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 http://goo.gl/iyjJT (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 (http://www.jdrf.org/index.cfm?page_id=115376); 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: http://www.diabetestrialnet.org/studies/ACD3.htm. 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.

It Get's Better for People With Diabetes: You Can Do This!

On Weds (5/5), Kim Vlasnik at "Texting My Pancreas" had a POST about a recent Google-sponsored TV commercial for the "It Gets Better" campaign which was started by Dan Savage. Mr. Savage is known for an online (mostly YouTube videos) campaign he started which began as a response to growing numbers of teen suicides for sexual orientation that were taking place across the country, from Billy Lucas' suicide in Indiana, to Justin Aaberg's suicide in Minnesota. Then there was the Tyler Clementi suicide at Rutgers University in New Jersey that coincided just as "It Gets Better" campaign was taking off.

The TV commercial for Google's Chrome browser (which is, incidentally, my browswer of choice these days, and has been for about a year now because of it's speed) features the "It Get's Better" project, and the spots premiered during the show Glee, which Newsweek called "the gayest show in the history of network TV." Whether that's true or not, Glee does focus on the perceived misfits and losers of an Ohio high school and their favored school social activity, the high school Glee Club. I am referring, of course, to the Newsweek interview issue in which the magazine featured Dan Savage and actress Jane Lynch (who stars as the cheerleading coach Sue Sylvester on Glee). To read that interview, please see http://goo.gl/ljKGt. The mere fact that former Fox News TV talkshow host Glenn Beck feels threatened by "Glee" (see HERE) is even more reason for me to want to watch it ... with glee!

In that interview, Mr. Savage said something I found very interesting: "I think the gay community does a disservice to a lot of gay kids when we beat the drum of 'come out, come out, come out.'" and Jane Lynch echoed his sentiment by adding "It can be really dangerous to come out to families and to school" because, the article noted, quite frequently, those institutions are the biggest part of the problem. Of note is the fact that 40% of all homeless teenagers are actually kids who were thrown out by their parents when they came out or were outed by someone else. Good, Christian parents, ready to discard their kids for being something THEY don't believe in. But this story isn't about the "It Get's Better" project, it's about something kind of like it for the people with diabetes (PWD) community.

You Can Do This

Kim's thought was that perhaps the diabetes community deserves a program like the "It Gets Better" campaign. I very much like that idea, but I would kind of like to echo Dan Savage and Jane Lynch's caveat from their Newsweek interview, I would support a similar initiative in the diabetes community only if we didn't try to "sugar-coat" everything the way doctors and CDEs too often do, depicting life with diabetes as if it was a mere inconvenience -- talk about misleading patients! Dan Savage was truthful when he told Newsweek "There's no promise that it's going to be a birthday party for you thrown by your mother for all of your life. Bad things happen, and we all die eventually. But there's enough space for you to create a life for yourself, to find friends, lovers, and a community."

Diabetes According to the Medical Profession, Featuring a Lack of Honesty

That's also my take on life with diabetes, and I think it echoes what Kim is doing with The "You Can Do This" effort which mirrors the sentiment about honest talking about life with diabetes. Rather than yet another campaign by doctors, CDEs, nutritionists who tend to marginalize the amount of ongoing effort is required to manage this disease for the rest of people's lives, we as PWD's are going to offer something that hasn't been done before: honesty about life with a chronic disease like diabetes. Anyone expecting Sprinkles the Unicorn is going to fart glitter all over the place when you have diabetes is living in Never, Neverland. I agree that we need to speak the truth in a way that the medical profession simply doesn't have the balls to do themselves: by telling things like they ARE. A comment I received on a blog post said it best: "Diabetes is not a death sentence, but it IS a life sentence." (Get used to it!)

While that's funny on the surface, the reality is that no one frankly admits what a CHRONIC disease really means. But, just as Dan Savage said, bad things happen (like diabetes) but there's enough space for you to create a life for yourself (with diabetes), find friends and a community (like the Diabetes Online Community). But we get enough misrepresentation of the truth about how livable with diabetes is from doctors and CDEs. Living with a chronic disease is neverending, and $#!tty things happen even when you follow the rules. To succeed with diabetes, this really is a marathon, not a sprint, so beating the drum of who has the lowest HbA1c is actually very destructive in my opinion, and I have NEVER shared that on any social media community (TuDiabetes, DiabetesDaily, etc.) because I think it sends the WRONG kind of message IMHO. Guess what? I have opted NOT to join these efforts!

Your HbA1c is YOURS; Don't Feel Obliged to Share It

Personally, I don't want to share that information, and I choose not to, and I find medical researchers lusting after this data to be kind of deplorable. Incidentally, while I'm on that subject, the TuDiabetes campaign that I avoided like the plague was recently chronicled in the online, open-access scientific journal PLoS ONE, see HERE for details. The authors refer to us as an "an early adopter community" claiming that success with them "may comprise efficient platforms for bidirectional communication with and data acquisition from disease populations". David Mendosa wrote about it HERE. I have always been a big privacy advocate, and let me go on record as saying, don't share ANYTHING you don't want to. If it's none of anyone's business, don't feel compelled to share it. I don't, and guess what, I still see myself as an active, longtime member of the diabetes online community.

Don't Publish Details Online You Don't Want to Share, You're Not Obliged to Share Everything

Since when did personal privacy disappear just because of the internet? Seriously. For example, my readers may be somewhat shocked to learn that they won't find my personal e-mail address online even though I am what could arguably be called a diabetes blogger veteran (since 2005!), and I'm on most social media including some diabetes-specific outlets like the JDRF's Juvenation, TuDiabetes, DiabetesDaily and a few others. It's true, because I don't publish my e-mail address, and you shouldn't feel compelled to share yours, either! (There are ways around that, as I have recently added a feature that enables me to have people contact me from my blog without publishing my personal e-mail address). This comes down to not wanting to share every intimate detail about yourself just because of online social media. You are entitled to have things you keep for yourself and you don't have to share EVERY single detail. Also, I have been known to decline Facebook friend requests from people I've never met. I would recommend that everyone think about these things, because the way things are online, there are starting to be some permanent footprints that you cannot simply erase because you think you're done with social media!

I have a camera, but haven't recorded my own "You Can Do This" video ... yet, but I'm working on it. In the meantime, have a look at some of the videos posted already on the "You Can Do This" YouTube channel (more details can be found HERE). Hopefully, this will enable a large and growing group of us in the online space to make sure others know that they are not alone in living with this chronic disease!