Teplizumab (by MacroGenics / Eli Lilly) Fails in phase-III Trials
It appears that MacroGenics lead phase-III trial of Teplizumab has failed. Here are some quotes from their press release:
The Data Monitoring Committee concluded that the primary efficacy endpoint of the study, a composite of a patient’s
Following careful evaluation of the Data Monitoring Committee’s recommendations for [this clinical trial], based on the lack of efficacy, [MacroGenics and Eli Lilly] have decided to suspend further enrollment and dosing of patients in two other ongoing clinical trials of teplizumab in type 1 diabetes: the Protégé Encore Trial, a second Phase 3 trial of the same design as Protégé, and the SUBCUE trial, a Phase 1b trial that is exploring the subcutaneous administration in patients with type 1 diabetes.Discussion
Obviously, this is a huge blow to this drug as a possible cure for type-1. MacroGenics might try to salvage this drug by reanalyzing the data from this experiment to see if there was a subpopulation which was helped. But it is a long shot.
Another ominous question is what about similar drugs also under development? Teplizumab is a monoclonal antibody targeting CD3 T-cells. There are two other drugs in that category currently in clinical trials: Otelixizumab and NI-0401. I don't know if Teplizumab failed because attacking CD3 is the wrong technique, or there was a problem specific to that one drug. I hope the latter, because if it is the former, all three of these drugs will fail.
The President and CEO of ToleRx (developers of Otelixizumab) has a blog ("The Green Chair") which you can read here:
His whole blog entry on this is worth reading. Here is his quote on this particular issue:
Next, I’d like to underscore some of the reasons why we continue to have a strong belief in our lead product candidate, otelixizumab. Otelixizumab’s biochemical structure is fundamentally different from other anti-CD3 monoclonal antibodies, such as teplizumab. We believe this unique molecular structure is inherently important in mediating or delivering the “right” signals to T cells, and it is these signals, we believe, that are responsible for the effects, both in efficacy and tolerability, that were observed in our previous clinical trials.ToleRx expects to publish their phase-III results in the second quarter of 2011.
I haven't found any comment by Novimmune (makers of NI-0401).
Prior to this news, there were four treatments in phase-III of clinical trials aimed at curing type-1 diabetes. And phase-III is the last stage before market approval. Teplizumab was one of these, and Otelixizumab is another. NI-0401 is in phase-II clinical trials. If you're a "glass is half empty" kind of person, you can say that this news has lowered the number of phase-III possibilities by 25%, and cast a pall over another 25%. If you're a "glass is half full" kind of person, you can say that 5 years ago he had only one drug in phase-III trials, and even after this news, we still have three. For myself, I would point out that over 30% of treatments in phase-III trials end up failing for one reason or other. So of the four we had, we should expect 1 or 2 to fail. And now, 1 has.
News article: http://www.reuters.com/article/idUSN2024945620101021
Press release: http://www.macrogenics.com/press_releases-284.html
Biz news article: http://www.bioworld.com/servlet/com.accumedia.web.Dispatcher?next=bioWorldHeadlines_article&forceid=56170
Sitagliptin and Lansoprazole Start a Phase-II Clinical Trial
I had previously blogged about this trial here:
but at the time they were planning the trial, but now they have started it:
These are two drugs currently used for type-2 diabetes, but this trial is aimed at using them on people who have type-1 diabetes.
Another Encapsulated Beta Cell Cure in Human Trials
I've been following LCT (encapsulated pig beta cells) for years, and just last month I found a second encapsulated beta cell trial (that one using human cells). Now this month I found a third group doing encapsulated beta cell trials in people. Thanks to kisiliz (of CWD) for pointing this out to me:
Unfortunately, the results of this phase-I study of about 14 people. (4 of whom were actually treated) were not good. C-peptides were detected only immediately after the implantation. Although slight amounts of generated insulin could be detected years later, Insulin usage and BG numbers did not change. Basically, it was a proof of concept, but no practical impact. However, this study was just published in 2009, so they might well improve things, and move forward.
This makes for a total of three encapsulated beta cell research teams active right now, and that's a good sign.
Below is Animal Research, so Years Away from Human Trials
I don't usually blog about research that has not started human trials, but I thought the following two research areas were particularly interesting. Remember that anything that has not yet started clinical trials is well over 10 years away from general availability, and has a less than 50/50 chance of ever even starting human trials:
Alternate Artificial Pancreas Design
I would describe this as a "cool hack" (which is a software engineering way of saying "a really elegant design, which solves a complex problem in a simple way"). You can think of it as a hybrid of self dosing insulin and an implanted device. If you prefer, you can think of it as an artificial pancreas with no moving parts or computer software.
The trick is as follows: you create an artificial pancreas, which is nothing more than an insulin reservoir, a chemical barrier, and a tube so the insulin (once it gets past the barrier) goes directly into the liver. The barrier is key. It reacts to the BG levels in blood to either let more insulin out, or less insulin. This is very much like the "self dosing" insulins being researched by SmartInsulin and others, but it is different in that the "self dosing" chemistry is in a barrier which is separate from the insulin itself. I don't know if this is a better or worse approach (than combining the self dosing chemistry into the insulin), but it is different. And I believe that in early research, different is good, because we don't care how many fail, just that one succeeds. Sending the insulin straight to the liver is an interesting refinement as well. Naturally generated insulin goes to the liver very quickly, before it circulates through the blood or is deposited in the fat cells under the skin. So dripping the insulin into the liver should result in faster response, and in a sense is a more natural flow. Injecting insulin in the fat just below the skin is very easy to do, with almost no training, which is why we do it, but that does not mean it is the best from a biological point of view, just that it is the most practical.
Since there are no batteries, moving parts, electronics, etc, this type of artificial pancreas should be much easier to care for as an implanted device, and have fewer parts that can break or need to be replaced. Only insulin will need to be added. Unfortunately, I have not found any published animal research on this device, but I haven't looked very hard (and I'm not so familiar with the tools to search for animal trials, as I am for human trials.)
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.