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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, March 28, 2010

Revealing the Clamour Against Biotech in "TheStreet"

When one person makes an accusation, check to be sure he himself is not the guilty one. Sometimes it is those whose case is weak who make the most clamour. ~ Piers Anthony

On March 21st, I highlighted coverage of TheStreet's Senior Columnist Adam Feuerstein's controversial March 19th opinion piece focused upon Generex Biotechnology's efforts at developing Oral-lyn buccal insulin spray. In my article, I detailed how I believed his opinion piece to be defamatory and based upon untrue statements. Specifically, I proved his argument that none of the Oral-lyn data collected by Generex has been peer-reviewed in credible medical journals, nor has it been presented at the top-flight diabetes meetings was utterly false. In reality, I cited the numerous peer review articles which have been published by the independent researchers studying Oral-lyn in its Phase I, II and III trials, and named the plentiful "top-flight diabetes meetings" where Oral-lyn data has been presented, including having Oral-lyn data being selected for a prestigious podium presentation at last year's American Diabetes Association's Scientific Sessions.

On March 23rd, Generex issued a press release demanding a retraction and apologies for the inaccuracies published in Feuerstein's entry titled "Biotech Stock Mailbag: Generex". Generex stated that they wish to correct the public record by making clear the facts as outlined in a letter to TheStreet's counsel. Generex informed that a number of independent, peer-reviewed studies of Generex Oral-lyn have been published in journals including "Diabetes Care". The company remarked that Generex Oral-lyn trial data has been presented in podium posters and abstracts at the annual meetings of the American Diabetes Association, the Endocrine Society, the European Association for the Study of Diabetes and the International Diabetes Federation on a regular basis over the past ten years. Generex routinely presents Oral-lyn data at all of the major diabetes events and the latest peer review article was published as recently as last month.

On Friday March 26th, TheStreet corrected Feuerstein's article to note that "Oral-lyn has been discussed in medical journals and presented at medical association meetings over the last ten years" and that TheStreet "regrets the error". TheStreet may regret further errors since on the same day the correction was printed, Feuerstein offered a subsequent article (see here) focused upon Generex and Oral-lyn which contained false information and childlike innuendo. In the article, Feuerstein does not acknowledge how his previous offering contained conclusions that were built upon faulty premises. Rather, I contend that he stubbornly embarks down the same unrighteous path where he strong arms conclusions which are left to clumsily stand upon an inaccurate foundation.

Generex's Oral-lyn is a buccal insulin spray that is in a Phase III trial in the U.S. and which has recently been conditionally approved by the FDA under a Treatment IND [Investigational New Drug]. The FDA website states that they will permit an investigational drug to be used under a Treatment IND if there is sufficient evidence of safety and preliminary evidence of drug efficacy. The drug must be intended to treat a serious or life-threatening disease, or if there is no comparable alternative drug or therapy available to treat that stage of the disease in the intended patient population. The Treatment IND approval for Oral-lyn was the first awarded by the FDA to treat diabetes.

In the latest article, I find that Feuerstein again makes claims that are false and which illustrate his lack of knowledge about the regulatory requirements surrounding a new drug that will be targeted for approval to treat Type 1 diabetes. Since Feuerstein, a TheStreet's representative as a professional biotechnology journalist, is incapable of understanding the regulatory hurdles a company such as Generex will face in vying for FDA approval for Oral-lyn to treat Type 1 diabetes, I believe their financial news service cannot serve as an adequate outlet for investors to gain a diligent perspective for developments within that specific sector.

Among many of the inaccurate claims I find Feuerstein to make, he states that MannKind tested Afrezza in 5,300 patients total. That is false and Feuerstein just powered Mannkind's study population by an additional 2,850 subjects. Mannkind submitted a NDA for Afrezza "inhalable" insulin to the FDA based on testing in 2,450 subjects with Type 1 or Type 2 diabetes who were randomly assigned to treatment with their inhalable powder insulin. Feuerstein also mentions the large study population total to support a NDA from Eli Lilly and Amylin for Byetta LARS.

What Feuerstein seemingly fails to comprehend is that Generex is currently vying for approval to treat Type "1" diabetics with Oral-lyn buccal insulin, and its new drug does not have to undergo the pulmonary testing associated with inhalable insulin, or strict cardiovascular studies associated with Amylin's Type 2 oral pill. Feuerstein can also eliminate from his mind the entire Type 2 population that was tested in these other drugs, at least until a time frame when Generex is targeting Type 2 approval. Feuerstein also must be unaware that Biodel recently submitted a NDA, under a 505(b)(2) pathway approved by the FDA, for ViaJect injectable human insulin with less patient power than Generex currently has recorded for Oral-lyn. In short, the professional biotechnology journalist is confusing the regulatory path for drugs that treat Type 1 patients, with ones that treat Type 2.

Among other false statements Feuerstein makes is that regular insulin is slow acting and isn't used by diabetics around mealtime, which makes the Oral-lyn data irrelevant. This is false. Humulin R and Novolin R are bolus mealtime regular insulins, and Feuerstein is evidently confusing them with basal NPH insulin, also known as Eli Lilly's Humulin N and Novo Nordisk's (NVO) Novolin N. The standard protocol for any bolus insulin to gain FDA approval is by a non-inferiority study comparing HbA1c levels of the new insulin versus Humalin R. Subsequent labeling studies may be designed to compare the new bolus insulin versus the newer and faster acting meal time analogues which have been approved, but the comparison versus reglular insulin is imperative for approval.

In my opinion, Feuerstein rushed to conclusions in order to support a negative opinion on Generex's developmental path for Oral-lyn. I uncovered his effort in his first article, where he proposed an argument that the effort to develop a non-injectable insulin delivery system is market driven and not the result of a real need experienced by diabetics. While he informed that he gains his perspective from "the thought leaders at the American Diabetes Association", I noted in my original report that he overlooked how in February the American Diabetes Association published a well publicized study which found that out of 502 diabetics surveyed, 57 percent said they had intentionally missed an insulin dose, and 20 percent said they regularly skipped insulin injections. Among the reasons for skipping insulin injections were complaints of injection pain, embarrassment by the need for insulin and thought that the injections interfered with their daily life. One in five stated they skip insulin injections often.

As I had noted, the report in Diabetes Care was presented on the heels of a similar report issued in 2008 by the American Association of Diabetes Educator. The report found that 33% of the surveyed patients have experienced "dread" in relation to insulin injections, 14 percent surveyed feel that insulin injections have a negative impact on their life, and more than 29 percent of the surveyed feel that injecting insulin is the hardest aspect of their diabetes care. Feuerstein and his "thought leaders at the American Diabetes Association" evidently failed to take notice.

In Feuerstein's newer article, he quotes my prior claim detailing how he was wrong in stating that there have been no peer reviews focused upon Oral-lyn's studies and that that the company has not presented buccal insulin study data at various top flight diabetes conferences. He makes no mention that TheStreet admitted his errors. Feuerstein continues by remarking upon my citation of the most recent peer review published related to Oral-lyn (February 2010 edition of Diabetes, Obesity and Metabolism), authored by two of the independent clinical study investigators who have led Oral-lyn human research studies. The authors are Dr Paolo Pozzilli and Dr Philip Raskin, and the title is "Review of Clinical Trials: An Update on Oral Insulin Spray". Dr Pozzilli has studied Oral-lyn buccal insulin in multiple Phase II studies of Type 1 diabetics and Type 2 diabetics, as well as those with Impaired Glucose Tolerance (pre-diabetics). Dr Raskin is the principal investigator of Oral-lyn's current worldwide Phase III trial for treating Type 1 diabetics.

In the report, they state that on "all of the studies conducted, the oral insulin spray was generally well tolerated", that the "ease of use of the insulin spray formulation may increase patient acceptance and treatment compliance, thereby potentially reducing complications and improving quality of life for patients with insulin-dependent diabetes" and in "all of the studies discussed, results showed that oral insulin spray was absorbed in direct relation to the amount given and had a faster onset and a shorter duration of action when compared with SC regular insulin". They further state that this "fact alone would seem to make the oral insulin spray an ideal candidate for prandial glycaemic control" and that "ease of use of the insulin spray formulation may increase patient acceptance and treatment compliance, thereby potentially reducing complications and improving quality of life for patients with insulin-dependent diabetes".

Feuerstein charges the article actually demonstrates quite clearly the lack of any credible clinical data to support the insulin spray's efficacy or safety. He is quite confused and his research into Oral-lyn's development is noticeably weak. Feuerstein remarks how Drs Raskin and Pozzilli, in the discussion section of this particular review, write that a key limitation to this review is the lack of studies that compare oral insulin spray with rapid-acting analogue insulin; none of the published studies (to date) have provided this comparison. This particular review does not provide a complete overview of all of the buccal insulin studies that Generex has presented at various top flight diabetes conferences. I believe this fact eludes Feuerstein, whose statements and follow up comments document his ignorance that studies have been completed comparing the activity and efficacy of Oral-lyn versus newer insulin analogues to aid in providing a more robust assessment of the clinical utility of the oral formulation.

Escaping Feuerstein's research is the study comparing Oral-lyn to meal time analogue insulin, co-authored by researchers from the Institute for Endocrinology IEMYR, Quito, Ecuador, and the University of Florida, Gainsville. The year-long Oral-lyn study examined 26 subjects with type-1 diabetes. Members of the control study group received insulin glargine (an insulin analogue) once a day as their basal dose, and a faster-acting insulin analogue before meals. Members of the treatment group received a non-analogue long-acting insulin twice a day as their basal insulin; before meals they took Oral-lyn, a rapid acting liquid version of human regular insulin, that is absorbed through the lining of the mouth. Study results illustrate the rapid onset of action and superb glycemic control of Oral-lyn as compared to the analogues. "When Oral-lyn is absorbed through the buccal mucosa, its rapid entry into the blood stream mimics and improves upon the rapid acting analogues", commented Dr. Jaime Guevara, a study author and clinician that has conducted studies for Generex's Oral-lyn.

Feuerstein's article was published by TheStreet in his Biotech Stock Mailbag column on March 26th, and first appeared on financial and stock oriented web pages at 7 am. That same morning, Feuerstein posted on his Twitter page that "another body blow delivered to GNBT today in this week's Biotech Stock Mailbag". The entry time listed on his Twitter page was 4 am (see here), however the time zones may vary. The comment about a "body blow to GNBT" is juvenile and questionable. I believe that the body blow was delivered to the self serving biotechnology journalist that is heavy on clamor, and absent of intelligent or accurate analysis.

In summary, Feuerstein alternates from comparing apples to oranges, and at all times appears completely uninformed. He apparently is unaware that there is Oral-lyn data from Italy, England, Israel, Canada and the U.S. from earlier (pre-Phase III) trials, and erroneously states the data is only from a couple of small studies conducted in Ecuador. Perhaps in his next article, he can wisely contact Dr. Gerald Bernstein at Generex, who is the expert on Oral-lyn's utility and development. An ignorant opinion can not be disguised as professional analysis. In my opinion, if this type of commentary is indicative of the quality of the content in TheStreet, biotechnology and pharmaceutical minded investors should look elsewhere.