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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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Wednesday, November 18, 2009

How Generex can win over Mannkind

As biotech companies and large pharma embark on paths to usher in more effective diabetes drugs to market, one of the more significant concerns regarding diabetes related drug development is safety. The FDA has increasingly issued new alerts from previously approved drugs such as GlaxoSmithKline's (GSK) Avandia, Eli Lilly's (LLY) Byetta and Bristol-Myers Squibb's (BMS) Onglyza while deciding whether the safety risks of new drugs such as Novo Nordisk's (NVO) Victoza and Mannkind's (MNKD) Afresa have benefits to outweigh the safety risks. In thinking of Afresa, most insulin drugs have mainly been regarded as safe by US drug regulators, however Pfizer and inhalable insulin attracted an inordinate amount of scrutiny and requirements of pulmonary testing and Phase IV monitoring. Also in June, the FDA said it is reviewing data on the safety of Sanofi-Aventis's (SNY) popular Lantus insulin over highly publicized and inconsistent cancer findings.

There has only been one new diabetes related drug that has risen above the questions of whether the risk of taking the drug has outweighed the positive effect of its intended claims. That new drug is Generex's (GNBT) buccal insulin Oral-lyn. The most obvious example of the proven safety profile of Generex's buccal insulin came this past September when the company announced the FDA granted approval for the Treatment IND usage of Oral-lyn buccal insulin under the FDA's Treatment Investigational New Drug program. Drugs that are granted approval by the FDA for the Treatment IND program must demonstrate the prospect of efficacy through clinical testing without the concern for safety issues that call any benefit into question. Generex's Oral-lyn is the only developmental drug intended to treat diabetes that has ever been approved in this special access program. This is a noteworthy achievement for Generex's regulatory team, led by Mr. George Markus, which also illustrates their ability in successfully communicating with the world's most stringent regulatory body.

The unique safety profile of Generex's buccal insulin stands apart from other new diabetes related drugs both in development and on the market. In particular, I will focus upon Mannkind's inhalable insulin Afresa since these two are the most advanced oral insulin drugs and as such offer the greatest glucose controlling effects as opposed to any other type of offering from the pipelines of large pharma. Generex's Oral-lyn may well be the only new diabetes related drug in development that has never had a serious adverse event due to its usuage in any study to date. In March 2009, Generex reported preliminary Type 1 Phase III results for Oral-lyn buccal insulin where they stated "non-inferiority to injectable meal-time (prandial) insulin appears to be maintained". This was in alignment with previous Phase II studies, where in2007 clinical researchers of Generex's Oral-lyn found "a superior effect of Generex Oral-lynover subcutaneously injected regular insulin" and in 2008 that a "regimen consisting of basal BID s.c. NPH and prandial orally-absorbed regular insulin (Generex Oral-lyn) attained lower pre-meal glucose, HbA1c and Fru concentrations, than a regimen using basal and pre-prandial insulin analogue injections in Type-1 DM during a 372-day period."

In an article titled "Review of clinical trials: update on oral insulin spray formulation" to be published in Diabetes, Obesity and Metabolism this January and which has recently been made available early online, the two main researchers of Oral-lyn buccal insulin provide an update of the detailed clinical findings supporting both efficacy and safety. One of the authors is Dr. Paolo Pozzilli, Head of the Department of Diabetes and Endocrinology at University Campus Bio-Medico of Rome and he has been studying the pharmacokinetic and pharmacodynamic effects of Oral-lyn since the earlier studies in the beginning of this decade. The secondary author is Dr. Philip Raskin, who is also a highly regarded diabetes clinical author and researcher who serves as MD of The University of Texas Southwestern Medical Center at Dallas and is the principal investigator of Oral-lyn's Phase III trial.

In the pending article the authors state that 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. This fact alone would seem to make the oral insulin spray an ideal candidate for prandial glycaemic control." The efficacy of Oral-lyn, a liquid formulation of human regular insulin that acts more like an analogue version of meal time insulin, has been proven in all studies to date. The authors continue to say that the "oral insulin spray is a tasteless liquid aerosol mist formulation" and that "on all of the studies conducted, the oral insulin spray was generally well tolerated." They conclude by stating 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."

Proving the commercial viability of a new drug in development is sometimes more difficult than establishing clinical efficacy and safety. Both Generex's Oral-lyn and Mannkind's Afresa have shown success in clinical trial settings. Mannkind has studied Afresa in far more patients than has Generex for Oral-lyn, but recently Generex's partner in the India market, Shreya Life Sciences, has presented a Phase IV study conducted in various sites for Type 2 patients. The results for the first time speak of the commercial appeal oral insulin may bring to insulin dependent diabetics. This is an example of the Type 2 market that has eluded the major insulin analogue manufacturers up to this point and this was a prime market which spurred earlier development in oral insulin programs in the earlier part of this decade.

The study was reported at the IDF 20th World Diabetes Congress last month in Montreal and is titled "A 12 week phase IV study of recombinant human regular insulinmetered dose buccal spray on subjects with type 2 diabetes whoare suboptimally controlled while on oral antidiabetic agents". The findings in "40 type 2 diabetic patients on OHA (oral-diabetic agent) who received metered dose buccal insulin spray showed improvement in glycemic control in terms of improvement in HbA1c values (Mean HbA1c value: 7.8% vs 7.3%) and fall in both fasting and postmeal glucose." The efficacy was again proven and a secondary outcome was to monitor "changes from baseline in clinical and laboratory findings and changes in buccal cytology at the end of 3 monthstreatment". The conclusion stated that except "for minorhypoglycaemic episodes, transient burning sensations and transient numbness in mouth, no other adverse effects were observed". This Phase IV, in India and conducted by Generex's regional partner, again affirmed the unique safety profile to set aside any questions of safety and which again highlighted the potential role Oral-lyn will have in controlling post-prandial hyperglycemia. The Phase IV results also stated that "recombinant human regular insulin metered dose buccal spray (Generex Oral-lyn and known as Oral Recosulinin India) appears to be well tolerated and highly preferred by patients." It continued to say that Oral-lyn "had high acceptability in patients". When have you ever heard Type 2 patients that were not yet treated with insulin therapy to say they actually "preferred" insulin?

With no safety issues in over 10 years of trials and the FDA recognizing both the reports of efficacy and the unique safety profile, it is no wonder Drs. Pozzilli and Raskin remarked in regards to Oral-lyn's onset and duration of effect that this "fact alone would seem to make the oral insulin spray an ideal candidate for prandial glycaemic control." Mannkind's Afresa has also had positive efficacy data, and while it has been studied in a far greater amount of patients it has not enjoyed the level of post-prandial hyperglycemia control as has been reported to Oral-lyn. Afresa lingers in the bloodstream longer than what investigators have found for Oral-lyn. Oral-lyn is available as a 1 UNIT per spray dose, while Afresa comes in two larger dose sizes, so while Mr. Mann claims no titration is needed with Afresa inhalable insulin, a diabetic that finds him or herself eating an unplanned piece of chocolate cake one or two hours post meal may find his glucose levels do not agree. For Oral-lyn, the delivery devise is built to provide fine tuning post meal dosing. It is as simple as taking another quick spray. While with Afresa, this part of the equation appears much more complex. Mannkind executives insist this is not the case, and I will leave it to them to convince skeptical diabetics and their endocrinologists.

I do not believe physicians and diabetics have similar reason to have confidence in the safety profile of Mannkind's Afresa as they will with Generex's Oral-lyn. And here is where I would like to deeply explain my thoughts. The reasoning is more complex and goes beyond Mannkind's inhalable insulin to the ill effect diabetes already plays upon the lungs. I recall a study which was published in the April 2008 issue of Diabetes Care titled "Cross-Sectional and Prospective Study of Lung Function in Adults With Type 2 Diabetes". The main author, Dr. Hsin-Chieh Yeh, presented findings showing that lung function in people with diabetes decreased at a more dramatic rate than in people without the disease. The data supported previous evidence that the lung is vulnerable to diabetic complications. The results of the study showed that "at baseline, adults with diabetes had significantly lower predicted FVC (96 vs. 103%, P < 0.001) and predicted FEV1 (92 vs. 96%, P < 0.001) than those without diabetes."

In an accompanying article, Drs. Philip Raskin (yes, the same Dr. Raskin I mentioned for Oral-lyn) and Connie Hasia wrote that the study by Dr. Yeh "serves to further enhance recognition of the lung as a target of diabetic injury." They ask why should this issue matter to patients and physicians? They reason to "think of the lung as a crime victim who unwittingly abets the perpetrator to hasten the demise of the host." I will footnote the study and article because Drs. Raskin and Hasia express perceived strengths and weaknesses within the study design. However, they explain there is a solid body of literature from the 1980s and 1990s which "established the occurrence of ventilatory restriction in type 1 diabetes" as well as cumulative data which demonstrates "a pattern of modest lung restriction in type 2 diabetes qualitatively similar to that in type 1 diabetes".

Drs. Raskin and Hasia point to the findings in a Pfizer Exubera study that showed "chronic use of inhaled insulin could potentially trigger or exacerbate pulmonary dysfunction. Though shown to be efficacious and well tolerated, inhaled insulin has also been reported to cause a small early drop in spirometry and DLCO at rest that did not progress during 2 years of follow-up". They continue in their mention of Exubera by stating as "inhaled insulin products continue to be developed, the spectacular collapse of Exubera notwithstanding, the issue of their potential impact on lung function will linger." The Footnote section of the article reveals that Dr. Raskin "is a member of a scientific advisory board for Novo Nordisk and has received research grants and/or honoria from Novo Nordisk, Pfizer, and MannKind."

At the EASD conference this past Fall, Mannkind presented an abstract titled "Pulmonary functions (over 2 years) in diabetic subjects treated with Technosphere insulin or usual antidiabetic treatment". The conclusion of the abstract stated that "small declines from baseline in PFTs were observed in diabetic subjects treated with TI and UC and also in subjects without diabetes. Observed differences between TI and UC groups in the change from baseline in FEV1 and DLCO were small, noted at the first post-baseline assessment visit (3 months) and thereafter remained non-progressive over 2 years of continuous therapy."

However, the abstract noted that the "annualized change in FEV1 between 3 to 24 months was -0.047 l/year for TI-treated subjects" (comprised of Type 1 and Type 2 patients). The UC comparator group (UC meaning usual antidiabetic treatment) had a change in FEV1 between 3 to 24 months of -0.036 l/year. Highlighting the data, we see Mannkind reporting an annualized change in FEV1 -0.047 l/year in Afresa subjects and -0.036 l/year in usual antidiabetic treatment patients. A previous Exubera study presenting findings for a group of Type 1 patients showing annual rates of change in FEV1 between months 3 and 24 were −0.041. Other published studies showAsthma patients with annualized change in FEV1 -38ML/Year and healthy persons with annualized change in FEV1 - 22 ML/Year.

The populace design of these studies should also be monitored since it is known that different ethnicities have lower average FVC and FEV1 results. For example, the 1999 study titled "Spirometric reference values from a sample of the general U.S. population" by Dr. JL Hankinson et all (source 6) presented clear results that FVC and FEV1 levels are lower in African Americans than in Caucasians after adjustment for sex, age, and height. Mannkind's press releases aside, I believe many feel there is not yet adequate proof that Afresa will not have a significant negative effect on pulmonary function in Type 1 and Type 2 diabetics.

Reports of the efficacy of Afresa do not outweigh the apparent need to study the potential ill effects of their version of inhalable insulin over a much longer period (+ 10 years) of time. If we listen to Drs. Raskin and Hasia and vision the lung of a diabetic "as a crime victim who unwittingly abets the perpetrator to hasten the demise of the host", is it wise to develop diabetic preventative medicine which is adminsistered into the body in a fashion which may eventually be found to accelerate this rate of pulmonary function decline? If long term usage brings the negative effects that some fear, Mannkind may as well shape the Dreamboat device with a push button shaped like a trigger.

Quite often the simplest solution to a problem is the best. There is no debating the horrendous effects the diabetes pandemic plagues upon our society. For those living with the complications caused by diabetes, or those who love those afflicted, we can only hope that all novel treatments that provide a friendlier and more natural way to manage the illness not only survive but thrive. My own interest stems from the overwhelming compliance issues that my sister battled daily. From earlier social issues that spawned bouts of bulimia to a fear of needles coupled by a sense of weakness a life term on injections represented, she resented the needles no matter how fine the tip or convenient the pump. She matured, but the damage was done. She now lives free of multiple injections. The payoff was a kidney transplant from my father and the pancreas of a teenage boy who died in a car crash and who was heroic in filling out an organ donor card. Life is no longer simple, since her vision is tunneled and her feet have no feeling. The doctors keep a close watch on her heart and other organs. As the transplanted pancreas is now within her for a few years, there may soon be a time when it is in need of an assist before teetering out. At that point, she has told me she will seek out Generex's Oral-lyn.

After all this time, Susan still hates the thought of needles. One aspect is that her skin is very, well, frailsh and weak. So is her body, although her spirit is strong. At this stage, could her lungs take a few years of any inhalable insulin, or is that a question that is silly to even ask? I believe it is out of the realm of possibility, and she has no need to risk another organ as her doctors monitor many others. The FDA delved deeply into Generex's Oral-lyn data in a timeframe when they are telling all other diabetes related developmental companies to stay in the clinic and bring more data. For Generex, they said bring the patients this new safe insulin drug and approved their only ever diabetes Treatment IND.

Disclosure: The author is long GNBT and has no position in MNKD.