Thursday, June 09, 2011

Teplizumab and DPT-1: "Not Dead Yet"?

Hopefully, Phil Southerland will pardon me for borrowing the title to his new BOOK (as far as I know, he cannot copyright a mere 3 words, although they can be trademarked, but that process takes a number of years of using the term consistently as a brand name before the U.S. Patent and Trademark Office will even consider it), but I felt like it made a compelling headline for today's post.

How many of my readers remember an experimental anti-CD3 monoclonal antibody treatment called teplizumab that had trials with a cutesy name: Protégé? That trial was being undertaken by a closely-hold, Maryland-developer named Macrogenics, Inc. and it's big-pharma partner Eli Lilly and Company (a marriage that was the result of the JDRF pairing the two companies together). You might, because this product has been promoted as a promising autoimmunity treatment for type 1 diabetes for a while now.

Unfortunately, last October, the teplizumab Protégé trial was the first of several recent failures for late-stage autoimmunity treatments (and the first of TWO that that the JDRF worked to help find big-pharma partners for) that FAILED to meet their clinical endpoints (the other was the also-cutesy trial name DEFEND sponsored by Massachusetts-based Tolerx, Inc. and it's big-pharma partner GlaxoSmithKline, also facilitated by the JDRF ... the third was the Diamyd trial which was NOT facilitated by the JDRF). The results of these trials, because they were funded (in part) by the JDRF, fortunately, will actually be published in medical and/or scientific journals and are due to be discussed at the forthcoming ADA Scientific Sessions in San Diego in late June.

I found one of the endpoints that pharma partner Eli Lilly and Company insisted on using for the Protégé teplizumab trial to be inappropriate: they used a composite of a patient's total daily insulin usage and HbA1c level at 12 months as the efficacy endpoints, but curiously, not a patient's C-Peptide count, nor did the trial exclude participants who had good glycemic control, raising questions just how they could realistically expect to see any improvement in HbA1c for some participants -- after all, this was NOT a noninferiority trial. A patient's daily insulin requirement might be an acceptable measurement, but I still find the absence of C-Peptide count perplexing because they have no quantitative measure of how much endogenous insulin is even being produced without it. Whatever the measures, the teplizumab treatment failed to meet the defined endpoints.

The reality is that when it comes to measuring whether the pancreatic beta cells function, really, the ONLY appropriate measure is C-Peptide, and the former head of the FDA's Metabolic Group including diabetes (for some 12 years, I would add), Dr. G. Alexander Fleming has made just that argument (he's now CEO of Kinexum LLC, which is the angel-investor for a company known as Exsulin, Inc. which is developing a beta cell regeneration therapy (see his scientific journal article which makes this very argument, as well as the self-imposed quandry the FDA has historically had in trying to approve type 1 diabetes autoimmunity treatments HERE), although until fairly recently, there have been relatively few applicants for type 1 diabetes autoimmunity treatments the FDA has even had to evaluate.

In any event, Tuesday's (June 7, 2011) Wall Street Journal had an interesting article entitled "Trying to Prevent Type 1 Diabetes" by Shirley S. Wang. For readers who have paid access to the Wall Street Journal's content, the link to this article can be viewed at (it's a long link, so I've shortened it for ease-of-use).

I won't share the entire WSJ article here, but the Wall Street Journal had a video clip that nicely summarized most of the key points shared in that article HERE:

One of the most noteworthy take-aways (for me, anyway) in this story was the fact that it was citing two clinical trials that were presumed to have failed, including the Diabetes Prevention Trial (a.k.a. the "DPT-1") using insulin that was pretty much declared dead several years ago (there was a leg of that trial that used injected insulin, and another that used insulin given orally -- the idea being that introducing synthetic insulin might help create a state of immune tolerance to the insulin-producing beta cells the body's immune system is likely to destroy in patients who are at high-risk for autoimmune-mediated type 1 diabetes). The other clinical trial cited was for teplizumab (noted above) which made news last autumn (in October 2011) because that Phase III human clinical trial had failed to meet it's primary endpoint (see HERE for details on that), which was a composite of a patient's total daily insulin usage and HbA1c level at 12 months.

In April 2008, Eli Lilly and Company's chief executive officer (CEO), John Lechleiter, referred to teplizumab as one of that company's three most promising experimental drugs in the company's pipeline in an investor event, yet Lilly rapidly dumped it following the failure of the Phase III clinical trial.

This is why the news that the drug might not be dead after all is so interesting.

It's important to note that Lilly hasn't exactly been a good pharma partner for the JDRF or in pursuit of type 1 diabetes treatments; frankly, in my honest opinion, they've been a downright $#!tty partner -- having screwed the JDRF over twice in two partnerships the organization facilitated. In my post last autumn entitled "The $100,000 Diabetes Cure", I cited evidence of another JDRF partnership with Lilly in which the Indianapolis-based drugmaker essentially screwed the JDRF over by turning a therapy designed to regenerate islets in patients with type 1 diabetes into a trial for patients with type 2 diabetes (most likely because Lilly saw more potential dollars as a type 2 treatment; it is a company that has a fiduciary responsibility to its shareholders), but when the trials in type 2 didn't work out, Lilly dropped the gastrin-based therapy (with the unglamourous name "TT-223") faster than a hot potato (see HERE for more detail) -- in spite of receiving initial financial support from the JDRF!

Shortly after that event, me and another diabetes blogger (Joshua Levy) reached out and the JDRF confirmed that the evidence still suggested that TT-223 may indeed work in patients with type 1 (and also in type 2, as the endpoint measurements in the type 2 trial were again, quite suspect). The Toronto-based developer of that drug, Transition Therapeutics, Inc., was forced to regroup and the JDRF may again play matchmaker with another company (assuming, of course, that Lilly's dumping the molecule hasn't poisoned others from touching it). However, as I suggested in my "$100,000 Diabetes Cure" post, I believe the JDRF has learned some lessons from the early experiences and has indeed made changes to more recent industry partnerships, making funding contingent upon meeting various milestones rather than up-front payments, for example.

An excellent example of that is contained in a brand-new partnership announced this morning (also for autoimmunity) between the JDRF and Massachusetts-based Selecta Biosciences, Inc. The news of this partnership can be viewed HERE, HERE and HERE. Of note is the fact that with this latest industry partnership (which, incidentally, JDRF plans to increase fairly dramatically the number in the next few years). I heard this from the source, when I met face-to-face with Richard Insel and Karin Hehenberger a few weeks ago at JDRF headquarters a few blocks down the street from my office (I haven't addressed that meeting in a post yet, but I will!). In particular, note the language in one of the JDRF press releases on the Selecta Biosciences noted above:

"Through the research partnership, JDRF will provide milestone-based [emphasis mine] financial support and expertise, with the goal of applying Selecta's vaccine technology toward the development of vaccines for type 1 diabetes."

The key term here is MILESTONE. In effect, the JDRF is telling the partner "we'll give you funding, but it's contingent upon your meeting some requirements, it won't be a lump sum distribution up-front". This is a pattern that has been evident in several recent JDRF-announced industry partnerships. Without getting too far off topic, I would like to say that had these negative experiences with the Lilly partnerships not occurred, the lesson of milestones would not have been taught. After all, there really was not much experience in industry partnerships among other nonprofits, so JDRF was indeed charting a new course. Hopefully, the Selecta partnership will be beneficial for all parties involved.

Getting back on topic for "Not Dead Yet"

The Wall Street Journal article also cited the presumed-dead DPT (Diabetes Prevention Trial for type 1 diabetes), specifically the leg of the trial involving oral insulin. As journalist Shirley S. Wang noted, although taking insulin orally has absolutely no impact on glucose level (there's no therapeutic benefit), but taking insulin (in it's current form) orally may introduce self-tolerance to the beta cells that produce and effectively stop the body's immune system from attacking itself. Although one leg of the DPT-1 had already failed to meet it's efficacy endpoint, there was plenty of skepticism that the trial wasn't working. One thought was that perhaps the dosage of insulin was insufficient, others believed that the efficacy measurements weren't correct.

In any event, the trials are apparently not dead -- yet. The reality is full trial details have yet to be disclosed for many of these, but the JDRF did ensure that the trial results do not get buried in the pharma and biotech cemetery. Typically, results for government-funded trials get published in medical and scientific journals, but drug trial results are buried by the companies and the FDA. For the oral insulin trials being pursued by the U.S. National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases, apparently there there is sufficient evidence that a follow-up trial is worth the cost to taxpayers. Some of the early critiques of the DPT-1 was that the dosage may not have been sufficient to have a measurable difference. The same holds true with the Macrogenics teplizumab trials, even though that trial did not involve U.S. Government funding.

Back in March, I asked the JDRF some specific questions about not only the teplizumab trial, but also the failed Tolerx/GlaxoSmithKline otelixizumab DEFEND-1 study which also failed in March 2011 (see HERE for details on that). This leaves the JDRF with relatively few late-stage trials in the autoimmunity front (one of which is Bayhill/Roche, which the former Genentech executives were claiming is being delayed not due to lack of interest, but resource constraints at the company. I don't necessarily believe that explanation, but again, because it was an earlier partnership, the JDRF may not have had milestone requirements for payments built into the agreement. Call it a lesson well-learned).

However, its typical that full trial results for any drugs in development are rarely (if ever) published in medical journals in their entirety, rather pharmaceutical companies are quite notorious for selectively releasing data which make treatments appear most favorable, although the results must still be submitted to the FDA and TrialNet, that's the extent for which trial data is actually shared.

So I asked the JDRF to comment.

My first question was whether JDRF had any rights to full-scale trial results (data, etc.) for both otelixizumab and teplizumab? After all, there is considerable learning that can be attained from these trials even if the drugs failed to gain FDA approvals?

Second, it may still be possible that these medicines worked in certain subsegments of the trial population. If that is true, it might be important for JDRF to know which segments the drugs worked in. Again, having access to the full trial results would be critical to know this, and perhaps more importantly, having these trial results published in medical/scientific journals would be even more important to advance type 1 diabetes research, and autoimmunity treatments in particular. What, if anything, can JDRF do to ensure these trial results are published?

I believe the JDRF appreciated my questions, but did have to research before responding to me, which they did (Bennet Dunlap and I were also able to meet some of the JDRF's Scientific leaders shortly after that, catch his post HERE). Here is how the JDRF responded to my questions:

"Thanks for getting in touch about this. Your questions are very thoughtful. I’m sure you saw JDRF’s statement on the DEFEND-1 trial that we posted on our website last week when the results were announced (; however, you’re seeking more in-depth information. I will discuss your questions with our internal Research team and get back to you with a response."

A follow-up e-mail with the following was sent a week or two later:

"Hi Scott,

I spoke with our Chief Scientific Officer, who provided some information to help me respond to your questions. JDRF agrees that sharing and understanding the data from the DEFEND-1 trial is important, in order to provide context for the results and help us understand what didn’t work and what, if anything, did. As you know, the data we glean from therapeutics like this one that don't succeed in trials is still important to inform our research efforts, especially for planning future new onset type 1 diabetes trials.

Specifically, JDRF plans to review the data from the trial once it has been thoroughly evaluated by our partners Tolerx and GSK to help us determine what the results mean for otelixizumab specifically, and anti-CD3 in general. Our understanding all along has been that Tolerx has been planning to present the data from the study at a major diabetes conference [the ADA Scientific Sessions in San Diego], and/or submit it for publication in a peer-reviewed journal. We will certainly look forward to the data being presented in one of these forums.

Regarding the MacroGenics Protégé trial, it’s true that teplizumab did not meet its primary endpoints in people with recent onset type 1 diabetes as well. However, the NIH is recruiting for a new trial to test teplizumab for preventing type 1 diabetes in people at risk: So there is still an opportunity to learn more about this anti-CD3 treatment and whether it is effective in slowing down or stopping the autoimmune response that causes type 1.

I hope this information answers all your questions. We will be sure to communicate further if we learn any new information about these trials, or anti-CD3 in general."

I appreciate the JDRF's candor, and I honestly believe these experiences and the fact that people like myself, Bennet Dunlap, Joshua Levy and others who are challenging the organization on these issues is indeed being recognized. The fact is that JDRF's new CEO Jeffrey Brewer is also cognizant of these issues, and changes appear to be moving in the right direction. Let me add that we are entering a brand new era for industry-nonprofit partnerships, so the early (negative) lessons learned have been valuable, and its better that these lessons are learned early so that future agreements address these, and the evidence of milestones (payment contingencies) is evidence of that.


Kathy said...

This is so interesting and so important to follow and understand. Thanks for the sharing and interpretation of this complex information. This makes up the threads of hope for all Type 1s.

Bennet said...

Scott -

I think milestones have been part of the IDDP process from the outset. I know that that JDRF spoke of milestone payments when I first started asking questions about IDDP back in '07 (

I think you are right to bring attention to milestones. How the function is not clear. I think that we, as a community that supports JDRF, should be asking about milestones.

I don't think JDRF or the industry partners like talking about them. Part because it is a level of specificity that is uncomfortable, probably in part FDA discourages public specificity about things under review and part some notion about proprietary info in the marketplace.

I think JDRF would do itself and the public that supports it a favor by being more open about milestones, how they relate to type 1 and what the status of reaching them is and has been.

That needs to be done in a way that does not inflate expectations. This is risky business. An honest evaluation, simply based on statistics, is that most projects will not meet milestones, so probably will most IDDPs. That doesn't mean that JDRF should not do them. In fact the whole point is to be an intermediary that facilitates risk taking around finding cures and better therapies for type 1.

As you so eloquently point out a key part of all this is learning from failing to make end points.

All the best


I share your passion for getting information about milestones out. I still wonder if the Lilly deals were trigger points that returned IDDP investment to JDRF. See:

Patent Attorney said...

According to an article posted in WSJ, new steps are being taken to prevent Type 1 diabetes which is a growing disease among children these days and can lead to many health complications.

Scott S said...

Dear Patent Attorney: In reference to the Wall Street Journal article: your understanding is mistaken, as research is not the same as proven methods, and presently, there is NO way to prevent autoimmune type 1 diabetes from occurring. The methods noted in the WSJ are experimental, but have not yet been proven effective. You will also note that I have removed the links contained in your comment, which is standard practice at this site. I trust I have addressed your questions, and that you will take note that I do not post comments for the sake of promoting links to third-party websites.