Xoma Starts a Phase-II Human Trial

My local JDRF chapter is setting up a "Research Information Committee" to help spread the word about type-1 diabetes research, and I was asked to be a member. We had our first meeting a few days ago, and one of the other members mentioned the following human trial was just getting started:

Xoma Starts a Phase-II Human Trial

Xoma is starting a phase-II clinical trial of their "Xoma 052" drug.

The study is placebo controlled and double blind, and the primary end-point is C-peptide levels (so good design). It is being done in Zurich and I'm not sure how many people will be enrolled. Only people who have had type-1 diabetes for 2 years or longer will be enrolled. So this is not a honeymoon study: quite the opposite; honeymoon diabetics are excluded.

There are already two separate phase-I clinical trials underway to see if Xoma 052 improves type-2 diabetes. (I assume that is why they could go directly to phase-II trials in type-1 diabetes: the basic safety was already established.) Xoma inc. is also doing animal research to see if this drug can be used for many other inflammation related diseases, such as rheumatoid arthritis and gout.

This clinical trial is being funded by JDRF.

Xoma 052 is a monoclonal antibody which is a broad anti-inflammatory, and works by blocking the IL-1 inflammation pathway. Xoma is in the business of developing monoclonal antibodies which are then marketed by much larger companies. They already have a couple of drugs on the market.

Discussion

Earlier this year (and in 2008) there was some excitement about inflammation based treatments as cures for type-1 diabetes. The idea as that the body's autoimmune response triggered inflammation and it was the inflammation which actually killed the beta cells. So lowering inflammation could cure or prevent type-1 diabetes. This is a minority opinion, to be sure. Most researchers believe that inflammation is a side effect of the beta cells being destroyed, not a cause of their destruction. This trial is the third one, that I know of, based on the idea that anti-inflammatories can cure type-1 diabetes.

One of the best things about this research, is that they expect results next year, and as a phase-II trial, it should be big enough, so that the results should be pretty clear as to the basic success of the drug. We should have a basic "thumbs up / thumbs down" result by the end of 2010. Another good thing, from my point of view, is that this is not a honeymoon only treatment or trial.

Personally, I'm a little dubious about the whole "anti-inflammation as a cure" path. But I'm also very data-driven, and we now have 3 different studies going on to try to cure type-1 using this path. If any one of those studies gives successful results, then all my doubts will be erased. :-)


Xoma's press release:
http://www.xoma.com/company/news-events/press-releases/index.cfm?releaseID=421746
Clinical trials record for this research:
http://www.clinicaltrials.gov/ct2/show/NCT00998699
Clinical trials records for Xoma's other diabetes research:
http://www.clinicaltrials.gov/ct2/results?term=xoma+diabetes
Previous blog entry on inflammation (including some general discussion):
http://cureresearch4type1diabetes.blogspot.com/2009/04/two-new-trials-to-test-kineret-anakinra.html

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

Update on Gitelman's ATG Phase-II Clinical Trial

Dr. Gitelman at UCSF has started a Phase-II human trial aimed at using ATG to cure (or lessen) type-1 diabetes. The goal of this study is to preserve remaining beta cells for people within 100 days from diagnosis. This study started in August 2007, and is expected to run until June 2011. So far it has enrolled 11 out of an expected 66 patients. It's a four day treatment (in hospital), and 12 follow up visits over a 2 year period. They are recruiting at a total of 9 sites (growing to 13), which are listed in the clinical trial page linked below.

Here is a quick summary of how they hope ATG (Thymoglobulin) will work:

Type 1 diabetes is caused by destruction of insulin-producing beta cells by T cells, part of the immune system. Thymoglobulin is a mixture of different antibodies that target T cells. This mixture includes the anti-CD3 antibody (and anti-CD3 treatments are in Phase-III trials already, having completed successful Phase-I and II trials). The researchers hope that this multi-faceted approach will be even more successful and have a longer lasting effect than with anti-CD3 alone, and may treat diabetes by several mechanisms. First, it lowers the number of T cells, so there are fewer to attack the beta cells. It also seems to alter the T cells remaining behind, rendering them less likely to be destructive. Following this depletion, the T cells that grow back in the following weeks may be reset and have a healthier balance (meaning that a special type of T cells, called regulatory T cells, will help keep the destructive T cells in check).

Using ATG to cure type-1 diabetes is an idea that flows from two sources. The first source is a line of clinical trials aimed directly at curing type-1 with ATG. Eisenbarth's work of long ago, a Phase-I trial done in Europe, etc. But it also has another source, which is Burt's Brazilian research as described below.

Discussion: How to Follow Up Burt?

One of the questions that I'm occasionally asked is this: when will there be a follow up to Burt's Brazilian research? When will there be a Burt, phase-II? This is a natural question, because Burt has -- by far -- the best results of any one. Many patients on that trial went years without using external insulin. No other study comes close. So an obvious question is: how do you move forward with that research.

Burt's research is the opposite of most. Most researchers use the smallest possible doses during phase-I. Phase-I is targeted at safety, so they use small doses to assure safety even at the expense of effectiveness. So for most studies, for phase-II studies, they move forward by raising the dose to try to make a safe treatment a more effective one. But Burt's research is the opposite. The effectiveness is the strongest yet, but there are real questions about safety. So you would NOT follow it up by raising the doses!

One way to follow up Burt's relative success, is by turning down the dose. Trade off a little effectiveness for added safety. Oversimplified a little: Burt's research involves using three drugs (ATG, GCSF, and cyclophosphamide), and reinjecting the patient's own precursor bone marrow cells (previously removed). Dosing with just ATG can be viewed as a "kinder, gentler" Burt. Especially since the cyclophosphamide is the most risky drug of the bunch. (I'll be posting on two GCSF clinical trials in the coming weeks.)

Since I'm a software engineer, I'll use a software analogy: Burt is doing a "hard reboot", Gitelman is trying for a "soft reboot".

Notes

One of the complexities of following the research, is that ATG is referred to by many different names by different groups. For example: Thymoglobulin, rATG, hATG, ATGAM, antithymocyte globulin, etc.

The cells that Burt is removing and then reinjecting are sometimes called "precursor bone marrow cells" and other times "adult stem cells".

The lead investigator for this clinical trial is Dr. Gitelman at UCSF. For those of you at Bearskin Meadows: yes, this is the same "Dr. Steve" who is often up there. I'm indebted to Dr. Gitelman for his insights into Burt's research and how it relates to other research, including his own. All mistakes, opinions, and oversimplifications are my own.

Patient oriented information on this trial:
http://www.type1diabetestrial.org

Previous Blog postings on this
http://cureresearch4type1diabetes.blogspot.com/search/label/ATG (blog on ATG)
http://cureresearch4type1diabetes.blogspot.com/search/label/Burt (blog on Burt)
http://cureresearch4type1diabetes.blogspot.com/search/label/Gitelman (blog on Gitelman)

Web pages (but these need updating):
http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials#ThymoglobulinalsoknownasATGbyGitelman (Gitelman)
http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials#ATGandothersbyBurtatUniversityofSaoPaulo (Burt)

Clinical Trial records for this study:
http://www.clinicaltrials.gov/ct2/show/NCT00515099 (Phase-II ATG)
http://www.clinicaltrials.gov/ct2/show/NCT00190502 (Phase-I ATG)
http://www.clinicaltrials.gov/ct/show/NCT00315133 (Burt)

Joshua Levy

Update on Pescovitz's Rituximab Phase-II trial

Pescovitz (and team from TrialNet) have finished a phase-II human trial of Rituximab, and the results have been accepted for publication at a big-name scientific journal. Unfortunately, that journal has embargoed the result data until publication, so I don't actually know the details of how well it worked. The good news, is that the study's authors did an oral presentation at ADA 2009, and (I'm told) that the results were good, but not as good as with the anti-CD3 monoclonal antibody drugs from Macrogenics or ToleRx. Those drugs preserved beta cell functionality for at least a year after treatment. Basically, untreated people lost half their ability to produce insulin in the year after onset of type-1 diabetes, but treated people retained about 95% of their ability. Rituximab was not as successful as that, but did preserve some insulin production.

Rituximab is a monoclonal antibody, a product of Genetech (now a division of Roche), and already approved by the US FDA for rheumatoid arthritis and several cancers. You can read more about it here:
http://en.wikipedia.org/wiki/Rituximab

It works by attacking B cells that have the CD20 marker. These B cells are part of the immune system and completely different that the beta cells (sometimes called B cells) in the pancreas. The immune system has many different types of both B cells and T cells. Most drugs currently being tested to cure type-1 diabetes target T cells. (For example: MacroGenics, ToleRx, Diamyd, Faustman, ATG, Abatacept, etc.) Rituximab is targeting a completely different type of cell (B rather than T). It is thought to work because B cells may interact with T cells influencing their targeting to attack beta cells. So this study is interesting, both because the results are good, but also because it potentially opens up a whole new area to understand as part of the cause of type-1 diabetes, and that means a whole new area where a cure or treatment might be found.

A follow on trial of Rituximab is currently being designed. It will probably involve repeated dosing of the drug. Obviously, I'll post when that clinical trial starts.

Discussion (Why many different treatments might be more effective.)

Right now, we have at least 5 drugs in phase-II or III human trials that, when given during the honeymoon phase, result in the patient loosing only half as much insulin production capacity, as if they were not given the drug. These include Rituximab, Diamyd's GAD65, several different anti-CD3s, and (maybe) Alpha Interferon. There are three ways of looking at these results:

The pessimist: "I don't want five half-way cures. I want one actual cure. Come back when you have something that works."

The engineer: "If it works half way now, then maybe we can improve it a little so it is three quarters working in a year or two, and 90% working a year or two after that and...."

The optimist: "Maybe we don't need a single cure. Maybe the proper combination of the many half cures we have will work right now, or will work for some people."

So if you're an optimist, then having several different treatments for type-1 diabetes which each target a different part of the autoimmune attack, is a good thing. We're used to thinking of a cure as being one pill or one operation or one something. In fact, for many of the more complex diseases (such as cancers, etc.), it is a cocktail of drugs which work together to have the best effect. And type-1 diabetes is surely a complex disease!

Of course "drug cocktails" are harder to test and harder to get approval for, and generally slower to market. In the past there has been discussion of pairing something that stops the autoimmune attack with something that regrows beta cells. That is one type of "drug cocktail", but it also may be that the thing that stops the autoimmune attack with the fewest side effects is itself a mixture of several drugs which target different parts of the autoimmune response.

Thanks to Dr. Gitelman for insightful discussions of this research. All mistakes here are my own.

Clinical Trial Record for the Rituximab trial is here:
http://www.clinicaltrials.gov/ct2/show/NCT00279305

Joshua Levy

Brod Completes Phase-II trial of Alpha Interferon

Brod has finished a Phase-II clinical trial of oral interferon alpha, as a possible honeymoon cure of type-1 diabetes, and has published the results. The study involved 128 people, some of whom got 5k units of interferon, others got 30k, and others got none at all; daily doses for one year. After a year, natural insulin production in response to a meal was measured. The experiment was random assignment and double blind.

The results were this: The untreated group lost 56% of their insulin production one year after diagnosis. The group treated with 30k lost 46% but the group treated with 5k lost only 29%. So the best-to-worst summary is that the treated group lost about half as much insulin production as the untreated group. This result is very similar to Diamyd's and ToleRx's Phase-II results.

The press release describes Brod's theory this way:

Brod's theory is that autoimmune diseases, which occur when the body is attacked by its own immune system, are actually an alpha interferon immunodeficiency syndrome. Interferons are a group of proteins produced by cells in response to an attack by a virus.

My translation of this, is that he thinks that type-1 (and other autoimmune diseases) are caused by a lack of alpha interferon. Therefore, dosing with alpha interferon is an obvious path to a cure.

This clinical trial was funded by Diabetes Action Research and Education Foundation, the US Gov and the Children's Hospital of Minnesota Foundation.

Press release is here:
http://www.sciencedaily.com/releases/2009/07/090701083049.htm

Abstract of the results is here:
http://www.ncbi.nlm.nih.gov/pubmed/19564474?dopt=Abstract

Clinical Trial Record is here:
http://www.clinicaltrials.gov/ct2/show/NCT00024518
(By the way: this is one of the worst clinical trial records I've seen. Especially since the US Gov is a major contributor to this work. There is no end date, Brod is not listed as primary investigator, no description of how many patients got which treatment, etc.)
There is also another clinical trial record here, but I'm not sure if this is the same clinical trial, a related one, or a totally different one:
http://www.clinicaltrials.gov/ct2/show/NCT00005665

Joshua Levy

NovImmune to enter Phase-II with NI-0401 (Another CD3 targeted drug)

It looks like NovImmune (a Swiss company) will start phase-II trials of NI-0401, a CD3 targeted drug "this quarter" and hope to have results in 2011 "at the earliest". The trial is expected to be multi-site and have between 100 and 200 patients enrolled, making it pretty big for a phase-II. The drug has already completed a phase-I clinical trial for Crohn's disease, another diseases where the immune system attacks it's own body. I can't find any record of a phase-I trial for this drug in type-1 diabetes, so I assume they are using their safety data from the Crohn's testing to justify a phase-II trial for type-1 without a separate phase-I.

News article is here:
http://www.bioworld.com/servlet/com.accumedia.web.Dispatcher?next=bioWorldHeadlines_article&forceid=50851

If treatments targeting CD3 sound familiar, that is not surprising. There are two other CD3 targeted treatments already in human trials. ToleRx's Otelixizumab (in phase-III trials now), and MacroGenics's Teplizumab (in phase-II trials now).

More information on ToleRx (Otelixizumab previously TRX4) :
http://cureresearch4type1diabetes.blogspot.com/search/label/Otelixizumab
http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials#TRX4alsoknownasChAglyCD3byToleRx

More information on MacroGenics (Teplizumab):
http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials#MacroGenics

Joshua Levy

Haller Cord Blood trial, results from Phase-I and Starting Phase-II

Haller at University of Florida is running a research program to transfuse into honeymoon diabetics their own (previously frozen) umbilical cord blood. Umbilical cord contains stem cells and also a lot of a specific type of T-cell (part of the immune system) called T-regulators. These cells help to regulate the immune system, and since type-1 diabetes is caused by a lack of immune regulation, this seems like a reasonable thing to try. Especially since more and more people are "banking" their children's umbilical cords at birth. The Phase-I study was focused on two possible paths to a cure: adult stem cells would migrate to the pancreas and help grow new beta cells, and/or T-regulators would help suppress the bad immune response. It appears that the adult stem cells path did not pan out, and the phase-II trial only discusses the T-reg mechanism, and not the adult stem cell mechanism.

So the basic status is that Haller has completed a phase-I trial, and gotten good results, and has started a phase-II trial.

The Phase-I Trial
It is supposed to involve 23 patients and run from April 2005 to July 2010, however the data I've seen covered 8 patients and was published in June 2007, so it is an interim result.

That said, the results were good: a few months after the transfusion, the treated kids had an average A1C 1 point lower than untreated (7 compared to 8), they used about 2/3 as much insulin per kg of body weight as the untreated patients, and they generated more C-peptide in response to food (meaning they generated more of their own insulin).

For the phase-I trial:
http://cordblood.cryosite.com/UserFiles/File/Cord%20Blood%20and%20Diabetes.pdf Nice summary
http://www.ncbi.nlm.nih.gov/pubmed/18358588 Phase-I Results Abstract
http://cordblood.net/cbrblog/haller-abstract.pdf Phase-I Results Whole Paper
http://clinicaltrials.gov/ct2/show/NCT00305344 Phase-I US Clinical Trial Record

The Phase-II Trial
It involves 15 patients (10 get treatment, 5 are the control group), and is scheduled to start March 2009 and finish collecting data by March 2012.

More details are described here:
http://clinicaltrials.gov/ct2/show/NCT00873925 Phase-II US Clinical Trial Record

My thoughts on this line of research are here; these are all personal opinions:
First, I think it is pretty limited in direct application, since it requires banked cord cells and is a honeymoon treatment. But I'm always hopeful that they might learn something that could be applied more broadly.
Second, I'm very interested in how long the effect lasts. Is it permanent, or does it go away over time?
Third, I think their "phase-II" experiment is tiny. Only 15 patients makes it smaller than some phase-I experiments that I've followed, and that's not a good sign.
Forth, this research "feels" to me like basic research where they're trying to better understand how adult stem cells and T-regulator cells might help type-1 diabetics, by experimenting on people. Rather than research on a short, straight line path to a cure.

Thanks to Ellen over at www.childrenwithdiabetes.com for pointing the phase-II trial out to me.

Joshua Levy

The short life of Efalizumab (BRiTE) Phase-II Clinical Trial

In early April, I found out about a new phase-II clinical trial, called BRiTE, that tested Efalizumab as a possible honeymoon cure for type-1 diabetes. Efalizumab (tradename "RAPTIVA") is a product of Genentech and is already approved for use on psoriasis and rheumatoid arthritis, which are autoimmune diseases in some ways similar to type-1 diabetes. I was in the process of writing up the summary when the news turned bad.

Later in April, Genentech and the US FDA announced that Genentech was voluntarily withdrawing Efalizumab from the market. I assume that this will mark the end of the type-1 clinical trial as well. Genentech has received 3 reports of progressive multifocal leukoencephalopathy (PML) in people treated with RAPTIVA. This disease is caused by a virus and is almost always fatal (survivors are often brain damaged), and is very rare.

This is a cautionary story for our testing process for new treatments. As the US FDA has said:

Raptiva was approved for the treatment of moderate to severe plaque psoriasis in 2003. There were no cases of PML seen in the clinical trials that supported the approval of Raptiva. At the time of approval, a total of 2,764 patients had been treated with Raptiva. Of those 2,764 patients, 2400 had been treated for three months, 904 for six months, and 218 for one year or more.

Since the approval of Raptiva (efalizumab) in October 2003, the FDA has received reports of three confirmed cases and one possible case of progressive multifocal leukoencephalopathy (PML) in patients who were 47 to 73 years of age who were using Raptiva for the treatment of moderate to severe plaque psoriasis. Two of the patients with confirmed PML and one patient with possible PML died. All four patients were treated with Raptiva continuously for more than three years. None of the patients were receiving other treatments that suppress the immune system while taking Raptiva.

Notice that there is no discussion of clinical testing lasting longer than 2 years, and that the people who got PML had all been taking the drug for over 3 years. The testing that RAPTIVA got is pretty much the same testing that the various type-1 cures currently under development are getting.

And you may want to think back to the bravebuddies discussion of a few months ago ("Ask the FDA to better serve diabetes patients" and "COMMENT ON FDA PETITION", when people were complaining about extra testing that the FDA wanted to require to make sure drugs approved for diabetes did not cause heart problems. Those drugs were getting approved with less than 1 year of testing, and people were howling that the FDA wanted two years or maybe more!)

This is also something to remember if an immunity drug based cure becomes available. If one does we will all be asking ourselves the same question: should my child be first in line to get this cure? It's now been FDA approved, should I get it for my kid right now, or wait. And if I wait, how long? These are not going to be easy questions to answer.

My understanding is that Efalizumab lowers the autoimmunity by targeting a specific type of T-cells, called CD11a. Several other treatments for type-1 diabetes which are currently in clinical trials work by targeting specific types of T-cells, although I don't know of any other drug that targets CD11a cells specifically. ToleRx and MacroGenics both target CD3 cells, while Pescovitz's research targets CD20 cells, and Faustman is targeting certain CD8 cells.

Here is the Clinical Trial record for the type-1 test: http://www.clinicaltrials.gov/ct2/show/NCT00737763
And a press release of the withdrawal: http://www.raptiva.com/raptiva/index.jsp?p=Raptiva&fr=yfp-t-501&toggle=1&cop=mss&ei=UTF-8

Joshua Levy

Atorvastatin (Lipitor) in New Onset Type 1 Diabetes Mellitus

This is a "new to me" study, that actually started in July 2007 and is expected to end July 2010. It is phase-II and included 54 people, who are within 6 weeks of dx for type-1 (so honeymooners only). 2/3 of the people will get Atorvastatin (Lipitor) and will be compared against the 1/3 who don't get the drug.

The US clinical trial record is here: http://www.clinicaltrials.gov/ct2/show/NCT00529191

Now, for those of you who did a double take, when you saw that Lipitor was involved: Yes, this is the same statin drug which is used to lower cholesterol, and is the best selling drug in pharmaceutical history. There was no phase-I study for this treatment, because they knew the drug was safe, they went straight to phase-II.

Apparently, Atorvastatin (Lipitor) results in lower insulin requirements when give to "rodent models". I assume they are talking about NOD mice. I'm not sure why this drug might work, but it does lower inflamation, so maybe that's it.

I know of one study which gave Atorvastatin (Lipitor) to people with established type-1 diabetes in the hopes it would limit artery damage. It was not successful. However, I don't see that those guys reported A1C, BG, or insulin usage numbers turning the trial:
http://www.freundpublishing.com/Journal_Pediatric_Endocrinology_Metabolism/JPEM22p65.pdf
Of course, the studies are focused on different time frames, honeymoon vs. non-honeymoon so they may well come to different results.

Joshua Levy

Two New Trials to Test Kineret / Anakinra

I recently found out about two clinical trials into the drug Kineret also known as Anakinra (an Anti-Interleukin-1 treatment). A phase-I study which started in March 2008, and a phase-II study which started in January 2009. Last year there was some interest in the idea that inflammation was a causative factor in type-1 diabetes. These are the first human trials that I know of which are based on attacking inflammation to try to cure type-1 diabetes (in honeymooners only, however). This drug is already approved by the US FDA for the treatment of rheumatoid arthritis. It has also already be used in clinical trials focusing on type-2 diabetes and some autoimmune diseases (in addition to RA).

The phase-I study is 15 kids (aged 6 to 18) who are within one week of diagnosis. The trial is scheduled to end in July 2009. It is being done by Soumya Adhikari at Children's Medical Center Dallas, Texas, United States, and is funded by their own foundation. You can read the US Clinical Trail Record here: http://clinicaltrials.gov/ct2/show/NCT00645840. I can find no other information on this trial on the web.

The phase-II study is being done by the Steno Diabetes Center in Denmark is testing using Kineret on newly diagnosed type-1 diabetics. The study is called "AIDA". It is multi-site, all in Europe. You can read more about it here: http://www.aidastudy.org. The study is funded by JDRF, Steno, and Oresund.

This is their description of the drug:

Kineret® is already being used in the treatment of patients suffering from arthritis and studies are now suggesting that it may also be useful for patients with Type 1 diabetes. The active substance in Kineret is interleukin-1 receptor antagonist, a blocker of an immune-signal molecule named interleukin-1. During inflammation this blocker is produced by your body to limit tissue damage caused by inflammation, and kineret is an exact copy of this naturally occurring molecule.

The study will use 160 patients, starting in January 2009 and ending (they hope) in September 2011. Half will get the drug, half placebo. After 80 patients have been followed for 6 months, they will do analysis on the available data, and decide if it is worth continuing the trial, and if it is safe to do so. I don't know if this interim analysis will be published or not. (I hope so!)

Patients will inject themselves once a day, for two years, so this is a pretty big commitment on their part. Since patients must be 18 or over, and with in 12 weeks of diagnosis, I suspect it will take them quite a while to enroll 80 people, even as they have 23 sites participating. Although the fact that it is using an already approved drug should make it easier to recruit.

The US Clinical Trial Record for this is NCT00711503, which you can see here: http://www.clinicaltrials.gov/ct2/show/NCT00711503

There is more information on the Steno center here: http://www.stenodiabetescenter.com/documents/home_page/document/index.asp

If you are newly diagnosed (less than 12 weeks), and in Europe, here is a list of trial sites:
http://www.aidastudy.org/centers/index.htm

A Little Discussion

Everyone knows that type-1 diabetics have a lot of inflammation in their pancreas and especially around their beta cells. Most researchers believe that inflammation is a result of the body's immune attack on it's own cells. That is, the underlying immune problem causes inflammation and also causes beta cells to die (which causes the symptoms of type-1 diabetes). However, some researchers believe that the underlying immune problem causes inflammation, and that this inflammation kills the beta cells, which causes the symptoms of type-1. The difference is that, in the second model, if you stop the inflammation you can stop the symptoms of type-1 diabetes (the high BG numbers and the low numbers). And that is a big difference. But this second model is still a minority opinion.

The treatment being tested should lower inflammation, so if the second model is correct, it will lessen the symptoms of type-1 diabetes, maybe remove the symptoms entirely: the body will naturally produce more insulin. In any case, one of the great things about this research, is that we should have some solid data soon. The phase-I trial should complete mid this year, the early data from the phase-II later this year, and the final data from the phase-II by year after next.

Joshua Levy

Diamyd Starts Phase-II Trial Aimed at Established Type-1 Diabetics

Diamyd has announced NIDDK is starting a clinical trial to study a combination of their GAD65 immunesupressive together with two drugs designed to stimulate the body's own beta cell growth and insulin generation.

You can read the press release here:
http://www.diamyd.com/docs/PressClip.aspx?PageID=4&ClipID=486
the headline is:

DIAMYD® COMBINATION TRIAL AIMED AT REGENERATING INSULIN-PRODUCING CAPACITY IN ESTABLISHED TYPE 1 DIABETES GETS APPROVAL FROM FDA

Background
Diamyd's product is an immunesupressive that specifically targets GAD, which is one of the markers for type-1 diabetes. This treatment is currently in two large phase-III trials for honeymoon (recent onset) type-1 diabetics, one in the US and one in the EU. Data from phase-I and phase-II trials, also on honeymooners, show that treated patients use less insulin than untreated patients. Some quite a bit less, and some did not need to use insulin at all for short periods of time. So this is all good news for honeymoon diabetics.

This phase-II human trial takes the same basic treatment and combines it with drugs already approved for type-2 diabetics in an attempt to cure (or improve) non-honeymoon diabetics.

The Study that is Starting Now
They want to enroll 164 people, starting Feburary 2009.
There is no information on how long it will last, or when results will be available.
It is Randomized, Double-Blind, and Placebo Controlled.
One interesting wrinkle is that it is only open to honeymoon diabetics, even thought the treatment is clearly focused on non-honeymooners. I think this is because GAD65 has only been tested on honeymoon diabetics, and is not yet approved for the mass market, so limiting these tests to honeymooners only will speed things along (no extra safety testing for a new population). Anyway the press release makes clear that they are trying to regenerate the body's own ability to make new beta cells (and thus more insulin), and that it is designed for non-honeymooners.

Here is how Diamyd describes it:
This new Phase II study will be the first to combine regenerative agents and Diamyd®. The regenerative agents to be evaluated are lansoprazole and sitagliptin, which are both marketed drugs in the US. The study, to be led by Professor David Harlan at NIDDK, aims to enroll 82 adult patients. "We are excited to start this study to investigate if combining Diamyd® with potentially regenerative stimuli can meaningfully improve treatment of established type 1 diabetes", says Professor Harlan, chief of the Diabetes Branch at NIDDK and professor of medicine at the Uniformed Services University of the Health Sciences.

Notes: NIDDK is part of NIH: the National Institues of Health, part of the federal [USA] government. Also, I think the 82 people listed above is the number who will get the treatment. Another 82 will get placebos, for a total of 164.

You can read more about it at the US Government's Clinical Trials site: http://www.clinicaltrials.gov/ct2/show/NCT00837759

Why is this Important?
In my mind, this clinical trial is very important for two reasons:

First is the tactical reason: Because Diamyd's drug is already undergoing phase-III trials, it could be approved for general use (with a prescription) in 3 or 4 years. The other drugs used in this trial have been generally available for several years. So in just 3 or 4 years we will have results of this phase-II trial and general availability of all the drugs needed. So if this trial is successful, you could actually get the treatment as an "off label" use, if your doctor was willing to write the prescriptions.

Second is the strategic reason: There are several drugs in phase-III and phase-II clinical trials which are targeted at honeymoon type-1 diabetics and which work by stopping the immune attack and "saving" some insulin production. This trial is the first attempt that I know of to take a honeymoon only cure, and make it work on non-honeymooners. But if it works, the same idea could be applied to ToleRx's treatment, Andromedia's treatment, MacroGenic's treatment, Rituximab, Thymoglobulin, Abatacept, etc. That gives us all a lot more chances for a cure using treatments which are already well into the approval process.

Also, one of the controversies in type-1 cure research today is this: does the body naturally regenerate beta cells (and thus insulin production) or not? If the body does, then every honeymoon only cure will become a cure for everyone, if you just wait for the body to regrow it's own beta cells. However if the body does not, then those cures will only work for honeymooners. However, if this clinical trial is successful in finding a path that works with non-honeymooners, then the whole question of regeneration of beta cells is not important: if they naturally regenerate: great. If not, this experiment (if successful) shows how they can be regrown anyway. Type-1 can be cured in either case.

This is big news. This is good news.

New Phase-II clinical trial: Abatacept

I'm in the process of adding a new human trial to my list of clinical trials aimed at curing type-1 diabetes. This is a phase-II trial of Abatacept, a drug already approved for rheumatoid arthritis. It is a honeymoon treatment. The hope is by giving this drug early in the process, some insulin production can be preserved, or (if that fails) the honeymoon phase can be extended.

This drug is already approved for use on rheumatoid arthritis (in certain situations), and is currently part of many human trials for several different "self immunity" based diseases such as Psoriasis Vulgaris, Asthma, Scleroderma, Ulcerative Colitis, Lupus, Multiple Sclerosism and Graft or Organ Rejection.

Unfortunately, there was no phase-I trial targeting type-1 diabetes for this drug, so there is no data on it's effectiveness against type-1 diabetes. Since it was already approved for use in people, they could skip the phase-I trial because the drug's safety was already known. It did prevent diabetes from developing in NOD mice.

Estimated Enrollment:	108
Study Start Date:	February 2008
Estimated Study Completion Date:	June 2013
Estimated Primary Completion Date:	February 2012 (Final data collection date for primary outcome measure)

Sponsors include several US government agencies (NIDDK, NIAID, and NICHD) , JDRF and ADA.

The ClinicalTrial record for this study is: http://www.clinicaltrials.gov/ct2/show/NCT00505375
Wikipedia has general article on Abatacept: http://en.wikipedia.org/wiki/Abatacept
TrialNet's record for this trial is here: http://www.diabetestrialnet.org/patientinfo/studies/CTLA.htm

This study is recruiting people right now. The first requirement is that you be within 100 days of diagnosis. You can get more information from TrialNet (link above) or by calling 800-HALT-DM1 (1-800-425-8361). It is being run out of 15 different US sites, and a couple of sites in other countries. For the locals: both UCSF and Stanford are trial sites.

The primary investigator is Orban, out of the Joslin center. The same guy who took Faustman's research in a different direction. I think he has the distinction of being the only guy with two different human trials to try to cure type-1 diabetes active at the same time, or almost the same time. He must be one busy dude.

Joshua

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

Osiris Therapeutics has started a Phase II trial

Osiris Therapeutics has started a Phase II trial of their Prochymal cure for type-1 diabetes. This is an adult stem cell based cure, which has already completed Phase I and II trials and is undergoing Phase III trials targeting other immune diseases, such as Crohn's and Organ Rejection, etc. I think it is being tested on 6 or so different diseases right now. The company's description is this: "Prochymal is a preparation of mesenchymal stem cells specially formulated for intravenous infusion. The stem cells are obtained from the bone marrow of healthy adult donors."

The trial is 60 people, all within 16 weeks of initial diagnosis. It started in June 2008 and is expected to end in June 2010. The study is being done in Tennessee, and is partly funded by JDRF. Here is the company's description: "The design will be a double-blind, placebo-controlled trial at multiple sites with a target enrollment of 60 patients, and patients will be randomized to either Prochymal or placebo at a 2:1 ratio. The primary endpoint of the trial will be the measurement of C-peptide produced during a Mixed Meal Tolerance Test in patients treated with Prochymal, compared to those receiving placebo."

As far as I know, this is the first Phase II human trials for any stem cell based cure for type-1 diabetes. So it represents a whole new approach to a cure, into Phase II trials. Very good news.

For more information:
http://www.medicalnewstoday.com/articles/112956.php
http://www.osiris.com/clinical_trials_prochymal_t1d.php
http://www.osiris.com
http://clinicaltrials.gov/ct2/show/NCT00690066