Not Hype, EVIDENCE of Hope!

It's not every week that there are so many "good things" (as Martha Stewart likes to call them) in the news when in comes to diabetes. First, it's worth noting that earlier this week, the New Zealand government voted to allow a small, well-regulated clinical trial involving the transplantation of pig beta cells (xenotransplantation) by Living Cell Technologies (LCT) to proceed in that country. LCT has already undertaken Phase I Human Clinical Trials in Russia, and the preliminary results of those trials were revealed earlier this year. The results showed noteworthy reductions in daily insulin requirements ranging from 23% to as much as 100%, and very good control of blood glucose levels in 80% (4 out of 5) patients.

But as recently as 2005, the New Zealand Medical Association (NZMA) warned that a deadly virus transmission through this pathway could potentially kill millions of people, although LCT says it can limit risks by using tissues from piglets in a special breeding line said to have been isolated from other pigs for over 150 years on the Auckland Islands. Many of the concerns expressed were unsubstantiated by scientific evidence, rather they were simply concerns. The approval by New Zealand authorities will enable the next phase of human clinical trials to be undertaken under the close watch of a highly-regarded, Western regulatory agency and thus serves as a landmark of sorts. Company founder David Collinson said the $2M, two-year trial would kick off at Auckland's Middlemore Hospital with 8 patients in February 2009.

In response, Alastair (Al) Gordon of the Islet Foundation wrote:

"This decision has the potential to make New Zealand a biotechnology leader of the new millennium. The restoration of normal blood sugar control to people with diabetes will dwarf the discovery of insulin by Banting and Best over eighty years ago. The same technology used in this trial also has the potential to advance the field of tissue transplantation, raising the possibility of transplanting tiny quantities of cells rather than whole organs, and ending the lifelong regimen of toxic, expensive immune-suppressing drugs that often ravage the bodies of transplant recipients. The benefits to families, to the national treasury, and to the intellectual capital of your nation will be immense.

On behalf of the millions of people who live with juvenile diabetes, I am honoured to offer our thanks and our support for this historic decision."

This is indeed very good news for those who would like to see research progress on islet transplantation, which has been aggravatingly slow and often delayed by what is seen as unnecessary government intervention (which critics argue pharmaceutical companies seem to regularly bypass all the time with almost no consequence). In fact, the FDA is in the process of revising its guidance on diabetes treatments and also had some perspective on islet transplantation which I wrote about this summer. In essence, the FDA's guidance was based on old information and limited trials to a finite universe of people, rather than a broader pool of potential people.

In another development, today, SmartCells, Inc. (whose company CEO I interviewed a few years ago) announced a partnership of sorts with the Juvenile Diabetes Research Foundation (JDRF) to advance SmartCells' SmartInsulin™ for the treatment of type 1 diabetes. Unlike an expensive, artificial pancreas which fuels a costly medical supplies industry and obliges patients to wear unattractive, burdensome external equipment and will require costly supplies for perpetuity, SmartCells is different. Assuming the company continues down its thus-far successful path, SmartInsulin will be a once-a-day, glucose-regulated subcutaneous insulin formulation for treating diabetes. SmartInsulin is injectable, like today's currently available insulins, but designed to maintain continuous, tight control of blood glucose levels while largely eliminating the risk of hypoglycemia. As part of the agreement, JDRF will provide $1 million in first-year funding to support preclinical safety and efficacy testing. The partnership is structured to support milestone-based funding through proof-of-concept human clinical trials. Although exact terms were not specified, it could also pave the way for non-exclusivity agreements assuming it successfully meets the milestones outlined, meaning that JDRF could step in to assure that the product is not necessarily granted to a single, greedy insulin manufacturer in much the same way that insulin's discoverers Banting and Best gave the discovery away to make it more widely available and affordable to many.

If these news items weren't enough, I thought I would share a widely-cited (in the drug industry, anyway) chart that was created by the Boston Consulting Group:



The content in red are events I have added to the chart to show some of the key developments (there aren't that many) relative to type 1 diabetes treatments. According to this observation (as you can see, most of it is retrospective), we stand on the edge of a new era in medicine and pharmaceutical development, and top on that list are treatments to address the core issue of autoimmunity, a group of some 80+ diseases (including type 1 diabetes) which have largely been poorly addressed by the medical profession, largely treating the symptoms of these ailments rather than the disease itself because medicine lacked the knowledge to effectively intervene. But you can see that around 2010 (less than 2 years away), the next "wave" of drug development is expected to emerge. Obviously, the timing may not be precise, but there IS ample evidence that this trend is already underway. Listed here are some very concrete examples of autoimmunity treatments now in various stages of human clinical trials:

1. The 2007 Eli Lilly & Co./Macrogenics partnership facilitated by JDRF last year to produce immuno-modulation treatments with monoclonal antibodies already proven in clinical trials. The main issue is that while trials in Europe proved successful (treatment with anti-CD3 monoclonal antibodies) in arresting the autoimmune attack on the pancreatic beta cells, at present, no pharmaceutical or biotechnology companies manufacture these treatments, meaning it only happens in a clinical trial setting. But with a big drug company behind the product, we are likely to see much more muscle in getting the product to market.

2. Less we overlook it, no autoimmunity research list would be complete without acknowledging the BCG trials now being undertaken at Massachusetts General Hospital using Denise Faustman's concept. There are no guarantees, of course, as BCG is not the same as Freund's Adjuvant (the treatment used on Dr. Faustman's mouse trials), but the researchers believe this drug (which ironically enough, is already an inexpensive generic drug) will have the same impact. Only the trials will answer this question, but it too could address the root-cause of the disease: autoimmunity.

3. In addition to these elements, we have seem some progress being made with INGAP (which stands for Islet Neogenesis Associated Protein) in islet regeneration, and INGAP has already undergone several phases of clinical trials successfully. While much of the initial progress took place at the Eastern Virginia Medical School under the leadership of Dr. Aaron Vinick, the next phase of work appears likely to occur with the co-discoverer, Dr. Lawrence Rosenberg who works at McGill University in Montreal. Thanks to the generosity of some wealthy Canadians, Dr. Rosenberg has funding to conduct some of the additional research needed to advance this therapy to the next level. The initial theory behind the trials was kind of like trying to fill a bucket with holes in it full of water. As long as the rate of water flowing into the bucket is greater than the rate which water is flowing out, then the idea was that INGAP might have worked as a treatment by itself. While INGAP was proven to regenerate islets, the autoimmune element remained a problem in patients with type 1 diabetes, and the autoimmune response was underestimated. So the researchers next move is to combine INGAP with some kind of immuno-modulation therapy. In this case, they have decided to trial lisofylline (LSF). In May 2008, a partnership was announced regarding the next phase of trials (see here for details). A Phase 2 human clinical trial with the new combination therapy, consisting of DiaKine's
Lisofylline (LSF) and Kinexum's INGAP peptide, is expected to begin in late 2008.

4. Not to be overlooked is DiaPep277®. This treatment has changed hands repeatedly over the last decade, having once belonged to insulin maker Sanofi Aventis, which explains why this product has yet to be commercialized. But last year, Israel's pharmaceutical giant (also the world's largest generic drug manufacturer), Teva signed a deal to commercialize DiaPep277 along with partner Clal Biotechnology Industries Ltd. DiaPep277 is a synthetic peptide of 24 amino acids derived from the sequence of the human heat shock protein 60 (Hsp60). The peptide modulates the immune system that leads to autoimmune diabetes by diminishing or blocking the destruction of beta cells by the immune system. In essence, the drug performs a very similar function as MacroGenics' anti-CD3 monoclonal antibody treatment: stopping the immune system attack on the pancreatic beta cells. The backers note that treatment of type 1 diabetes patients with DiaPep277 may have several medical benefits including prevention of deterioration of disease, improved metabolic control, reduction of diabetic complications and reduction of daily insulin dose requirements.

Based on the phase II clinical trials, a phase III clinical trial at 40 sites in Europe, Israel, and South Africa was designed and is currently being conducted. The study involves 400 patients which includes adults and adolescents for a treatment period of two years. An interim analysis was performed on 137 patients who completed 12 months of treatment, of which 100 of them completed 18 months of therapy. An Independent Data Monitoring Committee (IDMC) carefully reviewed the findings from the trial and recommended proceeding with the study as originally designed. The results showed that no significant drug related adverse events, serious adverse events or lab abnormalities were reported and that there are no safety concerns in continuing the study. In the study, it was observed that when comparing a population similar to those who participated in the phase II studies, the effect of the drug was similar. The observed trend of the effect may become more significant once a larger sample size is analyzed.

It was recommended to test a larger number of patients to confirm the effect observed in the current analysis. In addition, it was recommended to proceed with the study without ANY changes to the design and continue the enrollment of new patients, so we should see more coming on this treatment in the next few years!

5. The profits for insulin and analogues are enormous, and on September 26, 2008, Novo Nordisk A/S updated its corporate strategy at its Capital Markets Day. Essentially, it was a dog and pony show for investors. There are a number of presentations which you may review and/or download for future reference -- to see them, visit http://www.novonordisk.com/about_us/download-center/dowloadcenter.asp (2008) and click on "Capital Markets Day". Novo talks ad nauseum about the next generation of insulin analogues whose primary benefit is not an elimination of hypoglycemia, but being weight-neutral which the company sees as key to converting millions of type 2 patients to insulin therapy, and its other type 2 drug liraglutide (to carry the brand-name "Victoza") which the company has released endless streams of press-releases and studies which show only marginal benefits over rival Byetta. Ironically, the company did not even note that they opened a research facility near Seattle, Washington (USA) this summer specifically to pursue developing autoimmunity drugs meant for type 1 diabetes (they call them "inflammation" drugs). This is because Novo presently has nothing in its pipeline, but needs to get moving or they risk being left behind. They are undoubtedly trying to reassure investors that their insulin and Victoza will carry the company, and the reality is that Novo simply cannot afford to ignore autoimmune treatments because if any of them works, it really spells the end of its insulin business (75% of insulin users have type 1 diabetes). You can catch my write-up on Novo's Seattle investment here and here.

6. Finally, this week, researchers in Boston revealed a protein made by the liver in response to inflammation and used to treat patients suffering from a genetic form of emphysema has been shown to restore blood glucose levels in a mouse model, according to a new study led by researchers at Beth Israel Deaconess Medical Center (BIDMC). Mice models do not automatically translate into human success. This research adds a new finding which suggests that autoimmune treatments alone may not be sufficient.

"To cure Type 1 diabetes, it will not be enough to halt the destructive T-cell-dependent autoimmune attack on beta cells," explains the study's lead author Maria Koulmanda, PhD, Director of Non-Human Primate Research in the Transplant Center at Beth Israel Deaconess Medical Center (BIDMC) and Associate Professor of Surgery at Harvard Medical School (HMS). "We think that it will also be necessary to restore proper insulin signaling, and the way to do that is by eliminating the curious inflammatory state that exists in muscle, fat and other insulin-sensitive tissues."

Look for more research on this to emerge in the coming years!