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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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Thursday, December 11, 2008

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

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.