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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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Sunday, September 19, 2010

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

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

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

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

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

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

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

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

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

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