidity on an immediate basis. As the CEO explained, that liquidity will be further enhanced should Antigen Express be successful in attaining a national stock exchange listing, and this should provide them with ready access to the capital markets to finance their ongoing clinical initiatives.

There are many other aspects to Generex's strategy, as well as a subsequent plan to initiate a rights offering of common stock and warrants to their stockholders, in the event Generex receives approval for a reverse stock split. All of this is slated to occur at the next Annual Meeting of the Generex's stockholders scheduled for Wednesday, June 8, 2011, and if Generex's common stock is listed for trading on a national stock exchange.

During the webcast, Mr Joseph Moscato of Seahawk Capital introduced himself as Generex's strategic advisor. I have written about Joe and his consultancy role with Generex before, and he has since grown to play even a more prominent role in designing the company's strategy for the future. Joe helped Generex attract an impressive array of scientific experts, and he leads their business plannings, while finding accredited investors to fund their initiatives. I've had quite a few vibrant debates with him over the last few months. As Generex's plans were unveiled, I realized I had no clue to what I was talking about as I challenged him. One concern that I had expressed to Joe was how Medicares Competitive Bidding policy may affect the planned acquisition of Global Medical Direct. This concern was eased during the webcast and subsequent conference call.

During the day, we were told how the plan will protect Generex stock from shorting and selling pressure after a reverse stock split is implemented. Generex shareholders will earn another dividend in Antigen Express stock, providing they still hold their Generex stock after a certain date. I asked if the company could still offer Generex shareholders the free dividends of the new Antigen Express stock if the reverse split proposal was denied, or if there could still be a rights offering. I was told that free dividends of Antigen Express stock would no longer be practical, and there would then be no rights offering. I was told that such tactics would lead to huge dilution for both Generex, and the new Antigen Express. However, without the reverse stock split proposal being approved, the company would still spin out Antigen Express. In such a scenario, shareholders would gain no free dividend in the new company, and the only benefit they would see is the new value of a publicly traded Antigen Express being on Generex's books, as Generex will have controlling interest in the new company.

In other words, if Generex's shareholders vote down the reverse stock split proposal, they will be shooting themselves in the foot. Reverse stock splits are very unpopular, and usually for good reason, but the steps Generex has taken in planning an additional dividend award after a certain time period will protect against the company's stock from being shorted. Since Antigen Express is highly popular among Generex shareholders, I feel most would want to hold onto their Generex shares to win that second free dividend, which will help support Generex's stock.

Later in the day, we joined the Generex team at the conference call. Many shareholders that called into the conference call expressed concern about the developmental status of Oral-lyn. I was watching the team as they responded, and they looked poised, and eager to take as many callers as possible. They waited until the caller que was empty before ending the event. During the conference, I also asked Dr Anderson if the company could provide results for the amount of patients that are enrolled. He explained that this would compromise the data, and he needs to gain the guidance from the FDA before mapping out the companies next developmental steps. The company expected this guidance in December, and they recently learned it will arrive in another couple of weeks.

After the call, I questioned Dr John Anderson about a concern that the company may not be as confident in Oral-lyn as they were in the past. He reminded me that he was the person at Eli Lilly that brought Generex into an earlier partnership for buccal insulin. He said he believed in Oral-lyn then, and he does more so now. I asked Mr Fletcher a similar question regarding Oral-lyn, and he said if he was concerned about Oral-lyn, he would not spin out Antigen Express. He said the opposite is true, that the company is only planning the spin out because they are very confident in Oral-lyn, and in the RapidMist delivery system. Once the company receives their guidance from the FDA, he promised transparency in alerting the investment community of what they have learned, and how they will proceed. It is possible that another study will be required, and the company is also planning a study with Type 2 diabetics.

In any scenario, Generex will need to conduct clinical studies, and access to less diluting funds is most beneficial to the company's shareholders. While the company ultimately failed to gain continued listing on a national exchange last year, this is a new Generex, and Mr Barratt explained that this is why the Special Committee of Generex's Board of Directors, formed in September of last year, executed bold changes. Mr Barratt stated that many steps have been taken to maximize shareholder value.

I did look them in the eye during the course of the day, and what I saw was confidence and commitment. Mr Fletcher, along with Joe Moscato, told us that the day's unveiling of the company's new strategic plan is only the start. Over the next 60 days, leading into the Annual Meeting on June 8th, more will be announced, including what Joe termed as "meat being added to the bones". The details of the continued developments will be exciting to learn, as the known elements of the plan are surprisingly transformational.

Dr Eric von Hofe appeared quite at ease with the new team, as I was still watching as he relaxed after the conference call with Pfizer's Dr Craig Eagle. During that time, my friend and I interacted with them all, and they appeared excited as they talked about the new Generex and Antigen Express. Mr Fletcher and Joe were most accommodating to shareholders in attendance, as Mr Barratt held court with the team's group of scientists and finance experts, and he had a distinct look of great satisfaction on his face.

Beyond all of this, both of the company's top pipeline assets will be featured at industry events this week. The 4th International Congress on Prediabetes and the Metabolic Syndrome will take place in Madrid, Spain, on April 6-9. There is an abstract that will be presented on April 7th, titled "A New Way to Treat Subjects with Impaired Glucose Tolerance: Buccal Spray Insulin", which reports the Phase II study results for Oral-lyn with IGT patients. Also, the 102nd AACR Annual Meeting starts April 2nd. During the Late-Breaking Poster Session, two abstracts will be presented detailing immunological and safety findings for Antigen Express' AE37 HER-2/neu peptide vaccine from a Phase II study with early stage breast cancer patients.

Generex and Antigen Express have significant IP, with a pipeline that is full of potential. Generex belongs on a national exchange, their pipeline deserves access to adequate funding, and the new team deserves support, so they can complete their goals. I'm voting for Generex's new plan, for my free dividend shares in the new Antigen Express, and for a better future for the new Generex Biotechnology. I believe that this is change in the right direction, and a change that benefits Generex's current shareholder base.

Updated Phase II data for Generex's HER-2/neu AE37 Vaccine to be Presented at AACR 2011

2011-03-22T15:29:00.000-07:00

The American Association for Cancer Research will hold their 102nd AACR Annual Meeting starting April 2nd. The event highlights the latest in cancer research, and ends on April 6th. AACR 2011 will be held at the Orange County Convention Center in Orlando, Florida. Late breaking clinical research includes two abstracts pertaining to Generex's preventative AE37 HER-2/neu HLA class II peptide vaccine.

Late breaking abstracts are ones submitted after the normal deadline, as outlined on the AACR website. The only available information regards the titles and authors of the two late breaking abstracts. This is what I have found:

Late-Breaking Poster Session
Clinical Research
Tue, Apr 5, 1:00 - 5:00 PM

#1. Presentation Title: Comparison of in vitro and in vivo immunologic responses in a prospective, randomized, single-blinded phase II trial evaluating the HER-2/neu peptide vaccines GP2 and AE37 in breast cancer patients.

Author Block: Alan K. Sears, Guy T. Clifton, Mark G. Carmichael, David C. Van Echo, Jarrod P. Holmes, Athina Zacharia, Yusuf Jama, Mohamed Mursal, Anna Chiplis, Elizabeth A. Mittendorf, George E. Peoples, Sathibalan Ponniah. Brooke Army Medical Center, Fort Sam Houston, TX, Cancer Vaccine Development Program, Bethesda, MD, The University of Texas MD Anderson Cancer Center, Houston, TX

#2. Presentation Title: Circulating regulatory T cells (CD4+CD25high CD127low) decrease in breast cancer patients after vaccination with a modified HER-2/neu HLA class II peptide (AE37) vaccine.

Author Block: Alan K. Sears, Guy T. Clifton, David C. Van Echo, Jarrod P. Holmes, Athina Zacharia, Yusuf Jama, Mohamed Mursal, Anna Chiplis, Elizabeth A. Mittendorf, George E. Peoples, Sathibalan Ponniah. Brooke Army Medical Center, Fort Sam Houston, TX, Cancer Vaccine Development Program, Bethesda, MD, The University of Texas MD Anderson Cancer Center, Houston, TX

Click on the abstract titles to view the abstract pages.

While no additional data is currently available for these abstracts, the title of the second one presents a clear indicator that the AE37 vaccine is providing the desired inter cellular response. I'll borrow words from Dr Tai-You Ha: "There has been an explosion of literature focusing on the role of regulatory T (Treg) cells in cancer immunity. It is becoming increasingly clear that Treg cells play an active and significant role in the progression of cancer, and have an important role in suppressing tumor-specific immunity. Thus, there is a clear rationale for developing clinical strategies to diminish their regulatory influences, with the ultimate goal of augmenting antitumor immunity."

Previous data from AE37's Phase I and interim Phase II studies with HER2+ breast cancer patients, as well as the completed Phase I study with HER2+ prostate cancer patients illustrated significant decreases in circulating TReg frequencies. Those earlier reviews also highlighted an increase in DTH levels of vaccinated patients, via a Delayed-type Hypersensitivity Test, as well as a good correlation between TReg cell reduction and size of DTH to AE37. The earlier research led the review authors to conclude that AE37 "may be clinically useful". This modest statement appears to need a more stronger emphasis, as further research reveals the consistency of the vaccine's immunotherapeutic prowess.

We will learn more at AACR 2011.

A New Way to Treat Subjects with Impaired Glucose Tolerance: Buccal Spray Insulin

2011-03-13T18:35:00.000-07:00

The 4th International Congress on Prediabetes and the Metabolic Syndrome will take place in Madrid, Spain, April 6-9, 2011. There is an abstract that will be presented on April 7th, titled "A New Way to Treat Subjects with Impaired Glucose Tolerance: Buccal Spray Insulin", which reports the Phase II study results for Oral-lyn with IGT patients.

In people with IGT, the levels of blood glucose are between 140 - 199 mg/dL after a two-hour oral glucose tolerance test. This level is higher than normal but not high enough to be classified as diabetes. Recent data suggests that higher glucose levels within the normal range increase risk for developing prediabetes. The prevalence of pre-diabetes is high. According to data from the 2011 National Diabetes Fact Sheet, 79 million people in the U.S. have prediabetes (IGT).

This is the accepted abstract (#1138):

A. Palermo1, N. Napoli1, E. Maddaloni1, A. Lauria Pantano1, S. Manfrini1, M. Altomare2, S. Leotta2, P. Pozzilli1
1Endocrinology and Diabetes, University Campus Bio-Medico, 2Diabetes, Hospital Sandro Pertini, Rome, Italy

In patients with impaired glucose tolerance (IGT), upon implementation of life style changes and metformin, a third returns to normal glucose tolerance, a third continues with IGT and the rest develops type 2 diabetes. An increased risk for cardiovascular disease occurs in the latter two groups. A previous study demonstrated that treatment with 12 puffs of buccal spray insulin (BSI) was followed by a significant 29.6% decrease in mean plasma glucose at 2h and by a 26.8% decrease at 3h.

This is a randomized controlled trial in patients with IGT comparing BSI (12 puffs per meal) plus physical exercise and diet (n=16, entry HbA1c 6.06%+0.5 ) vs. physical exercise and diet only (n=16, entry HbA1c 5.9%+0.3). HbA1c, metabolic parameters and insulin antibodies (IA) were measured at baseline, at 3 and at 6 months. Primary endpoint is the reduction of HbA1c of 0.3% at 6 month treatment between the experimental and the control group. Secondary endpoints include evaluation of IA, changes in body weight and number of hypoglycaemic events.

Subjects treated with BSI achieved a significant reduction of HbA1c compared to the control group (ΔHbA1c 0'-3' month -0.3% vs+0.09% p= 0.002). No difference in body weight and no hypoglycaemic or other adverse events were observed in both groups. No generation of IA was observed in subjects treated with BSI.

These results indicate that BSI is an effective treatment in patients with IGT in reducing HbA1c without adverse effects. A larger trial is required to demonstrate the long term effects of this therapy.

To view the abstract, click here.

New Phase II Data for Generex's AE37 Breast Cancer Vaccine to be Presented at SSO 2011

2011-03-02T16:21:00.000-08:00

The 2011 SSO Annual Cancer Symposium runs from March 2nd through March 5th. The SSO Annual Cancer Symposium attracts more than 1,500 surgical oncologists, general surgeons, exhibitors and guests. Attendees come from more than 40 countries.

This year's event is being held at the Henry B. Gonzalez Convention Center & Grand Hyatt Hotel in San Antonio Texas. SSO received a record-breaking 612 abstract submissions for this meeting, and one details vaccine specific immmunologic responses to Generex's AE37 HER2/neu Ii-Key hybrid peptide vaccine. This is the accepted abstract for the event:

"Vaccine-Specific Immmunologic Responses to the Novel Ii-Key Hybrid HER-2/neu Peptide (AE37) Vaccine in a Phase II Clinical Trial"
A. K. Sears, G. T. Clifton, S. A. Perez, K.S. Clive, J. P. Holmes, K. Georgakopoulou, M. Papamichail, S. Ponniah, G. E. Peoples, E. A. Mittendorf
Vaccine-Specific Immunologic Responses to the Novel Ii-Key Hybrid HER-2/neu Peptide (AE37) Vaccine in a Phase II Clinical
Trial A.K. Sears,1* G.T. Clifton,1 S.A. Perez,2 K.S. Clive,1 J.P. Holmes,3 K. Georgakopoulou,2 M. Papamichail,2 S. Ponniah,4 G.E. Peoples,1 E.A. Mittendorf.5 1. Brooke Army Medical Center, San Antonio, TX; 2. Cancer Immunology and Immunotherapy Center Saint Savas Cancer Hospital, Athens, Greece; 3. Naval Medical Center San Diego, San Diego, CA; 4. Uniformed Services University of the Health Sciences, Bethesda, MD; 5. M.D. Anderson Cancer Center, Houston, TX.

Introduction AE37 is the Ii-Key hybrid of the HER-2/neu peptide AE36 (HER-2/neu: 776-790), and is capable of stimulating CD4+helper T-cells with anti-tumor activity. We are currently conducting a prospective, randomized, single-blinded, phase II trial of AE37 + GM-CSF (immunoadjuvant) vs. GMCSF alone for the prevention of breast cancer recurrence. Here we present safety and immunologic data for this clinical trial.

Methods Node positive or high-risk node negative breast cancer patients with any level of HER-2/neu expression (IHC 1+, 2+ or 3+), disease-free after standard treatments were enrolled. Patients were randomized to receive either AE37 + GM-CSF (VG)or GM-CSF alone (CG). Vaccines were given in six monthly intradermal inoculations. Ex vivo (3H-thymidine proliferation assay) and in vivo (delayed type hypersensitivity [DTH]) responses were measured before (R0), mid-series (R3), upon completion (R6), and at six (RC6) and 12 (RC12) months after completion of the vaccine series.

Results We have enrolled 197 patients (VG=86, CG=111). Systemic toxicities were grade ≤ 2 in 96% of VG and 93% of CG; there were no grade 3-5 local toxicities. In the VG, proliferative responses to AE37 and AE36 increased from R0 to all other measured times (AE37: R0=0.98, R3=3.29, R6=3.38, RC6=3.64, RC12=3.68, p <0.001; AE36: R0=0.95, R3=1.92, R6=2.12, RC6=2.18, RC12=1.80; p<0.001) while they did not change in the CG (Figure 1). DTH responses increased in the VG from pre- to postvaccination (AE37: 2.7 vs 30.2 mm, p<0.001; AE36: 2.2 vs 16.3 mm, p<0.001) while there was no change in the CG.

Conclusions In a prospective, randomized, single-blinded, phase II vaccine trial with a GM-CSF only control group, the novel Ii-Key hybrid HER-2/neu AE37 vaccine appears safe and well-tolerated with minimal toxicity. AE37+GM-CSF is effective at generating HER-2/neu-specific immunity as demonstrated by a significant increase in ex vivo and in vivo immune response in vaccinated patients.

Search for poster #60 (P60) here. The PDF for the general program is here.

My Take The post-vaccine DTH levels for AE37 are a very promising hint of the effectiveness of the vaccine. An increase in DTH levels from pre to post vaccination, combined with a decrease in Tregs, are what researchers of a peptide vaccine hope to see. In my previous blog, I relayed information from a new peer review from the United States Military Cancer Institute. The report states that DTH testing has been described as a very reliable method of monitoring immune response to cancer vaccines. The USMCI researchers believe large DTH reaction may correlate with clinical outcome. The post vaccination DTH responses to AE37 have similarly been reported in a Phase I study with HER2/neu early stage breast cancer patients, as well as a Phase I study with HER2/neu early stage prostate cancer patients. I believe a non-expert ad hoc look the combined DTH response is telling us that the immunological response to AE37 is not only potent and as desired, but consitient and reliable.

The response of patients was also measured by reactivity of their T cells to AE37 as measured by their ability to proliferate after being exposed to the peptide. The proliferation assay appears to show consistent and potent responses among the patients. These findings also confirm previous data supplied by AE37's investigators.

This latest abstract once again finds AE37 to be well-tolerated with minimal toxicity. The findings illustrate that there were no grade 3-5 local toxicities, as has been the case in all prior findings. These toxicity findings are in stark contrast to other cancer drugs, and bode well for the peptide vaccine program at the USMCI. Last month, Generex stated in a press release that they are increasing the number of patients enrolled in the study from 190 to 330, and these results show that 197 have been enrolled to date of submission of this abstract. This abstract may have been submitted to SSO a few months ago. Generex is listed as an exhibitor at ASCO's Annual Meeting that will be held between June 4th and 6th. We may see more data presented at this event. AE37 is doing very well.

Putting My Experiences Watching Quincy, M.E. to Good Use, While Reading the Latest Peer Review Related to Generex's AE37 Vaccine

2011-02-21T20:06:00.000-08:00

Sometimes, we have to amuse ourselves, and laugh at the absurd. As the stock for my favorite biotech continues to falter, I'll try and accomplish both, by making a futile attempt to analyze that latest peer review that includes data from Generex (GNBT) Biotechnology's AE37 HER2/neu Ii-Key peptide based vaccine. Researchers from the United States Military Cancer Institute have authored a new report, titled "Comparison of Different HER2/neu Vaccines in Adjuvant Breast Cancer Trials: Implications for Dosing of Peptide Vaccines", that appears in the February 2011 edition of Expert Review of Vaccines.

As I've noted before, the USMCI has conducted multiple adjuvant clinical trials using immunogenic peptides from the HER2/neu protein [AE37/E75/GP2] plus GM-CSF given intradermally to breast cancer patients. Adjuvant therapy for breast cancer is any treatment given after primary therapy to increase the chance of long-term survival. Researchers have surmised that peptide based cancer vaccines may have limited clinical tumor response in metastatic cancer, meaning cancer that has spread to other parts of the body, so the USMCI has chosen to study peptide based vaccines in the adjuvant setting.

I hope I am not being overly simplistic, I barely understand all of this myself. Last fall, Col George Peoples, the Director & Principal Investigator of the Cancer Vaccine Development Program, and the Deputy Director of the USMCI, explained to me in an email exchange that "all the data that we have indicates that vaccines are most effective at a point when the immune system can get a handle on the cancer before it gets too aggressive and less recognizable to the immune system". The latest report, of which he is the main author, represents their first attempt to compare all three of the HER2/neu peptide vaccines tested in their clinical trials, with an emphasis on the dosing strategy needed to gain the greatest clinical benefit. At least, I think, so you can buy the report here to decide for yourself.

The publicly available abstract reads:

We have performed multiple adjuvant clinical trials using immunogenic peptides from the HER2/neu protein (AE37/E75/GP2) plus (GM-CSF) given intradermally to breast cancer patients. Four trials were performed with similar dose-escalation design with increasing doses of peptide (AE37/E75/GP2) and varying amounts of GM-CSF. Dose reductions (DRs) were made for significant local and/or systemic toxicity by decreasing GM-CSF for subsequent inoculations. Ex vivo and in vivo immunologic responses were used to compare groups. Of 132 patients, 39 required DR (30 for robust local reactions [DR-L]). DR patients, particularly DR-L, had greater immune responses both ex vivo and in vivo. Postvaccine delayed-type hypersensitivity in DR-L patients compared with all others was larger for E75 (p = 0.001), AE37 (p = 0.077) and GP2 (p = 0.076). All three peptide vaccines were safe and well-tolerated. These findings have led to a clinically relevant optimal vaccine dosing strategy, which may be applicable to other peptide-based cancer vaccines.

The report highlights the dose-escalation trial results for the three HER2/neu derived peptides that have been studied in their clinical trials. For AE37, owned by our own Generex Biotechnology, the report includes data from the Phase I study in early stage breast cancer patients that was completed a couple of years ago. I know, we want Phase II data, but take this for now. The same type of study is included for GP2, while data available for E75 included completed Phase I and Phase II results. E75 has been studied far longer than AE37 or GP2, and this vaccine is licensed to Apthera, Inc. At this point, I am only interested in AE37, and admittedly for selfish reasons. The AE37 Phase I study included 15 disease-free, node negative breast cancer patients, 60% of whom required dose reduction for robust local reactions. AE37 is coupled with the Ii-Key modification, which I believe increases its potency as compared to GP2 and E75.

When I first noticed the p values in the abstract, showing that post vaccine delayed-type hypersensitivity, or DTH, in DR-L patients was larger for E75 than AE37 or GP2, I thought they were finding increased potency in that particular peptide vaccine, which isn't coupled with the Ii-Key. Evidently, they are looking specifically at DR-L patients, or 30 of 139 patients, when making that analysis. The goal is to create personalized, or tailored, vaccines. All of these sub groups become important, as dosing plays a key part of their approach. As long as they understand what that means, we are in good shape, since I get a little lost in the scientific jargon.

The researchers explain that the three peptides studied in their trials are similar, but have unique differences. AE37 is the most individual, as it is a HLA class II-binding peptide, stimulating CD4 T-helper cells, and appears generate longer term specific immune responses as compared to the others. GP2 and E75 are HLA class I restricted, that stimulate CD8+ T-helper Cells, while AE37 is a promiscuous peptide allowing for a broader relevancy. I have noted that difference in previous blogs. The researchers remark that HLA-A2+/HLA-A3+ patients, or those that GP2 and E75 are restricted to, make up 60–75% of the population. AE37, the promiscuous peptide, can benefit them all. I should say potentially, but my shares in GNBT forced me to leave that word out of the sentence. I apologize, the beaten down shares get a little promiscuous as well.

The report states that DTH testing has been described as a very reliable method of monitoring immune response to cancer vaccines. It was work by Dr Mary Disis, from the Tumor Vaccine Group at the University of Washington, whose research I have also studied, that found DTH responses correlate with better antigen-specific T-cell responses and reflect systemic immunization. That thought brings the USMCI researchers to consider whether large DTH reaction correlate with clinical outcome. They looked at their E75 data, which as I informed is more expansive due to the longer duration of study, to find that greater post vaccine DTH reactions were associated with decreased recurrence and mortality. This why the abstract contains data specific for 30 of 139 patients, since they represent those requiring dose reductions due to larger local reactions.

The USMCI concludes the report with their optimal method of dosing for the HER2/neu peptide vaccines under their care, which they believe are relevant to other peptide based vaccines. Their data shows that AE37's enhanced potency is demonstrated by the largest DTH reaction produced in their overall analysis of the three peptide vaccines. DTH reactions reveal that AE37 is greater than GP2, which is greater than E75, for both DR and NDR patients. I'm not sure what it means, but I think this shows AE37 is the greatest, at least in providing DTH reactions, which may correlate with positive clinical outcome.

The ultimate goal of the USMCI is to develop a "combinational multiple epitope breast cancer vaccine with broad patient applicability to be given to disease-free patients with the aim to prevent recurrences and decrease breast cancer mortality". Since GP2 and E75 are HLA class I restricted, I imagine that any truly potent and long lasting multi-epitope vaccine would require the promiscuous AE37 Ii-Key Hybrid. The authors of the study didn't necessarily conclude that, I did, although my science experience is limited to watching Quincy, ME.

I'm not sure if that counts. I'm certain I've only succeeded in being absurd. The science points towards a bright future, even if the current day is cold and stormy. I'll take that thought to heart as we await meaningful news from the good folks at Generex, and hope it comes soon. GNBT shares could use a dose of enhanced potency.

SABCS 2010: Data from a Phase II Trial AE37+GM-CSF Sequentially or Concurrently with Herceptin

2010-12-11T22:42:00.000-08:00

Mittendorf EA, Perez SA, Tzonis P, Clifton GT, Ardavanis A, Holmes JP, Lekka E, Baxevanis CN, Ponniah B, Peoples GE, Papamichail M. The University of Texas M. D. Anderson Cancer Center, Houston; Saint Savas Cancer Hospital, Athens, Greece; Brooke Army Medical Center, San Antonio, TX; Naval Medical Center San Diego, CA; Uniformed Services University of the Health Sciences, Bethesda, MD

Background. AE37 is a HER2-derived peptide (AA:776-790) modified to enhance antigen-specific stimulation of CD4+ T cells. A phase I trial has shown that AE37 mixed with GM-CSF (GM) is safe and effective in raising HER2-specific immunity. Our group is conducting a prospective, randomized, single-blinded phase II clinical trial of AE37+GM vs GM alone. The goal of the current study is to determine the effects on cardiac safety and immunologic response of vaccinating sequentially or concurrently with administration of trastuzumab (Tz).

Methods. The trial is enrolling high-risk breast cancer patients with tumors having any degree of HER2 expression (IHC 1-3+). At the time of enrollment, all patients are disease-free having completed surgery, chemotherapy and when indicated, XRT. Patients receiving Tz as part of their standard therapy were administered the vaccine sequentially after completion of Tz or concurrently with Tz. Cardiac toxicity was assessed by determining ejection fraction (EF). Immunologic response was monitored by delayed-type hypersensitivity (DTH) responses and [3H]thymidine proliferative assays for the hybrid AE37 and native AE36 (unmodified AA:776-790) peptides.

Results. To date the trial has enrolled 102 patients at our international site, including 51 receiving Tz as part of standard therapy. Of these, 30 were randomized to receive AE37+GM; 13 sequentially after Tz (group 1) and 17 concurrently (group 2). 21 patients were randomized to receive GM alone. There was no change in EF pre- and post completion of vaccination series for patients in group 1 (mean 63±1.7% vs 65±2.9%, p=.32) or group 2 (mean 68±3.7% vs 63±%, p=.14). There was a statistically significant difference in DTH response pre- vs post-vaccination with AE37+GM in both group 1 (mean 1 mm vs 20 mm, p<.001) and group 2 (2 mm vs 29 mm, p<.001); however, there was no significant difference in the post-vaccination DTH response when comparing group 1 to group 2 (p=.16). There was no significant difference in the DTH response pre vs post inoculation for patients receiving GM alone. There was a significant proliferative response to AE36 and AE37 in both group 1 and 2 with the response greater in group 2. There was no proliferative response in patients receiving GM alone.

Conclusions. Administration of the AE37+GM peptide vaccine with Tz administered either concurrently or sequentially is safe without any increase in the incidence of cardiotoxicity. Vaccination with AE37+GM concurrently with Tz results in enhanced proliferation suggesting that there may be clinical benefit to such a combination immunotherapy strategy. Patients will continue to be followed to determine the effects of vaccination with sequential vs concurrent Tz administration on clinical outcome.

Friday, December 10, 2010 7:00 AM

Generex Taps Former Eli Lilly Senior Medical Director to Strengthen Clinical and Regulatory Efforts for Oral-lyn

2010-12-09T16:18:00.001-08:00

"Having worked with the Generex team in the fledgling stage of Generex Oral-lyn development while at Eli Lilly, I believed then that the product had the potential to become a first-in-class therapeutic insulin treatment even though the companies ultimately headed in different directions as is often the case with early stage collaborations." - Dr. James H Anderson Jr on December 9, 2010

Generex Biotechnology (GNBT) announced on Thursday the appointment of Former Eli (LLY) Lilly Senior Medical Director Dr. James H. Anderson, Jr., MD, FFPM, FACE to the company's Scientific Advisory Board. While such news is not often met with much fanfare, there is an unique element to this announcement when considering the history between Generex and Eli Lilly. A look back may help us realize where we are today as we wait for Oral-lyn's future to unfold.

In September 2000, Generex and Eli Lilly entered into a Development and License Agreement for Oral-lyn buccal insulin. In May 2003, the companies mutually agreed to end the deal. During that two and a half year time period, Lilly did not conduct a single clinical trial to assess either the safety or efficacy of Generex's buccal insulin, while they were actively spending their resources developing the AIR inhaled insulin system, as part of a developmental agreement with Alkermes (ALKS) that was signed in 2001. Lilly had held rights to separate buccal and inhalable insulin programs, and like many large pharmas at the time, they were placing their bet that inhalable insulin was the right path to take.

Like clowns jumping into the same car, many pharma companies were competing with one another to develop inhalable forms of insulin. Pfizer, with partner Nektar (NKTR) Therapeutics, led the foray, and in 2006 they were the first inhalable insulin to win FDA approval. The Exubera story is well known, and I won't repeat the entire saga. Pfizer's failure to earn commercial success with Exubera led to their costly decision in late 2007 to abandon the product and return rights to Nektar. Pfizer recorded a $2.8 billion pretax hit on the product, one of the drug industry's costliest failures. Industry giant Novo (NVO) Nordisk followed Pfizer's lead, and in January 2008 they decided to end development of the AERx inhaled insulin system while the product was deep into costly Phase III testing.

Later in 2008, Lilly terminated their agreement with Alkermes to develop inhalable insulin. Their first quarter results for that year reveal the asset impairment and exit costs associated with betting on the wrong non-invasive insulin to be $132.6 million. Today's news reminds me that sometimes large pharma places the wrong bet, and in this case quite a few found themselves racing down the same dead end. Mannkind is the sole surviving biotech developing a promising form of inhalable insulin, they have a PDUFA date for Afrezza inhalable insulin later this month. This comes after they received a Complete Response Letter a few months ago. Their product offers definite advantages over the failed inhalable insulins such as Exubera, and I actually have come to hope they succeed so diabetics later have greater choices for administering their required insulin.

While thinking of all the money the large pharmas lost while following each other into development of inhalable insulin, I recall a quote attributed to Generex representative Todd Falls in 2003 after Lilly terminated their agreement to develop buccal insulin. He remarked at the time that Lilly "didn't want to put the money into us. Lilly felt, I guess, they had some other interests, and didn't want to be the lead on the project." That decision didn't work out very well for Lilly, and Generex is still here with Oral-lyn being studied in a worldwide Phase III trial, and conditionally approved by the FDA in the first Treatment IND awarded to a diabetes drug.

I continue to believe that Oral-lyn, a tasteless liquid aerosol mist formulation that is administered to the buccal mucosa using a proprietary delivery system, has many advantages over inhalable and injectable forms of insulin, although they must be further proven in the Phase III study. These include the small and simple hand held metered dose device, significantly lowered risk of postprandial hypoglycemia, lack of insulin resistance amongst subjects, an actual decrease in Body Mass Index, with no absorption into the lungs. One spray equals one unit of meal time insulin, and this provides greater flexibility in usage, as well as the ability to take small dose sprays before a snack when a treat simply can not be resisted. The unique time action profile for Oral-lyn may be its greatest advantage, with its ability to mimic the first-phase insulin response seen in a healthy person.

Dr James H Anderson was involved with Oral-lyn when Eli Lilly held developmental rights, and has returned all these years later to talk so optimistically about its development. His statement that he believed even then that Oral-lyn had the potential to become a first-in-class therapeutic insulin treatment even though the companies ultimately headed in different directions helps erase doubt formed by the demise of the deal between the two companies. Since we know that Lilly did not conduct a single test to evaluate Oral-lyn, we can see that a business decision was made void of negative data and full of faulty strategy. Dr Anderson is surely needed to assist Generex, and his background is proven. After all, he was a key player in getting Lilly's blockbuster Lispro approved. That is the type of experience the team at Generex needs to help get Oral-lyn to the finish line.

As Generex continues to align the company with expert talent to strengthen the company's clinical/regulatory efforts, the news always strikes me as sort of a validation of the state of the pipeline. New additions to the Scientific Advisory Board, such as Amgen (AMGN) co-founder Dr Joseph Rubinfeld, Pfizer's (PFE) Vice President of Strategic Alliances and Partnerships Dr Craig Eagle, and now Former Eli Lilly Senior Medical Director Dr. James H. Anderson Jr, also have their own reputations on the line, yet they are quoted making remarks that speak volumes about the hidden worth of Oral-lyn, as well as the company's immunotherapeutic cancer vaccines. Generex's faithful shareholders sure hope some of that hidden worth soon comes into vision.

Generex's Antigen Express and France's Stallergenes Co-Author Allergen Research

2010-11-25T19:23:00.000-08:00

Scientists from Antigen Express, a wholly owned subsidiary of Generex Biotechnology (GNBT), and France's Stallergenes (GENP.PA) have co-authored a peer review article titled "Researchers Distinct Characteristics of Seasonal Bet v 1 vs. Perennial Der p 1/Der p 2 Allergen-Specific CD4+ T Cell Responses". The article will appear in a future edition of "Clinical & Experimental Allergy" and is available online ahead of print as of November 24th. Stallergenes is a biopharmaceutical company dedicated to immunotherapy treatments for the prevention and treatment of allergy-related respiratory diseases, such as allergic rhinoconjunctivitis, rhinitis and asthma.

Stallergenes has been researching the potential of using Ii-Key peptide tetramers as an assay to monitor T cell responses to allergens as part of a collaboration with Antigen Express that was signed in 2005. Since Antigen Express' proprietary Ii-Key peptide hybrids are potent at stimulating CD4+ T cells, in theory they would be useful in detecting the presence of allergen-specific autoimmune T cells in the blood. The CD4+ T cell responses to the Ii-Key assay will evidently help Stallergenes identify which patients would benefit from the specific immunotherapies which they are developing.

The new research article compares the CD4+ T cell responses against seasonal (Bet v 1) and perennial (Der p 1, Der p 2) allergens. Bet v 1 refers to birch pollen allergen while Der p 1, Der p 2 are considered to be the major allergens derived from house dust mites. The researchers inform that "major histocompatibility complex class II peptide tetramers were engineered to monitor allergen-specific T cell responses". A little cheating from Wikipedia tells us that "histocompatibility is the property of having the same, or mostly the same, alleles of a set of genes called the major histocompatibility complex. These genes are expressed in most tissues as antigens, to which the immune system makes antibodies".

The new report from Antigen Express and Stallergenes states that "tetramer+ cells were detected in 19 patients allergic to house dust mites (HDM), seven allergic to birch pollen, 13 allergic to both and nine non-allergics". The report concludes that "different memory CD4+ T cell responses are elicited in the context of chronic vs. seasonal stimulation with the allergen(s). The heterogeneity in the patterns of CD4+ T cell responses observed in patients allergic to HDMs should be taken into account for specific immunotherapy".

A previous peer review published in 2008 by Antigen Express and Stallergenes, titled "Single Cell Assessment of Allergen-Specific T Cell Responses with MHC Class II Peptide Tetramers", revealed that the complex class II peptide tetramers, such as those mentioned in in the new report, were peptides that are "chemically conjugated with the Ii-Key peptide from the MHC invariant chain to facilitate peptide exchange and binding to MHC class II molecules". In the report, the researchers described that the CD4+ T helper cells that are activated to respond to specific allergens can be identified with high sensitivity ex vivo using Ii-Key hybrids. The researchers of the article remarked that Ii-Key peptide tetramers "will also be extremely useful to monitor the efficacy of various immunotherapeutic strategies in humans, using an immunological readout, possibly helping to identify surrogate biological markers of clinical efficacy" and that "Ii-Key conjugate peptides is the most efficient procedure to expand Bet v 1(141-155)-specific CD4+ T cells, allowing to detect such cells in both allergic and healthy individuals".

In April, Stallergenes announced the positive results of a phase III clinical trial conducted in the US for its sublingual grass pollen immunotherapy tablet, Oralair. The Phase III study is the first conducted in the US, after successfully completing four Phase III clinical trials conducted in Europe. Oralair has already been approved by German regulators, and Stallergenes has retained Torreya Partners in hopes of helping them secure a partner for the US market by mid-2011. Stallergenes is currently planning their NDA filing to be submitted to the FDA.

Stallergenes is aware that they also need help in evaluating which patients would most benefit from their allergen immunotherapy tablets, and in their scientific research reports we find evidence that this help may come from an Antigen Express designed assay. Antigen Express' ability to turn their Ii-Key peptide tetramer assay research into a revenue generating asset may not be such a far fetched dream. While that dream remains to be seen, this positive research report concerning Antigen Express' proprietary Ii-Key technology is certainly a step in the right direction.

The Tehran Study of Insulin Buccal Spray (Oral-Lyn) efficacy in Type 1 Diabetes

2010-11-08T14:54:00.000-08:00

Insulin Buccal Spray (Oral-Lyn) efficacy in Type 1 Diabetes

Zohreh Annabestani1, Sasan Sharghi1, Samimeh Shahbazi1, Seyed Sajad Mohseni Salehi Monfared1, Farzaneh Karimi1, Eghbal Taheri1,
Ramin Heshmat1, Bagher Larijani1

1-Endocrinology and Metabolism Research Center, Tehran University of Medical Sciences, Iran

Background: To determine efficacy and side effects of oral insulin spray (Oral-Lyn) in comparison to subcutaneously injected regular human insulin.

Methods: Fifteen patients with type 1 diabetes entered in this open-label single arm study with historical control of the same patients for 8 weeks conducted at the Endocrine and Metabolism Research Institute (EMRI). Some biochemical and hormonal lab tests were taken before and at the end of the study. All patients used Oral-Lyn spray instead of regular insulin in dinner time and peripheral glucose measurements were self-monitored by them via similar type glucometer in four different times included fasting, two hours after breakfast, before dinner and two hours post dinner time blood glucose measures.

Results: This study demonstrated that buccal spray had not serious complications and had the same effects on blood glucose control in comparison with regular insulin injections. Also, the rate of hypoglycemia was decreased to 33.3% at the end of the study from 50% at the beginning. Hemoglobin A1C (HbA1c) values did not show any significant changes throughout the study.

Conclusion: Oral-Lyn provides similar postprandial glucose control and caused lower hypoglycemic episodes when compared to regular insulin injections.

Introduction
Conventional injection insulin therapy is recognized to be inconvenient due to multiple daily injections. As we know, insulin is a large peptide molecule that might be absorbed from gastrointestinal tract, but it rapidly degraded in acidic gastric condition. Many efforts have been performed to deliver insulin via oral roots. So, a rapid-acting, orally administrated recombinant human insulin formulation (Oral-Lyn, Generex Biotechnology, Toronto, ON, Canada) has been identified to improve absorption properties in compare with subcutaneous injection of human regular insulin, but with an earlier maximum effect and a shorter duration of action (1, 2).

In the present study, buccal spray insulin was administrated to patients with type 1 diabetes to determine its efficacy in lowering blood glucose levels and evaluation of possible side effects in compare with subcutaneous regular insulin at mealtime.

Methods
This was an open-label single-arm study with historical control of the same patients for eight weeks since May to November 2009 which involved 15 patients with type 1 diabetes (12 males and 3 females). All the participants received information about the purpose of the study, procedures, and possible side effects of buccal spray, in detail. Screening evaluations included physical examinations and clinical and laboratory tests before study recruitment. Also, we questioned about the history of previous hypoglycemic episodes.

Inclusion criteria were at least 1-year history of type 1 diabetes mellitus, which is currently managed with daily insulin injections totaling 0.3 to 0.8 IU/kg of body weight. Their HbA1c should be greater than 6.5 % and less than or equal to 9.5%. Exclusion criteria were oral lesions and/or disease involving the oral cavity. They should not have history of severe hypoglycemia with seizure or coma within the past 6 months. All the participants underwent training about how to use an identical placebo spray device to avoid improper using of the device. Moreover, all the patients were given a certain glucometer device to check their blood glucose at different 4 times included fasting blood sugar (FBS), 2 hours post breakfast (2hpp), and specially before dinner and 2 hours after throughout the study period. We assigned a visit session one week before the recruitment for adjusting the dose of regular insulin injection and Oral-Lyn spray puffs. Each puff was considered as one unit insulin. Oral-Lyn was considered in divided doses with 50% of the dose before the meal and the rest after the meal as recommended. We just substituted regular insulin in dinner time with Oral-Lyn and regular insulin in the morning and lunch times were unchanged. We assigned some visits to collect information about any new problem or side effect and results of self-monitored blood glucose values recorded by the patients. Before start and at the end of the study, the participants were evaluated for some laboratory tests included: cell blood count (CBC), HbA1c, lipid profile, liver enzymes, blood urea nitrogen (BUN) and serum Creatinine (Cr), 24 hours urine protein and microalbumin values. The study protocol was approved by the Ethics Committee of Endocrine and Metabolism Research Institute of Tehran University of Medical Sciences and all the participants signed informed consent.

Results
Insulin which administered via the buccal root was well-tolerated in all the patients. No serious complication was observed among the patients; nonetheless just one patient had bleeding gum that was in case of dropouts. Two patients had mouth numbness and one of them reported vertigo which lasted no longer and had no serious sequel (Table 1). More than 50% of the patients at the beginning of the study reported hypoglycemia episodes and this rate decreased to 33.3% at the end of the study (Table 2).

Mean glucose values before dinner and 2 hours after the dinner at start and at the end of the study has shown in Table 2. Also, this Table shows that the mean values of patients' weight were not changed throughout the study. Mean values of HbA1c did not significantly change throughout the study period. There were no changes in hormonal and biochemical lab test values except Creatinine which was raised in patients at the end of the study (Table 3).

Discussion
Our study showed that Oral-Lyn provided similar postprandial glucose control in patients with type 1 diabetes comparing with regular insulin. Also, it caused lower hypoglycemic episodes when compared to regular insulin injections. Hypoglycemia rates decreased from 54% to 33% as evidenced by our results which suggest that lesser risk of hypoglycemia is expected by using this root of insulin delivery; although it was not statistically significant due to low sample size, it seems clinically meaningful. As we know, the pharmacokinetic properties of Oral-Lyn have been found to be similar to that of rapid-acting regular insulin in patients with type 1 and type 2diabetes (1-4). The Oral-Lyn peptide has some advantages such as rapid absorption, no need for injection, and decrease postprandial hyperglycemia. Also, this formulation causes no major complication or discomfort in the mouth as we observed in our study and is rapidly absorbed within 5-10 min which is faster than subcutaneous injected regular insulin. Although, our results derived from a small number of patients, which considered our study limitation, it was revealed that insulin delivered via oral root at mealtime could be considered as an acceptable substitute for regular insulin injections.

Acknowledgements
This project was financially supported by Sinamode Pars organization. The link for the above study can be found here.

Talking Big Pharma, Vaccines and Baseball with Generex's Dr. Eric von Hofe

2010-10-27T20:39:00.000-07:00

Last week, Generex (GNBT) Biotechnology held a live web cast from Nasdaq's Market Place in NYC, and the event served as an optimistic reminder of the potential of their pipeline, and highlighted the strong group of scientists united in seeing their top drugs and vaccines find eventual commercialization. One day before the Nasdaq web cast took place, I had the opportunity to meet with the top scientist leading their vaccine efforts.

Dr. Eric von Hofe is the President of Worcester-based Antigen Express, a wholly owned subsidiary of Generex. Antigen Express is building an impressive pipeline of next generation synthetic peptide based therapeutics aimed at a variety of major diseases, including cancer and infectious diseases. Dr. von Hofe and I settled in a small NYC deli, and we talked about corporate developments, his background, large pharma, the future he envisions for their platform technology, and my disdain for the Red Sox. Antigen Express is currently evaluating its leading candidate, the novel Ii-key hybrid HER2/neu peptide AE37 vaccine, in a multi-center Phase II trial for patients with breast cancer.

I have followed Dr. von Hofe's career for the last five years, and had briefly met him on two prior occasions. This was the first time I was able to speak with him for an extended time frame, or in an informal setting. I began by asking Dr. von Hofe his thoughts about the vast amount of corporate related changes that have taken place since we last met during Generex's Annual Meeting of Shareholders in July. Beyond the stock related issues, the Board of Directors terminated the employment of long serving CEO Anna Gluskin. Dr. von Hofe appreciated Ms. Gluskin's efforts, and said that working in the biotechnology field comes with the realization that there will often be changes that come rather quick. He recalled his own background, when he was working for Hybridon, where he coordinated research that critically validated gene targets for novel antisense medicines, and one day during a tough financial cycle he suddenly found himself unemployed. He quickly gained work consulting for other firms, and being able to adapt to change brought fun and learning experiences that helped him later.

With Generex's stock on less stable ground, questions about the company's financial condition come into play. I asked Dr. von Hofe if he was confident that interim CEO Mark Fletcher would be able to win enough funds to funnel to Antigen Express to finish the ongoing Phase II study for AE37 with HER2/neu expressing breast cancer patients. He quickly responded "yes, and with help from Joe". Joe is Joe Moscato from Seahawk Capital based in NYC, who is playing a pivotal role in Generex's business development and financing activities. I smiled and told Dr. von Hofe that I knew Joe, and that as a shareholder I tried to help him secure votes for last week's failed reverse split. The vote was actually supported by a strong majority of the shareholders that participated in the vote, but a unique law in Delaware required that 51% of all outstanding shares needed to to vote in favor of the proposal in order for it to pass. The final tally fell just under 3% short of that daunting hurdle. Dr. von Hofe stated that funding will not be an issue and he is not concerned.

Dr. von Hofe confidently said that their "is large pharma interest" in the AE37 vaccine for HER2/neu expressing breast cancer patients. Interim results were released at the San Antonio Breast Cancer Symposium in December 2009. As a reminder about the study, two hundred disease-free, high risk, breast cancer patients who had completed standard adjuvant therapy are being enrolled and randomized to receive six monthly inoculations of either the AE37 peptide vaccine or the adjuvant GM-CSF alone to compare their ability to prevent cancer recurrence. The December interim analysis followed the first 49 patients in the AE37 group and the first 71 for the control group. At a median follow up of 13 months, there were no (0.0%) recurrences in the AE37 group of patients, 0/49, compared to 7.0%, 5/71, in the control group. Dr.von Hofe stated that he hopes more significantly powered interim results will be available by mid-2011, although a public release of those results may not be made until later that year. Often, abstracts of results are submitted months in advance to prestigious events, like SABCS, and the general public may have to wait to see what an interested pharma company can see right away. The goal is for a large pharma to join the effort in funding a large scale Phase III study.

Generex has been active in recruiting top oncology scientists to their newly formed Scientific Advisory board, and in August I had the pleasure of speaking to newly signed Dr. Craig Eagle. Dr. Eagle is the Vice President of Strategic Alliances and Partnerships for the Oncology business unit at Pfizer (PFE), and an account of our discussion can be found here. Dr. Joseph Rubinfeld, one of the original founders of Amgen (AMGN), has agreed to act as Generex's Chief Scientific Advisor, and Col. George E. Peoples, lead researcher of the United States Military Cancer Institute, is serving as a top consultant in the ongoing clinical and regulatory development of Generex's proprietary breast cancer vaccine.

In a related email exchange, Col. Peoples remarked that his "personal campaign has been to get vaccines into the adjuvant setting as opposed to the majority of trials that have been conducted in the metastatic setting". He said that "Big Pharma is not quite ready to invest given the dismal track record of previous therapeutic vaccines in the metastatic setting. Their oncology drug development strategy has always been to establish a market in metastatic patients, and then once there is a revenue stream, then go after the adjuvant market (ie, Herceptin)."

Dr. von Hofe said that he often has to remind himself to make people aware that the target for AE37 is well defined and the same as that for Herceptin, although AE37 may reach a much broader population base. Herceptin, which also zeroes in on cancer that is over-expressing HER-2/neu, can be used only in patients expressing the highest level of HER-2, or about 25 percent of breast cancer patients. In comparison, the AE37 peptide vaccine stimulates the immune system to recognize tumor cells in patients with a lower expression of HER-2, so that 75 percent of breast cancer patients may respond to Antigen's vaccine. Ovarian, prostate, lung, colon, stomach and pancreas cancers are also HER2/neu over expressing, and as such are potential targets for AE37.

Dr. von Hofe noted that Dendreon (DNDN) Corporation's approval for Provenge, the first ever therapeutic cancer vaccine approved by the FDA, ushered in a lot of new interest into the immunotherapy sector. Provenge is designed to treat metastatic prostate cancer, while Generex is gearing up for a Phase II study for AE37 in early stage prostate cancer patients. Dr. von Hofe stated that preparations are well underway, and clinical sites are currently being identified. The Phase I results for patients with prostate cancer were first announced at the 2009 ASCO Annual meeting, and are consistent with those of prior clinical trials of AE37 in patients with breast cancer. Results have shown the vaccine is targeted and effective, while causing very limited toxicity, with no patients experiencing toxicity over Grade 2.

I asked Dr. von Hofe about Apthera's E75 peptide vaccine, since I am aware that the immuno effects of this CD8 T Cell targeting vaccine are short lived. I had read previous preclinical data stating that a combined effect of E75 linked with AE37, which targets CD4 T Cells, may help E75 gain prolonged memory. Dr.von Hofe acknowledged the preliminary data suggests a combination may prove useful for E75, but that his interest is in proving AE37 is effective and safe on its own, and that AE37 is already long lasting. Also, AE37 is already the subject of a combined approach with another CD8 targeting peptide vaccine. To me, it sounds like Apthera, a private company, can figure out their problems on their own, because Generex has moved on to better opportunities.

Dr. von Hofe sat back and smiled while recalling his phone ringing and hearing of this combined peptide vaccine opportunity provided by the Mary Crowley Cancer Research Center in Dallas. Mary Crowley researchers proposed a Phase I study to assess the safety and immunological response in patients with either breast and/ or ovarian cancer with AE37 linked with GP2, a CD8 targeting T Cell peptide vaccine under research at the USMCI, and they wanted "no claims on IP". Dr. von Hofe called that a "no brainer", and said he was pleased that they recognized the potential of the AE37 vaccine. This particular study is ongoing, although Generex has no control over the slower pace of recruitment. I laughed and told Dr. von Hofe he would like more phone calls like that, and he quickly agreed.

My time with Dr. von Hofe was near complete, but I had to tell him one area I had of concern. I said that I see one problem with Antigen Express, and I asked if they were all Boston Red Sox fans? I told him that I am a Yankees fan, and he chuckled. He recalled reading a story in the newpaper of a bird in Boston that flew down and hit the head of a young girl. She was not hurt, and her named turned out to be the same as Alex Rodriguez's daughter. I mockingly protested that he would find that to be funny. It was nice to see a vaccine researcher whom I have followed and admired for so long act casual and at ease. He told me that his children were all happy when the Red Sox won the World Series, and in this case I'll make an exception to my rule. I have found a Red Sox fan that I acknowledge to be smarter than me. As he roots for the dreaded Red Sox, I root for Generex to revolutionize how early breast cancer is treated. There will be no stock exchange big enough for the company that follows in the footsteps of Herceptin and Provenge, only to potentially surpass them both.

Generex 's Acquisition into the Direct to Consumer Diabetes Market Provides Synergistic Value

2010-10-10T15:59:00.000-07:00

Generex Biotechnology's (GNBT) shareholders have read a lot of corporate news as of late, from a management change to the signing of sales and distribution agreements. Last week, Ms Gluskin was replaced as CEO by VP and General Counsel Mark Fletcher. Generex has a loyal base of shareholders, due to the leadership provided by Ms Gluskin and Ms Perri, who have brought the company very close to achieving the success they dreamed of, and today another step appears to have been taken to strengthen the foundation of the corporation. Undoubtedly, this could not have come together without the work of the former CEO, since the management change only occurred last week. She should be recognized for her effort, and I begin by doing so.

Generex announced Monday morning that they have reached an agreement to acquire a 51% ownership stake in Global Medical Direct LLC. This news comes after a weekend full of wild speculation, due to an after hours press release by Generex alerting investors that they would be making a key material announcement before this morning's market opening. Many shareholders were guessing partnership news could be brewing between Generex's oncology subsidiary and Pfizer for the small biotechnology's immunotherapeutic peptide vaccine that has drawn attention due to the very promising interim Phase II results for early stage breast cancer patients that were last updated at ASCO in June. While news of a partnership nature for Generex waits for a later date, I feel Monday's news, once digested, is a surprisingly smart strategic development that brings synergistic strength most often seen in much larger companies completing channel distribution deals to support product growth.

Typically, such deals seeking turn-key solutions enabling solid growth potential and key competitive advantages come at marked premiums, and the costs associated with setting up such an infrastructure on their own would be well beyond anything Generex could afford. Most microcap biotechnology companies, focused solely on research and development, overlook business development deals with direct to consumer firms, such as Global Medical Direct, as a means to solve packaging and shipping facility concerns, as well as the other numerous handicaps they face while preparing to bring their new drugs to market. Over reliance of relationships with large pharma weakens future revenue potential, and Generex is unique to many of its peers due to an OTC line of products that are already on the market, including a diet spray that is currently sold in CVS stores across the US. In the future, this marriage may put Generex in a stronger negotiating position with large pharma since their own product launches could now be in part handled internally.

Generex's early attempts at generating revenue, while simultaneously navigating their main drugs and vaccines in development through clinical trials, has recently brought in further progress, as sales and distribution agreements were announced with Merck S.A. de C.V. in Mexico and Elias Shaker in the US. In my opinion, this strategy of generating sales to offset costs of R and D will now be greatly aided by having direct to consumer access to over 65,000 diabetic patients that make up Global Medical Direct's customer roster. Generex has a line of diabetes related products, including Glucose Rapidspray, GlucoRx test strips, NutriMed diabetic soap, OraSweet drops, Crave-Nx diet spray, and a line of vitamins that will debut through GMD's educated staff and support center. But I think the real value lays in the unforeseen opportunities to support both the current FDA approved Treatment IND program for Oral-lyn buccal insulin spray, as well as its future full label US launch.

Global Medical Direct, beyond providing access to thousands of doctors that can now learn about Oral-lyn and consider their patients for the Treatment IND program, can assist Generex with a staff experienced in overcoming hurdles related to reimbursement policies as the company attempts to make Oral-lyn available to a wider group of diabetics. Education and awareness campaigns to doctors and diabetics is essential for a novel an unique insulin solution such as Oral-lyn, and the synergy found in this business development position Generex in the right place at the right time.

The one aspect of timing that may concern us as shareholders is Friday's upcoming special meeting where the company is again requesting the passing of a proposal allowing the Board of Directors permission to enact a reverse stock split. I speak and communicate with many shareholders that are steadfast in their opinion to vote no to the proposal, but as of late my own mind has shifted where I will change my no vote to yes. This is most likely the part of the article where I am cursed, since that is surely an unpopular stance to take! For the last couple of months, I have been very concerned with the prospect of Generex's stock trading on the bulletin boards, but I had voted no to the proposal because I thought the company can keep Nasdaq at bay as long as they were at least attempting approval of the proposal to enact a reverse split.

Generex's problem with Nasdaq's minimum bid listing requirement stems from a toxic loan they entered during the financial meltdown. At the time, investment cash was near impossible to find, and many biotechs facing similar situations either sold assets at pennies on the dollar or went bankrupt. Generex's management tried diligently to raise capital in more conventional ways but ultimately were forced to enter an unconventional loan for approximately $20 million. Shareholders like me, who went along for the ride, watched our shares quickly enter a downhill spiral. Generex's founders decided it best to protect shareholders by repaying a couple monthly payments in cash, which temporarily offset dilution. One default was triggered, which was not due to failure to make a payment, but is somehow tied to the amount of cash on hand in relation to the amount of the debt. The creditors did not offer any alternative, and actually, many shareholders are unaware that Generex's cash holdings fell to the point where money owed to Ms Gluskin and Ms Perri, from a cash award made by the Board of Directors for failure to pay amounts due from the company's earliest years, was the sole source of cash that held up the company in the final few weeks of the loan.

Nasdaq, due the financial calamity, was quickly becoming the equivalent of the bulletin board. Generex was not alone, stocks for many microcap companies fell below the $1 minimum, and the exchange was forced to extend the time frame for which the companies needed to regain compliance. Many failed, and many were forced to enact reverse stock splits. Today, access to capital is a bit easier, and Generex was able to help the company survive the toxic debt and began raising cash through registered direct offerings off of its conventional SHELF filing. Generex had signed on a new business development and financial consultant, Seahawk Capital, led by Senior Managing Partner Joe Moscato, and together they worked hard to find a new slate of investors and to clean out the toxic warrants from the prior loan. Generex was successful in raising capital a few times at increasing prices in the second half of 2009, but do to the ill effect of the number of shares issued to repay the prior loan, all of the offerings were below $1. However, they were not accompanied by the more toxic forms of warrants, and the pipeline remained intact and in position to better lives.

When Generex entered that 2008 toxic loan, and a decade after being born from an idea jotted down on a piece of paper by its founders, the outstanding share total was near 115 million. Two years and a few months later, the outstanding share total is near 265 million. In my opinion, while the market cap is currently vastly undervalued, the real problem with the stock is the amount of common shares issued as payments towards the 2008 loan, because capital was as hard to find on Nasdaq as it currently is on the bulletin board. In other words, I owned GNBT as if it were on the bulletin board, because I owned GNBT as it raised cash on Nasdaq's Capital Market in 2008. The bulletin board remains as toxic as it ever was for microcap biotechs that have unique needs to raise capital to support costly R and D. That is where the real dilution lays, and I vote no to that possibility.
Undoubtedly, this new agreement signed by Generex, also brings some concern about future dilution to support the acquisition. Dilution to gain something valuable in return, with synergistic opportunities that enhance Generex's metabolic pipeline of OTC items and drugs, is in my opinion a true value proposition. We'll learn more in the next two days. I feel the deal offers exciting mutual beneficial opportunities with a company that has earned double digit growth over the last few years. With Global Medical Direct's proven management team remaining in place, Generex may see impressive levels of revenue gain while completing the studies for Oral-lyn and AE37. The deal creates a stronger Generex, where future terms for raising capital should only improve, as will they for partnership talks involving Oral-lyn or Metcontrol Gum. Turn key solutions will be in place. A stronger corporate structure for Generex is beneficial to shareholders with long term vision. I'm voting yes to this future for Generex. The company's plan to initiate a rights offering of common stock and warrants to its existing stockholders in the event that the stockholders approve a reverse stock split is a nice caveat for existing shareholders who can participate, while my own business efforts will force me to take a pass. The amount of the offering is anticipated to permit an aggregate investment of at least $25,000,000, which I am told would be the high end anticipated for the acquisition. However, my current shares are locked and ready, as we move forward with the company

In this article, I intentionally paid homage to Generex's founders. We welcome the future best by honoring the past, although I hope all of the aforementioned parties continue to work together in some capacity. All of the shareholders share in Generex's dream, and with today's news, I believe that the company is better positioned and the dream is closer to being a reality. I'm voting yes to this future for Generex.

The United States Military Cancer Institute to Reveal New AE37 Vaccine Data at SABCS 2010

2010-09-20T18:44:00.000-07:00

The 2010 CTRC-AACR San Antonio Breast Cancer Symposium is presented by Cancer Therapy & Research Center at UT Health Science Center San Antonio, the American Association for Cancer Research, and Baylor College of Medicine. The prestigious event will be held between December 8-12, and brings together the top cancer researchers from around the world.

At this year's event, unexpected new data will be presented from the Phase II study of the AE37 HER2/neu Peptide Vaccine for early stage breast cancer patients will be presented by researchers from the United States Military Cancer Institute. The Phase II study is a prospective, randomized, multi-center clinical trial investigating whether the AE37 Vaccine can prevent recurrence in disease-free, conventionally treated, node-positive and high-risk node-negative breast cancer patients who are at significant risk for recurrence. Generex is collaborating with the USMCI in this exciting study.

The data is unexpected, since we are currently unaware of any clinical work where the AE37 Vaccine is given to early stage breast cancer patients either sequentially or concurrently with Herceptin. The researchers at the USMCI have been conducting preliminary work to assess any advantage in a combination immunotherapy with Herceptin and HER2/neu peptide-based vaccines (see here). However, these efforts apeared to focus more on the first generation E75 Peptide Vaccine and the second generation AE37 Peptide Vaccine was not mentioned. In previous blogs, I have speculated that Herceptin used with AE37 may make Herceptin more potent. My theory came from reading available abstracts that evaluated the therapeutic role Herceptin has in "modulating the activity of the cellular immune system in patients with breast cancer". I borrowed that quote from a peer review that appeared in the British Journal of Cancer. The report is titled The Effects of Trastuzumab (Herceptin) on the CD4+CD25+FoxP3+ and CD4+IL17A+ T-cell Axis in Patients with Breast Cancer. The concluding sentence of the report states that "the coadministration of trastuzumab along with therapies that either promote Th17 or reduce Treg cells may be a particular direction, with the aim of ultimately improving the prognosis for patients unresponsive to trastuzumab or other therapies".

We learned from an abstract presented at ASCO 2010 that the AE37 Vaccine is reducing the levels of Treg cells (see here). The conclusion of the abstract stated that the "AE37 + GM-CSF vaccine decreases Tregs during and after completion of vaccination while GM-CSF alone does not alter Treg levels. This suggests that AE37 may allow the immune system to more effectively fight cancer and correlates with an observed decrease in recurrences." I suppose the USMCI also looked at that AE37 data and recognized the potential for combining AE37 either sequentially or concurrently with Herceptin. The title of the unexpected abstract at this year's SABCS Annual Meeting is Combination Immunotherapy for Breast Cancer Patients: Safety and Immunologic Data from a Phase II Trial Administering a HER2/neu-Derived Peptide vaccine (AE37+GM-CSF) Sequentially or Concurrently with Trastuzumab in the Adjuvant Setting. Trastuzumab = Herceptin. Click on the title for the link to view Poster Sessions 2 Treatment and scroll down to "Therapeutic Strategies: Immunotherapy Clinical" and circle December on your GNBT calender. Generex Oncology, aka Antigen Express, is on the cusp of developing a targeted immunotherapeutic vaccine that may revolutionize how cancer is treated in the near future.

EASD 2010: Important Antibody Data from Novo Nordisk, Amylin and Generex

2010-09-19T15:19:00.000-07:00

Our Immune System Makes Antibodies to Respond to Therapeutic Proteins that are Recognized as Being Foreign to our Body

When a therapeutic protein is detected by the immune system as being a potential threat, several types of cells work together to respond. These cells trigger the B lymphocytes to produce antibodies. For example, when insulin is injected, the body views it as a foreign substance and the immune system starts to work to neutralize the drug. As a result, increased levels of insulin may later be needed to have the same effect, which is called insulin resistance. However, as new research detailed in three separate abstracts at this week's EASD Annual Meeting reveal, antibody formation is not only a potential consequence of insulin treatment, but is also seen in clinical trials with diabetic patients using other well publicized drugs. The three abstracts concern Amylin (AMLN) and Eli Lilly's (LLY) Byetta/Bydureon, Novo Nordisk's (NVO) Victoza, and Generex (GNBT) Biotechnology's Oral-lyn.

An EASD 2010 abstract funded by Amylin and Eli Lilly for Byetta and Bydureon, titled "Antibodies to Byetta did not Cross-React with Human GLP-1 or Glucagon or Alter the Efficacy or Safety of Exenatide", is interesting. As most are aware, Bydureon is an investigational medication designed to deliver continuous therapeutic levels of Byetta in a single weekly dose. In this abstract, researchers focused on whether antibodies formed in response to Byetta or Bydureon cross-react with human GLP-1 or glucagon, however they also reveal surprising differences in the level of antibodies formed between the two treatments. Pooled data from numerous clinical trials were evaluated, and a closer look finds interesting bits of information. For example, the researchers found that 37% of patients were positive for antibodies to Byetta, while 56.8% of patients were antibody positive to Bydureon. Of those positive for antibodies to Byetta, 5% had higher antibody titers, while 11.8% of those positive for antibodies to Bydureon had higher titers. The researchers state that in the small number of patients with higher antibody titers, the impact on efficacy was variable, with the majority experiencing a glycaemic response consistent with antibody-negative patients. They further find that other than injection-site reactions, no other increased incidence of adverse events was observed with antibodies to either drug. What isn't discussed is why there are significantly higher levels (of low and high titer) antibodies formed in response to Bydureon as opposed to Byetta, and I feel this contrast should be evaluated.

The abstract funded by Novo Nordisk at EASD 2010, which highlights antibody response to Victoza, is titled "The Incidence of Antibody Formation and the Levels of Antibodies are Lower with Victoza than Byetta in a Head-to-Head Comparison". A deeper look will show how this abstract contradicts some of the previous findings from the Amylin and Eli Lilly funded report. This study is 56 week extension of the 26 week LEAD-6 trial. After 26 weeks, subjects taking Byetta were switched to Victoza for the extension study. The researchers of this abstract report that at 26 weeks, 61% of patients were positive for antibodies to Byetta. Recall that in the previous abstract, this figure was 37% at week 30. The study does report further antibody data relating to Byetta, where they measured antibody response to Byetta at weeks 40 and 78, or 14 and 52 weeks after switching treatment from Byetta to Victoza. At 40 weeks, 50% still had antibody response to Byetta, with 18% reported at week 78. That proves the antibody levels decline after treatment ends, but at a slow pace as the immune system stays on alert. The study finds that "high-titer Byetta antibodies affected glycemic response to Byetta, but after switching to Victoza, persistent Byetta antibodies did not compromise glycemic response to Victoza". Interestingly, researchers state that only 3.0% patients who switched from Byetta to Victoza for 1 yr had antibodies to Victoza.

No mention is made of previously reported data illustrating that approximately 50-70% of Victoza-treated patients in the five clinical trials of 26 weeks duration or longer were tested for the presence of anti-Victoza antibodies at the end of treatment. Cross-reacting anti-Victoza antibodies to native glucagon-like peptide-1 occurred in 6.9% of the Victoza-treated patients in a previous 52-week monotherapy trial and in 4.8% of the Victoza-treated patients in the 26-week add-on combination therapy trials. In previous reports antibody formation was not associated with reduced efficacy of Victoza, and the most common category of adverse events among patients who developed anti-Victozza antibodies was that of upper respiratory tract infections.

In August, I wrote an article alerting that data that Generex (GNBT) Biotechnology will be presenting at EASD 2010 which details a unique study conclusion for any insulin option regarding insulin antibodies. The title of the abstract funded by Generex is "No Generation of Insulin Antibodies in Subjects with Impaired Glucose Tolerance Treated with Buccal Spray Insulin". The abstract details the findings in a limited Phase II trial for subjects with impaired glucose tolerance, or prediabetes. Amylin and Eli Lilly, as well as Novo Nordisk, are also seeking data on their drugs among this population, as it represents a huge untapped market. The researchers for this Oral-lyn study begin by noting informative basic facts about IGT, and report that "in patients with impaired glucose tolerance, upon implementation of life style changes and metformin, a third returns to normal glucose tolerance, a third continues with IGT and the rest goes on to develop clinical type 2 diabetes. An increased risk for cardiovascular disease occurs in the latter two groups even though there is no progression to diabetes." Over 60 million people in in the United States have impaired glucose tolerance, and as obesity rates rise, so does the need to medically treat this group when the current recommendations of diet and exercise fall short.

The study abstract for Oral-lyn details a randomized controlled trial in 36 subjects with IGT comparing Oral-lyn buccal insulin plus physical exercise and diet vs. physical exercise and diet only as the control group. Upon conclusion of the study, insulin antibody levels were measured, and surprisingly none were found in the treatment group. The researchers conclude that "preliminary data show that subjects treated with buccal spray insulin do not develop autoimmunity vs insulin as usually occurs with subcutaneous or other forms of insulin delivery (pulmonary). This may represent an additional benefit of buccal insulin, considering also the more acceptable route of administration." It is important to note that in all previous studies of insulin, this has never been seen. The level of antibodies formed as result of insulin treatment is much higher in pulmonary insulin, such as Mannkind's (MNKD) Afrezza. The abstract for Oral-lyn is not nearly powered as much as those for Byetta/Bydureon or Victozza, but they are in line with the preliminary trends from their Phase III study of Type 1 patients where there are no reports of insulin resistance.

As noted in the opening remarks from the abstract about Novo Nordisk's Victoza, "antibody formation to therapeutic proteins can potentially affect pharmacokinetics, trigger adverse events, and/or diminish clinical response". I am not a doctor or a scientist, but I feel when the immune system develops antibodies to a medication, it is because our body is trying to tell us an important message. Often, we hear of drugs developed to treat diabetes that are later found to be unsafe. Physicians are well aware that the surest way to lower blood glucose levels in a patient is by introducing insulin therapy. In my opinion, Generex has developed a novel way to deliver insulin that avoids the complications and unpleasantness of injections, or the safety concerns that many fear may arise from pulmonary insulin or GLP-1 receptor agonists.

At EASD 2010, I hope some of the large pharmas take the time to listen to the positive reception the immune system of diabetics are giving to Oral-lyn, and match it to the known and continued reports of efficacy. Sometimes the simplest solution to a problem is the best. This is just one of the many reasons I feel Generex's Oral-lyn is the most promising of all the new drugs in development to treat diabetes.

Analyzing Generex and Throwing Darts with Pfizer's Craig Eagle, M.D.

2010-08-17T16:41:00.000-07:00

In July, my friend TC and I attended Generex's (GNBT) Annual Meeting of Shareholders. While at the meeting, I had the opportunity to meet Joseph Moscato, the managing partner at Seahawk Capital based in New York City, a consultant of Generex's who has advised them on strategic planning and business development opportunities over the past year and a half. He is also quite a colorful character and we enjoyed talking to him about his consultancy role at the company. Near the end of our trip at Generex's hometown of Toronto, TC and I spoke to Joe about catching up near his NYC office since we both live nearby.

Last week, TC and I made our way to the Capital Grille in downtown NYC to join Joe and to learn about his company. I was mainly interested in gauging Joe's long term sentiment for Generex and to determine if it matched my own. While spending time with Joe, I found it very comforting that he knew in great detail many aspects of the company and that his vision is long term with hopes to help them reach their full potential. I realize that is an easy sentiment for him to portray, but it takes deep due diligence to talk with the depth of knowledge about Oral-lyn and AE37 that we shared while standing near the bar. We appreciated learning that Joe shares in our belief that Generex is headed for great success.

To our surprise, we learned from Joe that Dr. Craig Eagle, Vice President of Strategic Alliances and Partnerships for the Oncology business unit at Pfizer (PFE) and recent addition to Generex's oncology scientific advisory board, would also join us later in the evening for an informal introduction. To be able spend time with a professional involved with guiding small biotechs in their financial and business opportunities, as well as a true pharma expert that leads them on the proper scientific course, is an unique opportunity for a couple of retail shareholders. Many NYC based brokers stood near us at the bar, and we felt like we had a glimpse of life with the movers and shakers. As Joe's Blackberry buzzed all night, TC and I joked that our phones must be broken.

The Eagle Has Landed

I was primed to talk more with Dr. Eagle about Generex's active pipeline of diabetes drugs and cancer vaccines, and when he arrived, I wasted no time. He was a friendly guy with no hint of arrogance, and he was surprisingly open to numerous topics of discussion. Fresh beers in our hands, we were the only guys in a NYC bar talking about peptides the way others talk about the Yankees or Mets. TC and I listened, as Dr. Eagle began by telling us the scientific promise he sees in Generex as a whole. To show how amateurish I am, I placed down a copy of a recent analysis I had written about Antigen Express and their AE37 HER2/neu peptide-based breast cancer vaccine. Later, I noticed Dr. Eagle use the paper as a coaster for his beer.

Dr. Eagle explained why he felt that Generex contains great scientific value in its pipeline; from the the potential for revenue streams from the Rapidmist delivery system, to a positive opinion about prospects for Oral-lyn, to how AE37 could have the potential to completely change how breast cancer is treated. Dr. Eagle's words reminded me of similar sentiment given earlier in the year by one of the original founders of Amgen (AMGN), Dr. Joseph Rubinfeld, who joined Generex in mid-2009 to act as the company's chief scientific advisor. You can read Dr. Rubinfeld's words here where he talks about the vast potential he envisions for the technologies and science of Generex and Antigen Express.

We must have talked to Dr. Eagle for an hour straight, the poor guy, as I delved into Ii-Key hybrids, CD4 T Helper Cells, and other peptide based vaccines such as E75 and GP2. To look cool, I mentioned other vaccine researchers I admire, such as the Mayo Clinic's Keith Knutson and UW's Mary Disis. To be honest, that didn't make me look any cooler. He fluently discussed numerous details of the research I mentioned, as I tried to relate this to Generex's Ii-Key hybrid technology. I believe that he appeared equally passionate. Our discussions led me to feel that there is some sort of pharma interest in AE37, and that this interest was born from the positive interim results from the ongoing multi-center Phase II HER2/neu breast cancer vaccine study being conducted with the United States Military Cancer Institute.

We know that in December 2009, AE37 data as a preventative HER2/neu breast cancer vaccine (see the actual poster here) was presented at the San Antonio Breast Cancer Symposium. Lead researcher from the USMCI, Col George Peoples, reported to the symposium that at a median follow-up of 13 months, there were NO relapses in 49 patients receiving the AE37 vaccine for breast cancer while relapses were observed in 5 of 71 patients in the control group. Col. Peoples also reported data regarding a significant increase in DTH levels which illustrated that AE37 was providing the desired immunological effect, and that there were no serious levels of toxicity reported for any of the subjects receiving AE37. Generex's management has publicly stated that they have begun discussions with pharma companies in light of this data, and I feel this is the reason they signed on Dr. Eagle as a scientific advisor.

Dr. Eagle explained that in his role he helps get them up to snuff on protocols, and offers guidance to them in their next developmental and regulatory steps. His role, among others, is to get them ready for a potential partner to take the risk in partnering with them on, let's say, AE37 for their pending Phase III breast cancer study. He told us, upon questioning, that his obligation is to help them no matter which partner eventually emerges with the right pocket book. As a result of my own due diligence, from analyzing Roche (RHHBY.PK) and Genentech's (DNA) blockbuster breast cancer drug Herceptin, as well as Dendreon's (DNDN) metastatic prostate cancer vaccine Provenge, I feel AE37 as a preventative breast cancer vaccine should currently be valued over $1 billion. Yet, we see that Generex's market cap is currently in the low range of $100 million.

To give a brief on that analysis, consider that while only 25% of breast cancers have levels of HER-2/neu expression high enough to be candidates for treatment with Herceptin, those cancers expressing lower levels are expected to be good candidates for AE37. The advantage of this is that the immune system, once activated, is capable of detecting lower levels of the target protein than is Herceptin and that the anti-tumor activity lasts long after termination of AE37 treatment. And also consider that since AE37 is being developed to prevent cancer recurrence, I hope it will eventually make a vaccine such as Provenge, designed to treat metastatic cancer, one that stays in the back room of the pharmacy. AE37 may lead to longer and healthier lives, while Dendreon's significant advance has been shown to extend the last stage of life by a few precious months. I hope both may prove to be great medical advances that take us beyond this era of Herceptin, and they usher in a new era of immunotherapeutic vaccines that may revolutionize how cancer is treated.

Throwing Peptides As Darts

Throughout our discussion, Dr. Eagle would make an analogy to study data as being like throwing darts. Yes, he knows the seriousness of the disease being researched, but the analogy was to simplify a complex statistical metric to help TC and I understand. He said if one person in the bar throws a dart for a bullseye, that this would not be significant. The amount of times an attempt was made is very important, as well as other factors including the distance to the board. To establish the bulls eye as a trend among a group of people playing darts, it would then be important to know how many are actively involved. I asked if that meant the study has to be powered enough and with a properly defined endpoint. He said yes, and that this is an area that is very important.

I referred to the Phase I results for AE37 in both breast and prostate cancer patients as also being positive. For prostate cancer subjects in the Phase I, results were presented at the 25th Annual EAU Congress this past April. I talked about how out of 32 subjects, 23 patients had positive DTH responses following immunization, and the median progression-free survival for DTH responders was 18 months compared to 1 month for DTH non-responders. (You can see those results here.) He again reminded me of the analogy of throwing darts. I mildly protested that similar DTH responses have been found in AE37's Phase II breast cancer study. I guess I was trying to increase their score!

In reality, Generex and Antigen Express are not playing darts, but appear to be entering a transformative period of development where the goal is commercializing medical advancements that will better peoples lives. A partner for AE37 may or may not be close at hand, but I do feel the vaccine technology of Antigen Express is closer to gaining widespread attention based on all of the promising early results. I sure hope so, because like other Generex shareholders, I'd like the focus to return towards the pipeline and not NASDAQ or a reverse split of our shares.

In my opinion, a pharma could be watching for further AE37 data that is deeper into the Phase II breast cancer study and with a higher amount of patients included in order to make that judgement call. That would mean more darts need to be thrown by AE37 in order to establish the current trend as being significant. In the meantime, Dr. Eagle is helping them get ready. When that data can be made available is not something I can guess, and I've over speculated enough. Dr. Eagle gave no signal about big pharma's current interest in potentially partnering with Generex for AE37. I developed that opinion strictly on my own.

I also know these things can change in a heartbeat, and for the last week I have been conflicted about even writing this blog. However, I feel other shareholders may be interested in our discussions with Dr. Eagle. While speculating is a fool's game, it is hard not to notice that we were not only talking to Generex's scientific advisor, but also Pfizer's Vice President of Strategic Alliances and Partnerships for the Oncology business unit.

I'll never think of darts in the same way again.

The Quest for a Safe, Effective and Non-Invasive Meal Time Insulin

2010-08-14T22:24:00.000-07:00

"I poke my fingers to check my sugar. I have to take shots before I eat. I’m tired of all this. I wish it was easier. I can’t go to my friends’ houses. They don’t know what to do". ~ Josh from An Anthology of Poems by Kids with Diabetes

While subcutaneous insulin is effective in controlling blood glucose and HbAIc concentrations, the required injections can be a burden for patients, which can impact compliance. Patients and physicians hesitate initiating insulin therapy for several reasons, such as concern that injections are painful, difficult to administer, inconvenient, and the overall perception that initiating insulin treatment signifies a dramatic worsening of the disease. These inherent limitations are among other possible reasons why diabetics often have poorly controlled HbA1c levels while on conventional insulin therapies.

Everyone taking injected insulin develop antibodies to insulin. The antibodies bind to and neutralize the insulin. Researchers have found that if you form antibodies to insulin, your body reacts as if the insulin is foreign. In some cases, this may make insulin less effective, or not effective at all. The antibodies can also change the amount of time it takes insulin to work, putting a diabetic at risk for hypoglycemia. As a result, increased levels of insulin would later be needed to have the same effect, which is called insulin resistance.

Inhalable insulin and Insulin Resistance

Inhalable insulin has been associated with much greater antibody response than subcutaneous insulins, but this has not yet clearly been correlated with any serious adverse clinical effect. There is debate in this area with some health care professionals calling for longer term studies to be conducted to clearly determine the effect these greater levels of insulin antibodies have on a diabetics body. The debate is now more pertinent since the FDA is once again considering a new drug application for an inhalable form of insulin.

The first approved inahable insulin was Pfizer's (PFE) Exubera, which was later withdrawn from the market due to a lack of acceptance amongst diabetics and their physicians. There are many reasons for Exubera's demise; from its bulky size and confusing dosing, to its required lung function tests mixed with the safety concerns of long term usage. Results pooled from subjects using Exubera's in Pfizer's Phase 2 and 3 trials found they had much higher levels of insulin antibody binding activity. Greater antibody responses were seen in patients with type 1 diabetes, also known as Juvenile Diabetes, which would naturally lead to greater levels of insulin resistance in this population. The higher anitbody responses were found in pediatric patients (<18 years) and in females (see page 181).

The new inahalble insulin the FDA is currently reviewing for marketing approval is Mannkind's (MNKD) Afrezza, which differs from Exubera in particle structure, pharmacodynamics, and glucodynamics. However, Afrezza doesn't appear to greatly differ from Exubera in antibody responses. The development of insulin antibodies in Type 1 and Type 2 study patients exposed to Afrezza was presented at the American Diabetes Association's 70th Scientific Sessions in June. Insulin antibodies were measured and found to increase as early as 2 weeks upon Afrezza initiation, rising over time, while plateaued or spontaneously declined after 10 to 18 months. As seen with subjects who participated in the Exubera studies, insulin antibodies were more pronounced in Type 1 patients exposed to Afrezza. Three months after discontinuation of Afrezza treatment the subjects levels of insulin antibodies returned to near-baseline values, indicating that the insulin antibodies response to pulmonary inhalation of Afrezza is reversible.

At this point in research, no associations are noted between insulin antibodies levels and key clinical outcomes for Afrezza subjects. Mannkind noted that this effect was expected as the lungs function as a port of entry for exogenous substances and contain a large concentration of immunoactive tissue and that no clinical consequence of insulin antibodies have been observed.

Generex Oral-lyn Buccal Insulin and Insulin Resistance

A limited study involving insulin antibodies in subjects using Generex's (GNBT) Oral-lyn will be in the spotlight this September at the EASD Annual Meeting in Stockholm, Sweden. Generex has developed a proprietary platform technology for the delivery of drugs, such as insulin, into the human body through the oral cavity with absolutely no deposit into the lungs. Researchers evaluating Generex Oral-lyn in an ongoing Phase II study with Impaired Glucose Tolerant patients will present an abstract aptly titled "No Generation of Insulin Antibodies in Subjects with Impaired Glucose Tolerance Treated with Buccal Spray Insulin". The abstract can be found in the EASD 2010 abstract book. There is an embargo on the abstracts being presented at the event, but I will inform that once again the highly regarded independent endocrinology researcher Dr Paolo Pozzilli leads the study, and the title itself reveals their conclusion and yet another apparent difference between buccal and inhalable insulin.

In July, Generex reported preliminary outcomes and trends from their ongoing Phase III pivotal study of Generex Oral-lyn buccal insulin in Type 1 patients. This subject group is the same that has shown greater levels of insulin antibodies in both Exubera and Afrezza. While both forms of inhalable insulin have been found to form heightened levels of insulin antibodies that in turn may lead to insulin resistance, this effect has not been found in subjects using Oral-lyn. Generex reported that insulin resistance has not observed for the Type 1 subjects using Oral-lyn. When the study is completed, it will be of great interest to see data assessing insulin antibody levels in subects using Type 1 diabetes.

Result trends are showing that Oral-lyn, comprised of human insulin and GRAS (Generally Regarded as Safe by the FDA) excipients, is more naturally accepted by the body and therefore does not result in insulin resistance. These results are preliminary, with a full analysis of the Type 1 Phase III study expected to be complete in early 2011, while three month results for all patients are expected much sooner.

Generex has also reported in their preliminary trends announcement of their Phase III study of Type 1 patients that subjects using Oral-lyn have demonstrated NO weight gain and have had, on average, an actual decrease in their Body Mass Index. These results compare favorably to control subjects in the study using injectable insulin who have, on average, gained weight and experienced an increase in BMI. When comparing hypoglycemic events, subjects using Oral-lyn were observed to have a better Adverse Event profile than subjects using injectable insulin. This also compares favorably to prior studies for Afrezza inhalable insulin where slight weight gains are rightly mentioned as a noteworthy achievement.

For all of these reasons, I believe that Oral-lyn will be found to be the first insulin to safely and effectively mimic the normal pancreatic insulin release of a healthy person, without any of the safety concerns that some believe swirl around inhalable insulin. Since the development of insulin antibodies is greater in pulmonary insulin than subcutaneous injectable, and Mannkind says the condition is reversible after a patient stops taking Afrezza, then I hope that those same patients can start taking Oral-lyn in the first ever diabetes related Treatment IND (see FOX TV video) that the FDA has already granted Generex. This way those diabetics may potentially not have to worry about any of the insulin antibody or pulmonary concerns, while freeing themselves from the burdensome effects that come with subcutaneous insulin.

Generex shareholders themselves are currently burdened with fears concerning the effect of a potential reverse stock split, or a negative response from Nasdaq's Hearings Panel. However, if Generex continues to find successful results in their ongoing Phase III study of Type 1 patients, shareholders and diabetics alike will be welcomed by a much brighter future. Considering that Generex recently announced they have achieved 75% of the required number of per-protocol completers in the six month pivotal global Phase III study, that brighter future may be close at hand.

My Visit With Generex Biotechnology at the Annual Meeting of Shareholders

2010-07-30T05:55:00.000-07:00

Generex Biotechnology held their Annual Meeting on Wednesday July 28th in Toronto. I'll keep this blog a bit more informal than I usually write, since I am expressing more about personal experiences rather than any detailed pipeline analysis. I flew in from New Jersey Tuesday afternoon and was pretty excited to meet the people at Generex and share in my opinions on company developments. As the taxi driver slowed down to approach my hotel, I looked over to my right and was quite surprised. On the ground floor next to my hotel was a sign that read "Generex Biotechnology". I had no idea I was staying so close to their corporate headquarters.

The time was a little before 8 pm, and instead of checking into my hotel room, I grabbed my bags from the trunk of the taxi and walked straight over to this building to see if I could find anyone from Generex. Their offices were closed, but it sure felt strange to be looking right at the site of the company I have followed so closely over the last five years. In a way, it felt surreal. I felt a little like a tourist looking at a landmark site. I don't mean to sound so much like a fan of the company, although I admit I do fall into that category. I admire and respect how difficult it must for the founders to start a microcap biotech company from one or two patents to a burgeoning specialty biopharmacuetical company with a surprisingly active pipeline. If anyone reads my blog or my articles at Seeking Alpha, I have already detailed my assessment of this promising pipeline of diabetes and oncology technologies, so I'll skip a repeat overview.

Generex's offices were closed, but my camera was open for business. I took a few photos that I will share for others that also have an interest in this company that I believe is on the verge of significant medical advancement. Here are some photos I took while walking around the building on Harbour Square that houses their modest offices.

A shareholder friend, TC, that I communicate with on DigitalTradz.com, met me at the hotel the night before the meeting. We both share in optimism surrounding prospects for the company, but also were concerned with certain aspects of how the company portrays itself to the investment community. We feel that the company can do a much better job in this regard and wanted to address this issue at the ASM. I want to thank him for his time and friendship as we accompanied one another throughout the remainder of the trip. I may like to blog, but I don't necessarily like to speak in public forums. I also wanted to make sure I expressed myself with the level of respect that I believe the Generex team deserves. TC, and the open armed reception we received from Generex's management team, made the transaction from web blogger to in person communicator much easier than I could have imagined.

The main proposal of interest before shareholders at the meeting was a vote to approve a change the company's Certificate of Incorporation allowing for the implementation of a Reverse Stock Split while maintaining the number of Authorized Shares of Common Stock at 750,000,000. The company did achieve quorum for the meeting and proceedings began by opening any questions or comments to shareholders in attendance regarding any of the proposals. Over 180 million shares were represented, but only mine accompanied me to the microphone to question the strategy of not reducing the number of shares in their corporate treasury.

Ms. Anna Gluskin, Generex's CEO, explained that the company responsibly considers dilution concerns of shareholders. In the last two years, the amount of shares outstanding have doubled as the company struggled to repay a $20 million debt and subsequently raised capital in a handful of direct offerings. However, Generex has illustrated a level restraint in stopping dilutive transactions on three occasions during that same time frame. The first occurred in December 2008, which is when Generex repayed one of their final monthly debt payments in cash rather than in shares. That decision was quite noticeable since during that time the company's cash position was low. In October 2009, the company announced they will not exercise its right to issue and sell shares of its common stock under the At Market Issuance Sales Agreement with Wm Smith & Co. until further notice. And more recently, during June of this year, the company exercised its right to terminate the Common Stock Purchase Agreement entered into by Generex and Seaside 88 on April 7, 2010. Shareholders may disagree with Ms. Gluskin that the company responsibly considers dilution when planning their capital strategies, but I understand dilution is expected and I agree with Ms. Gluskin that the company does show restraint and care in how they proceed during the capital raising activities. As a shareholder, I simply wanted the company to hear my voice to remind them that small retail shareholders actively watch their plans and have concern about how this effects their holdings. To be honest, after my experiences chatting with them personally, I am confident they have always had our interests in mind. I think they face difficult decisions that we may not always understand.

The meeting proceeded and a general corporate presentation ensued. The presentation was very powerful and I was quite impressed. The webcast is available on the corporate website, so rather than offer a full repeat of the company's comments, I will advise all to take the time to listen. The presentations by Dr. Gerald Bernstein (Vice President, Medical Affairs and former President of the ADA) and Dr. Eric von Hofe (President of Generex's wholly owned subsidiary Antigen Express) were particularly inspiring and serve as a strong example of why I believe Generex's pipeline will eventually be valued above both Mannkind and Dendreon. I know that is quite a statement, but in a few years when current studies are completed and approvals are in hand, I strongly believe the market will respond.

When the formal session of the meeting was adjourned, Ms. Gluskin allowed shareholders in attendance to ask questions. I took the time to ask the questions you will hear concerning whether the amount of patients in the Phase III study with Type 1 patients may be powered enough to satisfy the FDA. Mr. Markus explained that with Oral-lyn's safety profile, a study of 500 patients may be suffice, although they are planning a formal meeting with the FDA to get proper guidance. I questioned Dr. von Hofe on the enrollment status of the Phase I AE37 Combo Vaccine for breast and ovarian cancer patients, and he informed that the study is closing in on the final enrollment and that the Mary Crowley Cancer Research Center is mainly in control of the pace of recruitment. This is a study that I find quite exciting, since it was the prestigious cancer center that initiated the collaboration and is providing the funds. That fact alone tells me quite a lot regarding a future valuation of this vaccine candidate and illustrates the scientific community's high opinion of Antigen Express' Ii-Key hybrid technology. I also asked Dr. von Hofe if the planned Phase III study for AE37 with HER2/neu breast cancer patients can proceed before the formal completion of the ongoing Phase II, and he responded quickly an emphatic "yes" since they have shown a display of efficacy and AE37 has a positive safety profile. Dr. von Hofe told us that they have already begun active discussions with the FDA. I queried if I was correct that AE37 has had no patients experience toxicity beyond Grade 2. Dr. von Hofe confirmed this fact, which is very unique for a new cancer treatment candidate. Dr. von Hofe also told the shareholders in attendance that promising signs have been seen in the area of business development.

I took a deep breath and embarked on a topic that has been like a plague on the internet. The discussion of Oral-lyn's (Oral Recosulin) status in India was first mentioned by an author for LiveMint quite some time ago. Additional articles were written by the same author and were later repeated by TheStreet's Adam Feuerstein. The controversy stems around whether the company has been accurate in stating that Oral-lyn is available for sale, or whether the DCGI in India rescinded approval and mandated a local Phase III trial. Ms. Gluskin stated "nothing has been rescinded" and explained that a Phase IV marketing surveillance study was part of the initial approval. During the November 2007 conference call for the India approval, Ms. Gluskin does mention that a Phase IV study was a condition of the approval. The company did later announce a "commercial" purchase order of 210,000 canisters of Oral-lyn, and in March 2009 announced 60 doctors were prescribing Oral-lyn to 100 patients. My friend TC mentioned this last item during his follow up questions.

I moved on and asked whether we can expect a Phase II study with IGT patients, since the proof of concept study conducted by Dr. Paolo Pozzilli revealed outstanding results. Ms. Gluskin informed that the new Phase II study will have partial results presented during the EASD conference in September and the original study has been submitted for peer review. That is great news since I was unaware that a Phase II had begun or that we will see a peer review for the Phase I. I also asked about a possible Phase III study for Type 2 patients, and we learned that a smaller study is being planned and that some secondary markets do not require a separate trial. Discussions will be held with the FDA regarding the US market. Ms. Gluskin talked about earlier use in Type 2 patients, and I remarked that showing a study in such patients will show how earlier intervention would be beneficial. Actually, if Generex can someday appeal to IGT patients or Type 2 patients that normally would not consider insulin treatment, they would revolutionize diabetic care. I believe they are slowly on that track. Future funding will propel their course.

After the question and answer period, TC and I were greeted by many in attendance. A member of the Board of Directors approached me and he said he was impressed by our questions. TC did a very thorough job which resulted in interesting and informative discussion. I began my appeal to have the company consider implementing quarterly conference calls. The Board of Director members I engaged in discussion said they will advance the request, and Ms. Gluskin also expressed consideration to adopt such an approach. I believe that at first the calls may be difficult, but would eventually result in a greater level of transparency and help Generex earn a higher level of confidence amongst the investment community. As I told Ms. Gluskin, we also would appreciate hearing of setbacks, and as long as we always have an accurate flow of information, our support would grow even stronger. I was pleased with how much time she gave us after the formal session.

Judging by the extraordinary amount of time the company gave to shareholders during the question period and after the meeting, I think the path towards new found openess is one in which they have already embarked. I was quite impressed throughout the entire day. The COO, Rose Perri, could not have been kinder or more accommodating, and allowed us to visit their headquarters and arranged a tour of their Oral-lyn filling facility. I greatly appreciate the warmth they showed to us, and I doubt any other biotech company would be as open armed. Before leaving for the tour, TC and I continued talking with others in attendance, and we were both struck by the amount of face time we had with the management team and Board of Directors. They were willing to discuss any of the topics we brought up during the meeting. Dr. Bernstein in particular was making a great effort at making us comfortable, as he also did before the meeting began.

Before the meeting, while Dr. Bernstein was talking with us, I asked a question that was on my mind for some time. I knew he was a Type 2 diabetic, and I asked if he ever used Oral-lyn in replacement of his regular meal time insulin. He said he did, and even used Oral-lyn before it was in the current formulation we hear about in the Phase III study. I asked if it worked in lowering his blood glucose levels as intended and he told us that it did. He went on to explain in detail all the reasons he feels Oral-lyn will better diabetic's lives and lead to greater health. He told of the significance of the FDA approved Treatment IND and then I first read the Phase III update while he told us the meaning of the findings. Now that was a fun way to read a Generex news release!

The company has shown positive Phase III reports regarding no insulin antibodies and an actual weight loss amongst Oral-lyn subjects. As I said to Ms. Gluskin during the question period, that is remarkable when we realize that this is never seen in injectable insulin patients and that Mannkind has been touting a small weight gain amongst Afrezza inhalable insulin users as a great statistic. Get Oral-lyn, Mr. Mann.

If you know me, you would understand that reading an Oral-lyn update with Dr. Bernstein had me on cloud nine. Dr. Eric von Hofe was on my right side, and Ms. Perri, whom I particularly like, was watching along. That was the exact moment Ms. Gluskin approached me with a big smile, and I just kept thinking how unfair this company has been treated by the snarly journalist from TheStreet. I didn't want the meeting to end. During the next fiscal year, I believe the uncertainty surrounding the stock will be long gone and the concentration of investors watching Generex will turn to what I see; a promising pipeline that will outweigh similar biotech's that currently have much higher valuations, led by a team of people that do care about the retail investor. I already know I'll be at the Annual Meeting next year.

The proposal for a reverse stock split was not approved at the meeting. The company stated in a press release today that "In an effort to prevent the Company's common stock from being delisted, the Company has requested that the Nasdaq Hearings Panel grant the Company additional time to hold a special meeting of the stockholders at which the requisite stockholder votes to approve the Amendment will be sought. To achieve the requisite votes, the Company will work with its proxy solicitation agent, Morrow & Co., LLC, to design and implement an aggressive, targeted solicitation strategy. The Company cannot be certain that the Panel will grant the Company's request." The feeling I have from the meeting is that the company does not actually want to implement such a split, and is trying to buy time to remain listed on NASDAQ as they continue with their business plan. From what I witnessed, a lot of positive activity is taking place that is not reflected in the market cap. Some day, I believe the problems surrounding Generex's stock will hardly be remembered.

Generex's Antigen Express: Creating the Next Generation of Cancer Immunotherapy

2010-04-28T19:40:00.000-07:00

Synthetically Designed Immunotherapy Cancer Vaccines

Antigen Express is the fully owned life science subsidiary of Generex Biotechnology (GNBT). Antigen Express is building an impressive pipeline of next generation synthetic therapeutics aimed at a variety of major diseases, including cancer and infectious diseases. The platform technology of Antigen Express allows for antigen-specific stimulation of a T-helper response to virtually any antigen of known pathogenic potential. Antigen Express is currently evaluating its leading candidate, the novel Ii-key hybrid HER2/neu peptide AE37 vaccine, in a multi-center Phase II trial for patients with breast cancer under a research agreement with the United States Military Cancer Institute.

AE37 is an immunotherapeutic synthetic peptide vaccine designed to prevent the recurrence of a variety of different cancers that express the HER-2/neu peptide. An advantage of Antigen Express' immunotherapy is that it causes none of the toxicities typically associated with classical chemotherapy. While the target of AE37 is the same as that of the Roche's (RHHBY.PK) blockbuster cancer drug Herceptin, the activity of AE37 relies on its ability to stimulate a patient's own immune system to recognize the cancer target rather than by interacting with the target directly.

New AE37 Data to be Presented at ASCO 2010

I found evidence that new data for the AE37 vaccine will be presented at the 2010 American Society of Clinical Oncology Annual Meeting to be held in Chicago from June 4-8, 2010. ASCO 2010 abstracts will be available on the company's Annual Meeting website in mid-May, although abstract titles can currently be found on the event itinerary page. The title of an AE37 abstract being presented at ASCO 2010 is Effect of a Novel Ii-key Hybrid HER2/neu Peptide AE37 Vaccine with GM-CSF as Compared to GM-CSF Alone on Levels of Regulatory T-cell Treg Populations. The listed author/speaker is Dr. Guy T Clifton, who has worked extensively on peptide based therapeutic vaccines at the USMCI with Antigen Express collaborator Col. George Peoples.

If Dr. Clifton highlights Phase II data that confirms previously reported Phase I data regarding AE37's effect on regulatory T-cell Tregs, that would be great news for Antigen Express. The Phase I trial for AE37 in breast cancer patients showed that Tregs were reduced in all patients tested pre- to post-vaccination. This smaller Phase I trial also found that DTH responses increased in all patients from pre- to post-vaccination p<0.0001. Boding well in this trial for the vaccine was that there was an inverse relationship between the degree of Treg reduction and the size of DTH response to AE37. The researchers concluded in this trial that the reduced levels of Tregs in vaccinated patients appear to be associated with more robust responses in ex vivo immune assays and in vivo DTH reactions suggesting that the AE37 vaccine may be clinically useful.

This pending update follows the impressive interim results for the AE37 vaccine in its current Phase II trial which were unveiled at the San Antonio Breast Cancer Symposium in December 2009. Two hundred disease-free, high risk, breast cancer patients who had completed standard adjuvant therapy are being enrolled and randomized to receive six monthly inoculations of either the AE37 peptide vaccine or the adjuvant GM-CSF alone to compare their ability to prevent cancer recurrence. This interim analysis followed the first 49 patients in the AE37 group and the first 71 for the control group. At a median follow up of 13 months, there were no (0.0%) recurrences in the AE37 group of patients, 0/49, compared to 7.0%, 5/71, in the control group.

Continue reading my article here.

Antigen Express AE37 Data to be Presented at ASCO 2010

2010-04-13T01:23:00.000-07:00

The American Society of Clinical Oncology (ASCO) is the world’s leading professional organization representing physicians who care for people with cancer. With more than 28,000 members, ASCO is committed to improving cancer care through scientific meetings, educational programs and peer-reviewed journals. Generex's wholly owned vaccine subsidiary, Antigen Express, is currently evaluating its novel II-key hybrid HER2/neu peptide AE37 in a multi-center Phase II trial vaccine for patients in breast cancer under a research agreement with the United States Military Cancer Institute. New data for the AE37 vaccine will be presented at the 2010 American Society of Clinical Oncology ASCO Annual Meeting that will be held in Chicago from JUNE 4-8, 2010.

The title of the abstract is "Effect of a novel II-key hybrid HER2/neu peptide AE37 vaccine with GM-CSF as compared to GM-CSF alone on levels of regulatory T-cell (Treg) populations". The author/speaker is Dr. Guy T Clifton, who has worked extensively on peptide based therapuetic vaccines at the USMCI with Antigen Express collaborator Col. George Peoples. The full abstract will be available at the ASCO Annual Meeting website in mid-May.

This update follows the impressive interim results for the HER2/neu AE37 vaccine in its Phase II trial which were unvield at the San Antonio Breast Cancer Symposium in December 2009. Two hundred disease-free, high risk breast cancer patients who have completed standard adjuvant therapy are being enrolled and randomized to receive six monthly inoculations of either the AE37 peptide vaccine or the adjuvant GM-CSF alone to compare their ability to prevent recurrence. This interim analysis followed the first 49 patients in the AE37 group and the first 71 for the control group. At a median follow up of 13 months, there were been no (0.0%) recurrences in the AE37 group of patients (0/49), compared to 7.0% (5/71) in the control group. You can view the SABCS poster here.

RESULTS FROM THE FIRST PHASE I CLINICAL STUDY OF THE NOVEL II-KEY/HER-2/NEU (776–790) HYBRID PEPTIDE VACCINE IN PATIENTS WITH PROSTATE CANCER

2010-04-04T10:03:00.000-07:00

European Urology Supplements publishes peer-reviewed original articles and topical reviews on a wide range of urological problems. Topics such as oncology, impotence, infertility, pediatrics, lithiasis and endourology, as well as recent advances in techniques, instrumentation, surgery and pediatric urology provide readers with a complete guide to international developments in urology.

Current Edition- April 2010

950 RESULTS FROM THE FIRST PHASE I CLINICAL STUDY OF THE NOVEL II-KEY/HER-2/NEU (776–790) HYBRID PEPTIDE VACCINE IN PATIENTS WITH PROSTATE CANCER

These results are more expansive than what was reported at during a podium presentation at ASCO 2009. Read the latest results here.

Once again, the AE37 HER2/NEU hybrid peptide vaccine has very limited toxicity, with no patients experiencing toxicity over Grade 2. That is a very important advantage, since most cancer drugs are hard to tolerate. The efficacy of AE37 is even more impressive, as the report details a lowering of PSA levels for most patients with a majority experiencing a DTH response, which in turn leads to vastly improved medium progression free survival (18 months to 1 month) for DTH responders.

Perhaps we get an update at the upcoming 25th Annual EAU Congress in Barcelona. At the EAU 2010 website, this AE37 Phase I study in patients with prostate cancer is slated for a poster presentation on Monday, 19 April 2010. Under session "Focal and systemic therapies", I found Dr T.K. Karaolides from Saint Savas Cancer Hospital in Athens is listed as the speaker. You can view the abstract titles from that session here.

Revealing the Clamour Against Biotech in "TheStreet"

2010-03-28T17:46:00.000-07:00

When one person makes an accusation, check to be sure he himself is not the guilty one. Sometimes it is those whose case is weak who make the most clamour. ~ Piers Anthony

On March 21st, I highlighted coverage of TheStreet's Senior Columnist Adam Feuerstein's controversial March 19th opinion piece focused upon Generex Biotechnology's efforts at developing Oral-lyn buccal insulin spray. In my article, I detailed how I believed his opinion piece to be defamatory and based upon untrue statements. Specifically, I proved his argument that none of the Oral-lyn data collected by Generex has been peer-reviewed in credible medical journals, nor has it been presented at the top-flight diabetes meetings was utterly false. In reality, I cited the numerous peer review articles which have been published by the independent researchers studying Oral-lyn in its Phase I, II and III trials, and named the plentiful "top-flight diabetes meetings" where Oral-lyn data has been presented, including having Oral-lyn data being selected for a prestigious podium presentation at last year's American Diabetes Association's Scientific Sessions.

On March 23rd, Generex issued a press release demanding a retraction and apologies for the inaccuracies published in Feuerstein's entry titled "Biotech Stock Mailbag: Generex". Generex stated that they wish to correct the public record by making clear the facts as outlined in a letter to TheStreet's counsel. Generex informed that a number of independent, peer-reviewed studies of Generex Oral-lyn have been published in journals including "Diabetes Care". The company remarked that Generex Oral-lyn trial data has been presented in podium posters and abstracts at the annual meetings of the American Diabetes Association, the Endocrine Society, the European Association for the Study of Diabetes and the International Diabetes Federation on a regular basis over the past ten years. Generex routinely presents Oral-lyn data at all of the major diabetes events and the latest peer review article was published as recently as last month.

On Friday March 26th, TheStreet corrected Feuerstein's article to note that "Oral-lyn has been discussed in medical journals and presented at medical association meetings over the last ten years" and that TheStreet "regrets the error". TheStreet may regret further errors since on the same day the correction was printed, Feuerstein offered a subsequent article (see here) focused upon Generex and Oral-lyn which contained false information and childlike innuendo. In the article, Feuerstein does not acknowledge how his previous offering contained conclusions that were built upon faulty premises. Rather, I contend that he stubbornly embarks down the same unrighteous path where he strong arms conclusions which are left to clumsily stand upon an inaccurate foundation.

Generex's Oral-lyn is a buccal insulin spray that is in a Phase III trial in the U.S. and which has recently been conditionally approved by the FDA under a Treatment IND [Investigational New Drug]. The FDA website states that they will permit an investigational drug to be used under a Treatment IND if there is sufficient evidence of safety and preliminary evidence of drug efficacy. The drug must be intended to treat a serious or life-threatening disease, or if there is no comparable alternative drug or therapy available to treat that stage of the disease in the intended patient population. The Treatment IND approval for Oral-lyn was the first awarded by the FDA to treat diabetes.

In the latest article, I find that Feuerstein again makes claims that are false and which illustrate his lack of knowledge about the regulatory requirements surrounding a new drug that will be targeted for approval to treat Type 1 diabetes. Since Feuerstein, a TheStreet's representative as a professional biotechnology journalist, is incapable of understanding the regulatory hurdles a company such as Generex will face in vying for FDA approval for Oral-lyn to treat Type 1 diabetes, I believe their financial news service cannot serve as an adequate outlet for investors to gain a diligent perspective for developments within that specific sector.

Among many of the inaccurate claims I find Feuerstein to make, he states that MannKind tested Afrezza in 5,300 patients total. That is false and Feuerstein just powered Mannkind's study population by an additional 2,850 subjects. Mannkind submitted a NDA for Afrezza "inhalable" insulin to the FDA based on testing in 2,450 subjects with Type 1 or Type 2 diabetes who were randomly assigned to treatment with their inhalable powder insulin. Feuerstein also mentions the large study population total to support a NDA from Eli Lilly and Amylin for Byetta LARS.

What Feuerstein seemingly fails to comprehend is that Generex is currently vying for approval to treat Type "1" diabetics with Oral-lyn buccal insulin, and its new drug does not have to undergo the pulmonary testing associated with inhalable insulin, or strict cardiovascular studies associated with Amylin's Type 2 oral pill. Feuerstein can also eliminate from his mind the entire Type 2 population that was tested in these other drugs, at least until a time frame when Generex is targeting Type 2 approval. Feuerstein also must be unaware that Biodel recently submitted a NDA, under a 505(b)(2) pathway approved by the FDA, for ViaJect injectable human insulin with less patient power than Generex currently has recorded for Oral-lyn. In short, the professional biotechnology journalist is confusing the regulatory path for drugs that treat Type 1 patients, with ones that treat Type 2.

Among other false statements Feuerstein makes is that regular insulin is slow acting and isn't used by diabetics around mealtime, which makes the Oral-lyn data irrelevant. This is false. Humulin R and Novolin R are bolus mealtime regular insulins, and Feuerstein is evidently confusing them with basal NPH insulin, also known as Eli Lilly's Humulin N and Novo Nordisk's (NVO) Novolin N. The standard protocol for any bolus insulin to gain FDA approval is by a non-inferiority study comparing HbA1c levels of the new insulin versus Humalin R. Subsequent labeling studies may be designed to compare the new bolus insulin versus the newer and faster acting meal time analogues which have been approved, but the comparison versus reglular insulin is imperative for approval.

In my opinion, Feuerstein rushed to conclusions in order to support a negative opinion on Generex's developmental path for Oral-lyn. I uncovered his effort in his first article, where he proposed an argument that the effort to develop a non-injectable insulin delivery system is market driven and not the result of a real need experienced by diabetics. While he informed that he gains his perspective from "the thought leaders at the American Diabetes Association", I noted in my original report that he overlooked how in February the American Diabetes Association published a well publicized study which found that out of 502 diabetics surveyed, 57 percent said they had intentionally missed an insulin dose, and 20 percent said they regularly skipped insulin injections. Among the reasons for skipping insulin injections were complaints of injection pain, embarrassment by the need for insulin and thought that the injections interfered with their daily life. One in five stated they skip insulin injections often.

As I had noted, the report in Diabetes Care was presented on the heels of a similar report issued in 2008 by the American Association of Diabetes Educator. The report found that 33% of the surveyed patients have experienced "dread" in relation to insulin injections, 14 percent surveyed feel that insulin injections have a negative impact on their life, and more than 29 percent of the surveyed feel that injecting insulin is the hardest aspect of their diabetes care. Feuerstein and his "thought leaders at the American Diabetes Association" evidently failed to take notice.

In Feuerstein's newer article, he quotes my prior claim detailing how he was wrong in stating that there have been no peer reviews focused upon Oral-lyn's studies and that that the company has not presented buccal insulin study data at various top flight diabetes conferences. He makes no mention that TheStreet admitted his errors. Feuerstein continues by remarking upon my citation of the most recent peer review published related to Oral-lyn (February 2010 edition of Diabetes, Obesity and Metabolism), authored by two of the independent clinical study investigators who have led Oral-lyn human research studies. The authors are Dr Paolo Pozzilli and Dr Philip Raskin, and the title is "Review of Clinical Trials: An Update on Oral Insulin Spray". Dr Pozzilli has studied Oral-lyn buccal insulin in multiple Phase II studies of Type 1 diabetics and Type 2 diabetics, as well as those with Impaired Glucose Tolerance (pre-diabetics). Dr Raskin is the principal investigator of Oral-lyn's current worldwide Phase III trial for treating Type 1 diabetics.

In the report, they state that on "all of the studies conducted, the oral insulin spray was generally well tolerated", that the "ease of use of the insulin spray formulation may increase patient acceptance and treatment compliance, thereby potentially reducing complications and improving quality of life for patients with insulin-dependent diabetes" and in "all of the studies discussed, results showed that oral insulin spray was absorbed in direct relation to the amount given and had a faster onset and a shorter duration of action when compared with SC regular insulin". They further state that this "fact alone would seem to make the oral insulin spray an ideal candidate for prandial glycaemic control" and that "ease of use of the insulin spray formulation may increase patient acceptance and treatment compliance, thereby potentially reducing complications and improving quality of life for patients with insulin-dependent diabetes".

Feuerstein charges the article actually demonstrates quite clearly the lack of any credible clinical data to support the insulin spray's efficacy or safety. He is quite confused and his research into Oral-lyn's development is noticeably weak. Feuerstein remarks how Drs Raskin and Pozzilli, in the discussion section of this particular review, write that a key limitation to this review is the lack of studies that compare oral insulin spray with rapid-acting analogue insulin; none of the published studies (to date) have provided this comparison. This particular review does not provide a complete overview of all of the buccal insulin studies that Generex has presented at various top flight diabetes conferences. I believe this fact eludes Feuerstein, whose statements and follow up comments document his ignorance that studies have been completed comparing the activity and efficacy of Oral-lyn versus newer insulin analogues to aid in providing a more robust assessment of the clinical utility of the oral formulation.

Escaping Feuerstein's research is the study comparing Oral-lyn to meal time analogue insulin, co-authored by researchers from the Institute for Endocrinology IEMYR, Quito, Ecuador, and the University of Florida, Gainsville. The year-long Oral-lyn study examined 26 subjects with type-1 diabetes. Members of the control study group received insulin glargine (an insulin analogue) once a day as their basal dose, and a faster-acting insulin analogue before meals. Members of the treatment group received a non-analogue long-acting insulin twice a day as their basal insulin; before meals they took Oral-lyn, a rapid acting liquid version of human regular insulin, that is absorbed through the lining of the mouth. Study results illustrate the rapid onset of action and superb glycemic control of Oral-lyn as compared to the analogues. "When Oral-lyn is absorbed through the buccal mucosa, its rapid entry into the blood stream mimics and improves upon the rapid acting analogues", commented Dr. Jaime Guevara, a study author and clinician that has conducted studies for Generex's Oral-lyn.

Feuerstein's article was published by TheStreet in his Biotech Stock Mailbag column on March 26th, and first appeared on financial and stock oriented web pages at 7 am. That same morning, Feuerstein posted on his Twitter page that "another body blow delivered to GNBT today in this week's Biotech Stock Mailbag". The entry time listed on his Twitter page was 4 am (see here), however the time zones may vary. The comment about a "body blow to GNBT" is juvenile and questionable. I believe that the body blow was delivered to the self serving biotechnology journalist that is heavy on clamor, and absent of intelligent or accurate analysis.

In summary, Feuerstein alternates from comparing apples to oranges, and at all times appears completely uninformed. He apparently is unaware that there is Oral-lyn data from Italy, England, Israel, Canada and the U.S. from earlier (pre-Phase III) trials, and erroneously states the data is only from a couple of small studies conducted in Ecuador. Perhaps in his next article, he can wisely contact Dr. Gerald Bernstein at Generex, who is the expert on Oral-lyn's utility and development. An ignorant opinion can not be disguised as professional analysis. In my opinion, if this type of commentary is indicative of the quality of the content in TheStreet, biotechnology and pharmaceutical minded investors should look elsewhere.

New March 2010 Antigen Express patent work for their Ii-Key/HPV16 E7 HUMAN PAPILLOMAVIRUS Vaccine

2010-03-25T20:37:00.000-07:00

(WO/2010/027973) HUMAN PAPILLOMAVIRUS / LI-KEY HYBRIDS AND METHODS OF USE

Applicants: ANTIGEN EXPRESS, INC. [US/US]; Biotech Three, 4th Floor One Innovation Drive Worcester, MA 01605 (US) (All Except US).
XU, Minzhen [CN/US]; (US) (US Only).
HOFE, Eric, Von [US/US]; (US) (US Only).
Inventors: XU, Minzhen; (US).
HOFE, Eric, Von; (US).

Every year, 470,000 cases of cervical cancer are diagnosed. Essentially 100% of cervical cancers contain HPV of the high-risk type (HPV 16 or 18), persistent infection of the cervix with these viruses is considered to be the necessary cause of the disease (90% of other ano-genital cancers also contain HPV). Oral cancer, penile cancer and some neck cancer might be related to HPV infection as well. There are no good therapies when metastasis of HPV induced cancers such as cervical cancer occurs and thus effective new therapies are needed urgently.

Gardasil, a virus like particle that targets the L1 protein of HPV types 6, 1 1 , 16 and 18 protects women from infection by HPV close to 100%. This type of vaccine mainly induces a humeral immune response generating antibodies that can neutralize the virus. Gardasil is thus an effective vaccine for preventing HPV infection. However, this kind of vaccine is ineffective for treating HPV+ cancers since both CD4+ and CD8+ T cell immunity must be induced in order to eradicate the HPV+ cancers.

Accumulating data indicate that immunotherapy for cervical cancer and other HPV+ cancers holds promise. The expression of the HPV E6 and E7 genes is found in most cervical cancers as well as other HPV+ cancers, indicating that the HPV oncogenic proteins, E6 and E7, are critical for the induction and maintenance of cellular transformation. The specific expression of these genes in the majority of the HPV+ carcinomas suggests that they are good targets for immunotherapy.

Presented herein, are embodiments of the present invention including a novel and non-obvious method that significantly enhances the efficiency of HPV peptide vaccine. In this regard, the present invention is directed towards compositions comprising li-key/HPV hybrid peptides and nucleotide sequences encoding said peptides. The present invention is also directed towards methods of prevention of HPV infection by administration of one or more compounds of the present invention to a subject. Further, the present invention is directed towards the treatment of diseases in which HPV infection is at least part of the etiology of the disease. Such diseases include, but are not limited to, warts and precancerous or cancerous lesions such as cervical cancer, penile cancer and certain neck cancers. In another aspect of the present invention, it is contemplated that the HPV sequences of the present invention are useful for the inoculation and vaccination of subjects for the treatment or prevention of diseases in which HPV infection is at least part of the etiology of the disease.

In another aspect, the present invention relates to a method to improve the potency of DNA and peptide vaccines containing MHC Class ll-presented epitopes of HPV antigens of interest. The present invention involves priming the immune system of a subject with li-Key hybrid peptides such that the potency of a subsequently administered DNA or peptide vaccine is augmented. The li-Key construct may be administered in the form of a nucleic acid construct encoding the li-Key hybrid peptide.

See WIPO details here.

Diabetics may be able to skip the shots thanks to a spray

2010-03-23T15:11:00.000-07:00

Copyright 2010 / Article from Medstar:

No one likes shots. However, if you're an insulin-dependant diabetic, those injections are a requirement. But there is a new way to deliver insulin, one spritz at a time.

If you didn't know better, you'd think Steven Elkman has asthma.

"And nobody really notices because so many people use inhalators for asthmatic medications, that, you know, it doesn't really attract any attention," said Steven.

But Steven's actually managing Type 2 diabetes with a unique insulin delivery system.

"It's literally a spray that goes into your mouth, and the spray actually is in, in a form so that about one unit per spray of insulin can get absorbed into your body," Dr. Dennis Gage, an endocrinologist at Beth Israel Medical Center in New York City.

The experimental spray, called Oral-lyn, may offer an option for patients who fear injections.

"You know the ‘insulin' word, and they get nervous and they just would rather not go there and that, that's a frequent problem," Dr. Gage said.

In this case, the insulin is packaged in a spray bottle, and is spritzed in the mouth just before meals.

"Depending on how much they're on, they may need five sprays, six sprays, ten sprays," said Dr. Gage. "But we build that up based on their blood sugar ‘til it's really perfect."

The insulin is absorbed through mouth tissue and enters the bloodstream from there. If Oral-lyn gets FDA approval, the spray may be the only medication some Type 2 diabetics will need.

"We're trying to remove one oral medication at a time, and ideally then I would just be on this," said Steven.

An injection-free device that may revolutionize the way insulin gets into the body.

link is here.

Investigating Adam Feuerstein: Clearing the Garbage from TheStreet

2010-03-21T14:33:00.000-07:00

A problem for small retail investors looking for trusted financial news websites lies in deciphering which ones serve their interests and which ones simply offer analysis more suited for the message board forums. Often the barrier between news and bluster is blurred and one example comes to mind which I would like to highlight. Adam Feuerstein is a Senior Columnist at TheStreet.com who blogs about the pharmaceutical and biotechnology industries. I feel that Feuerstein also serves as an example of how the flow of information from "news" sources to the retail investor is distorted and broken.

Last Friday, I read first hand an example of Adam's "reporting" on a biotechnology company I follow, Generex Biotechnology (GNBT). Since Generex is a micro cap company, having an article from a "news source" featuring them can result in volatile trading activity for their stock. A columnist offering a negative opinion on a company or stock can often result in a more well rounded perspective and be helpful. However, when the article presents a defamatory opinion based on untrue statements, the small retail shareholder holding shares can watch his investment deteriorate for potentially manipulative reasons.

Feuerstein takes a negative approach towards Generex in his daily featured article, titled Biotech Stock Mailbag. The problem is that he states his opinion based upon premises which I find to be blatantly false. Feuerstein belittles Generex's efforts in developing Oral-lyn buccal insulin spray by stating that "none of the Oral-lyn data collected by Generex has been peer-reviewed in credible medical journals, nor has it been presented at the top-flight diabetes meetings".

In the lively comment section that follows his article, I cited the numerous peer review articles which have been published by the independent researchers studying Oral-lyn in its Phase I, II and III trials, and named the plentiful "top-flight diabetes meetings" where Oral-lyn data has been presented, including having Oral-lyn data being selected for a prestigious podium presentation at last year's American Diabetes Association Scientific Sessions. In reality, Generex routinely presents Oral-lyn data at all of the major diabetes events and the latest peer review article was published last month.

Please continue reading this blog here.

The Day the FDA Served Notice

2010-03-15T19:38:00.000-07:00

The biotech world had been impatiently awaiting the FDA to deliver some type of Action Letters to Mannkind and Amylin/Eli Lilly/Alkermes regarding the NDA's for Afrezza inhalable insulin and Byetta LARS. As I blogged in previous posts, some of these new diabetes drugs have been controversial due to perceptions about their safety profiles. While original Byetta had been linked to certain serious side effects (see here), these were safety alerts and no proof currently exists that Byetta is the cause of the kidney problems. Similarly, much of the safety concern swirling around Afrezza has to do with the previous safety alert issued for Exubera, the first inhalable insulin to gain FDA approval (but not market place acceptance). That alert centered around a small amount of clinical trial patients developing lung cancer, but a direct link to Exubera has not been determined (see here.)

Complete Response Letters

Today, the FDA served notice, in the form of Complete Response Letters, resulting in a setback for both Afrezza and Byetta LARS. Currently, it is too early to tell how severe of a blow these CRLs are to both new drug candidates, and it appears more concerns plague Afrezza as opposed to Byetta LARS. In Afrezza's case, the FDA is requesting information regarding the clinical utility of Afrezza, and more information is needed to determine the thinking at the FDA. The news release regarding Afrezza is here, while the news release concerning Byetta LARS can be found here.

Clinical Utility

While thinking of Generex Oral-lyn buccal insulin spray, my thoughts center around the recent FDA approved Treatment IND which Generex secured in the Fall of 2009. A Treatment IND can only be issued if the new drug candidate is thought to be safe, and if there is no suitable alternative drug currently approved on the market to treat a segment of the population. In my opinion, that bodes well for how the FDA may view the clinical utility of Oral-lyn buccal insulin, and its safety profile. A delay in Afrezza's development may also increase the potential enrollment success for Generex Oral-lyn into the Treatment IND program.

The ultimate success for Oral-lyn will be determined in its current Phase III study for Type 1 patients, however the Treatment IND program also allows the inclusion of Type 2 patients. All of these patients have a need for a non-invasive insulin therapy that is designed to offer treatment of postprandial hyperglycemia with less risk of postprandial hypoglycemia. In a nutshell, I believe that is positively the unique clinical utility for Generex Oral-lyn.

Type 2 Diabetes Drugs: Treating One Disease by Causing Another?

2010-03-11T16:19:00.000-08:00

The Food and Drug Administration (FDA) will reveal on Friday the fate for a once-weekly form of the popular diabetes drug Byetta. Eli Lilly, Amylin Pharmaceuticals and Alkermes are collectively developing the drug, named Byetta LARS. LARS stands for long acting release formula. Patients treated in clinical trials with the once-weekly formulation showed a statistically superior reduction in blood sugar than those taking standard Byetta. Byetta is currently approved as a twice daily injection option for Type 2 diabetics and has annual sales of about $700 million.

In January, the FDA approved the new diabetes drug Victoza, developed by Novo Nordisk. Victoza is in the same class as Byetta, called GLP-1 receptor agonist. These drugs are designed to slow glucose absorption in the gut. This allows a Type-2 diabetic’s slow insulin response to catch up. The GLP-1 agonist class also attaches to an appetite receptor in the brain and decreases hunger, leading to weight loss in patients. However, there have been some reports of other side effects for GLP-1 that are far less appealing than lower blood sugar levels and weight loss.

Byetta has been publicly linked to cases of severe pancreatitis since mid-2008. Byetta has been prescribed to millions, and these cases represent a small fraction of them, but the FDA has alerted healthcare professionals. Eli Lilly and Amylin have defended Byetta's safety track record, but that has become more difficult since the FDA has also now warned health care professionals that Byetta had been possibly linked to kidney problems, including renal failure. Again, this was an overall small percentage of users, but this has resulted in the long-acting version of Byetta being feared, rightly or wrongly, to the same problems. An additional emphasis may be made since it will be in a patient’s system for a full week.

The FDA's approval of Victoza, administered as a once-daily injection, has led to speculation that Byetta LARS will clear its last major regulatory hurdle. In clinical trials pancreatitis occurred more often in patients who took Victoza than in patients taking other diabetes medicines. That does not sound like a clinical trial endpoint that the FDA should find appealing. In animal studies, Victoza caused tumors of the thyroid gland in rats. The FDA approval of Victoza came with a Black Box warning regarding the drug's thyroid tumor risk. Of course, that wouldn't comfort a diabetic who gets his blood sugar under control only to find out he has thyroid cancer. If these drugs present risks that are unknown, than the FDA should require longer testing.

Recently, the Senate Finance Committee issued a 334 page report which concluded the findings of a two-year investigation after a 2007 study published in the New England Journal of Medicine reported a link between Avandia and heart attacks. The 334-page report by the Senate Finance Committee criticized the FDA, stating that agency overlooked or overrode safety concerns found by its staff. According to the Senate report FDA scientists estimated in July 2007 that Avandia was associated with approximately 83,000 heart attacks since the drug came to market.

The report highlighted other damning decisions by the FDA. In 2007, a FDA panel recommended by a vote of 22-1 that Avandia should remain on the market despite an analysis showing links to increased risk of heart attack. The vote was not binding, but a suggestion to FDA regulators. At the same meeting the panel also voted 20-3 in support of data that showed Avandia increased the risk of cardiac ischemia in patients with the most common type of diabetes. However, even in 2010 the decision making process of the FDA in regards to Avandia continues to bewilder.

Just after the senate report was made public the FDA stated that patients should not stop taking the diabetes drug. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, said during a teleconference with diabetes doctors that the FDA feels "it is time for a thorough evaluation of all the cardiovascular risks with that drug". They apparently are in no rush since they planned an advisory panel meeting in July and the drug remains on the market. We find out tomorrow if the Type 2 diabetes market grows more crowded with drugs that not only treat their disease, but potentially cause another.

With the FDA already well extended past the original PDUFA date for Mannkind's inhalable insulin, we can expect another decision soon concerning their new drug that also comes with questions that long term usage may have on the lungs. I believe that the latest news released by Generex Biotechnology, concerning the FDA Treatment IND for Oral-lyn buccal insulin, gives me hope this simple spray can fill the need of Type 2 patients who may be wary of all the controversial drugs their doctors and federal regulators push their way.

Byetta, Byetta LARS, Victoza, Avandia, or Actos; none of them are insulin. Nothing is as effective as controlling blood sugar levels as insulin, and the problem is getting Type 2 diabetics to consider initiating insulin therapy into their routine. When that problem is solved, the giant market for all of these other options will subside. With no serious safety issues to date for buccal insulin, diabetics may feel confident that their medicine is not causing additional illness. In time, diabetics and physicians may find Oral-lyn to be the simplest of solutions.

Oral-lyn Buccal Insulin- No serious adverse events in any study to date

2010-03-07T22:28:00.000-08:00

This is an interesting time for those of us that have long followed the companies developing needleless insulin delivery options. A new report was published in Diabetes Care (February 2010 issue; vol 33: pp 240-245) which asked 502 people with diabetes who used insulin to complete an internet survey. More than half of those surveyed, 57 percent, said they had intentionally missed an insulin dose, and 20 percent said they regularly skipped insulin injections. Among the reasons for skipping insulin injections were complaints of injection pain, embarrassment by the need for insulin and thought that the injections interfered with their daily life. One in five stated they skip insulin injections often.

This study further validates the original rational the large pharmaceutical companies had in researching inhalable insulin, an effort they all subsequently abandoned due to safety and marketing related issues. A large pharma may or may not pay large fees to partner with Mannkind for Afrezza inhalable insulin, and all eyes are on the FDA as they have extended well beyond the original PDUFA date for deciding the fate of Mannkind's New Drug Submission. That will be interesting to watch and to see the FDA's action, and if they send an approval with certain label restrictions.

In my opinion, Generex Biotechnology appears to be the stand out in the quest to develop a needleless insulin delivery sytem, since they are not developing an insulin that is absorbed in the lungs. Generex has had no serious safety concerns for Oral-lyn buccal insulin, at least so far, and the final Phase III results are pivotal. For Oral-lyn, Generex is busy with the Phase III, expanding access to the Treatment IND, and hopefully with preparing new submissions for a growing number of markets. Let the safety concerns swirl around prospects for inhalable insulin while the Oral-lyn buccal insulin Treatment IND sounds like a great marketing advantage, since more and more diabetics and physicians will learn of buccal insulin as Generex works towards full approval.

Those 57 percent of diabetics that stated they sometimes skip insulin injections represent a true market of patients that may be open to a safe and effective non-invasive insulin. In my mind, Generex's buccal insulin is the best looking candidate to succeed in making insulin available to a wider spectrum of patients that would typically avoid insulin treatment. To read the report in Diabetes Care click here.

Last month, Diabetes Care (January 2010 vol. 33 no. 1 55-60) reported a new study result which makes me feel that if the FDA does give Afrezza a restrictive label, Mannkind may find themselves finding apprehension amongst the physicians that treat the diabetics currently free of pulmonary disease, since they are at increased risk for developing these pulmonary conditions. The fear, whether it is valid or not, may be that inhalable insulin could hasten the demise of the lungs leading to these pulmonary issues.

The STUDY CONCLUSIONS- "Individuals with diabetes are at increased risk of several pulmonary conditions (asthma, COPD, fibrosis, and pneumonia) but not lung cancer. This increased risk may be a consequence of declining lung function in patients with diabetes." The FDA may grant approval for Afrezza just like they had for Exubera, but to the chagrin of Mannkind the market for Afrezza may also more closely resemble what was seen for Exubera. To read this second report click here.

Previously Reported Oral-lyn Buccal Insulin Study Results

2010-03-04T15:26:00.000-08:00

Buccal Spray Insulin for the Management of Post-Prandial Hyperglycaemia in Subjects with Impaired Glucose Tolerance

Results: Postprandial hyperglycemia (PPHG) occurs as the consequence of a reduced early insulin response after a meal and has been linked with an increased risk of cardiovascular events and raised mortality risk. Subjects with PPHG often present with dyslipidaemia, hypertension, abdominal obesity, microalbuminuria, endothelial dysfunction and markers of inflammation.

The objective of this phase II study was to investigate the safety and efficacy of treatment with buccal spray insulin (Generex Oral-lyn™) on post-prandial plasma glucose excursions and insulin levels in subjects with impaired glucose tolerance (IGT). A total of 15 Caucasian subjects, mean age 50.1 ±13.7 SD years, 10 females and 5 males with IGT were included in the study. Subjects were randomized to take 4, 6 or 12 Generex Oral-lyn™ puffs, split in two doses each, before and 30 minutes after a standard 75 gr oral glucose tolerance test (OGTT). Glucose excursions and insulin levels were measured at baseline and at 30, 60, 90, 120, 180 min.

There were no significant differences in glucose levels during OGTT with 4 or 6 U.I. doses compared to baseline OGTT. Treatment with 12 Units was followed by a significant 31.2% decrease in mean plasma glucose (mg/dl) at two-hours (from 179.0± 10.9 to 124.0±42.8, p=0.01) and a 28.4% decrease at three-hours (from 126.8±55.1 to 86.5±24.8, p=0.04). Considering all time points of OGTT, there was a mean reduction of 16.5% in plasma glucose levels. There was a trend for increased insulin (µU/L) levels at all measurements reaching statistical significance at 30 min (from 59.6±17.2 to 76.4±18.2, p=0.04). No adverse events were observed during the study period.

In conclusion, this proof of concept study demonstrates that treatment with buccal spray insulin is a simple and valuable therapy for PPHG in subjects with IGT.

A 12 week phase IV study of (Oral-lyn aka Oral Recosulin in India) recombinant human regular insulin metered dose buccal spray on subjects with type 2 diabetes who are suboptimally controlled while on oral antidiabetic agents

Background: Evidence suggests that early insulin therapy for glycemic
control provides additional benefits over conventional therapy in DM. However, subcutaneous route of administration is a barrier to initiating early insulin-therapy in majority of these patients. Postprandial glucose control by buccal route of insulin administration may overcome this barrier, improve glycemic control and provide further benefits.

Objective: This prospective open label phase IV multicentric study in India evaluated efficacy and safety of insulin metered dose buccal spray (Generex-Oral-lyn; Oral RecosulinTM) given pre- and post-meal in adult subjects with Type 2 DM that are suboptimally controlled with oral anti-diabetic agent(s).

Recombinant human regular insulin metered dose buccal spray (Generex Oral-lyn™ ; Oral RecosulinTM) appears to be well tolerated and highly preferred by patients. The detail data and its finding will be presented in the meeting. Interpretation and conclusions: Treatment with insulin metered dose buccal spray (Generex Oral-lyn™; Oral RecosulinTM) in type 2 diabetes mellitus patients on OHA, resulted in glycemic improvement and was well tolerated. Oral Recosulin had high acceptability in patients.

Insulin Analogue (Basal + Pre-Prandial Injection) vs. Human Insulin (Basal Injection + Prandial Oral Insulin (Generex Oral-lyn™) in Type-1 Diabetes Mellitus: A 372-Day Comparison

Results: This report is of Phase-3 of a 585-day study at which over than 45,000 daily pre-meal glucose measurements, and 2-week Fructosamine (Fruc) and Glycated Hemoglobin (HbA1c) determinations were obtained. Stabilization Phase-1 and First Comparison Phase-2 results were previously reported.

Briefly, 26 subjects were allocated to Two Cohorts of 13 subjects each for a 372-day Comparison. Control Cohort (CC) subjects received Basal Once a Day subcutaneous (s.c). glargine insulin-analogue and Pre-meal s.c. lispro insulin analogue. Treated Cohort (TC) subjects received Basal twice daily sc-isophane insulin (NPH) + Meal time Generex Oral-lyn™.

For HbA1c, Fruc and mean pre-prandial glucose, the levels were significantly lower in TC cohort (P<0.001 regardless of whether parametric or non-parametric tests were employed). A regimen consisting of basal BID s.c. NPH and prandial orally-absorbed regular insulin (Generex Oral-lyn™) attained lower pre-meal glucose, HbA1c and Fru concentrations, than a regimen using basal and pre-prandial insulin analogue injections in Type-1 DM during a 372-day period.

Comparison of Pre-prandial s.c. Regular Insulin vs Prandial Oral Insulin in Adult Type-1 DM Subjects Receiving Basal s.c. Twice Daily Isophane Insulin

Results: Participating subjects were 25 Type-1 DM subjects (17M; 8F); Age 28.6y (9.0); Height 164.8cm (8.53); Weight 62.4kg (8.68); BMI 22.9 (1.97); BMI 23.8 (2.0). Duration of DM 9.7 (5.1) years. Stabilization period: All subjects received standard therapy (ST) with basal s.c. twice daily (BID) isophane insulin (BID-NPH) and 3 pre-prandial s.c. injections of regular insulin (TID-RI). Subsequent to SP subjects were allocated to 2 cohorts: Control Group (CG): 11 subjects (5M; 6F); Treated Group (TG): 14 subjects (14M; 2F). Subjects in CG continued receiving BID-NPH and TID-RI.

Subjects in CG continued receiving BID-NPH and TID-RI. Subjects in the TG received BID-NPH and TID prandial split doses of Oral Insulin (Generex Oral-lynTM -OI). Comparison Phase (CP) lasted 99 days. Fructosamine (F) and Glycated Hemoglobin (HbA1c) were determined every 14 days.

After SP, 25 adult Type-1 DM subjects underwent a 99-day CP. Near normalization of parameters of DM metabolic control was achieved in all subjects. Direct comparison of HbA1c concentrations during CP demonstrate a superior effect of Generex Oral-lyn™ over subcutaneously injected regular insulin.

6-Month Safety and Efficacy of Lunch-Time Oral Insulin in Juvenile Type-1 DM Subjects Receiving Basal Glargine Insulin and Pre-Breakfast and Pre-Dinner S.C. Regular Insulin

Results: Adolescence in DM is associated with changes that make metabolic control difficult and injection at lunch time is frequently missed; therefore, replacement of lunch-time injection with oral insulin (Generex Oral-lynTM) was studied.

Participants were 24 adolescents (12M; 12F) and 5 young adult (2M; 3F) Type-1 DM subjects. Age 15.7y(3.0); Height 155.1cm(10.2); Weight 53kg(10.8); BMI 21.9(3.0); DM duration 6.8 (2.6). Stabilization period with Standard therapy (ST): s.c. BID insulin analogue + 3 pre-prandial s.c. regular insulin injections (RI). Comparison Phase: 28 days of ST; thereafter, split doses of Generex Oral-lynTM replaced lunch-time injection of RI for 6 months.

At study end, 6 independent evaluators blinded to biochemical results assessed compliance using a 9-parameter method. 21 subjects had good compliance (GC); 8 subjects had very poor compliance (PC). GC score: 51.86 (14.97) vs. PC score 14 (10.87) p<0.001. 29 nine juvenile Type-1 DM subjects replaced lunch-time dose of regular insulin with Generex Oral-lynTM for 6 months. Metabolic control depended on compliance.

Large Pharma and Small Biotech Deals Expected to Increase in 2010

2010-02-07T17:36:00.000-08:00

Andrew Baum, a health care investment analyst from Morgan Stanley, issued a report last week titled "Exit Research and Create Value" advising large pharma companies to drastically cut back on their in house R and D spending in favor of in-licensing drugs from biotech firms that have reached later stage studies. The report mentioned large pharma firms such as AstraZeneca (AZN) and Sanofi-Aventis (SNY) which he believes should turn from the costly high failure rates of their experimental drugs by expanding the pace of licensing agreements with biotech firms that often provide experimental products at a fraction of the cost.

From the Morgan Stanley report: "Reinvestment of internal research savings into in-licensing will yield three times the likely return, we calculate. Under in-licensing deals, downside risk for pharma companies is currently materially lower than for internally developed drugs. Although upside is also capped by pay-aways and milestone obligations, the net present value of these payments is more than offset by the lower risk-adjusted invested capital. Over one-third of pharma R&D spend is in pre-phase II, where the probability of reaching the market is <10%. Our proprietary analysis indicates that, unless the probability of an in-house molecule reaching the market is 30% or more, the risk-adjusted economic value added, or EVA, is three times higher under the external research model, with a greater predictability."

This scenario is also playing out with Pfizer (PFE), where the belief that partnering or licensing products from smaller biotech firms would cut failure rates and boost profits while improving safety during the development stage. Pfizer executives stated last week that the company expects to spend between $9.1 and $9.6 billion on R and D in 2010, which is less than Wall Street analysts had expected. Also, Pfizer offered guidance that it expects R and D spending falling between $8 billion / $8.5 billion by 2012. As Morgan Stanley notes, these bloated pharmas spend approximately 1/3rd of their overall budget during the earliest stages of product development with only 10% of these early experimental drugs making it to market. However, the odds increase to 20% for drugs in Phase II testing and closer to 50% for developmental drugs in Phase III.

This surely makes the case as to why smaller biotechs with promising products in Phase II and Phase III testing are worth a gamble by diligent investors. One thing that will not change is the risky nature of investing in smaller biotechs, and any investor should complete their own strong level of due diligence before following the recommendation of a professional analyst, never mind a non-expert blogger. I believe an investor in risky plays should only invest what they can afford to lose.

I am a shareholder in a small biotech, market cap $150 mil, that has a buccal insulin spray in US Phase III testing. The insulin spray has been approved in a handful of countries, and recently the FDA granted the first ever diabetes related Treatment IND approval to this potential blockbuster. To be clear, Morgan Stanley researchers did not mention my speculative biotech in their research report, however their reasoning for large pharma in-licensing from biotech firms brought me renewed confidence in my own analysis. The biotech is Generex Biotechnology (GNBT) and their buccal insulin spray is named Oral-lyn.

I previously reported here that Oral-lyn buccal insulin had been the proposed subject of a Single Technology Appraisal by the UK's National Institute for Health and Clinical Excellence with a scoping workshop set for November 2009. In an update, the Ministers at the UK's Department of Health formally referred the topic to NICE commencing the work programme to set official guidance for buccal insulin within its licensed indication for the management of type 1 diabetes. The listed January 2010 NICE work programme referrals from the Ministers at the UK's Department of Health can be seen here.

Generex also has a wholly owned cancer vaccine unit, Antigen Express, that has a synthetic peptide vaccine for her2/neu breast cancer in US Phase II testing in conjunction with the United States Military Cancer Institute. This vaccine just illustrated its efficacy in the interim results showing no recurrences for patients taking this vaccine at 13 months. This vaccine is named AE37 and the company is planning a Phase III study later this year. Generex and Antigen Express are also currently planning a Phase II study for the AE37 vaccine for prostate cancer patients after reporting successful Phase I results at ASCO in 2009. There are zero safety issues reported for either of Generex's top two new drug candidates.

Generex also has developed a patented drug delivery system, called Rapidmist, that enables large molecule drugs that are currently prescribed by pill to instead be sprayed into the mouth cavity where the drug is absorbed through the mucosa lining of the inner cheek wall. The technology behind the Rapidmist delivery system is being validated by the positive clinical results reported for Oral-lyn buccal insulin. Such a novel drug delivery system may not only improve patient compliance, but also help large pharma firms extend the patent protection of their blockbuster drugs. A large pharma with a blockbuster drug facing patent expiration may consider novel drug delivery options, such as Rapidmist, to extend the life cycle of their blockbusters via newly issued patent protections.

Since a small biotech such as Generex has fully funded their promising drug candidates to late phase trials on their own, they have eliminated the main risk for any potential partner(s). The small biotech shouldered the full R and D costs and as a shareholder I can tell you that process is often painful. Since the trend towards large pharma either partnering or in-licensing with promising small biotechs is clearly increasing, the odds may have also increased that a great reward will come our way.

Disclosure: Disclosure: The author is long GNBT.
Stocks: SNY, AZN, PFE, GNBT

How Generex can win over Mannkind

2009-11-18T20:02:00.000-08:00

As biotech companies and large pharma embark on paths to usher in more effective diabetes drugs to market, one of the more significant concerns regarding diabetes related drug development is safety. The FDA has increasingly issued new alerts from previously approved drugs such as GlaxoSmithKline's (GSK) Avandia, Eli Lilly's (LLY) Byetta and Bristol-Myers Squibb's (BMS) Onglyza while deciding whether the safety risks of new drugs such as Novo Nordisk's (NVO) Victoza and Mannkind's (MNKD) Afresa have benefits to outweigh the safety risks. In thinking of Afresa, most insulin drugs have mainly been regarded as safe by US drug regulators, however Pfizer and inhalable insulin attracted an inordinate amount of scrutiny and requirements of pulmonary testing and Phase IV monitoring. Also in June, the FDA said it is reviewing data on the safety of Sanofi-Aventis's (SNY) popular Lantus insulin over highly publicized and inconsistent cancer findings.

There has only been one new diabetes related drug that has risen above the questions of whether the risk of taking the drug has outweighed the positive effect of its intended claims. That new drug is Generex's (GNBT) buccal insulin Oral-lyn. The most obvious example of the proven safety profile of Generex's buccal insulin came this past September when the company announced the FDA granted approval for the Treatment IND usage of Oral-lyn buccal insulin under the FDA's Treatment Investigational New Drug program. Drugs that are granted approval by the FDA for the Treatment IND program must demonstrate the prospect of efficacy through clinical testing without the concern for safety issues that call any benefit into question. Generex's Oral-lyn is the only developmental drug intended to treat diabetes that has ever been approved in this special access program. This is a noteworthy achievement for Generex's regulatory team, led by Mr. George Markus, which also illustrates their ability in successfully communicating with the world's most stringent regulatory body.

The unique safety profile of Generex's buccal insulin stands apart from other new diabetes related drugs both in development and on the market. In particular, I will focus upon Mannkind's inhalable insulin Afresa since these two are the most advanced oral insulin drugs and as such offer the greatest glucose controlling effects as opposed to any other type of offering from the pipelines of large pharma. Generex's Oral-lyn may well be the only new diabetes related drug in development that has never had a serious adverse event due to its usuage in any study to date. In March 2009, Generex reported preliminary Type 1 Phase III results for Oral-lyn buccal insulin where they stated "non-inferiority to injectable meal-time (prandial) insulin appears to be maintained". This was in alignment with previous Phase II studies, where in2007 clinical researchers of Generex's Oral-lyn found "a superior effect of Generex Oral-lynover subcutaneously injected regular insulin" and in 2008 that a "regimen consisting of basal BID s.c. NPH and prandial orally-absorbed regular insulin (Generex Oral-lyn) attained lower pre-meal glucose, HbA1c and Fru concentrations, than a regimen using basal and pre-prandial insulin analogue injections in Type-1 DM during a 372-day period."

In an article titled "Review of clinical trials: update on oral insulin spray formulation" to be published in Diabetes, Obesity and Metabolism this January and which has recently been made available early online, the two main researchers of Oral-lyn buccal insulin provide an update of the detailed clinical findings supporting both efficacy and safety. One of the authors is Dr. Paolo Pozzilli, Head of the Department of Diabetes and Endocrinology at University Campus Bio-Medico of Rome and he has been studying the pharmacokinetic and pharmacodynamic effects of Oral-lyn since the earlier studies in the beginning of this decade. The secondary author is Dr. Philip Raskin, who is also a highly regarded diabetes clinical author and researcher who serves as MD of The University of Texas Southwestern Medical Center at Dallas and is the principal investigator of Oral-lyn's Phase III trial.

In the pending article the authors state that in "all of the studies discussed, results showed that oral insulin spray was absorbed in direct relation to the amount given and had a faster onset and a shorter duration of action when compared with SC regular insulin. This fact alone would seem to make the oral insulin spray an ideal candidate for prandial glycaemic control." The efficacy of Oral-lyn, a liquid formulation of human regular insulin that acts more like an analogue version of meal time insulin, has been proven in all studies to date. The authors continue to say that the "oral insulin spray is a tasteless liquid aerosol mist formulation" and that "on all of the studies conducted, the oral insulin spray was generally well tolerated." They conclude by stating the "ease of use of the insulin spray formulation may increase patient acceptance and treatment compliance, thereby potentially reducing complications and improving quality of life for patients with insulin-dependent diabetes."

Proving the commercial viability of a new drug in development is sometimes more difficult than establishing clinical efficacy and safety. Both Generex's Oral-lyn and Mannkind's Afresa have shown success in clinical trial settings. Mannkind has studied Afresa in far more patients than has Generex for Oral-lyn, but recently Generex's partner in the India market, Shreya Life Sciences, has presented a Phase IV study conducted in various sites for Type 2 patients. The results for the first time speak of the commercial appeal oral insulin may bring to insulin dependent diabetics. This is an example of the Type 2 market that has eluded the major insulin analogue manufacturers up to this point and this was a prime market which spurred earlier development in oral insulin programs in the earlier part of this decade.

The study was reported at the IDF 20th World Diabetes Congress last month in Montreal and is titled "A 12 week phase IV study of recombinant human regular insulinmetered dose buccal spray on subjects with type 2 diabetes whoare suboptimally controlled while on oral antidiabetic agents". The findings in "40 type 2 diabetic patients on OHA (oral-diabetic agent) who received metered dose buccal insulin spray showed improvement in glycemic control in terms of improvement in HbA1c values (Mean HbA1c value: 7.8% vs 7.3%) and fall in both fasting and postmeal glucose." The efficacy was again proven and a secondary outcome was to monitor "changes from baseline in clinical and laboratory findings and changes in buccal cytology at the end of 3 monthstreatment". The conclusion stated that except "for minorhypoglycaemic episodes, transient burning sensations and transient numbness in mouth, no other adverse effects were observed". This Phase IV, in India and conducted by Generex's regional partner, again affirmed the unique safety profile to set aside any questions of safety and which again highlighted the potential role Oral-lyn will have in controlling post-prandial hyperglycemia. The Phase IV results also stated that "recombinant human regular insulin metered dose buccal spray (Generex Oral-lyn and known as Oral Recosulinin India) appears to be well tolerated and highly preferred by patients." It continued to say that Oral-lyn "had high acceptability in patients". When have you ever heard Type 2 patients that were not yet treated with insulin therapy to say they actually "preferred" insulin?

With no safety issues in over 10 years of trials and the FDA recognizing both the reports of efficacy and the unique safety profile, it is no wonder Drs. Pozzilli and Raskin remarked in regards to Oral-lyn's onset and duration of effect that this "fact alone would seem to make the oral insulin spray an ideal candidate for prandial glycaemic control." Mannkind's Afresa has also had positive efficacy data, and while it has been studied in a far greater amount of patients it has not enjoyed the level of post-prandial hyperglycemia control as has been reported to Oral-lyn. Afresa lingers in the bloodstream longer than what investigators have found for Oral-lyn. Oral-lyn is available as a 1 UNIT per spray dose, while Afresa comes in two larger dose sizes, so while Mr. Mann claims no titration is needed with Afresa inhalable insulin, a diabetic that finds him or herself eating an unplanned piece of chocolate cake one or two hours post meal may find his glucose levels do not agree. For Oral-lyn, the delivery devise is built to provide fine tuning post meal dosing. It is as simple as taking another quick spray. While with Afresa, this part of the equation appears much more complex. Mannkind executives insist this is not the case, and I will leave it to them to convince skeptical diabetics and their endocrinologists.

I do not believe physicians and diabetics have similar reason to have confidence in the safety profile of Mannkind's Afresa as they will with Generex's Oral-lyn. And here is where I would like to deeply explain my thoughts. The reasoning is more complex and goes beyond Mannkind's inhalable insulin to the ill effect diabetes already plays upon the lungs. I recall a study which was published in the April 2008 issue of Diabetes Care titled "Cross-Sectional and Prospective Study of Lung Function in Adults With Type 2 Diabetes". The main author, Dr. Hsin-Chieh Yeh, presented findings showing that lung function in people with diabetes decreased at a more dramatic rate than in people without the disease. The data supported previous evidence that the lung is vulnerable to diabetic complications. The results of the study showed that "at baseline, adults with diabetes had significantly lower predicted FVC (96 vs. 103%, P < 0.001) and predicted FEV1 (92 vs. 96%, P < 0.001) than those without diabetes."

In an accompanying article, Drs. Philip Raskin (yes, the same Dr. Raskin I mentioned for Oral-lyn) and Connie Hasia wrote that the study by Dr. Yeh "serves to further enhance recognition of the lung as a target of diabetic injury." They ask why should this issue matter to patients and physicians? They reason to "think of the lung as a crime victim who unwittingly abets the perpetrator to hasten the demise of the host." I will footnote the study and article because Drs. Raskin and Hasia express perceived strengths and weaknesses within the study design. However, they explain there is a solid body of literature from the 1980s and 1990s which "established the occurrence of ventilatory restriction in type 1 diabetes" as well as cumulative data which demonstrates "a pattern of modest lung restriction in type 2 diabetes qualitatively similar to that in type 1 diabetes".

Drs. Raskin and Hasia point to the findings in a Pfizer Exubera study that showed "chronic use of inhaled insulin could potentially trigger or exacerbate pulmonary dysfunction. Though shown to be efficacious and well tolerated, inhaled insulin has also been reported to cause a small early drop in spirometry and DLCO at rest that did not progress during 2 years of follow-up". They continue in their mention of Exubera by stating as "inhaled insulin products continue to be developed, the spectacular collapse of Exubera notwithstanding, the issue of their potential impact on lung function will linger." The Footnote section of the article reveals that Dr. Raskin "is a member of a scientific advisory board for Novo Nordisk and has received research grants and/or honoria from Novo Nordisk, Pfizer, and MannKind."

At the EASD conference this past Fall, Mannkind presented an abstract titled "Pulmonary functions (over 2 years) in diabetic subjects treated with Technosphere insulin or usual antidiabetic treatment". The conclusion of the abstract stated that "small declines from baseline in PFTs were observed in diabetic subjects treated with TI and UC and also in subjects without diabetes. Observed differences between TI and UC groups in the change from baseline in FEV1 and DLCO were small, noted at the first post-baseline assessment visit (3 months) and thereafter remained non-progressive over 2 years of continuous therapy."

However, the abstract noted that the "annualized change in FEV1 between 3 to 24 months was -0.047 l/year for TI-treated subjects" (comprised of Type 1 and Type 2 patients). The UC comparator group (UC meaning usual antidiabetic treatment) had a change in FEV1 between 3 to 24 months of -0.036 l/year. Highlighting the data, we see Mannkind reporting an annualized change in FEV1 -0.047 l/year in Afresa subjects and -0.036 l/year in usual antidiabetic treatment patients. A previous Exubera study presenting findings for a group of Type 1 patients showing annual rates of change in FEV1 between months 3 and 24 were −0.041. Other published studies showAsthma patients with annualized change in FEV1 -38ML/Year and healthy persons with annualized change in FEV1 - 22 ML/Year.

The populace design of these studies should also be monitored since it is known that different ethnicities have lower average FVC and FEV1 results. For example, the 1999 study titled "Spirometric reference values from a sample of the general U.S. population" by Dr. JL Hankinson et all (source 6) presented clear results that FVC and FEV1 levels are lower in African Americans than in Caucasians after adjustment for sex, age, and height. Mannkind's press releases aside, I believe many feel there is not yet adequate proof that Afresa will not have a significant negative effect on pulmonary function in Type 1 and Type 2 diabetics.

Reports of the efficacy of Afresa do not outweigh the apparent need to study the potential ill effects of their version of inhalable insulin over a much longer period (+ 10 years) of time. If we listen to Drs. Raskin and Hasia and vision the lung of a diabetic "as a crime victim who unwittingly abets the perpetrator to hasten the demise of the host", is it wise to develop diabetic preventative medicine which is adminsistered into the body in a fashion which may eventually be found to accelerate this rate of pulmonary function decline? If long term usage brings the negative effects that some fear, Mannkind may as well shape the Dreamboat device with a push button shaped like a trigger.

Quite often the simplest solution to a problem is the best. There is no debating the horrendous effects the diabetes pandemic plagues upon our society. For those living with the complications caused by diabetes, or those who love those afflicted, we can only hope that all novel treatments that provide a friendlier and more natural way to manage the illness not only survive but thrive. My own interest stems from the overwhelming compliance issues that my sister battled daily. From earlier social issues that spawned bouts of bulimia to a fear of needles coupled by a sense of weakness a life term on injections represented, she resented the needles no matter how fine the tip or convenient the pump. She matured, but the damage was done. She now lives free of multiple injections. The payoff was a kidney transplant from my father and the pancreas of a teenage boy who died in a car crash and who was heroic in filling out an organ donor card. Life is no longer simple, since her vision is tunneled and her feet have no feeling. The doctors keep a close watch on her heart and other organs. As the transplanted pancreas is now within her for a few years, there may soon be a time when it is in need of an assist before teetering out. At that point, she has told me she will seek out Generex's Oral-lyn.

After all this time, Susan still hates the thought of needles. One aspect is that her skin is very, well, frailsh and weak. So is her body, although her spirit is strong. At this stage, could her lungs take a few years of any inhalable insulin, or is that a question that is silly to even ask? I believe it is out of the realm of possibility, and she has no need to risk another organ as her doctors monitor many others. The FDA delved deeply into Generex's Oral-lyn data in a timeframe when they are telling all other diabetes related developmental companies to stay in the clinic and bring more data. For Generex, they said bring the patients this new safe insulin drug and approved their only ever diabetes Treatment IND.

Disclosure: The author is long GNBT and has no position in MNKD.

A N.I.C.E. Development for Generex Oral-lyn in the U.K.

2009-10-17T20:32:00.000-07:00

The United Kingdom's National Institute for Health and Clinical Excellence (NICE) has begun the draft scope for Generex's novel buccal insulin for the management of type 1 diabetes. Oral-lyn is currently in Phase III trials for patients with Type 1 diabetes and Generex is moving closer towards submission to the Medicines and Healthcare products Regulatory Agency MHRA. At present, over 350 patients have been enrolled in the program in 70 clinical sites around the world.

NICE recently entered the first stage to "appraise the clinical and cost effectiveness of buccal insulin within its licensed indication for the management of type 1 diabetes". They began consultation on suggested remit, draft scope and provisional matrix of consultees and commentators on September 21st and this process continues until October 19th. A scoping workshop in scheduled on November 11th in London.

This is not the first time that a needle free insulin delivery system has been appraised ny NICE. Early in 2006, NICE ruled that Pfizer's inhalable insulin, Exubera, not be prescribed to UK patients at all. However, after appeal from Pfizer NICE altered final guidance. They remained sceptical, saying that Exubera should not be used as routine treatment. They ruled that diabetic patients in the United Kingdom must prove "needle phobia" before they can be prescribed Exubera. The decision caused a storm of controversy, since patients would first have to be diagnosed with the phobia by a psychologist or psychiatrist.

Exubera offered an uncompetitive healthcare value proposition, priced at a premium while lacking dosing flexibility combined with significant safety concerns. The negative edict from doomed Pfizer's launch of Exubera in the UK, and the negative publicity played a major role in Exubera's subsequent failure in the US. In 2007, Pfizer chose to abandon Exubera and took a $2.8 billion pretax hit by discontinuing their marketing efforts in one of the drug industry's costliest failures.

One inhalable insulin system remains in development, Mannkind's Afresa, and while it appears to be a more effective and convenient in comparison to Exubera, questions regarding the safety of inhaling a growth agent like insulin into the lungs persist. Oral-lyn is a new alternative to subcutaneous injections of prandial insulin and is conveniently delivered to the membranes of the oral cavity by a four inch metered device with no pulmonary (lung) deposition. Oral-lyn fully avoids the potential risks of chronic lung tissue exposure and in Oral-lyn's clinical trials to date there has never been a serious adverse event reported to usage of buccal insulin.

In the NICE's draft scope of the Health Technology Appraisal for Oral-lyn, they state they will evaluate the cost effectiveness in terms of incremental cost per quality-adjusted life year. They add that the time horizon for estimating clinical and cost effectiveness should be sufficiently long to reflect any differences in costs or outcomes between the technologies being compared. Costs will be considered from an NHS and Personal Social Services perspective. Quality-adjusted life-year represents the morbidity of diseases by a scale of 0 to 1.0, representing the extremes of death and full health. For instance, if you have diabetes and a foot amputation due to diabetic complications, your quality of life will be reduced by 35%. In other words, your quality-adjusted life-year would be only 0.65.

Evaluating the cost effectiveness of Oral-lyn over a long time horizon should be favorable to Generex. The cost per unit of buccal insulin vs regular injected insulin is higher, but overall health care savings may be seen when an insulin hesitant diabetic leads a more compliant regimen. Further, NICE states in the draft proposal that they intend to appraise Oral-lyn through its Single Technology Appraisal (STA) Process. In November 2005, NICE launched the Single Technology Appraisal process, which is designed to enable assessment of single drugs and devices close to when they are first licensed, allowing NICE’s existing system to be reserved for more complex issues. This shortens the process and final guidance will come quicker.

There are approximately 2.5 million people in England and Wales with diabetes, approximately 10% of whom have type 1 diabetes. Generex's website states that Oral-lyn has been approved in India, Lebanon, Algeria, and Ecuador for the treatment of subjects with Type-1 and Type-2 diabetes. Generex recently announced that the FDA has granted approval for the treatment use of Oral-lyn in patients with Type 1 or Type 2 diabetes mellitus under the FDA's "Treatment IND" rules. The FDA's Treatment IND program allows companies to provide early access to investigational drugs for patients with serious or life-threatening conditions for which there is no satisfactory alternative treatment. Drugs that are granted approval by the FDA for the Treatment IND program must demonstrate the prospect of efficacy through clinical testing.

NICE's Proposed Technology Appraisals can be found here.

http://www.nice.org.uk/ourguidance/niceguidancebytype/technologyappraisals/proposedappraisals/proposedappraisalsnowave.jsp

The San Antonio Breast Cancer Symposium: A Focus on HER2/neu Research

2008-12-11T21:30:00.000-08:00

This year's San Antonio Breast Cancer Symposium contained many studies that pertain to HER2/neu treatment. Groundbreaking science is not always successful in the end, but it is possible that this prestigious event has brought evidence of the advances that may pave the way to an improved future of HER2/neu cancer treatment. Current treatment revolves around Genentech's (DNA) Herceptin, but the event brings together many researchers who present their findings and a glimpse of improved future HER2/nue cancer treatment options. Large pharma, as always, dominates the scene, but it always appears to be the smallest of biotechs that present the most promising pipeline developments.

Herceptin costs about seventy thousand US dollars for a full course of treatment and brought in $327 million in revenue for Genentech (DNA) in the fourth quarter of 2007. However, there is a wide group of breast cancer patients with low levels of HER2 expression that do not benefit from Herceptin treatment. However, researchers from the United States Military Cancer Institute are devloping peptide based vaccines that may be available to a much wider spectrum of breast cancer pateints with a dosing regimen that causes much less toxicity.

The Cancer Vaccine Development Program (CVDP)

The Cancer Vaccine Development Program considits of the United States Military Cancer Institute (USMCI), Department of Surgery, and the Uniformed Services University of the Health Sciences, Bethesda, Maryland. The Cancer Vaccine Development Program (CVDP) has performed phase I and II clinical trials using immunogenic peptides from the HER2/neu protein. The peptide vaccines used in the CVDP are E75, GP2 and AE37. E75 (Neuvax) is the most advanced of the peptide vaccines, and has been licensed to Apthera. Apthera recently raised over $51 million in Series C financing to fund their upcoming Phase III trials.

Apthera announced news concerning new developments for E75's Phase III at the kickoff for the San Antonio event. Earlier in the year, researchers from the CVDP announced that the HER2 peptide vaccine reduced mortality by 50% in patients with HER2/neu-positive breast cancer.

“E75, if validated in phase-3 testing, may represent a new form of HER2/neu-directed immunotherapy, which could be utilized in the HER2/neu low-expressing group of breast cancer patients — a group of patients for whom immunotherapy has not been available in the past,” Linda C. Benavides, MD, a resident in general surgery at Brooke Army Medical Center, said at an April 13 press briefing.

However, in San Antonio, while the CVDP presented three study abstracts concerning all the peptide based vaccines in their care (E75, GP2 and AE37), the findings that are presented underscore the AE37 vaccine as the most promising of the three (in both terms of safety and efficacy). The new findings will be presented by COL George Peoples, MD, who has been directing the trials at the Brooke Army Medical Center. AE37 is the invention of Massachusetts based Antigen Express, which owns all of the vaccine's rights. The small life science company is a fully owned subsidiary of Generex (GNBT) Biotechnology, and AE37 is currently in a large scale Phase II efficacy study. The stated goal of Antigen Express is developing novel immunotherapeutic peptide vaccines for use in patients with tumors expressing the HER-2/neu oncogene.

The CVDP Optimal Dosing abstract highlights the dosing benefits of AE37. For example, the AE37 optimal dose contains drastically less levels of the adjuvant GM-CSF as opposed to E75 and GP2. In the trials conducted with the CDVP for E75, GP2 and AE37, there has been minimal toxicity reported with no patients experiencing grade 3-5. The majority of the toxicity is due to the higher levels of the adjuvant used in the dosing series. AE37 patients experienced the fewest side effects, since the vaccine dosing series resulted in a continued reduction of the amount of adjuvant needed to harness the immunologic response. In some patients, the dose of the adjuvant had been reduced to the point where the researchers removed it entirely. AE37 is the first peptide based vaccine to bring positive and robust immunologic reactions in the absence of an adjuvant.

The researchers further state in the study: "AE37 (aa:776-790+Ii-Key) is HLA promiscuous whereas E75 (aa:369-377) and GP2 (aa:654-662) are HLA-A2/A3+ restricted." One of the main positives of the E75 vaccine is that it will potentially be made more available to many more patients than we see with Herceptin (or even the Phase II candidate Trastuzumab-DM1), and we can see that AE37 will also be available to many more than E75. AE37 can be used in all HER2/neu positive patients, and will be particularly beneficial to those with lowest levels of HER2/neu expression.

The post-vaccine DTH levels for AE37 are a very promising hint of the effectiveness of the vaccine. An increase in DTH levels from pre to post vaccination combined with a decrease in Tregs are what researchers of a peptide vaccine hope to see. With that in mind, the CVDP researchers on Friday reported that for AE37 the "DTH responses increased in all patients from pre- to post-vaccination (3.6+1.4 mm vs. 56.0+9.4 mm; p<0.0001)". Clinically, that is a trend towards significant.

For the continued results of the AE37 Phase I, it is concluded that Tregs (CD4+CD25+FOXP3+) were reduced in all 9 patients tested pre- to post-vaccination for both FOXP3 antibodies (Ab) (FOXP3 Ab1 = 2.1+0.2% vs. 1.1+0.1%, p=0.002; FOXP3 Ab2 = 2.0+0.2% vs. 1.0+0.2%, p=0.0009). Boding well for the vaccine is that there is an inverse relationship between the degree of Treg reduction and the size of DTH response to AE37 (R2=0.83).

The researchers from the CVDP conclude: "The novel AE37 HER2/neu peptide vaccine does not result in increased levels of Tregs. Furthermore, the reduced levels of Tregs in vaccinated patients appear to be associated with more robust responses in ex vivo immune assays and in vivo DTH reactions suggesting that the AE37 vaccine may be clinically useful."

AE37 Summary

Herceptin illustrates the most effective clinical response when Tregs are reduced as a result of treatment. The USMCI (CVDP) previously studied E75 with Herceptin and it appears reasonable to surmise that AE37 will also be studied to see if there is combined treatment benefit. A main advantage of AE37, and the Ii-key hybrid technolgy of Antigen Express, is that the AE vaccines are designed not only as effecvtive stand alone treatment, but to be linked with approved treatments causing a signifcant increase in immunologic response. This aspect of the AE vaccines creates a unique potential of multiple platform licensing arrangements.

While the target of AE37 is the same as that of the marketed cancer drug Herceptin, the activity of AE37 relies on its ability to stimulate a patient's own immune system to recognize the cancer target rather than by interacting with the target directly. The advantage of this is that the immune system, once activated, is capable of detecting lower levels of the target protein than is Herceptin and that the anti-tumor activity lasts long after termination of AE37 treatment.

Roughly 75% of patients with breast cancer show some level of HER-2/neu expression in their tumors. While only 25% of breast cancers have levels of HER-2/neu expression high enough to be candidates for treatment with Herceptin(R) (a humanized monoclonal antibody directed at HER-2/neu), those cancers expressing lower levels are expected to be good candidates for active immunotherapy as is being pursued at Antigen Express. A significant percent of other types of cancer, including prostate and lung cancers, also express HER-2/neu.

“Think of the vaccine as a Trojan horse: to get the soldiers into the city you put them into a delivery system. Except the ‘horse’ in this case does not really go inside the T-cell,” explains Dr. Peoples upon the announcement of one of AE37 new trials. “The vaccine helps the antigen find a ‘receptor’ on the surface of the T-cell so that the immune system, once ignited, will seek out and destroy the cancer.”

In August 2008, Antigen Express announced that researchers at Mary Crowley Cancer Center had begun enrollment of patients for a new Phase I clinical trial in breast and ovarian cancers employing the AE37 vaccine combined with the CVDP's GP2 peptide vaccine. The trial is being conducted as part of a collaboration between Antigen Express, Dr. George Peoples at the Brooke Army Medical Center and the Mary Crowley Cancer Center, which is completely funding the trial. The AE37 vaccine is also the subject of a Phase I trial in prostate cancer patients. Both vaccines are derived from the tumor-related HER-2/neu protein.

A recent research report by Scimitar Equity, LLC, stated that they estimate Antigen Express to be valued at approximately $96 million based on public information Generex has disclosed. Yet the current market cap for GNBT as a whole is approximately $60 million.

Four Drug Companies Vying for Diabetes Patients

2008-08-15T22:18:00.001-07:00

The American Association of Diabetes Educators (AADE) released results last week at their high profile 35th Annual Meeting from an innovative new survey entitled the “Injection Impact Report”.

The report highlights the level of communication between patients and healthcare providers relating to insulin injections and also spotlights how those injections can impact patients’ daily lives and treatment adherence. Conducted online between June 12 and July 7 2008, the report surveyed 502 people with diabetes who inject insulin using either a syringe or a pen and also queried over 300 healthcare professionals who treat them. The report has gained the attention of the diabetic community, although the results were expected by many that are familiar with the burden associated with daily injections of insulin.

The findings detail that 33% of the surveyed patients with have experienced "dread" in relation to insulin injections, 14 percent surveyed feel that insulin injections have a negative impact on their life, more than 29 percent of the surveyed feel that injecting insulin is the hardest aspect of their diabetes care. Of those patients surveyed, 52% reported not discussing their concerns about the emotional and physical aspects of insulin treatment with their health care providers, yet 47% said they would be more adherent to their insulin regimen if they knew how to ease the pain and discomfort associated with injections.

Within the survey, a mere 12% of the 301 health care providers reported that their patients have addressed their "quality of life" concerns regarding insulin treatment. Seventy-one percent said they were aware of the impact of insulin injections on their patient's quality of life, but a minority of 40% reported addressing these issues with patients. This lack of communication jeopardizes effective diabetes management.

"When developing the survey, we had two goals in mind," said Amparo Gonzalez, RN, BSN, CDE, president of the AADE. "The first was to encourage patients to take a more proactive role in communicating with their healthcare team about their concerns regarding insulin injections. The second was to dispel the myth that healthcare providers were unaware of or were unwilling to address the quality of life issues surrounding insulin injections. If we can improve the quality of life for 33% of people with diabetes who are insulin dependent, then we can be one step closer to lessening the impact of the disease on our patient's lives," Gonzalez said in a press release.

The AADE report may also serve as a barometer for measuring potential strong demand amongst the 33% of diabetics experiencing dread in relation to insulin injections for the novel needle-less insulin delivery methods that are in the final stages of testing, while underscoring the apparent soft support for the injectable insulin analogues of large pharmaceutical companies such as Novo (NVO) Nordisk and Eli (LLY) Lilly. Insulin analogues act similarly to human insulin, but provide a more rapid window of action coupled with effective glycemic control. The large pharma firms are in the midst of a successful marketing campaign resulting in the conversion of prescriptions away from regular human insulin towards their more expensive, and profitable, insulin analogues.

However, many diabetics are uncomfortable in accepting the safety profile of analogues. Respected diabetic bloggers, such as Allie Beatty, report on these concerns and are aware that these large pharmaceutical companies reap greater profits by switching their prescriptions away from standard human insulin towards their new more expensive synthetic laboratory inventions. My LONG choice within the biotech sector is aided by the AADE report and recently began presenting an interesting study countering the superiority claims associated with insulin analogues.

Recent research from Generex (GNBT) Biotechnology, a company focused on advanced insulin delivery and vaccine research, dispel both the advantages of insulin analogues and eliminate the fears associated with the needles and pens used in insulin injection. Investigators from the company have been presenting their data at diabetes conferences that is co-authored by researchers from the Institute for Endocrinology IEMYR, Quito, Ecuador, and the University of Florida, Gainsville.

The year-long study examined 26 subjects with type 1 diabetes, which is normally treated with basal injected injection once or twice a day to provide baseline glycemic control, and additional insulin injections before meals. The control study group received insulin glargine (an insulin analogue) once a day as their basal dose, and a faster-acting insulin analogue before meals. The treatment group received a non-analogue long-acting insulin twice a day as their basal insulin; before meals the they took Oral-lyn, a liquid formulation of regular human insulin, developed by Generex, that is absorbed through the lining of the mouth.

Study results illustrate a rapid onset of action and superior glycemic control vs. the anlogues. Oral-lyn uses a formulation that allows insulin to pass through the “buccal” mucosa – the soft tissues lining the inside of the mouth – and into the bloodstream rapidly and safely, without injection. Unlike inhaled insulin products such as Exubera, which Pfizer (PFE) has removed from the market due to disappointing sales stemming from safety concerns of using the sensitive lungs as a delivery route for a growth agent (insulin), the combination of Oral-lyn insulin and Generex's RapidMist delivery technology allows patients to deliver a precise 1 unit dose as needed, with no deposit of insulin into the lungs and no needles.

"When Oral-lyn is absorbed through the buccal mucosa its rapid entry into the blood stream mimics and improves upon the rapid acting analogues.” commented Dr. Jaime Guevara, a study author and clinician that has conducted studies for Generex’s Oral-lyn. “Claims that analogues provide superior convenience do have some merit when these agents are compared with insulin injected before meals. However, when compared with Oral-lyn, which is not injected, even those arguments fail to make the case for drugs that cost three times as much as standard insulin."

Generex's share price has been in decline as many investors shun microcap biotechs during the current market conditions and look for safer havens to protect their holdings. However, the company has recently enrolled over 150 patients in their worldwide Phase III trial for Oral-lyn and have recorded positive developments for their vaccine subsidiary "Antigen Express". With recent financing completed and the launch of sales expected of Oral-lyn to begin in India in the next couple of months, this may be a unique opportunity for biotech investors that seek emerging companies that are well positioned for future gains.

Buying while surrounded by bears demands caution, but many biotech investors often find this the preferred environment in which to begin their hunt.

The AADE Injection Impact Report was conducted online by Harris Interactive and can be viewed by visiting here.

The United States Military Cancer Institute: Armed with Antigens in the War Against Breast Cancer

2008-06-21T13:21:00.000-07:00

The United States Military Cancer Institute has been investigating peptide based vaccines for therapuetic value in the war against breast cancer. Previous attempts at developing peptide vaccines for breast cancer had been largely disappointing. However, those vaccines were designed to treat metastatic disease. In contrast, the USMCI researchers, based at Walter Reed Army Medical Center, have been investigating novel peptide vaccines as a preventive therapy for patients who have been treated for breast cancer and have a high risk of recurrence. In particular, the researchers have focused their efforts on two impressive peptide vaccines.

E75 Peptide Vaccine

E75 is a novel anti-HER2 breast cancer vaccine. The E75 protein is a rich target for therapy since it is specifically recognized by immune cells. The HER2/neu protein is an oncogene highly expressed in certain adenomas, including 20%-40% of breast cancers and some forms of colon cancer. E75 has been licensed to Apthera, a private company, which also renamed the vaccine candidate as NeuVax.

In April, Apthera and the USMCI announced results from analysis of a randomized safety and efficacy clinical trial studying NeuVax (E75) in the adjuvant treatment of early-stage (node-positive and high risk node-negative), HER2-positive breast cancer. The data showed that patients with low-expressing HER2 tumors experienced decreased breast cancer recurrence and no mortality to-date following treatment. Taken together these findings may be significant for the greater than 50 percent of breast cancer patients whose tumors fall into the HER2 low-expressing category and who are not typically eligible for Herceptin treatment.

The difficulties faced in further development of E75 is that it's effectiveness has been seen to wane after a few months. A Phase III trial is being planned as well as other studies investigating the need for a booster shot or higher doses of the peptide and the adjuvant GM-CSF. Unpublished data from researchers at the USMCI also appear to show the potential linking of E75 to a li-Key/HER2/neu MHC class II peptide which brings us to the subject of the other promising therpauetic vaccine in the USMCI's arsenal.

AE37 Vaccine

Like E75, AE37 is being tested under the direction of Colonel George Peoples, M.D., at Brooke Army Medical Center. The AE37 study is a collaboration among Antigen Express, USMCI, the Uniformed Services University of the Health Sciences (USU) and The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (HJF). Antigen Express entered into a Clinical Trial Agreement with HJF to enable work with Peoples, USMCI and USU, with the goal of advancing the company's HER-2/neu vaccine efforts for breast cancer.

Specifically, AE37 is a li-Key/HER2/neu MHC class II peptide discovered and patented by Dr. Robert Humphreys and Dr. Minzhen Xu of Worcester's Antigen Express. Antigen Express is a wholly owned subsidiary of Generex (GNBT) Biotechnology. The immunotherapeutic agent being developed by Antigen Express is a peptide derived from a tumor-associated protein that has been modified to enhance the stimulation of CD4+ T helper cells. The target protein is encoded by the HER-2/neu oncogene, which has been found to be over-expressed in tumors from a variety of cancers, including breast, ovarian, prostate, lung, colon, stomach and pancreatic cancers. Antigen-specific stimulation of T helper cells, which occurs after immunization with AE37, has been shown in prior studies to be critical for the immune system to mount an effective anti-tumor response.

Earlier this month at ASCO, Generex and the USMCI presented final Phase I data for AE37 in breast cancer. The vaccine was found to be safe and well tolerated in breast cancer patients. There were no patients that experienced toxicity over grade two. The remarkable aspect of this first human experience with Antigen Express's li-Key/HER2/neu MHC class II moiety is that the immunological response was so robust to AE37 that the investigators continued to lower the dose of the adjuvant GM-CSF. Eventually, they removed the adjuvant from the vaccine. This is remarkable because the investigators at the USMCI concluded that "AE37 is the first peptide vaccine derived from a tumor-associated antigen that elicits a robust immunologic response in cancer patients without the use of an immunoadjuvant".

While the target of AE37 is the same as that of Herceptin, the activity of AE37 relies on its ability to stimulate a patient's own immune system to recognize the cancer target rather than by interacting with the target directly. The advantage of this is that the immune system, once activated, is capable of detecting lower levels of the target protein than is Herceptin and that the anti-tumor activity lasts long after termination of AE37 treatment.

USMCI Future Plans

The USMCI and Apthera are planning E75's Phase III trial for later this year. In early 2007, Generex and the USMCI commenced patient dosing in AE37's Phase II trial. The AE37 trial is a randomized, multi-center study among patients who have completed standard therapy for node-positive or high-risk node-negative breast cancer expressing at least low levels of the HER-2/neu oncogene. These patients are at an increased risk for recurrence. The endpoint for the study will be a 50 percent reduction in rate of relapse of the disease at the two-year point. The AE37 Phase II was designed by the USMCI as a large scale efficacy study to take advantage of changing paradigms (not yet adopted) for the study of therapeutic cancer vaccines, which proposes a two-phase rather than a three-phase clinical investigation strategy.

In a recent interview, Col. Peoples discussed the development of the E75 vaccine. "This is a very basic vaccine and much less sophisticated than other cancer vaccines that are in development," he said. "Actually, most people felt that a simple vaccine like this could not work—that we would need multiple peptides to make a 'super vaccine.'" Compared to E75, Dr. Peoples commented, "AE37 is also safe and effective, and causes an even more dramatic immune system response."

In the war against breast cancer, novel peptide based vaccines are being developed at the United States Military Cancer Institute that pose a needed threat to cancer relapse. These vaccines will be more applicable to the whole spectrum of HER2 as compared to Herceptin. The peptide vaccines will be easier to manufacture and cost much less. The USMCI is also designing studies looking at the peptide vaccines used in conjunction with Hercpetin. In all wars, it is a unified front that brings the best chance of victory. Are Genentech and larger oncology players like GlaxoSmithKline (GSK) paying attention?

American Diabetes Association's 68th Scientific Sessions: A New Look at Insulin Therapy

2008-06-08T19:06:00.000-07:00

The American Diabetes Association's 68th Scientific Sessions kicked off in San Francisco on June 6th and ends June 10th. Large pharma dominates the exhibition and use the venue to present their latest study results in an effort to orientate health care professionals on the products they may be prescribing as well as the investment community on the potential value hidden in their pipelines. It was at last year's ADA event, held in Chicago, where all attention centered on GlaxoSmithKline's (GSK) Type 2 oral pill Avandia. First-quarter sales of Avandia declined 56 percent after it was linked to an increased risk of heart attacks while revenue from insulin is climbing fast.

A novel theme has emerged at this year's event emphasizing the merits of insulin therapy in Type 2 patients in the wake of this tumultuous year for oral pills. Two of the largest pharmaceutical companies have brought data to support initiating insulin treatment earlier which is in contrast to previous medical practice. If this trend continues, the future benefactors may not only include the current leaders of injectable insulin such as Novo Nordisk (NVO), Eli Lilly (LLY) and Sanofi-Aventis (SNY), but also Generex Biotechnology (GNBT) and their Oral-lyn Buccal spray. Oral-lyn is a liquid based spray where the insulin delivery occurs in the inner cheek wall with no deposition into the lungs, and is still standing strong after the collapse of Pfizer's (PFE) Inhalable Exubera led to the discontinuation of the inhalable efforts of Eli Lilly, Novo Nordisk and have placed considerable doubt on the future success of Mannkind's (MNKD) Inhalable Technosphere Insulin.

Novo Nordisk A/S, the world's largest insulin manufacturer, kicked off this year's event by releasing results of a study involving early insulin therapy in Type 2 diabetics. The controlled study, partially funded by Novo, involved 382 people from 2004 to 2006 who were newly diagnosed with Type 2 diabetes. Patients randomly received either insulin shots throughout the day, infusions of insulin via a pump, or diabetes pills to bring down their blood sugar levels. The results show that the Type 2 patients who received insulin achieved better glucose controlling results than those who took traditional oral pills. Twice as many patients who received insulin reached their target blood glucose levels in a shorter amount of time than the group who took pills. Nomura Code analyst Paul Diggle believes the new research is likely to increase the $10.2 billion annual worldwide insulin market by more than 10 percent. "We're already seeing an impact of earlier use of insulin,'' Diggle said June 4 in an interview in London. "Early use is one of the things that has people interested in Novo Nordisk.''

Sanofi-Aventis was also presenting data at this year's ADA event to try and boost it's share of the $23 billion global diabetes market with help from increased sales of Lantus, the drugmaker's fastest-growing product. Sanofi has presented study results showing that it's Lantus insulin controlled blood sugar levels for patients in the early stages of diabetes better than traditional oral methods. The company finds that more doctors are starting prescribe insulin during diabetes's early stages to slow the disease's progress and lessen the risks it poses to the heart and kidneys. "Early insulinization is definitely one of the big opportunities we're looking at,'' said Alexandre Moreau, head of Sanofi's diabetes unit, in an interview in Paris. "We have a continuous flow of evidence that we can treat earlier and better. The proportion of patients today who are treated with insulin is around 27 percent. When you see the number of patients who are uncontrolled, it's quite a simple calculation to make if we can grab that percentage of people.''

Generex Biotechnology was also at this week's ADA event and presented convincing results of a 372 day Phase II study comparing Basal and Pre-Prandial Injection vs. Basal Injection and Generex Oral-lyn in Type-1 Diabetics. The investigators of the study written conclusion reads that "A regimen consisting of basal BID s.c. NPH and prandial orally-absorbed regular insulin (Generex Oral-lyn™) attained lower pre-meal glucose, HbA1c and Fru concentrations, than a regimen using basal and pre-prandial insulin analogue injections in Type-1 DM during a 372-day period." Generex also announced at the event that patient dosing has begun in their worldwide Phase III trial for Oral-lyn. Oral-lyn is a room tempeture stable liquid based formulation and a small handheld metered spray that has been proven to administer doses that measure exactly 1 unit. With its very fast onset and offset of action, Oral-lyn possesses less risk of hypoglycemia when compared to standard injections.

Generex Oral-lyn is especially enticing when considering this new trend towards earlier insulin treatment and recalling another study that was presented at last year's event. That study found that of 100 people with Type 2 diabetes, 33 would be unwilling to take insulin even if doctors recommended it. The researchers, led by Mary Larkin of Massachusetts General Hospital in Boston, found that 60 percent of that group is afraid of needles. Another fear for a Type 2 regarding initiating insulin therapy is the fear they may overshoot their insulin dose and risk suffering a hypoglycemic episode. DWS Investment fund manager Noushin Irani, who helps manage $773 million in Frankfurt, was quoted by Bloomberg last month as stating "Patients don't want to use an injection and they especially don't want to use insulin, because of the complexity in controlling blood glucose and also because it makes them feel they really are sick."

Since Oral-lyn is a 1 U handheld spray, overshooting the dose is not likely and this provides the diabetic with a "fine tune" dosing approach. Since the device is small and familar looking, it will not attract attention during use in public and may eliminate the perception that initiating insulin makes them "feel sick". The end result, as shown by studies at this year's ADA event, clearly show that the earlier insulin treatment will make them "feel better" and improve upon their health. The Novo Nordisk and Sanofi-Aventis studies are surely meant to bring attention and sales to their insulin products, but may aid Generex Oral-lyn the most.

Generex Oral-lyn granted Special Acces Programme Authorization from Health Canada

2008-06-07T06:14:00.000-07:00

This article regarding GNBT was also published at Seeking Alpha. The date was May 5th 2008.

about stocks: GNBT / LLY / MNKD / NKTR / NVO / PFE

Generex Biotechnology (GNBT) quietly released an 8K SEC filing on May 1st. In this "Current Report" they note:

"Generex Biotechnology Corporation (the "Company") has received Special Access Programme authorization from the Therapeutic Products Directorate of Health Canada for a patient-specific, physician-supervised treatment of Type-1 Diabetes Mellitus with Generex Oral-lyn™, the Company's proprietary oral insulin spray product. Health Canada's Special Access Programme [SAP] provides access to non-marketed drugs for practitioners treating patients with serious or life-threatening conditions when conventional therapies have failed, are unsuitable, or unavailable."

The filing states that a Type 1 patient will be allowed access to Oral-lyn. Her Doctor will record her therapuetic response to Oral-lyn and alert the Director. Investors in Generex hope that positve results may lead to an expansion of the program.

With this development, Generex Oral-lyn is continuing with its positive momentum at a time the inhalable sector is in decline due the discontinuation of development of inhalable insulin devices by Eli Lilly (LLY) and Novo Nordisk (NVO) and the lung fuction decline and more recent lung cancer concerns raised by Pfizer (PFE) and Nektar's (NKTR) Exubera. These hightened pulmonary safety concerns have brought strong doubt on the efforts of Mannkind (MNKD) in developing it's own inhalable insulin device. Only Generex's Oral-lyn is a fine mist liquid spray where all absobtion takes place in the inner lining of the buccal cavity with no deposition into the lungs.

What this Special Access Programme [SAP] Authorization from Health Canada illustrates is that current treatment for this Type 1 patient have either failed, were unsuitable, or are unavailable. It is interesting to note that this SAP prgram is allowing the patients Doctor to prescribe Oral-lyn to fill an unspecified and unmet need. This SAP is evidence that current standard insulin injectables, pens or pumps have failed to help this patient. Through this special program, the patients doctor specifically turned to Generex Oral-lyn and Health Canada approved the treatment.

In one SEC filing, we may find evidence not only of Oral-lyn's superiority vs inhalable insulin, but potentially of it's superiority vs current approved treatment options for a specific Type 1 subgroup. This is encouraging news for Generex and their shareholders, as the microcap biotech continues with recruitment in North America for Oral-lyn's worldwide Phase III trial.

Oral Insulin: Balancing Safety with Efficacy

2008-06-07T06:10:00.000-07:00

This was published on Seeking Alp[ha on April 14th, 2008

about stocks: GNBT / MNKD / PFE

In the April issue of Diabetes Care, the long running "Atherosclerosis Risk in Communities" [ARIC] study led by Frederick Brancati, M.D., of Johns Hopkins, found that lung function declines faster in type 2 diabetes patients than in those without the disease. Dr. Brancati and his colleagues also said that there may also be implications for the use of inhaled forms of insulin.

The American Diabetes Association, which publishes Diabetes Care, issued a press release titled "Reduced Lung Capacity Accelerates with Diabetes Makers of Inhaled Insulin Should Take Note, Researchers Say". They warn in their article that "...people who have diabetes encounter a faster loss of lung capacity than those who do not have diabetes, a finding that may have implications for the potential use of inhaled insulin, according to a study appearing in the April issue of Diabetes Care."

On April 9th, Pfizer (PFE) said it updated the U.S. product labeling for Exubera Inhalation Powder to include a warning about lung cancer cases observed in patients who used the inhaled insulin treatment. Over the course of Exubera's clinical trial program, 6 of the 4,740 patients treated with Exubera developed lung cancer, compared with 1 of the 4,292 patients not treated with the drug. The six patients with cancer either had been or were current smokers.

In the April 10 Endrocine Today article titled "Inhaled Insulin May Be Associated With Lung Cancer", Editorial Board Member David S. H. Bell, MD noted: "Since insulin is a growth factor, endocrinologists have always been concerned that inhaled insulin would be associated with lung cancer. Because of this and in spite of earlier assurances from clinical trials that there was no such increase in the risk of lung cancer, many endocrinologists, like myself, have never prescribed inhaled insulin. Obviously, our worst fears have been realized. This is the final nail in the inhaled insulin coffin."

On April 10th, MannKind's (MNKD) response to the Pfizer announcement regarding a new warning label to existing packages of Exubera was as follows: "In contrast, the safety profile of Technosphere[R] Insulin has been examined in an extensive preclinical program, including a two-year carcinogenicity study in rats, in which we observed that Technosphere[R] Insulin and Technosphere[R] particles alone were well tolerated after daily inhalations for 104 consecutive weeks. There were no indications that our product or the carrier material alone had carcinogenic potential or caused cellular proliferation in the lungs. We also recently completed a six-month carcinogenicity study in transgenic mice that are prone to cancer. We found no macroscopic indications of carcinogenicity in animals treated with Technosphere[R] Insulin or Technosphere[R] particles for 26 consecutive weeks. The analysis of the histology data is in progress and will be completed later this quarter."

Is it fair to conclude that MannKind's response is based on pre-clinical carcinogenicity safety data in rats and a more recent one in "animals"? The FDA may take a harsh look at that data and say 'let's see carcinogenicity safety data in humans over a longer duration of time than "104 week" mice study or the current "26" week animal study'. Is it plausible the FDA will ask for an additional follow up on the "human" Phase III patients? If MannKind has not made carcinogenicity data part of one of the "human" Phase III protocols, then will the FDA possibly request more safety results requiring added trial time exposure?

From an investor standpoint we need to ask: What is the best case scenario for MannKind after a filing a submission for approval for Technosphere? Would positive efficacy data in the current Phase III's be enough to warrant approval during this disconcerting juncture? Perhaps an "Approvable Letter" could be the outcome instructing MannKind that more safety data is needed. Even with potential approval, would MannKind still face the burden of convincing professionals such as David S. H. Bell, MD of Endrocine Today or Frederick Brancati, M.D., of Johns Hopkins to prescribe MannKind's billion dollar drug?

Natixis Bleichroeder analyst Jon LeCroy downgraded MannKind to "sell" from "hold" after the news. "We view this as an absolute disaster for MannKind and do not see a believable scenario in which the FDA would approve another inhaled insulin," LeCroy said. Leerink Swann analyst Bill Tanner titles a MannKind research note to clients Friday morning"[b]TI's Challenges Potentially Insurmountable[/b]." He quotes a "regulatory consultant" who believes "the bar has been substantially raised for TI's approvability as this safety concern will likely be treated as a class effect." In essense, that means the Food and Drug Administration will look at all inhalable insulin products as having the same potential problems.

On April 10th, MannKind issued a press release stating: "Given the current market sentiment, we have decided to suspend partnership discussions." MannKind acknowledges that it "will be unable to achieve an appropriate valuation for Technosphere Insulin until Phase 3 (late-stage) data are available that confirm our belief in the safety and efficacy of TI."

It may be true after the completion of TI's Phase III and the current "six-month carcinogenicity study in transgenic mice" that MannKind is convinced in the safety and efficacy of Technosphere. But what about the FDA, diabetics and their doctors? Diabetics and physicians have heard earfuls of stories regarding inhalable insulin and decreasing lung function and now whispers of potential cancer. A mouse or animal study will not halt these whispers surrounding inhalable insulin and that is the type of word of mouth never helps a marketing campaign. I would never count out a man as successful as Mr. Al Mann, but I remain unconfident in the future of MannKind.

Last month, an article appeared in Bioworld which informed biotech investors that the FDA issued new draft guidance for diabetes drugs calling for more patients and lengthier trials for companies with certain safety issues. In general, the FDA wants companies to exceed previous expectations considering the growing diabetes population and the increased complexity of treatments, but it will be an absolute stickler with those drugs exhibiting serious side effects.
At the time of the new FDA draft guidance, Aileen Salares of Leerink Swann & Co., would affect MannKind's inhaled Technosphere Insulin, a product she believed could show an advantage over the currently marketed inhaled product, Exubera, because of its reduced antigenicity and a lower hypoglycemia risk. The Pfizer announcement regarding the new arning label for Exubera may be the final nail in all inhalables coffin. I figure that must be news that Aileen Salares did not expect when making her analysis for TI. Surely, I would expect the FDA to now place any inhalable in the category of a drug that may present a serious side effect or, at the least, one that needs further pulmonary safety data.

The good news for MannKind is that we are halfway through April. My mother always told me to take my bad tasting medicine quickly and I would soon feel better. But the problem for MannKind would be that their medicine is simply "perceived" as bad, even if that turns out to be an unfair assesment.

In my first contribution on Seeking Alpha, I expressed my opinion on Generex Biotechnology's (GNBT) Oral-lyn Buccal insulin spray. In the same Bioworld article where I learned of the FDA's new draft guidelines concerning diabetes drugs, Navdeep Jaikaria, an analyst with Rodman & Renshaw, was quoted as telling investors in a research note that negative news of companies developing inhalable insulin has placed "unwarranted pressure on the shares of Generex." If anything, he said, their loss is Generex's gain, as safety issues with inhalable insulin only pave the way for Oral-lyn Buccal therapy as the only viable alternative to injectables. Mr. Jaikaira said there are observations that inhaled insulins lead to a decline in lung function, and there are formulation problems with converting insulin into an inhalable powder while Oral-lyn Buccal is a room tempature liquid formulation that deposits no insulin into the lungs.

My own analysis stems from research which I have conducted independently over the last few years and I am far from an expert. I wanted to share my opinions and gain valuable feedback as I continue to evaluate the sector. My interest stems from a family history of diabetes and the burdens that accompany non-compliance to the (unnatural) insulin injection regimen. Personally, I would rather they all succeed and allow needle resistant diabetics a broad delivery choice. As that does not appear to be the realistic case, I want to make my sentiment clear: I am long on GNBT and will avoid MNKD. Hopefully, we are nearing a time in the US where an improved choice of insulin delivery rests solely with diabetics and their doctors and not with which biotechnology company can successfully navigate the high regulatory and financial hurdles.

Generex Biotechnology: Oral-lyn Buccal Insulin Takes center Stage

2008-06-07T06:05:00.000-07:00

The first three blogs I'll bring here were my first publications at Seeking Alpha. This was published April 10th, 2008.

about stocks: ALKS / GNBT / MNKD / NKTR / PFE

Insulin was discovered in Toronto in 1921 and arrived on the market in 1922. Since that time there have been episodic attempts to escape the inevitability of injection.

The race for developing a successful needle-less insulin delivery system has taken some recent nasty turns as the inhalable efforts of large pharma companies have all come to an end. The latest news that Pfizer (PFE) is adding a new warning label to Exubera regarding instances of lung cancer in clinical trials may prove to be the final nail in the coffin for hopes of any inhalable insulin winning the hearts and minds of needle suffering diabetics.

The news caused a devastating effect on shares of Mannkind (MNKD) as analysts cried "SELL" and investors obeyed the call. In essence, it appears Mannkind's "Technosphere Inhalable Insulin" somehow was seen as failing a Pfizer/ Nektar (NKTR) "Exubera" Phase III trial. Call it "guilt by association", or even call it unfair, but it will be impossible for Mannkind to win those hearts and minds of diabetics when they are afraid of serious damage to their lungs.
And with the FDA issuing a hardened approach towards approving diabetes drugs that may present any adverse health effect, consider the odds of Technosphere ever gaining FDA approval to now be seriously in doubt. However, diabetics' hopes for freedom from needles may not be over.

Generex Biotechnology (GNBT) is developing a needle-less insulin delivery system that does not enter the lungs and is delivered to the inner cheek wall as a metered dose buccal insulin spray. Ironically, this small microcap biotech, incorporated in Delaware, originally partnered early in the decade with Eli Lilly (LLY) for development of Oral-lyn buccal insulin spray. But Eli Lilly was already financially committed to a developmental agreement with Alkermes (ALKS) for the development of their Air Inhalable Insulin. In two years of nothing, Lilly never conducted a single trial for Oral-lyn buccal spray.

The biotech rumor mills were running rampant that Eli Lilly simply stalled Generex's development of Oral-lyn Buccal. In 2003, Generex and Lilly mutually agreed to end the agreement and Lilly left tiny Generex for dead. But Generex did not die. The management team, led by founders CEO Anna Gluskin and COO Rose Perri, hung strong and continued Oral-lyn buccal spray's development with a new found independent spirit and successfully raised enough financing to survive.

Oral-lyn buccal spray was back in the clinic in 2004 and 2005 and, as Generex fought its way back from potential bankruptcy, positive results for safety and efficacy began to filter through. In 2005, Oral-lyn buccal spray was approved for commercial marketing and sales in Ecuador, which was the location of many of the Phase I and Phase II clinical trials. In the latest Phase II trial for Oral-lyn buccal spray, the investigators concluded that Oral-lyn illustrated a “superior effect” vs. Eli Lilly’s HumalinR as measured by the patients A1C levels (6.1) after 99 days.

In 2006, Generex completed a positive Pre-NDS with Health Canada. In November of 2007, Oral-lyn buccal spray was approved for marketing and sale in India- which is home to 1/3 of the world's diabetics. In April 2008, Generex announced the initiation of the North American sites (USA and Canada) for their worldwide Phase III trial of Oral-lyn buccal spray in Type 1 patients. The company has announced that this six month study will be modeled after the Phase II study where "superior effect" was illustrated, and that all of the major regulatory bodies, including Health Canada and the FDA, have approved the Phase III study protocol. Generex is hoping for Canadian approval of Oral-lyn buccal spray within 18 months and shortly after in the USA.

Can this small biotech accomplish what large pharma could not? Perhaps the difference is in the Oral-lyn formulation and device, termed Rapidmist, which is a small handheld metered spray whose doses measure exactly 1 unit. The onset of action is quicker than what was reported for Exubera. Also, Oral-lyn requires no refrigeration. That is another positive unique feature, for a diabetic can simply keep the small spray device (the size of an asthma inhaler) in their front pants pocket or purse and spray doses as needed before and after a meal or snack.

I guess since Generex's market cap is below $200,000,000, large investors have yet to pay attention. However, if sales of Oral-lyn in India, home to 40 million diabetics, are healthy, then Generex will certainly be a biotech that jumps to the spotlight. After all, safety and efficacy must be crystal clear for Oral-lyn buccal spray since it is winning some early regulatory approvals before the first patients have been dosed in the Phase III. Dr. Gerald Bernstein, former President of the American Diabetes Association, is a member of Generex's executive management team and is named in the company's press releases as the expert traveling the globe raising awareness of Oral-lyn at endroclonogical events.

Non-compliance is a serious issue complicating the conditions caused by diabetes and it is fair to say that I am rooting for the little team to help bring this growing epidemic under control. After all, with all the safety issues involving not only inhalable insulin, but the new class of Type 2 oral pills (i.e. Avandia), a simple 1 unit buccal insulin spray may prove to be the winning solution to the puzzle of needle-less delivery.

Finding a successful needle-less option has been called the 'Holy Grail of diabetes research' and this small biotech may actually have developed the next paradigm of diabetic care. As the current spotlight shines on the questionable safety problems of inhalable insulin, investors may be wise in paying attention to Generex and their Oral-lyn buccal spray. The positive safety profile and positive Phase II efficacy results are encouraging to GNBT shareholders in a time when the diabetic epidemic is growing and its needle-less competitors are all falling.

Generex recently completed new financing that brings their cash holding to just above $40 million. Generex's burn rate has been approximately $7 million per quarter and it would be wise to note that this burn rate should move higher with the manufacturing needed for the Indian market and the continuation of the worldwide Phase III trial. Shreya Life Sciences, the 4th largest insulin distributer in India, is Generex's marketing and distribution partner for the region. Last month, Shreya placed a purchase order for 210,000 units of Oral-lyn to be used in the marketing launch. Generex's marketing and distribution partner in the China region is Scigen Ltd of Singapore. The principle shareholder of SciGen is Bioton SA, an insulin crystal manufacturer in Poland.

Perhaps in 2008 we are bearing witness to the first safe and effective achievement of this elusive goal. Generex Biotechnology, whose headquarters are based in Toronto, may be the first to redesign and improve one of the world's most vital drugs. Biotech investing is ripe with risks coupled with the prospects for large rewards. All investors need to carefully weigh the potential and realities facing any biotech and especially a microcap. Due diligence is always a necessary ingredient to wise investing. Carefully investigate my opinions and then form your own.