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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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Saturday, August 14, 2010

The Quest for a Safe, Effective and Non-Invasive Meal Time Insulin

"I poke my fingers to check my sugar. I have to take shots before I eat. I’m tired of all this. I wish it was easier. I can’t go to my friends’ houses. They don’t know what to do". ~ Josh from An Anthology of Poems by Kids with Diabetes

While subcutaneous insulin is effective in controlling blood glucose and HbAIc concentrations, the required injections can be a burden for patients, which can impact compliance. Patients and physicians hesitate initiating insulin therapy for several reasons, such as concern that injections are painful, difficult to administer, inconvenient, and the overall perception that initiating insulin treatment signifies a dramatic worsening of the disease. These inherent limitations are among other possible reasons why diabetics often have poorly controlled HbA1c levels while on conventional insulin therapies.

Everyone taking injected insulin develop antibodies to insulin. The antibodies bind to and neutralize the insulin. Researchers have found that if you form antibodies to insulin, your body reacts as if the insulin is foreign. In some cases, this may make insulin less effective, or not effective at all. The antibodies can also change the amount of time it takes insulin to work, putting a diabetic at risk for hypoglycemia. As a result, increased levels of insulin would later be needed to have the same effect, which is called insulin resistance.

Inhalable insulin and Insulin Resistance

Inhalable insulin has been associated with much greater antibody response than subcutaneous insulins, but this has not yet clearly been correlated with any serious adverse clinical effect. There is debate in this area with some health care professionals calling for longer term studies to be conducted to clearly determine the effect these greater levels of insulin antibodies have on a diabetics body. The debate is now more pertinent since the FDA is once again considering a new drug application for an inhalable form of insulin.

The first approved inahable insulin was Pfizer's (PFE) Exubera, which was later withdrawn from the market due to a lack of acceptance amongst diabetics and their physicians. There are many reasons for Exubera's demise; from its bulky size and confusing dosing, to its required lung function tests mixed with the safety concerns of long term usage. Results pooled from subjects using Exubera's in Pfizer's Phase 2 and 3 trials found they had much higher levels of insulin antibody binding activity. Greater antibody responses were seen in patients with type 1 diabetes, also known as Juvenile Diabetes, which would naturally lead to greater levels of insulin resistance in this population. The higher anitbody responses were found in pediatric patients (<18 years) and in females (see page 181).

The new inahalble insulin the FDA is currently reviewing for marketing approval is Mannkind's (MNKD) Afrezza, which differs from Exubera in particle structure, pharmacodynamics, and glucodynamics. However, Afrezza doesn't appear to greatly differ from Exubera in antibody responses. The development of insulin antibodies in Type 1 and Type 2 study patients exposed to Afrezza was presented at the American Diabetes Association's 70th Scientific Sessions in June. Insulin antibodies were measured and found to increase as early as 2 weeks upon Afrezza initiation, rising over time, while plateaued or spontaneously declined after 10 to 18 months. As seen with subjects who participated in the Exubera studies, insulin antibodies were more pronounced in Type 1 patients exposed to Afrezza. Three months after discontinuation of Afrezza treatment the subjects levels of insulin antibodies returned to near-baseline values, indicating that the insulin antibodies response to pulmonary inhalation of Afrezza is reversible.

At this point in research, no associations are noted between insulin antibodies levels and key clinical outcomes for Afrezza subjects. Mannkind noted that this effect was expected as the lungs function as a port of entry for exogenous substances and contain a large concentration of immunoactive tissue and that no clinical consequence of insulin antibodies have been observed.

Generex Oral-lyn Buccal Insulin and Insulin Resistance

A limited study involving insulin antibodies in subjects using Generex's (GNBT) Oral-lyn will be in the spotlight this September at the EASD Annual Meeting in Stockholm, Sweden. Generex has developed a proprietary platform technology for the delivery of drugs, such as insulin, into the human body through the oral cavity with absolutely no deposit into the lungs. Researchers evaluating Generex Oral-lyn in an ongoing Phase II study with Impaired Glucose Tolerant patients will present an abstract aptly titled "No Generation of Insulin Antibodies in Subjects with Impaired Glucose Tolerance Treated with Buccal Spray Insulin". The abstract can be found in the EASD 2010 abstract book. There is an embargo on the abstracts being presented at the event, but I will inform that once again the highly regarded independent endocrinology researcher Dr Paolo Pozzilli leads the study, and the title itself reveals their conclusion and yet another apparent difference between buccal and inhalable insulin.

In July, Generex reported preliminary outcomes and trends from their ongoing Phase III pivotal study of Generex Oral-lyn buccal insulin in Type 1 patients. This subject group is the same that has shown greater levels of insulin antibodies in both Exubera and Afrezza. While both forms of inhalable insulin have been found to form heightened levels of insulin antibodies that in turn may lead to insulin resistance, this effect has not been found in subjects using Oral-lyn. Generex reported that insulin resistance has not observed for the Type 1 subjects using Oral-lyn. When the study is completed, it will be of great interest to see data assessing insulin antibody levels in subects using Type 1 diabetes.

Result trends are showing that Oral-lyn, comprised of human insulin and GRAS (Generally Regarded as Safe by the FDA) excipients, is more naturally accepted by the body and therefore does not result in insulin resistance. These results are preliminary, with a full analysis of the Type 1 Phase III study expected to be complete in early 2011, while three month results for all patients are expected much sooner.

Generex has also reported in their preliminary trends announcement of their Phase III study of Type 1 patients that subjects using Oral-lyn have demonstrated NO weight gain and have had, on average, an actual decrease in their Body Mass Index. These results compare favorably to control subjects in the study using injectable insulin who have, on average, gained weight and experienced an increase in BMI. When comparing hypoglycemic events, subjects using Oral-lyn were observed to have a better Adverse Event profile than subjects using injectable insulin. This also compares favorably to prior studies for Afrezza inhalable insulin where slight weight gains are rightly mentioned as a noteworthy achievement.

For all of these reasons, I believe that Oral-lyn will be found to be the first insulin to safely and effectively mimic the normal pancreatic insulin release of a healthy person, without any of the safety concerns that some believe swirl around inhalable insulin. Since the development of insulin antibodies is greater in pulmonary insulin than subcutaneous injectable, and Mannkind says the condition is reversible after a patient stops taking Afrezza, then I hope that those same patients can start taking Oral-lyn in the first ever diabetes related Treatment IND (see FOX TV video) that the FDA has already granted Generex. This way those diabetics may potentially not have to worry about any of the insulin antibody or pulmonary concerns, while freeing themselves from the burdensome effects that come with subcutaneous insulin.

Generex shareholders themselves are currently burdened with fears concerning the effect of a potential reverse stock split, or a negative response from Nasdaq's Hearings Panel. However, if Generex continues to find successful results in their ongoing Phase III study of Type 1 patients, shareholders and diabetics alike will be welcomed by a much brighter future. Considering that Generex recently announced they have achieved 75% of the required number of per-protocol completers in the six month pivotal global Phase III study, that brighter future may be close at hand.