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Generex Biotechnology, and their wholly owned subsidiary Antigen Express, are developing promising new drugs to treat diabetes, as well as synthetic peptide vaccines targeting HER2/neu cancer and pandemic flu. The flagship product for Generex is Oral-lyn buccal insulin. Antigen Express' leading vaccine is the AE37 HER2/neu synthetic peptide vaccine to prevent breast cancer recurrence. I am not qualified to offer investment or medical advice, and make no claims that I am an expert in these areas. I am a layman and a shareholder in this company. The left side of Pipeline Review holds blogs regarding Generex and Antigen Express, while the right side offers items of due diligence mixed with my analysis which may be of interest to others seeking to learn about Generex's pipeline. If the left side only shows the latest blog, click on the word home to view them all.

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Monday, May 30, 2011

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

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.