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.
This Is Generex Biotechnology Pipeline Review
Antigen Express
Antigen Express is the fully owned life science subsidiary of Generex Biotechnology. Antigen Express is a platform and product-based company developing proprietary vaccine formulations for large, unmet medical needs. Their focus is on stimulating critical members of the immune response, known as T helper cells. The technology allows for antigen-specific stimulation or suppression of a T-helper response to virtually any antigen of known pathogenic potential. Antigen Express is building a deep pipeline of therapeutics aimed at a variety of major diseases, including cancer, infectious diseases and autoimmune-based syndromes.
Early efficacy analysis of the AE37 vaccine in a Phase II study
Click the logo to see the results for AE37 that were presented at the 2012 ASCO Breast Cancer Symposium
Peptide Vaccine Stimulates Immune Response in Patients With Breast Cancer
Click the logo to read about the results for AE37 that were presented at AACR 2012
Antigen Express President Dr Eric von Hofe
The President of Antigen Express is Dr Eric von Hofe, who has been impressive with advancing Antigen Express' pipeline and entering into smart collaborations. Dr. von Hofe joined Antigen Express in November of 2003. Prior to this time he held two positions at Millennium Pharmaceuticals; first as Program Director for Target Validation, where he presided over technology development efforts for Aventis and Cereon, and second as Director of Programs and Operations, Discovery Research. He received his Ph.D. from the University of Southern California and was a postdoctoral fellow at the University Hospital of Zurich and Harvard. From 1989 to 1992 he was Assistant Professor of Pharmacology at the University of Massachusetts Medical School. Click on the image of Dr von Hofe to read the abstract for his latest peer review article regarding cancer vaccines.
The AE37 Ii-Key synthetic peptide vaccine
Click on image to enlarge. Harvard scientists, who founded and lead Antigen Express, have pioneered and patented technology that modify MHC class II epitope peptides with a fragment of the MHC class II-associated invariant chain. Antigen Express recently reported interim results from a Phase II trial of the AE37 HER2/neu Ii-Key modified peptide vaccine for patients treated for breast cancer who are at high risk of relapse. While there was a 7% relapse rate in the control arm, there were no relapses in the Ii-Key peptide arm (AE37) when analyzed at the 13-month time point. A review article co-authored by Dr. Eric von Hofe, Ph.D., President of Antigen Express, entitled "A New Era in Anticancer Peptide Vaccines", will appear in an early 2010 edition of the journal Cancer, the International Interdisciplinary Journal published by the American Cancer Society. An advantage of using the type of active immunotherapy offered by AE37, as opposed to passive immunotherapy such as treatment with Herceptin, is that activated immune cells can detect and destroy cancer cells expressing much lower levels of HER-2/neu than is needed for recognition by Herceptin.
San Antonio Breast Cancer Symposium December 2009
Positive AE37 Phase II Interim results were reported at the San Antonio Breast Cancer Symposium in December 2009. Click the SABCS logo to view the poster presentation for AE37's Interim Phase II results, while the abstract text will be provided below.
Antigen Express' Ii-Key Peptide Vaccine Platform Technology
Click on the image for Antigen Express' pipeline to enlarge. AE37 is a novel peptide vaccine that is the product of a proprietary technology platform established at Antigen Express designed to increase the antigen-specific stimulation of CD4+ T helper cells. AE37 is capable of eliciting HER2/neu-specific immune responses, even without the use of an adjuvant. AE37 is the first peptide-based cancer vaccine to show potency in the absence of an immunoadjuvant.
Mary Crowely Cancer Research Center is Fully Funding the AE37 Combo Vaccine Study
Click on the Mary Crowley logo, provided above, to see the clinical trial listing for the AE37 Combo Vaccine
About Me
- Rich Steffens
- Rich Steffens has grown up in New Jersey, is a successful businessman, and studies social media trends amongst life science and biotech companies. His family is deeply influenced by the ill effects of diabetes. I am not qualified to offer investment or medical advice, and make no claims that I am an expert in these areas. I seek to share and learn.
The Future of Insulin Treatment
Dr Gerald Bernstein, Generex VP and former Pres of the ADA, was featured in an online video at the Doctor's Channel in a segment titled "Diabetes & Endocrinology Oral Insulin Delivery with Oral-Lyn". With many new insulin based drugs on the horizon, Dr Bernstein explains both the history of insulin treatment and what he believes to be the best future option- Oral-lyn. Click on the image of the current new insulin based drugs in development to view the video.
Oral-lyn's time profile; insulin only when a diabetic needs it, bringing less risk of hypoglycemia
This image, which you can click to enlarge, illustrates that with its very fast onset and offset of action, Oral-lyn buccal insulin spray may offer less risk of postprandial hypoglycemia as compared to conventional injected insulin therapy. Hypoglycemia is a life-threatening risk, and along with injections is the most important obstacle towards achieving good metabolic control. With each spray of the RapidMist device one unit of meal time Oral-lyn buccal insulin is said to be rapidly delivered into the bloodstream. The amount of sprays given is determined by the amount of insulin each unique diabetic requires to cover a meal. The company informs that the insulin only remains in the bloodstream during the time period the diabetic needs it, promising a safer and simpler approach.
The extended action of injectables may lead to hypoglycemia; the insulin often lingers too long
In this graph, which you can click to enlarge, we can see the long tail of both meal time analogues and regular insulin. Analogue prandial insulin is dosed approx 15 minutes before a meal, peaks in an hour, and with a duration of effect of 4 hours. Regular insulin is dosed 30 minutes before a meal, peaks in 2 hours and lingers up to 6 hours in the bloodstream. This slow acting tail activity often causes low blood sugar levels to occur after the glucose spike provided by the meal starts to decline. Generex states that Oral-lyn is taken right before the first bite of the meal, immediately begins to be absorbed in the inner lining of the mouth, peaks in 30 minutes, and blood sugar levels cleanly return to baseline within two hours. Generex finds there is no tail of activity with Oral-lyn as there is with all other forms of injectable insulin, so they believe the risk of postprandial hypoglycemia is greatly minimized. If blood levels are back at baseline after the meal, there is no reason to gorge on post meal snacks to offset any lingering insulin, which helps avoid unhealthy weight gain. The unique time action profile for Oral-lyn, if proven in the Phase III study, may provide greater flexibility in usage, as well as the ability to take small dose sprays before a snack when that tasty treat simply can not be resisted. Another main advantage for Oral-lyn may be its ability to mimic the first-phase insulin response seen in a healthy person. This first-phase insulin release is one of the first functions that people with diabetes lose. In healthy people our bodies release insulin within 10 minutes after eating.
Oral-lyn Buccal Insulin X-RAY imagery proves no deposition into the lungs
Unlike Mannkind's Afrezza, in which a powder insulin formulation is inhaled into and absorbed by the lungs, Oral-lyn is delivered as a fine spray to the buccal cavity by the RapidMist delivery system. Generex states the result is rapid insulin absorption through the buccal mucosal lining of the mouth without pulmonary (lung) exposure. The lungs, like all other vital organs in the body, are already a target of diabetes leading to lower lung function over time. The lungs are meant to process gasses, and not proteins. I think that Generex, via Oral-lyn buccal insulin, avoids potential pulmonary complications in a simpler and safer approach. Click on the provided X-Ray image to learn more.
Prandial insulin dosing is now as simple as a spray
Oral-lyn is available in a US FDA approved Treatment IND as well as in Phase III trials as a 1 UNIT per spray dose. For Oral-lyn, the delivery devise appears built to provide fine tuning post meal dosing. It appears as simple as taking another quick spray. In my opinion, as the safety concerns swirl around prospects for inhalable insulin, 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.
Generex Oral-lyn Buccal Insulin
"Patients who are needle averse face a serious barrier to their recommended treatment," warns Generex "Generex Oral-lyn promises a pain-free alternative to injectable insulin, which is good news especially for older patients and children who find needles uncomfortable." Click on the image provided above to learn more about aversion to injections and diabetes.
Dr Gerald Bernstein, VP Medical Affairs Generex, former President of American Diabetes Association
Click on the photo of Dr Bernstein to view his interview on FOX Health. Dr Bernstein recently commented further on the unique safety profile for Oral-lyn: "It’s extremely safe by all the studies that have been done so far, including two years in animal tests. We haven’t seen allergic reaction. The lining of the mouth hasn’t shown any abnormalities. The buccal mucosa is an extra-tough and resilient tissue, it’s beaten up all the time. People bite themselves or burn themselves. Whatever doesn’t get absorbed is going to go to the stomach. Now the insulin molecule is unprotected and therefore it will be denatured by the acid and then broken down. There are no side effects." Dr Bernstein is an attending physician at Beth Israel Medical Center, and physician emeritus at Lenox Hill Hospital and Montefiore Medical Center, all in New York. He was formerly Director of the Beth Israel Health Care Systems Diabetes Management Program. Dr. Bernstein was president of the American Diabetes Association in 1998-99 and was for many years a member of the ADA's Board of Directors and its Executive Committee. He received the ADA's Banting Medal for Service in 1999. Dr. Bernstein presently serves on several ADA committees and on the Board of Directors of the American Diabetes Association Research Foundation.
Buccal Absorbtion
RapidMist Buccal Drug Delivery Device
