R.J Steffens

Oral-lyn vs. Afresa: How Generex Will Beat Mannkind

Bob, your link to the EASD abstracts is what I am speaking about in the articles. What I am concerned about is what happens to lung function after years of chronic usage of this or any inhalable insulin? Mannkind is vying for approval of Afresa and the MedTone device, and wishes to change from the MedTone to the newer Dreamboat. These abstracts are for the MedTone device and I understand decreases in FEV1 return to levels typically seen in diabetics "3 months after cessation" (discontinuing) of Afresa treatment. That bodes well in a sense because there are no structural changes within lung tissue at that point. But long term chronic usage without cessation? A diabetics lung function decreases faster than a healthy person. Diabetes is attacking even this vital organ and insulin treatment, unless new advances come along, are a lifetime burden.

Also, with the Dreamboat device delivering the insulin powder deep into the lung at a better rate than the MedTone, are the previous studies with MedTone relevant? Since Mannkind believes (and I agree they have a reputable team) a short bioequivalance study is all that the FDA may require, the answer very well may be yes. And then time will tell the true tale.

PS. The links in the SA articles about Oral-lyn lead to previously accepted ADA Scientific Session abstracts. I believe you when you say you "have no interest in learning much more about" Generex or Oral-lyn. Before you can learn more about a new drug, you may want to actually begin. To help, the reason the Phase III trial is vs. regular human injectable insulin is due to the fact that this is the main protocol required of developmental prandial insulins to gain FDA approval- with establishment of A1C non-inferiority being the main endpoint. And Generex's Oral-lyn IS a liquid formulation of human insulin. Buccal insulin is a very fast acting human insulin with a short duration of effect. One reason it is so fast has to do with the usual hexamer is broken up into monomers during the formulation process. So while this is a human insulin, it acts more like an improved version of a meal time analogue. The short acting nature of Oral-lyn, which is shorter than even Afresa, is the reason it carries less risk of hypoglycemia than anything currently on the market today.

For anyone, in contrast to Silent Bob, that wants to learn more about Oral-lyn they can view this PDF by Dr Gerald Bernstein from a few years back:

www.iptonline.com/arti...

Or listen to his latest broadcast on Health Radio when, or after, it becomes available on November 23rd:

healthradio.net/compon...

I am glad we helped Bob get over his silent problem.

Oral-lyn vs. Afresa: How Generex Will Beat Mannkind

sstrumello: "For the type 2 universe, I question that, as a large majority of insulin-using type 2's take basal insulin only, usually Lantus or Levemir. Is that going to make Oral-lyn (or Afresa) a hit with that group?"

Hi ss. A fast acting prandial insulin with a friendly and non-invasive delivery device is going to compete not only with other meal time insulins, but with the new class of type 2 oral pills. We read about safety issues concerning Avandia and Byetta every week, and what the developers of Oral-lyn will hope to see is some of those patients switching to their insulin. But as for basal control, no, that is not what Oral-lyn or any prandial insulin provides. I believe they are at the early stages of developing a buccal basal insulin, but they haven't made any formal announcements in that area.

ss: "you seem to blatantly neglects the fact that the draft guidance for the pharmaceutical and biotechnology industry issued by the FDA last year for "Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for Treatment and Prevention" was, after public comments, revised to address ONLY type 2 medicines."

I didn't mention the latest FDA draft guidance in this article. But I am very aware of the guidance and wrote about it in another article concerning Oral-lyn and Afresa (TI): "In general, the FDA wants companies to exceed previous expectations considering the growing diabetes population and the increased complexity of treatments, but it will be an absolute stickler with those drugs exhibiting serious side effects."

seekingalpha.com/artic...

ss: "therefore the final guidance released was only for type 2 drugs, therefore insulin was excluded."

No, a section of the report focused on inhalable insulin. That is also a reaason we see more patients enrolled in trials for certain drugs such as Afresa, or a type 2 oral pill with safety concerns. Those safety issues are not as dramatic in studies of buccal insulin.

ss: "If a company wants to succeed in selling insulin, they absolutely MUST reach the type 1 audience, and so far, Generx is ignoring that group, just as Pfizer did with Exubera."

No, that is the group Generex is targeting. They are vying for approval of Oral-lyn in Type 1 diabetes before they make a submission for Type 2 patients. Although, through the FDA approved Treatment IND they are providing Oral-lyn to the full spectrum of diabetic patients in the US.

Oral-lyn vs. Afresa: How Generex Will Beat Mannkind

Silent Bob: "Their other studies are usually not comparing versus other insulin"'

Hi Bob. That is simply not true. If you click on the links in the article you can see a couple exmaples, and it would also not be hard to do a little dd in finding many other trials vs. injectable meal time insulin.

Silent Bob: "They did not even have the guts to take on rapid acting insulin, probably because they knew Oralyn is inferior to rapid acting insulin."

Try this Bob: "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 liquid formulation of regular human insulin, developed by Generex, that is absorbed through the lining of the mouth. Study results consistently and clearly 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."

seekingalpha.com/artic...

Silent Bob: "The author says a lot of nonsense about Afresa but I don't think I should write about that again."

I have been following and writing about these companies for a few years. I admire Mr. Mann, but in making my case I tried to present a thoughtful reasoning on why I feel adding an inhalable insulin to a diabetic patients is problematic since it has been shown that their lung function is already decreasing at a more dramatic rate than in people without the disease. I sited research that reported these findings, but I can understand why you would not want anyone to mention the subject again. When you state the Generex is a trainwreck, when in reality the are a small biotech R and D with a very promising pipeline of diabetes and vaccine candidates it sounds as if you are more concerned with the performance of a stock while I am focused on the potential of the drugs. To say that "GNBT is scamming investors" tells us more about you than it does about Generex. Best of luck in your investment.

Big Pharma: Where's the Risk Management?

On Jul 07 06:58 PM upndown1313 wrote:

> Sorry not impressed, either with oral-Lyn data that has been presented or the concept of a metformin chewing gum. Based on PhII results, PhIII will not get approval fro Oral-Lyn.
**********************...

Recent Oral-lyn Phase II results:

ADA Scientific Sessions 2008 "Insulin Analogue (Basal + Pre-Prandial Injection) vs. Human Insulin (Basal Injection + Prandial Oral Insulin (Generex Oral-lyn™) in Type-1 Diabetes Mellitus: A 372-Day Comparison"

Conclusion: "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."

professional.diabetes....

ADA Scientific Sessions 2007 "Comparison of Pre-prandial s.c. Regular Insulin vs Prandial Oral Insulin (Oral-lyn) in Adult Type-1 DM Subjects Receiving Basal s.c. Twice Daily Isophane Insulin (NPH)"

Conclusion: "Near normalization of parameters of DM metabolic control was achieved in all subjects. Direct comparison of HbA1c concentrations during CP demonstrate a superior effect of Generex Oral-lyn™ over subcutaneously injected regular insulin."

professional.diabetes....

"It is not like the inhaled insulin, so it doesn't get into the lungs,” said study investigator Philip Raskin, MD, professor of medicine at The University of Texas Southwestern Medical Center in Dallas. “People seem to like it, and it does seem to lower the blood sugar [the way] it is supposed to.”

Dr. Raskin is among the researchers involved in an international phase 3 study of 750 patients.

www.renalandurologynew.../

Genentech and Generex: New HER2/neu Research

"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."

Results of the Phase II are not expected for some time, but I just found an early indication that appears in an upcoming peer review from the CVDP. It is part of the final paragraph in this 8 page article:.

Expert Opin Biol Ther. 2009 Jan ;9

CD4(+) T cells in antitumor immunity: utility of an Ii-Key HER2/neu hybrid peptide vaccine (AE37).

"Based on early observations of patients enrolled in our Phase II AE37 trial, we are confident that this Ii-Key hybrid peptide will effectively stimulate an HER2/neu-specific immune response and will be an important component as we move forward with our plans to develop a multiepitope vaccine."

lib.bioinfo.pl/auth:Pe...

Four Drug Companies Vying for Diabetes Patients

Hi GreenClay,

Generex has conducted dose-response studies on their buccal insulin spray. Their patented Rapidmist delivery device has been found to bring precision dosing where each spray measures approx 1 Unit- of Oral-lyn human insulin from the first spray to the last. This allows for tight titration and is one of the main positive features of Oral-lyn. If you email the company at generex.com, they can send you the published data from the peer review (I believe the report was dated 2005).

There are no pills or syrup this far along in Phase testing. Oramed and Biocon have pills that are in very early Phase IIa, and one has a pill whose dose measures 8 mg and the other measures 10 mg. Both have tested their pills in a small handful of patients. I have followed both, and Emisphere also has promising platform technology, but has had difficulties in translating their research into a successful pill form.

Exubera was also measured in mg, and not the unit that diabetics, such as yourself, are familiar with. Their dosing was confusing and one of the many reasons for its lack of success.

An effective oral one unit dose should make things easier to calculate, depending on weight and carbs per meal. The low dose aspect would be a negative if many units are required for certain Type 1's. It is interesting that Generex is set to begin a diabetes preventive trial for those that are pre-diabetic or at risk of developling diabetes. This is similar to TrialNet, and is an area to watch for future developments.

ADA's 68th Scientific Sessions: A New Look at Insulin Therapy

"the downtrend was not accompanied by any vlome to speak of, and that is the only are that is comforting. ;)"

I'll redo that one! LOL. I was watching the Yankee game and typing.

The downtrend was not accompanied by any substantial volume, and that is an area we may draw comfort. ;)

ADA's 68th Scientific Sessions: A New Look at Insulin Therapy

I think part of the problem has to do with the overall state of the market and how that has caused some problems for baby microcap biotechs such as Generex. All of the news coming from Generex has been positive- from new Phase II data for Oral-lyn regarding a one year and 372 day study in Type 1 diabetes to the positive AE37 results that were just published with the USMCI and Walter Reed in the Journal of Clinical Oncology.

If we look at what they are doing in the clinic, which is what is important, we see they have one Phase III (Oral-lyn) and one Phase II (AE37 in breast cancer) underway for drugs targeting diabetes and cancer. Metcontrol Gum will probably be an Abbreviated Submission and their next trial looks set to begin. The wholly owned subsidiary, Antigen Express, also has two Phase I's that are dosing and three other vaccines (AE37 Combo with/and funded by Mary Crowley Medical, the melanoma vaccine with the Mayo Clinic, and the RNAi/Ii-key with Dr. Daopei Lu in Beijing) getting ready for human trials. The HIV DNA vaccine could pop up sometime in late 2008.

But financing also occured a couple of months back that may have added 30 mm shares to the outstanding total, and we will see in the 10K (Oct 2009) what the current OS total equals. That may have augmented the woes seen in the market, because there appears to be no bad news associated with the company or stock. Pending early approvals in the Middle East or Asia (China) for Oral-lyn may sneak up and lift the stock, as well as any other positive developments that the company announces.

Oral-lyn was featured on FOX News Health segment this week with Generex's Dr. Gerald Bernstein (former pres of the ADA):

www.foxnews.com/video2.../

I don't think delisting is a concern, because there is too much positive action occuring in the pipeline. They have 180 days to regain compliance and that should offer them enough room for announcing the type of news that will generate investor confidence. the downtrend was not accompanied by any vlome to speak of, and that is the only are that is comforting. ;)

Generex Biotechnology and the USMCI: Armed with Antigens in the War Against Breast Cancer

I notice that Antigen Express, the life science company that is developing AE37 with the USMCI, has now entered into a collaboration with the prestigous Mayo Clinic in a new trial of AE37 for a melanoma vaccine:

www.primenewswire.com/...

I feel this validates the technology platform of Ii-Key hybirds and reinforces my view that these peptide vaccines may represent aviable therapuetic option in the near future.

ADA's 68th Scientific Sessions: A New Look at Insulin Therapy

There was a link in a posted comment there to an article about the event that I was talking about as being well written. Now I don't see it. That's funny, but I guess I'll now take the compliment to myself. LOL.

Genentech: Britain's National Health Won't Pay for Avastin

"The biotechnology industry counters that they must be paid huge sums for small innovations to promote expensive research. Progress is in slow and steady steps, with very few dramatic breakthroughs. The industry claims that traditional cost-benefits should not apply."

Interesting article, thanks. In a somewhat related note, I wrote an article about two promising peptide based BC vaccines that are in development in collaboration with the United States Military Cancer Institute:

seekingalpha.com/artic...

The peptide vacines mentioned would cost much less than Herceptin or Avastin. E75 has shown survival benefit in a subgroup of a completed Phase II, and AE37 is now in a large efficacy Phase II trial and last week AE37 was also announced that it is to be trialed at the Mayo Clinic for a melanoma vaccine. AE37 is already in a prostate cancer vaccine trial at prestigous St Savas.

Continued success for Col Peoples and these vaccines would be great news, and give her2 expressing cancer patients MUCH less expensive treatment options for safe and effective treatment. These peptide vaccines have had no safety concerns and in the case of AE37, it was the first ever to have a robust immuno response without an adjuvant.

Hence, the "dramatic breakthroughs" may come from the smallest of companies, whose research is attracting the greatest of collaborators. If approved, they would shake up the entire vaccine and oncology field. With much lower projected costs, it should be a new treatment the British National Health Service and our own insurance companies would support.

Generex Biotechnology and the USMCI: Armed with Antigens in the War Against Breast Cancer

My quote: "Antigen Express entered into a Clinical Trial Agreement with HJF"

4th item down: www.hjf.org/research/u...

www.usmci.org/generex....

My quote: "data from researchers at the USMCI also appear to show the potential linking of E75 to a li-Key/HER2/neu MHC class II peptide which brings us to the subject of the other promising therpauetic vaccine in the USMCI's arsenal."

Here is some JUNE 2008 data showing potential E75 and Ii-Key binding: www.ncbi.nlm.nih.gov/p...

My quote: "Earlier this month at ASCO, Generex and the USMCI presented final Phase I data for AE37 in breast cancer / the investigators at the USMCI concluded that "AE37 is the first peptide vaccine derived from a tumor-associated antigen that elicits a robust immunologic response in cancer patients without the use of an immunoadjuvant.""

The ASCO abstract:
www.ascocancerfoundati...

I would bet that Genentech and Glasko pay close attention to the peptide vaccine initiative of Col. Peoples and the USMCI. Antigen Express and Generex are entered into an impressive collaboration.

www.medicalnewstoday.c...

Mannkind: Overlooked Biotech With Excellent Prospects (Part VI)

Daddy One: Upon FDA approval of TI, your eleven year old daughter would have to wait until she is 18 to take this inhalable insulin product. Mannkind is not studying TI on children, and Exubera was not approved for diabetics under age 18. The prevailing thought has been that their young lungs are not well suited for insulin delivery through this vital organ. Many would include adults in this category and that one of Mannkind's marketing hurdles which they will be hard pressed to overcome. It will take many more years of Phase IV testing for this barrier to be put to rest- 'if' long term post approval safety results prove positive. Oral-lyn, the buccal insulin spray that has been mentioned, is also a 'rapid' acting insulin with a short duration of action and has been successfully studied in Type 1 juveniles in 2007.

It appears that your daughter has a good dad on her side, so she is a lucky girl.

Ahithophel Weissberger has done a nice job presenting his opinions. But I don't think the market is pricing in a discount with the thought the FDA will not approve TI. I think the market feels even after approval, TI would require a massive and costly orientation effort and sales potential that do not match the high burn rate and cummalitive losses. Commercial success is not tested in a clinic. Unfortunatly, Exubera did not pave the way for inhalable delivery systems and burned downed the bridge. The marketing and orientation campaigns could restore some of what has been lost in the public percetption, but how much would a potential partner be willing to risk?

The efforts of these companies are impressive and worthy. Watching market reaction to Mannkind's Phase III studies will certainly be interesting. Maybe A.W. is right that this was a good time to buy, and all of the concerns do not matter when you take your POP and run. I'm not sure, and eagerly wait to see what a partner would pay and if one can be found. If I am not mistaken, Mannkind has an unused $500 mm SHELF available. This could help them 'go it alone". But continued dilution is a concern of all biotechs, and especially when the biotech burns close to $70 to $100 mm per quarter.

Thanks for your efforts, A.W. For this reader, you have provided a well written and interesting series of articles in an area I am very interested. Hopefully, in time, we will discuss the many novel insulin delivery options available to diabetics in a new age of care. At some point, those needles will be seen as a very unnatural way to deliver a protein and a relic of the medicinal past. These biotechnology companies, such as Mannkind and Generex, are trying to be one of the solutions and that is a respectable business goal.

Best of luck to us all, and especially the eleven year old diabetic.

Mannkind: Overlooked Biotech With Excellent Prospects (Part IV)

PS. I hope you delve into the GLP1 product. I also wanted to use my real name and step into the light. The psuedos sometimes fall into default and cause confusion. Neither of us are psuedoname types of people. Keep up the good work.

Mannkind: Overlooked Biotech With Excellent Prospects (Part IV)

Hi Ahithophel. You have interesting thoughts and I look foward to your articles. I wrote a few about another biotech- Generex. Terms for a partnership should be more lucrative considering Mannkind has brought Technosphere into Phase III alone. They have done a great job and efficacy seems clear. The main concern to a potential partner would be the odds of success for another "inhalable" insulin and perhaps long term safety issues. All of the data Mannkind presents could show could be very positive, but diabetics and endros may shun another inhalable until time erases doubt. Not all, but a percentage. Right now this large marketing hurdles. That would bring with it a huge orientation and educational need, on top of what already would be needed for any new delivery option.

The regional deals do remind me of Generex's position. They have signed distribution deals with Shreya Life Science in India and Bioton's Sci Gen in the China region. The terms are unique- with the partner paying regulatory costs for submission of approval, marketing, educational and be responsible for sales and distribution. They also provide the insulin crystals used to make their Oral-lyn buccal spray. (Oral-lyn is not an inhalable.) For the US and other large markets, we do not know if a more typical partnership will ensue. Generex has also brought there product to Phase III and for such a tiny firm this was a great accomplishment:

Friday, June 13, 2008

Biomed Notebook
By Ryan McBride
Oral insulin back in Worcester

<In the turbulent business of developing insulin taken orally rather than by injection, a Canadian biotech with R&D operations in Worcester hopes to pick up where such drug industry giants as Pfizer Inc. and Eli Lilly & Co. left off.

Generex Biotechnology Corp., a Toronto-based firm with a 12-person lab in Massachusetts, said last week it has launched a Phase 3 clinical trial of an oral insulin spray. Once seen as a Holy Grail of drug delivery, orally administered insulin has lost some luster because New York’s Pfizer, Eli Lilly of Indianapolis, Denmark’s Novo Nordisk AS have all pulled the plug on inhaled insulin programs in the past year.

No large U.S. drug companies have formed partnerships related to the oral insulin product with Generex — as Eli Lilly did with Cambridge biotech firm Alkermes Inc. — but Generex CEO Anna Gluskin indicated that her firm wouldn’t jump into a partnership without a big payday. “They are the ones that failed,” Gluskin said of Pfizer, Lilly and Novo. “So they really have to look at paying us a lot of money.”>

www.masshightech.com/s...

I hope they ALL succeed and give diabetics the choice they deserve. That would be a welcome change from a prison sentance of needles. It will be interesting to see how this plays out for Mannkind and what kind of terms they could now procure. From the strong efforts of Mannkind to the novel system developed by Generex, a new dawn in diabetic care is near.