Andromedia's DiaPep227 gets delayed

This posting was based on a misunderstanding of the FDA (and EU) approval process, and therefore I have rewritten it.  The rewritten version was posted 30-Jan-2010 with the title "Andromedia's DiaPep 277 Preps for Second Phase-III Trial".  I'm very sorry for the misunderstanding.  Please read the updated version for the current research status.

Joshua Levy

Possible Cures for Type-1 in the News (Nov)

Diamyd Finishes Enrollment of their European Phase-III Trial

Diamyd has finished enrolling patients in their 300 person, phase-III European trial. Diamyd is a vaccine like treatment designed to train the body's immune system not to attack itself and is focused on GAD65, which is the most common antibody marker carried by people with type-1 diabetes. Several human trials have already completed, and several more are in process. This trial is newly diagnosed type-1 diabetics, only.

Why is finishing enrollment important? For a couple of reasons:

1. Once a trial is fully enrolled, everyone knows when it will end, or at least when they will finish gathering the required data. So in a very real sense, we can see the end of the tunnel now. This trial lasts 15 months, so the last person who enrolls in Nov-2009 will finish with the protocol in Feb-2011.
   
2. Phase-III is the last phase before marketing approval of a new drug, so these guys are now the treatment second closest to general availability. (DiaPep227 Phase-III fully enrolled a few months ago.)

These guys also have a similar, large phase-III trial going on in the US, and they are still recruiting for that one. Plus, there are other clinical trials by different people using the same drug.

More info:
http://www.pipelinereview.com/index.php/2009111230708/Vaccines/Diamyds-European-Phase-III-Study-Fully-Recruited.html

Exsulin Update: Vague Results and Another Phase-II Trial Starting

This news is actually from the Summer, but I haven't blogged about it before, so here it is:
Here is the highlight of the results from their last batch of clinical trials:

In the T1DM study (SPIRIT 1), Arginine-stimulated C-peptide (AUC0-30) significantly increased from baseline in the 600 mg group (p = 0.0058 versus placebo)

My translation: the treatment caused people to generate more of their own insulin in response to a meal, when given 600mg. There was a second group that got 300mg, but they did not see any benefit. The full paper includes more detail one what was seen, but it looked pretty small to me.

Of course, the good news, is that this clinical trial only took them a few months to run, so they could easily make improvements to their process, and try it again. And that is what they are going to do:

The new phase-II trial is already recruiting it's 30 participants and they are hoping to have results by Q2 2010. Because INGAP does not stay in a person's system for very long, in this trial they will give smaller doses three times a day (rather than larger doses once a day), and therefore hope to have better effects and fewer side effects. They have also changed the formulation to have less irritation at the injection site. In their previous study, 25% of the people who got the higher dose, dropped out of the trial because of "adverse effects" (often this irritation), so that is a problem they want to address.

Abstract of research of completed phase-II trail:
http://www3.interscience.wiley.com/journal/122518238/abstract

Press release:
http://www.medicalnewstoday.com/articles/161069.php

Clinical Trial record for new phase-II trial:
http://www.clinicaltrials.gov/ct2/show/NCT00995540

I want to particularly thank fellow BraveBuddy Ricardo Dolmetsch for providing a lot of of the information that I used to report results from the previous trial and for providing some useful insight. Also thanks to ChildrenWithDiabetes member Ellen for pointing out the second phase-II study.

Phase-II Results from DiaPep227

DiaPep227 entered phase-III trials before I started to track clinical trials, so I've never blogged about their Phase-II results. However, since they're phase-III was the first to be fully enrolled, I thought it might be interesting to look at their previous results. Here is the quote from their abstract:

At 18 months, stimulated C-peptide concentrations had fallen in the placebo group (p = 0.0005) but were maintained in the DiaPep277 group. The need for exogenous insulin was higher in the placebo group than in the DiaPep277 group. Mean HbA_1c concentrations were similar in both groups. After extension of the study, patients continuing treatment with DiaPep277 and those switched from placebo to DiaPep277 manifested a trend towards a greater preservation of beta-cell function compared to patients maintained on or switched to placebo. The safety profile of DiaPep277 was similar between the treatment and placebo groups, and no drug-related adverse events occurred.

When I look at that summary, the first thing that I notice is that there are no numbers in the results (except a p value, which isn't a result, its a measurement of a result). It talks about C-peptide and A1C numbers, but does not give them. For me that is a big red flag. Vague qualitative statements ("need for exogenous insulin was higher") don't give me confidence. I want to know how much more insulin? And I don't see that data here. Exsulin's abstract in the news item above had the same problem, and reading the whole paper just reinforced by belief that no numbers in the abstract does not bode well for the strength of the results.

The complete paper is pay-per-view, so I'm just working off the abstract.

Abstract of research:
http://www3.interscience.wiley.com/journal/113488533/abstract

All the views expressed here are those of Joshua Levy, and nothing here is official JDRF news, views, policies or opinions.

News from MacroGenics on Teplizumab

Two pieces of news from MacroGenics:
First, their phase-II human trial of teplizumab (called PROTEGE) is fully enrolled.
Second, they are starting a follow on phase-III study called PROTEGE ENCORE.

Teplizumab is a "humanized monoclonal antibody" which targets the CD3 part of the immune system in order to lower (or stop) the body's autoimmune response. This drug tries to prevent type-1, or lessen it's severity, by "turning down" the immune system's attack on the body's own pancreas cells. This basic approach has resulted in treatments (but not cures) for other autoimmune diseases. It does carry the risk that the body's immune system will not properly attack a real threat.

Fully enrolling a study (especially one this large: 530 people) is important because the major reason that studies are delayed, is trouble enrolling people in them. Especially a study like this where only "honeymoon" diabetics can participate, getting 530 often takes longer than planned. But once it is fully enrolled, that source of delay is removed.

The new study is a sign that MacroGenics is looking to productize this drug. The new study is focused on "clinical responses". That's research-speak to mean "does it help patients" or "do real people benefit in a useful way from this treatment". This is the kind of trial you do just prior to putting it on the market. The new study is 400 people and is scheduled from June 2009 to June 2012.

There is also a third PROTEGE trial which is ongoing, called PROTEGE Extension, which follows patients from the PROTEGE trial for an extended length of time.

If you view the path to a cure as a race, then with this announcement MacroGenics has pulled even with ToleRx which also has a CD3 targeted humanized monoclonal antibody in phase-III human trials. (That's the DEFEND trial of Otelixizumab.) It is interesting, to me at least, to see the dance of small companies and big companies. The PROTEGE trial is sponsored by MacroGenics. The PROTEGE Extended trial by MacroGenics / Eli Lilly, and the PROTEGE Encore trial by Eli Lilly, so you can see how Eli Lilly taking over the Teplizumab treatment from MacroGenics. Similarly, ToleRx has a partnership with GlaxoSmithKline for their Otelixizumab treatment.

(Note: MacroGenics/Eli Lilly calls PROTEGE a "phase-II/III trial", and the Encore trial a phase-III. But I considered PROTEGE a phase-II and Encore a phase-III.)

You can read more about it here:
http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials#MacroGenics
(although I really need to update this)

Read the press release here:
http://sev.prnewswire.com/health-care-hospitals/20090616/PH3265516062009-1.html

The web page home of this trial is here:
http://www.protegediabetes.org/

Here are the US Clinical Trial entries for all three studies:
http://www.clinicaltrials.gov/ct2/show/NCT00385697 (Protege)
http://www.clinicaltrials.gov/ct2/show/NCT00870818 (Extension)
http://www.clinicaltrials.gov/ct2/show/NCT00920582 (Encore)

Joshua Levy

JDRF Funding of Cure Research (phases II and III)

I was talking to someone today, and when I told him that I track cure research for type-1 diabetes that was being tested in humans (ie. "in clinical trails"). He asked me a question that really surprised me. He asked "Do you follow all cure research, or just the stuff funded by JDRF?" My answer was "I follow all research; however there's not much difference, because over their years of development, JDRF has funded almost all of the possible cures being tested in people today."

That's a strong statement, and I made it off the top of my head, without my notes in front of me. But in the evening, I double checked, and it is pretty impressive. JDRF has funded every cure currently in phase III human trials and every cure currently in phase II human trials. I haven't had time to check on all the phase I trials, yet. But still, 100% funding rate for the two phases of research closest to a cure is something to be proud of.

So lets look at the data.

Currently in phase III clinical trials are Diamyd (GAD65/DiamydT), ToleRx (TDX4), and Andromedia (P227). JDRF paid for early academic research on all three of these cures, and is directly funding ToleRx's phase III trial.

Currently in phase II clinical trials are Osiris (PROCHYMAL), Macrogenics (teplizumab), Transition Therapeutics (E1/G1), Pescovitz (Rituximab) and Gitelman (Thymoglobulin).
JDRF is helping to fund the clinical trials for every one of these, and funded some of the academic research on E1/G1. (They might have funded earlier research on Thymoglobulin and Teplizumab as well: I don't follow animal testing very closely, so am not sure where that funding came from.)

Currently there are about 10 phase I clinical trails, and I have not checked to see how many were funded by JDRF and how many were not. So that information will need to wait for a future posting. I can see that at least one was not funded (LCT), and at least two were (the Haller/Schatz work at Univ. of FL and Trucco's work at Pittsburg).

Some notes to remember:
1. All of the phase II and III cures are targeted at new-onset diabetics (we would call them "honeymoon" cures. They only work on people diagnosed a few weeks ago. There are a couple of non-honeymoon cures in phase I testing right now, but none farther along.
2. Some people think of Macrogenics's current trials as phase III rather than phase II. Officially, they call them "Phase II/III" so you can take your pick.
3. I consider JDRF to have helped fund the cure if they funded any part of the academic or commercial research that led directly to the current clinical trial. For example, I don't think that Diamyd the company has gotten any money from JDRF, but JDRF did fund some of the early GAD65 research which led directly to their human trial.
4. The Andromedia cure, which is called P227, has not made any forward progress in years, and does not look very promising right now, but it is in phase III trials, so I include it above.
5. Faustman considers her current work to be phase I, so I will discuss it when I cover all the phase I trails.

If you have any questions on this, or you think I've missed something, please don't hesitate to ask the question, or call out what you think I missed.

Joshua Levy

Disappointing News on DiaPep 227

Usually my research updates are happy and upbeat; but unfortunately, not this one.

To my knowledge DiaPep 227 was the first potential cure for type-1 diabetes to go into phase-III human testing. That was back in 2005. However, there have always been troubling signs. For example, they finished their phase-II testing in 2001, but were not able to start phase-III trials for 4 years. (For comparison, both Diamyd and ToleRx went from phase-II to III in less than a year and a half.) For the last few years the only news I've seen is corporate. DiaPep 227 was sold first to one company, then to another, until it was finally owned by Andromeda.

Finally, in June 2008 the released interim results of their phase-III trials. You can read about them here, but you'll notice there are no numbers. No actual data results; they basically just said "did as well as phase-II testing" (although that is not an exact quote). Then one of their investors, who had seen the actual data dropped the following bombshell in a press release:

The reason is that the interim result does not provide statistically significant results about the effectiveness of DiaPep 277

Basically, what they are saying is that -- so far -- the people treated with DiaPep 227 and the people who were not had about the same outcomes. That is the worst news you can get our of a clinical trial. Now all is not lost, maybe the end part of the phase-III trial will show great improvement. Maybe a future clinical trial will have success. However, right now, things look pretty grim.

Remember that treatments that are in phase-III trials generally have an 70% - 80% chance of going to market. So it is starting to look like DiaPep 227 is part of that 30% or 20% that gets to phase-III trials, but never gets to market. This is why research is a "numbers game" and I'm very happy to have both Diamyd and ToleRx in phase-III trials right now as well. (Although both of their cures are only being tested on honeymoon type-1 diabetics.)

I will continue to track news on DiaPep 227, but I'm not holding out much hope.

As always you can get updated on all the potential cures for type-1 diabetes on my web page: http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials and read these updates on my blog: http://cureresearch4type1diabetes.blogspot.com/

New Phase III Trial Starts: Otelixizumab from Tolerx

Good news! A new Phase III trial has started to test a honeymoon cure for type-1 diabetes!
You can read about it (from a technical point of view) here:
DEFEND Trial

Basically, this is a CD3 targeting drug, very similar toTeplizumab by MacroGenics. It is only being tested on honeymoon phase diabetics, but remember my hopeful comments on honeymoon cures becoming cures for everyone. This drug has been in phase II trials for a while, as has Teplizumab.

Press Release Reporting this (see the last paragraph)