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 Unpublished data from researchers at the USMCI also appear to show the potential linking of E75 to a li-Key/HER2/neu MHC class II peptide which brings us to the subject of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?
Saturday, June 21, 2008
Sunday, June 8, 2008
American Diabetes Association's 68th Scientific Sessions: A New Look at Insulin Therapy
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.
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.
Saturday, June 7, 2008
Generex Oral-lyn granted Special Acces Programme Authorization from Health Canada
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.
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
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.
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
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.
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.
Subscribe to:
Posts (Atom)
