2009 Mid-Year Progress Report: Part 1

At the end of 2008, I didn't do my annual review of the diabetes cure-advancement and treatment landscape (you can catch my 2007 summary, my 2006 summary and my 2005 summary), a tradition I began in early 2006 and continued for several years afterwords where I highlight some of the diabetes-related developments (from my perspective, naturally) during the preceding year and share my thoughts and insight into the coming year. Most of my readers know that my observations are far from casual, they are based on a thorough review of these trends for the past year (often more) and have a solid basis to substantiate them. Since we're now more than 3/4 into 2009, there's little point in trying to recap last year, as we'll be ready for a recap of 2009 in just a few months! But I can provide some perspective on where things stand right now, and perhaps frame where they're likely to be going in the foreseeable future.

Let me begin by saying that I had a very good reason for not writing a summary of 2008. I was in the process of moving into a new place. But United Moving didn't do the work for me, I did the move mostly by myself, and mostly when I had free time (meaning on the weekends and evenings). Of course, I still had a job to occupy my time during normal business hours. That resulted in blogging taking a back seat. Although I've since resumed, I haven't posted quite as often as I did, say, in 2005 or 2006 because the Diabetes OC community has grown so much since then that having thoughtful and unique content becomes more important today. Not all of my posts are the cheery, uplifting ones that some readers are necessarily seeking (that's never really been my focus or specialty ... there are plenty of others to fill that need, however), but from my perspective, I DO believe there is good news on cure-related progress to share. The challenge: where do I begin?

Some Good Sources for Research Progress Updates

First, let me share some places you might wish to be aware of related to progress reports. Ironically, I discovered these not from the JDRF website, but largely by accident. But this stuff is worthy enough of sharing with others -- the JDRF "shareholders"!!!

A while back, I have mentioned the Juvenile Diabetes Research Foundation (JDRF) New England project/blog, which had some very interesting presentations from their annual update near Boston this year. In fact, I lifted some of the New England chapter content and inserted it into my aforementioned blog posting. However, a few days ago, I received my college alma matter's alumni bulletin (the Bentley University Observer, page 12, although I found it took a long time to download). Anyway, that contained an interesting article I wanted to share with everyone (I scanned it, and you can download only that page/article here). Apparently, some faculty and students from Bentley were asked by the Bay State branch of the JDRF New England chapter to help create some online audio and video content for that particular blog. As might be expected, the article notes that the JDRF New England chapter's blog has since been recognized by other chapters throughout the U.S. and as an example of JDRF "best practices". We can certainly hope to see more of this type of stuff from JDRF's national organization in the future, and possibly other chapters following this lead, so that's good news indeed!

While some of my blogging peers (Kerri Morrone-Sparling of SixUntilMe.com, Manny Hernandez of TuDiabetes.com and a few others) have already joined, in 2006, JDRF's National organization evidently established a YouTube channel which anyone can join and follow at http://www.youtube.com/user/jdrfonline. That was done without much fanfare, but they've been better about putting some video content which is available to everyone (I don't find the TV commercials all that interesting, but some of the other stuff is).

Now, I could be mistaken, but the photo of the person on this YouTube channel appears to be Aaron Kowalski, who is perhaps best known for his work behind the "artificial pancreas" project, but has also been involved in the SmartCells/SmartInsulin deal signed last year. Anyway, the YouTube channel has some videos from JDRF's 2009 Annual Research Roundtable which took place in June 2009, including a short speech by international chairwoman Mary Tyler Moore, the new CEO Alan Lewis' 2009 State of the Foundation Address, and one from Dr. Richard Insel who is the Executive Vice President of Research for the organization. To the best of my knowledge, this is the first year that JDRF has featured videos of these speeches and presentations. I hope to see much more of this stuff in the future, but this is indicative of progress being made, although much of the work began under previous CEO Arnold W. Donald.

Finally, I would share a blogger who is relatively new to the diabetes blogging scene, Joshua Levy. He started a blog last June which can be found at http://cureresearch4type1diabetes.blogspot.com/. I knew of Josh, who has type 1 diabetes himself, from the Islet Foundation's Public Message Forum, and he is also a member of the Nathan-Faustman Yahoo! Group. Anyway, in the past, I followed his updates via an RSS feed of his Wiki updates/changes which alerted me of changes to his website related to diabetes. But his blog has some groundbreaking content, with the next item listed being a case-in-point.

JDRF-Backed Transition Therapeutics' Islet Regeneration Treatment Looks Dead for Type 1, Perhaps Not for Type 2

I generally share Josh's outlook and his definition of a cure, and although I don't always agree with everything he concludes, I'd say that 95% of the time, I do. Often, Josh has some observations which are well ahead of the public statements made by the JDRF or the researchers (not ALL research is funded by JDRF, even though much is). For example, he concluded (and I agree with him) that the JDRF's Transition Therapeutics islet regeneration treatment (based on gastrin, as Alan Lewis talks about) looks dead, at least for people with type 1 diabetes. See his posting here for more on that. Note that JDRF's 2009 Annual Update (which took place this summer) was still talking about this treatment, but as Josh writes:

"Transition Therapeutics is researching using a combination of two drugs to cause beta cell regrowth in an attempt to cure type-1 and type-2 diabetes. As of May 2009, they had officially marked their phase-I human trial for type-1 diabetes as closed. I haven't seen any published results for it, but I'm still looking. However, actions speak louder than words, and Eli Lilly (working with Transition Therapeutics) started a clinical trial in February 2009 using Transition Therapeutics's TT-223 product, but only for people with type-2 diabetes.

Also, in May 2009 they announced that JDRF and Transition Therapeutics had agreed that JDRF would stop funding clinical development of TT-223. Transition Therapeutics and JDRF terminated their agreement. Eli Lilly is taking over support for TT-223, but is applying the technology only to type-2 diabetes.

So the news from Transition Therapeutics for type-1 diabetics is not good. I will move Transition Therapeutics to my 'boneyard' of research that has not panned out if there is no good news in the next 6 months."

So far, JDRF has been pretty quiet about their decision to stop funding Transition Therapeutics, but unless something changes, we can probably conclude it is dead (at least for type 1 diabetes). For those interested in more background on this, and perhaps its applicability towards type 2, catch a video here for more details.

Exsulin Is Still Progressing

Not to worry on the regeneration front (at least not yet!), however, Exsulin Corp. (the name given to the treatment formerly known as INGAP) announced it's regeneration treatment is entering a second Phase 2 human clinical trial in people with type 1 diabetes (see here and here), so even if JDRF isn't behind this particular treatment, the progress will continue. The good news is that Dr. G. Alexander Fleming, Kinexum's CEO (and former Chair of professional education and training for FDA's Center for Drug Evaluation & Research [CDER] among other things), which is the company behind Exsulin Corp., is among the brightest people in diabetes research and knows this subject far better than most, as he also has intimate knowledge of the Food and Drug Administration, and can therefore help maneuver through this dysfunctional regulatory agency better than perhaps almost anyone else, so we can expect to hear more news from Exsulin in the coming year.

Before I get too far, though, let me take a step back and note that before we can get to regeneration (that's a separate topic I'll address in another blog posting I'll put in Part 2 or 3 of this subject), we need to acknowledge the not-so-little problem of autoimmunity, for which there are several possible treatments in various stages of clinical trials.

Consensus on What Will Be Required to Cure Type 1 Diabetes

Let me begin by acknowledging something that the consensus among most diabetes "experts" seems to be that a definitive therapeutic approach to a "cure" for diabetes will have to include a treatment(s) to control the autoimmune response that causes type 1 diabetes (T1DM) combined with another treatment(s) to replace and/or restore lost pancreatic beta cells, and in the case of type 2 diabetes, another treatment to also address the underlying metabolic defects as well. As a well-known diabetes (she's actually an immunologist) researcher, Dr. Denise Faustman, suggested in an interview with dLife (towards the end of the interview), that she expects it to be entirely possible for several autoimmunity "cures" to emerge although she declined to speculate on when such treatments might emerge. But we're closer today than we have been in decades!

First, I should begin by noting that the JDRF has a graphically-rich page on it's website dedicated to biotechnology and pharmaceutical "Industry Development and Industry Partnerships" that has updates on cure therapeutics which I highly recommend visiting: (click on the JDRF website and from there, select the "research" tab, and select "Industry Partnerships" or simply see click here. Because JDRF has an unfortunate habit of reorganizing it's website leaving some of its links dead, I felt it was useful to provide more detail than I have in the past).

First and foremost, on the autoimmunity front, inflammation is hot!

It's no secret that the drug industry is in the doldrums these days, with many blockbusters whose patents are due to expire soon and nothing much in the pipelines to replace these cash cow blockbusters. But one therapeutic area which seems to very hot these days is in drugs and biotech medicines to treat "inflammation".

Merriam-Webster defines the medical term "inflammation" as "a local response to cellular injury that is marked by capillary dilatation, leukocytic infiltration, redness, heat, pain, swelling, and often loss of function and that serves as a mechanism initiating the elimination of noxious agents and of damaged tissue."

In short, it's an immune response by the body used to heal infections or other ailments. Under normal circumstances, inflammation serves a protective purpose, so it should not necessarily be viewed as a bad thing. Inflammation helps to rid the body of infections and to heal itself, but too much of anything can have the opposite effect, having a destructive rather than protective effect. Both type 1 and type 2 diabetes have inflammation issues which lead to beta cell destruction, although the origins for inflammation in each disease is apparently quite different, as more recent research seems to suggest. At present, approved treatments for inflammation in each disease are mostly non-existent except for a few ailments such as cancer, although others for different autoimmune diseases have also started to emerge. Several aimed at addressing type 1 diabetes are in various stages in development.

Historically, the medical profession has treated most forms of inflammation the same way. The term "anti-inflammatory" usually refers to the property of a substance or treatment that reduces inflammation. In fact, anti-inflammatory drugs make up about half of all analgesics sold (including many over-the-counter products), remedying pain by reducing inflammation as opposed to opioids which affect the brain. Among the more common, over-the-counter ones are ibuprofin (brand names include Advil and Motrin) and naproxen sodium (brand name Aleve).

But this approach, to use a metaphor, is akin to sending out an entire army (using immunosuppresant drugs that largely shut the entire immune system down) to do the job that a single soldier with highly specialized skills could have done alone, and it also leaves patients prone to infections and other illnesses because the effectiveness of their own immune system has been reduced.

During the late 1980's and 1990's, newer research revealed that we could selectively target certain leukocytes (white blood cells) that caused specific types of cancer. The result was a gold mine for the drug and biotech industries, with extremely costly (and lucrative) medicines which seemed to work wonders for a handful of patients as well the bottom line of drug/biotech companies alike! But that business model has run into limits of governments and healthcare providers worldwide and their willingness to pay outrageous sums of money to save a mere handful of ill patients with specialized cancers. Like it or not, one might call this a form of performance-based medicine.

Certainly, an immunologic intervention resulting in an effective modification of the underlying immune process could potentially interfere with the etiology of an autoimmune disease and thereby preserve beta cell function, and/or set the stage for successful beta cell regeneration and/or replacement, or both. Ideally, immunotherapy offered to type 1 diabetes patients could be aimed selectively at salvaging the remaining beta cell mass (if any exists), while also creating a state of "immune tolerance" for the insulin-producing beta cells as immunologists refer to it. (The term "immune tolerance" collectively refers to the safeguards that the immune system naturally possesses to protect from harming self.)

A Newer Approach to Immune Tolerance

In contrast to immunosuppressant therapies which essentially shut the immune system down, immune tolerance therapies are designed to work in a different way. Rather than suppressing the immune system as a whole, these newer treatments aim to suppress only those parts of the immune system responsible for the autoimmune attack (or perhaps prevent it in the first place). The goal is to stop the autoimmune disease while leaving the body's infection and disease-fighting abilities intact.

Although a variety of approaches to immune tolerance have been successful in rodent (or even in some larger animal) models of autoimmune diseases, or in pilot clinical studies, to date, the achievements in larger human clinical trials have been rather modest. Researchers have learned that the similarities between mouse and human immune systems are pretty limited.

But according to the NIH Autoimmune Diseases Coordinating Committee, the range of potential therapeutic approaches available to treat autoimmune disease is expected to expand rapidly during the next decade as a consequence of progress in genetic and immunologic research conducted in the public and private sectors. These therapies are likely to include drugs, biologic agents, gene-based delivery systems, immunomodulation, cell-based treatments, tissue and organ engineering procedures, as well as therapies based on complementary and alternative medicine.

I've shown the following chart many times, but I use it for a reason: 2010 is the estimated time that some of the newer autoimmune treatments are expected to emerge, with more likely in the following years.



The question is if this is more of a retrospective look with a short window into the coming years, where is the future headed?

Here's where my references to some past efforts comes in. For example, in June 2009, I reported on some progress the JDRF had made with it's Industry Discovery and Development Partnership (IDDP) program (see here), whereby JDRF provides early-stage research funding to drug and/or biotech companies working on technologies and therapeutic candidates in an effort to provide incentives to more risk-averse drug and biotech companies to help commercialize products that would help facilitate JDRF's cure-related goals.

As a result of the trends noted above, a more mass-market approach to treatment seems to be taking place now. The basic idea is that these treatments will be delivered to a larger audience, but in order to do this, the costs must come down significantly. As a result, some are testing meds that were tried and approved for one condition to test their applicability in others. More recently, drug companies have engaged in trials to try and expand the market on certain existing drugs (for example, Gleevec, a drug that treats leukemia and other cancers) is reportedly being tested to treat the autoimmune response that causes type 1 diabetes in recently-diagnosed patients, and more recently, trials were announced to examine the use of several Rheumatoid Arthritis drugs such as Embrel, Remicaid, and Humira to see if they might also work in type 1 diabetes, not to mention other autoimmune diseases. It is very tempting to believe that one drug might treat another autoimmune disease, but as researchers have learned the hard way in the case of Lupus, that some drugs actually made the disease worse, not better. But the basic idea is that by ramping up production by leaving production up to drug and biotechnology companies, the cost can be brought down enough to make these drugs cheaper while also enriching biotech and drug companies by making their drugs applicable towards other types of autoimmune diseases. I could talk about each of these, but the reality is that right now, they're all in various stages of clinical trials. None is ready to address type 1 diabetes autoimmunity, but these could emerge in the coming years.

Autoimmunity "Cures" are Closer, But Not Likely Around the Corner

One of Josh Levy's postings summarizes some possible autoimmunity treatments in late-stage clinical trials. However, he includes some which aren't being tested with JDRF's help. To give you some idea of just how far along these are, consider that the following 4 programs are all now in Phase III Human Clinical Trials (note that there are a number of others in Phase I or Phase II Human Clinical Trials which I haven't even addressed here):

* Diamyd's GAD65 (several different studies; note: Josh considers this which is being trialed as a vaccine to be an autoimmunity treatment, I am not convinced yet, but let's see where it goes!)
* TolerRx/GlaxoSmithKline's CD3 (several different studies)
* MacroGenics/Eli Lilly's CD3 (several different studies)
* Teva/Andromeda Biotech's DiaPep227

He states "Now, make no mistake, these trials do not (emphasis mine) mean a cure is right around the corner." I'll borrow Josh's comment because he said it as well as I could:

"It is important to remember, however, that although there are four treatments in Phase-III trials, we are not close to a cure or established type 1 diabetes. All of the clinical trials in Phase-III and Phase-II are targeted at honeymoon type 1 diabetes; none at established cases. Even with that restriction. None of the treatments in Phase-III trials resulted in cures during their Phase-II trials. They all extended or increased the honeymoon phase in some way."

However, while his caveats are important to keep in mind, they DO demonstrate the type of quantifiable progress that has been lacking for a very long time on the autoimmunity front, and do suggest that quantifiable progress is being made (the same could NOT be said as recently as a decade ago).

A case-in-point: MacroGenics/Eli Lilly's teplizumab treatment is not without adverse events, no matter how glowing some reports may be. For example, a friend of mine who attended the Children With Diabetes Friends For Life Conference in Orlando this year said "Dr. Harlan from NIH wisely pointed out at CWD FFL that the anti-cd3 drugs can cause recurrent mononucleosis which can increase one's propensity to develop lymphoma. Why would someone put their child at risk for that simply for a year and a half of extended honeymoon?"

As I responded, "The issue is that they first seek approval on newly-diagnosed patients for anti CD-3 treatments, and then, will ultimately extend it to others, possibly long-standing T1DM patients if past drug approval history is any guide. This remains an area of discovery, and I suspect, we'll find that some treatments work for certain patients, while others will not. Of course, no one seems to question using Lantus (insulin glargine rDNA origin), a completely man-made creation for an entire lifetime which also has proven mitogenic effects, which I also find questionable for a relatively small improvement in HbA1c ... that logic also escapes me, but I am one of the few who seems to question this." At least there has finally been some attention paid to this, although most Lantus supporters cannot seem to be convinced otherwise, and most seem to make excuses for the technology rather than acknowledging the legitimacy of the question. That's a separate conversation, however.

Ultimately, what is likely to come out of the different autoimmunity-related trials is more refinement and perhaps better definitions on just which patients each treatment is likely to work, and perhaps improvements to these, with more similar types of treatments to follow. Also, hopefully, the adverse events from the early autoimmunity treatments can hopefully be reduced and/or eliminated.

I will follow-up on this Progress Report with a Part 2 in the coming months which will address another part of the cure equation (perhaps regeneration or replacement of insulin-producing beta cells), so be sure to check back!