Monday, November 23, 2009

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

Sunday, November 22, 2009

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:

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:

Press release:

Clinical Trial record for new phase-II trial:

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 HbA1c 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:

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

Wednesday, November 18, 2009

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.


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:
Clinical trials record for this research:
Clinical trials records for Xoma's other diabetes research:
Previous blog entry on inflammation (including some general discussion):

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

Friday, October 23, 2009

Possible Cures for Type-1 Diabetes in the News (October)

Living Cell Technologies Starts Phase-I Study in New Zealand

LCT is developing an encapsulated pig cell cure for type-1 diabetes. They have completed a phase-I study in Russia which resulted in one patient being off insulin for a few months, and another for a few weeks. They finally got approval from the New Zealand government, and have now treated their first patient. This clinical trial is very similar to the one they completed in Russia, but half the patients will get twice the dose that the Russians started with, and the second half will start out with three times the dose. Eight people total. This trial is scheduled to complete in January 2011.

This research has already shown that their encapsulated cells can have good effect for short periods of time. The big question they need to answer are these:
1. Will larger doses of encapsulated cells results in less need for injected insulin?
2. How long will the encapsulated cells continue to work?
This trial will directly address question 1. By using higher doses, they will see if they get more generated insulin, and a higher percentage of people who are off insulin entirely. Unfortunately, question 2 can only be answered by time. By following the patients from the Russian trial and from this new trial for a year or two. Although it may be that they'll learn more about duration by starting with a higher dose.

Another issue for me is this: is this a phase-I study or a phase-II study? That's a big difference because a phase-II study moves them closer to general availability, while a second phase-I study doesn't. Officially the study is "Phase-I / Phase-II". It's size is 8 people, and that's on the small size of phase-I. However, it's goal is to try different doses, and that's a phase-II type of goal. (Phase-I is more focused on basic safety.) The real measure is how the US FDA views it, and I don't know the answer to that question.


LCT also issued their yearly report
which is here:

There are a couple of pieces of meaty news buried in this report.
On page 10 there is a list of KEY TARGETS. Nothing about any US trials, but (in addition to finishing their current trials) they list these two items:
  • Commence pivotal trial in Russia.
  • Commence DIABECELL® commercialisation [sic] – initially in Russian market.
And that makes it sound like whatever they are doing, they are going to do it in Russia first. They have a wholly owned subsidiary there, already.
Their clinical trials are described on pages 14 and 15.

Osiris Therapeutics Announces Preliminary Results For Prochymal Phase III GvHD and COPD Trials

Osiris is running two phase-III trials for their Prochymal treatment, for diseases other than type-1 diabetes. Both of these results are in and both were failures. They have several separate phase-II trials going on, and one of these does target type-1 diabetes. So having all their phase-III studies fail is bad news, but what really matters is the results of their type-1 diabetes clinical trial. Those results are expected in mid-2010.

press release:

Effects of Sitagliptin (Januvia) in Adult Patients With Type 1 Diabetes

This is a 20 person study which started in September and is expected to finish in December. It is trying a drug already in use for type-2 diabetics to see if it helps type-1 diabetics. This is aimed at helping type-1s use less insulin, not curing them. Based on my quick read of how this class of drugs works, I don't see why it's expected to work on type-1 diabetics. It helps the body create more insulin. I understand how that would help type-2s, but not type-1s. Anyway the proof is in the results, and we will not need to wait long. The research is being done at the
Barbara Davis Center in Denver (which is top-of-the-line.) The good news is that we will have results very soon, and if they are positive, the drug is available right now.

Sernova's Animal Studies Continue

Sernova published results from some animal studies. You can read the links below for details. No date to start human trials was announced. This work is a follow on to Valdez's work in Mexico years ago, which was very controversial at the time it was done. He didn't do animal trials before going straight to people, and was eventually shut down by the Mexican government. It was also unclear if he was really getting as good results as he claimed. Sernova is trying to use the same ideas, but do the animal studies first, and then get Canadian or US FDA approval to do a clinical trial. So this treatment has been in clinical trials in the past, although not right now.

The basic trick was to get porcine beta cells, mix them with sertoli cells, and then implant the mix. Sertoli cells block the immune system, so the idea is that the immune system will not attack the new beta cells. So it's similar to encapsulated beta cells (LCT), but a little different.

Tuesday, October 20, 2009

Wilson's Pioglitazone Phase-I Study is half way enrolled

Dr. Wilson was kind enough to tell me that his Phase-I study of Pioglitazone is about half way enrolled. They are hoping to enroll 15 people total. The study is a pilot one, being done at Stony Brook, NY, USA. Pioglitazone has been approved for use in type-2 diabetes for about 10 years. Pioglitazone is part of a larger drug family called thiazolidinediones which have been shown to preserve beta cells in animals with type-1 diabetes, and to reduce death of beta cells in petri dishes.

This study is also unusual in that it will enroll children as young as six. I assume that is at least in part because they are working with an already approved drug with a known safety profile. Open to patients within 4 months of dx.

For those of you who are near Stanford University, the Dr. Wilson doing this trial is different than the Dr. Wilson who is at Stanford.

Joshua Levy

Thursday, September 24, 2009

Two Possible Cures go to the Boneyard

It's never good news when possible cures "go to the boneyard", but it is part of research. Some treatments work and many don't. Here is a little discussion of two treatments, one of which has not worked out (for type-1 diabetes), and the other is on hold, with no clinical trials in sight:

Transition Therapeutics's TT-223 goes to the Boneyard

Transition Therapeutics is researching using a combination of two drugs to cause beta cell regrowth in an attempt to cure type-1 and type-2 diabetes. As of May 2009, they had officially marked their phase-I human trial for type-1 diabetes as closed. I haven't seen any published results for it, but I'm still looking. However, actions speak louder than words, and Eli Lilly (working with Transition Therapeutics) started a clinical trial in February 2009 using Transition Therapeutics's TT-223 product, but only for people with type-2 diabetes.

Also, in May 2009 they announced that JDRF and Transition Therapeutics had agreed that JDRF would stop funding clinical development of TT-223. Transition Therapeutics and JDRF terminated their agreement. Eli Lilly is taking over support for TT-223, but is applying the technology only to type-2 diabetes.

So the news from Transition Therapeutics for type-1 diabetics is not good. I will move Transition Therapeutics to my "boneyard" of research that has not panned out if there is no good news in the next 6 months.


This result is not too surprising, and is similar to previous results with INGAP: because type-1 diabetes is an autoimmune disease, simply regrowing new beta cells can not cure it. The immune system attacks the new beta cells the same as the old ones. This type of treatment has more direct applicability on type-2 diabetes, where more beta cells are more likely to be helpful. Of course, if any of the treatments currently being developed succeeds in ending the autoimmune attack, then treatments that regrow beta cells will suddenly be in high demand. Unless the body regrows beta cells naturally without intervention.

A few months after stopping the funding of TT-223, JDRF started funding a large, general program (together with Genomics Institute of the Novartis Research Foundation) to test generic drugs for their ability to help regrow pancreas cells. Although I don't have visibility into JDRF's decision making, I think it is reasonable to say that since TT-223 did not pan out, JDRF is putting money into other research with similar goals. Unfortunately, that research is not in human trials yet, so I won't be following it.

These are records for Transition Therapeutics's phase-I studies: (type-1) (type-2)

And here is the clinical trial record for their phase-II study (which is type-2 only):

I'd like to thank Susan Mohr for some of the information used here.

Alba's Lazotide (previously AT-1001) goes to the Boneyard for type-1 diabetes, but not Celiac Disease

I recently moved Alba Therapeutics's Larazotide (previously known as AT-1001) from my "preparing for clinical trials" section to my "boneyard" for treatments that are no longer under development as cures for type-1 diabetes.

I did this before reading the following Scientific American article:
That article (written by a founder of Alba Therapeutics) says that the FDA approved human trials for Larazotide for type-1 diabetes. However, I can not find any references at the company's web site that they are planning such a clinical trial, and there is nothing in, either. So therefore it is staying in the boneyard for now.

If you read the article linked above, remember that the author did some of the original research into Larazotide and founded Alba Therapeutics, so is not an unbiased source! In particular, this quote:
Surprisingly, essentially the same trio—an environmental trigger, a genetic susceptibility and a “leaky gut”—seems to underlie other autoimmune disorders as well. This finding raises the possibility that new treatments for CD may also ameliorate other conditions.
This is the author's opinion, however I don't think it is general consensus among researchers. Most researchers believe that autoimmune disorders are built on a foundation of a genetic susceptibility and an environmental trigger. The idea that "leaky gut" underlies autoimmune disorders is a minority opinion. Of course, if Larazotide works the way Alba hopes it will, that might change.

All of the above comments pertain to using Larazotide for type-1 diabetes, not Celiac Disease. The situation for Celiac is much different: Alba is running human trials. There are several listed at, and I think some of them are phase-II. (But I don't follow Celiac closely so am unclear on the details. Also, there appear to be two different drugs called "AT-1001" and "AT1001" so don't get confused.)

Joshua Levy

Saturday, September 19, 2009

Possible Cures for Type-1 in the News (mid-Sept)

This is an experiment in "quick hits". I will provide a paragraph or two of information on recent news items about possible cures for type-1 diabetes. So, in no particular order, here we go:

Andromeda Completes Patient Recruitment in Phase III Trials for DiaPep 227

Andromeda has announced that their phase-III clinical trial of DiaPep277 is fully enrolled. This is an important milestone, because it now means the end of the study can be predicted. Since their protocol is 2 years long, they will be data complete around September 2011. They have also said that they will have results at end of 2011, which makes sense.

DiaPep277 is the oldest Phase-III clinical trial that I know of. Previous news has not been good. Their intermediate results were lackluster and they changed their experimental design and recruited more patients. I've never gotten around to reviewing their Phase-II results (which were published prior to my interest in clinical trials), but maybe I should.

Press release:

4-Year Follow-up of Diamyd(r) Phase II Study Shows Clear Positive Trend

Diamyd got permission to extend their Phase-II trial, and continue to follow the same group of patients for a total of 7 years. They talked about 4-year data in this way:
Initial analysis of new data shows, that patients treated with the Diamyd(r) vaccine early after diagnosis have a clearly better diabetes status compared to the corresponding placebo group, still 4 years after the injections.
Since there are no actual numbers here, I wouldn't read too much into it. "Clearly better" is pretty vague. There is no reference to anything published, so there is no place to look for more details or actual numbers.

press release:

Diamyd to include children over 10 yrs in US phase III study with Diamyd diabetes vaccine

Diamyd got FDA approval to lower the minimum age of enrollment in their US Phase-III study down to 10. That's young for a clinical trial, and a sign that the FDA thinks that Diamyd's treatment is very likely to be very safe. For comparison, ToleRx can accept people as young as 12, and MacroGenics down to 18 (and even 8, but only with special approval).

press release:

Faustman is Data Complete, Results by early 2010.

In 10-February 2009, the Nathan/Faustman group officially reported that they had enrolled the last patient into their Phase-I trials. They also updated their clinical trial record to show that they would be data complete in July 2009. (This makes sense, since the protocol only requires 3 months of data gathering after a patient starts.)

So, as of now, they should be working on analyzing the data, writing the paper, and getting it published. (And if we are lucky, getting reporters or bloggers to write about the results!)

They also have a facebook page which contains this quote:
"We hope to have all of the Phase I data submitted to our biostatistics center in November 2009", and their lab web pages talks about having results by early 2010, so I think we are close to hearing about their results. Their just-released newsletter also has the "early 2010" date.

Joshua Levy

Saturday, September 12, 2009

Background for the Artifical Pancreas

In the past, I have not posted updates for the artificial pancreas (AP) as a possible cure for type-1 diabetes. But I'm now going to spend more time on this area of research. This post provides background for how to follow progress on an Artificial Pancreas. At the end is a section on why I'm posting in this now, when I have not in the past.

Components of an Artificial Pancreas (AP)
I'm going to discuss an AP built out of the technology that we have now, so an "off the shelf" pump connected to an "off the shelf" CGM, with some extra software on the pump to handle the control functions. A successful artificial pancreas is going to involve several different components that can be developed and tested separately. Understanding these components will help help track progress toward the final goal. The components are:
  • A pump that can deliver small enough doses of insulin.
  • A continuous glucose monitoring system (CGM) that is accurate enough.
  • Insulin which acts quickly enough.
  • Software that can take the data from the CGM and do a good enough job of automatically calculating the commands to send to the pump.
  • Government approval of all of the above.
To create an implanted artificial pancreas (IAP), one that can be put inside a person,, there are three more required components:
  • Higher density insulin, so that a longer supply can be stored inside a person.
  • Enough miniaturization so that the pump, CGM, software, and insulin can fit inside a person.
  • And government approval of all these components.
Where are We Now? (what is "good enough")
Part of the uncertainty in the status I describe below, is that these components work together. So imperfections in one might or might not be overcome by advances in the others. For example, if CGM were perfectly accurate, that would make the control software much easier to create. Similarly, the faster acting the insulin that can be used, the easier the control software is to write, because it does not need to take into account the delay in the insulin or build up of insulin in the body. So the question is not do we have good enough CGM. It is more complex than that: do we have a good enough pump, CGM, software and insulin, so that together then can form an AP. And the same is true for all the major components.

For pumps and fast acting insulin, we are in good shape. Today's mass produced pumps are likely precise enough to support the first generations of AP, and currently available insulin is likely fast enough.

For the computer control of an AP, we are very close. There are several computer algorithms which have been tested in different clinical trials, and which seems to work well. The biggest hurtle remaining is to get the software good enough to work with the current generation of CGM.

For CGM, we are not there yet. There are two problem areas for CGMs, both important. First there is accuracy. BG meters in general are only accurate within 20%, but CGM are not even that accurate. No CGM has been approved as a replacement for regular BG meters for exactly that reason. One of the problems with CGMs is that the interstitial liquid that they measure sometimes has higher glucose levels than the blood which standard meters measure (and it is blood glucose levels that really matter). This means that the current generation of CGM devices can sometimes measure higher glucose levels than really exist (which would cause an AP to put in more insulin than it should).

But there are also non-accuracy related issues, which may be a larger problem. Many CGMs are not comfortable to wear, often fall off, have calibration problems, need to be replaced often, etc. My memory of comments in brave buddies, from people who tested CGMs, and from those who now use them, is that there are occasional worries about accuracy, but much more complaining about replacement, falling off, skin space, pain, recalibration work, etc. The bottom line is that no AP will be successful if the CGM component of it is constantly falling off, etc.

As for an implanted artificial pancreas:

There have been European tests of U-1000 insulin (which lasts ten times as long as the U-100 insulin commonly used). And this insulin was enough to operate an implanted pump for 3 months between refills. So I think we have the insulin needed, although it is not yet FDA approved in the US. There are currently clinical trials in the US on U-400 insulin, also.

Also, there have been clinical trials of an implanted pump in the US, including a pump produced by Minimed. So that too, is within sight, although not yet US FDA approved.

For a technical review of where we are, especially in terms of CGM systems, here is a whole journal issue focused on that question:

Six Stages to an Artificial Pancreas

The JDRF framework for a pump is based on six stages as described below. Note that stages 1 and 2 are more of emergency shut off functionality than artificial pancreas functionality, but you need to start somewhere! Indeed, I think it is fair to say that only at stage 4 is there a limited AP, and stage 5 is a full AP:

Stage 1. An emergency shut off when the patient experiences too-low BGs.
Many of us live in fear of extreme lows in the middle of the night which lead to seizures. In the worst case, type-1 diabetics occasionally die in the middle of the night from too-low BG. So a straightforward safety improvement which could be made to a pump, if it was attached to a CGM system would be to shut down the pump if the patients BG levels were too low for too long. Research has shown that most (although not all!) night time seizures are preceded by several hours of low BG numbers. So by simply telling the pump to stop putting in more insulin into the patient, many of these seizures could be prevented. Also, this plays into the strengths of the current CGM technology (the accuracy problems usually effect high BG measurements, not low ones). No any complex software is needed, and if the AP is wrong, BG may go up more than it should, but that is a relatively minor problem. The problem it solves ("dead in bed") is real (if rare) and terrifying. Finally, the FDA can view it as a simple safety interlock, for approval purposes.

Stage 2. A shut off when the patient is heading to a situation where they will have too-low BGs.
This is similar to stage 1, except that it uses software to predict when a low BG situation is likely to happen in the future, and causes the pump to dose less before the low BG situation occurs, hopefully avoiding it. This is much like stage 1, except that it requires more complex, predictive software.

Stage 3. Improving BG levels at all times (avoiding both too-low and too-high BG levels).
The goal of this stage is limit the time the patient spends with either too-high or too-low BG levels. This stage is not trying to keep the patient at ideal BG levels, rather it is just trying to avoid unhealthy BG levels.

Stage 4. Limited control with meal announcements ("overnight control")
At this stage the AP can control BG, aiming at optimum levels in the relatively undemanding time while the patient is asleep. And if it is notified ahead of time about eating. This stage does not need to worry about exercise, or emotional changes, or unexpected eating.

Stage 5. Fully reactive control of insulin.
This is what most of us consider to be an artificial pancreas. It keeps BG levels in the healthy range without having to do separate blood checks or counting carbs.

Stage 6. Fully reactive control of insulin and other hormones.
Beta cells produce other hormones besides insulin, and a better AP will provide those hormones as well as insulin, so this stage is icing on the cake.

Basically, steps 1 and 2 are designed to prevent serious low BG events, especially at night.
Steps 1, 2, and 3 are really focused on avoiding bad BG numbers, rather than keeping the patient with good BG numbers. They are fundamentally trying to avoid mistakes, rather than create a better system.
Steps 4, 5 and 6 are trying to improve what we've got.
Step 4 is sort of a night time AP, while 5 is an all the time AP.
Step 6 is a complete solution for multiple hormones.

How I Plan to Cover Artificial Pancreas Research
Except for this posting, I don't plan to cover each component separately, because that would be a lot of work, and I don't think it would be very useful. Instead, I will cover human trials of complete APs as they are tested, noting which components are in use for each test. I don't think it is useful to report of every trial of U-400 insulin, and U-500, and U-1000, etc. Instead, I will just note if an advanced insulin is used in a specific test of an AP.

Also, I'm probably going to limit my coverage to clinical trials where each patient uses the AP for at least 24 hours (not 24 consecutive hours, but 24 hours total), at least to start. There are a large number of clinical trials aimed at gathering data on a very specific algorithmic questions, and I don't plan to report on all of those. They are very important to the end goal, of course, but there are to many of them, and each one is individually such a small step, that I don't plan to cover them. These advances get incorporated into the longer studies which I will cover.

One problem that I have already hit, is how to name these studies. I don't want to name them after the company or institution running them, because one of those could be running many AP trials at the same time (Minimed, is running more than one right now.) Many of them have one researcher who developed the software being tested, and another who is running the clinical trials. Which one should I use? And what if several people worked together on the software, or in running the trials? I could name them all based on their Clinical Trial number, but that seems so sterile. I'll figure something out. (Maybe they will all get code names or something. :-)

In the next 2-3 weeks I will post a summary of clinical trials posting, which will give a very short status of a large number of current clinical trials involving APs. After that, I'll make follow up postings covering trials, much like I do with non-AP clinical trials.

Why I have not posted about the Artificial Pancreas before; Why I will Now
I have not previously posted about an Artificial Pancreas, for three reasons:
  1. Many don't consider it a cure at all.
  2. There was not that much news on it.
  3. I didn't have a framework to measure progress, in the same way I had a framework for drugs.
However, recently all three of these issues have resolved themselves.

First, I was particularly worried that a posting referring to an AP as a cure would trigger a long a pointless argument about weather an AP was a cure or a crutch. If you gave someone a new heart valve, have you cured their heart condition? If you gave someone a brace, had you cured their withered leg? It is a philosophical question and different people will have different answers. Even worse (for this discussion) I doubt one side could convince the other they were right, because it really is a philosophical difference, so the email discussion could last forever.

Personally, I had always considered an IAP as a cure, but I was not sure if an AP was a cure or not. However, in the past I also thought that this was a minority opinion, and that most people felt that APs were not cures, not even IAPs. However recent discussions with other parents of children with diabetes has convinced me that many people consider APs to be cures, or at least important enough to be very valuable even short of a cure.

The one thing that I don't want to happen, is a long email argument about if an AP is a cure or not. There is no doubt in my mind that some people will consider it a cure, while others will not. Therefore, I'm posting on it's progress for those who consider it a cure, and people who don't should ignore those posts.

Second, in the last four months or so, there has been several reports of progress toward an AP. I think that Weinzimer's work at Yale has been generating much of this press coverage, but others are moving forward in this area as well.

Third, the JDRF has published a framework for evaluating APs. These are the stages that I've discussed above. This framework is based on APs working in progressively more and more realistic (and difficult) situations. It is not based on progress in individual components of an AP, and so it is perfect for me to use as I report on progress.

In the past I have thought about covering APs by covering progress in each major component of an AP. However, this tended to scare me off because of the work involved in covering several different components all of which are making many small, incremental improvements all the time. By limiting my coverage to complete AP testing, I'm hopeful that it will be a reasonable amount of work, and our kids will end up using a complete AP anyway.

Thanks to Dr. Mary and Dr. Steve (both at Bearskin Meadows) for getting me to think about these issues, and providing some of the information used here. All mistakes are my own.

Joshua Levy

Sunday, September 6, 2009

JDRF Funding Research for a Cure

In the US, we are starting the "Walking Season" when JDRF asks us to walk to raise money for cure. So I'd like to do my part, by reminding you all how important JDRF is to the human trials of potential cures for type-1 diabetes, which I track.

Let me give you the punch line up front: 69% of the treatments currently in human trials have been funded by JDRF. (And the number is 86% for the later phase trials!) This is an amazing impact; one that any non-profit should be proud of.

Cures in Phase-III Human Trials
Summary: there are 4, and all of the treatments have been funded by JDRF.
  • GAD65 (several different studies)
  • TolerRx's CD3 (several different studies)
  • MacroGenics's CD3 (several different studies)
  • DiaPep227
Cures in Phase-II Human Trials
Summary: there are 10, and 8 of them have been funded by JDRF, either directly or indirectly through ITN. Here are the treatments that have been funded by JDRF:
  • MMF/DZG by Skyler
  • PROCHYMAL by Osiris Therapeutics
  • Rituximab by Pescovitz at Indiana
  • Thymoglobulin (also known as ATG) by Gitelman
  • Abatacept by Orban at Joslin Diabetes Center
  • Umbilical Cord Blood Infusion by Haller at University of Florida
  • Exsulin (previously INGAP) by Exsulin
  • Kineret / Anakinra by Mandrup-Poulsen at Steno Diabetes Center
Not funded by JDRF:
  • Atorvastatin (Lipitor) by Willi at Children's Hospital of Philadelphia
  • Brod at University of Texas-Health Science Center

Cures in Phase-I Human Trials
Summary: there are 12, and 6 of the are funded by JDRF and 6 are not. Here is the list funded by JDRF:
  • BHT 3021 by Bayhill Theraputics
  • Trucco at Children’s Hospital of Pittsburgh
  • IBC-VS01 by Orban at Joslin Diabetes Center
  • CGSF by Haller at University of Florida [*]
  • Proleukin and Rapamune by Greenbaum at Benaroya Research Institute
  • Lisofylline by DiaKine
Not funded by JDRF:
  • ATG and autotransplant by Burt at University of Sao Paulo
  • Diabecell by Living Cell Technologies
  • NI-0401 by NovImmune
  • Etanercept (ENBREL) by Quattrin at University at Buffalo School of Medicine
  • CGSF and autotransplant by Esmatjes at Hospital Clinic of Barcelona [*]
  • Pioglitazone by Wilson at Stony Brook [*]
The studies marked with a [*] are ones which I have not yet blogged about, but hope to in the next few weeks, as I work through my backlog. This summary does not include Artificial Pancreas research, which I will discuss more in a future posting.

Summary of all Trials
26 in total
8 not funded by JDRF
So 68% of the human trials currently underway are funded (either directly or indirectly) by JDRF. Everyone who donates to JDRF should be proud of this huge impact; and everyone who works for JDRF or volunteers for it, should be doubly proud.

It is important to remember, however, that although there are four treatments in Phase-III trials, we are not close to a cure for established type-1 diabetes. All of the clinical trials in Phase-III and Phase-II are targeted at honeymoon type-1 diabetes; none at established cases. Even with that restriction. None of the treatments in Phase-III trials resulted in cures during their Phase-II trials. They all extended or increased the honeymoon phase in some way.

We have a long way to go, and that is where JDRF comes in.

Compared to Last Year

In 2008 there were 3 treatments in Phase-III trials, in 2009 there are 4 (growth of 33%).
In 2008 there were 5 treatments in Phase-II trials, in 2009 there are 10 (growth of 100%).
In 2008 there were 10 treatments in Phase-I trials, in 2009 there are 12 (growth of 20%).

I do think that a little of this "growth" is because I have gotten better at finding clinical trials, so last year I missed some trials which I'm not missing this year. But I also think that most of the growth is real. There really are more clinical trials going on now.

  • I give an organization credit for funding a cure if it funded that cure at any point in it's development cycle.
  • I use the term "US Gov" for all the different branches and organizations within the United States of America's federal govenment (so includes NIDDK, NIAID, NICHD, etc.)
  • The ITN (Immune Tolerance Network) has JDRF as a major funder, so I count ITN as indirect JDRF funding.
  • I have made no attempt to find out how much funding different organizations gave to different research. This would be next to impossible for long research programs, anyway.
  • Funding of research is not my primary interest, so I don't spend a lot of time tracking down details in this area. I might be wrong on details.
  • I don't work for the US Gov, JDRF, or any of the other organizations discussed here. I'm not a member of JDRF or any of the other organizations discussed here. I do own stock in several of the companies discussed here.
This is an update and extension to a blog posting I made last year:

Joshua Levy

Saturday, August 29, 2009

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".


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:

Previous Blog postings on this (blog on ATG) (blog on Burt) (blog on Gitelman)

Web pages (but these need updating): (Gitelman) (Burt)

Clinical Trial records for this study: (Phase-II ATG) (Phase-I ATG) (Burt)

Joshua Levy

Sunday, August 23, 2009

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:

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:

Joshua Levy

Sunday, August 16, 2009

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:

Abstract of the results is here:

Clinical Trial Record is here:
(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:

Joshua Levy

Wednesday, July 15, 2009

News from Bayhill on their BHT-3021 Treatment

Bayhill is in the middle of a phase-I clinical trial of BHT-3021 which is designed to train the body's immune system not to attack itself. Recently they announced both scientific results, and a huge corporate deal.

First the science: the phase-I study is still ongoing, but based on 12 months of data for one dose level, and 6 months for other dose levels, BHT-3021 appears to preserve beta cell function in type-1 diabetics (as measured by C-peptide production and A1C levels, for example). The differences were small. For example the patients who got the highest level of drug reported on had A1C levels about .44 lower than those who were not treated. This study was open to anyone who had type-1 for less than 5 years, so not just "honeymooners only".

You can see the abstract here:

Second, the corporate deal. Basically, Genetech (now owned by Roche) is going to buy BHT-3021. Genetech will pay Bayhill for this drug, they will reimburse Bayhill for the ongoing costs of the phase-I trial, and Genetech will run future phase-II and III trials. Genetech will market any resulting drug, and Bayhill will get royalties.

For a small company, like Bayhill, this is really the pot of gold at the end of the rainbow. Their lead product candidate is being bought by a major player based on it's success to date. From a money point of view, for a treatment still in the middle of phase-I trials, this is about as good as you can do.

More details are in the press release here:

Joshua Levy

Thursday, June 25, 2009

LCT To Start Phase-I Human Trial in New Zealand

LCT has (finally) gotten government approval to start a phase-I human trial of their DiabeCell product. This is an encapsulated pig pancreas treatment for type-1 diabetes. The New Zealand government has promised this approval months ago, after years of dragging their feet, and now has finally made good on it's commitment. However one important limitation has been put on the trial: only so-called "brittle" type-1 diabetics can be enrolled.

Although LCT is downplaying the importance of this limitation, it has the potential to delay the end of the trial still further. Previously, almost any type-1 diabetic could take part in the trial, so it was easy to find patients to participate. But now, only "brittle" type-1s can participate and that will doubtless cause delays in recruiting participants. "Brittle" diabetics are those diabetics who's BG can drop very quickly. These are the guys who can pass out while driving, or regularly end up in the hospital after collapsing.

Limiting the study to brittle diabetics should make for better results, because these guys have the worst control, and therefore should see the biggest improvements. So from that point of view, it is a good thing. However, it will also slow the trial and delay completion, which is not good.

I view limiting the study to brittle diabetics as 100% political ass-covering (please excuse the language). I think the New Zealand minister of health had delayed so long, that he simply could not just say "yes", because he could have (and should have) done that months ago. So by forcing a change -- any change -- he can claim that the delay was for a good reason. But it's a pointless restriction, and totally unjustified. Pancreatic transplants, which have huge side effects are limited to brittle diabetics, but these encapsulated transplants have basically no side effects, when compared with whole organ transplants. Putting the same restrictions on the patients for one as for the other is really a farce.

LCT has previously started a phase-I human trial in Russia, and so far, 7 people have been treated as part of that study. Some have been treated more than once, and data has been publicized. Some patients in that study were insulin free for a period of a few weeks. I felt the overall results suggested that the treatment did work, but that the implants stopped working just a few months after they were implanted. Others were a lot more excited about these results than I was.

I can not find a USA Clinical Trial record for this work (probably because it is being done in New Zealand), and the information I've read in the press about the experiment make it sound like a repeat of the Russian human trial. Eight patients, for example. Hopefully they will at least use larger doses, so they can learn something new that way.

While getting permission to run this trial is a step forward, I'm not exactly sure how it leads to general availability of the treatment. It is the second phase-I study started, but no phase-II study is planned (that I know of). In the past LCT had talked about a phase-II study in Denver, but when the economy got into trouble a few months ago, they stopped talking about that, and laid off at least one of the key people involved in it. So overall, I'm happy to see them do another study, but I'm also waiting for some information on how they plan to get from phase-I trials (which they have done and are doing) to general availability of the treatment.

Joshua Levy

Tuesday, June 23, 2009

Update on Andromedia's DiaPep227: Money to Market

You might have seen this recently headline from Reuters:
Andromeda says Teva to market diabetes treatment

This headline is quite misleading. What has actually happened is this: "Teva had decided to exercise its option to complete a $13.5 million investment to market Andromeda's treatment for Type I diabetes." This is an announcement about money, not about the availability of a treatment for type-1 diabetes.

Andromeda's treatment, called DiaPep 277 is a a "heat shock protein". This is a protein that is generated naturally by the body when stressed, and is known to help modulate immune response. The following article:
contains a good overview of heat shock proteins, and how DiaPep 277 is supposed to work. But remember that the clinical trial discussed there are 7 years old at this point.

It is in the middle of a 5 year phase-III human trial, starting in June 2005 and ending in June 2011. I believe it was the earliest possible type-1 cure to go into phase-III human trials (the last phase before marketing approval). The early results were not very promising, but they added more people to the trial, and changed the way they analyzed the data, and are hoping for good results. So far, I have not seen any good news type results from this study, but Andromeda seems very positive, and Teva has put in over US$ 15 million over the last year, so they think that something is there. I just do not see it myself.

Press coverage:

Clinical Trial record for this study:

More information here:

Joshua Levy

Saturday, June 20, 2009

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:
(although I really need to update this)

Read the press release here:

The web page home of this trial is here:

Here are the US Clinical Trial entries for all three studies: (Protege) (Extension) (Encore)

Joshua Levy

Friday, May 29, 2009

Exsulin: New Phase-I Research Almost Ready to Start (for Non-Honeymoon Type-1 Diabetes)

The Exsulin company is hoping to start Phase-I human trials in June 2009 (so right soon now). They are testing a new formulation of INGAP called Exsulin, a drug designed to regrow beta cells in the pancreas.

Their Phase-I clinical trial is small, short, and open to people who have had type-1 diabetes for more than 2 years, so we should have some results soon. It is a three group design. One group gets nothing, one gets a full dose, the other gets a half dose. They are checking for all the right stuff: C-peptide, fasting glucagon, fasting glucose, total daily insulin dose, and HbA1c. They are using two sites Montreal and Rochester.

This is described on their web site:

INGAP (now renamed Exsulin) has a 12 year history of research. NOD mice trials worked well, but human trials didn't show much success (sound familiar?) The phase-I study is described here: The phase-II study is described here: It was funded by Proctor and Gamble but the results were not good enough to move forward.

The original developers of INGAP got back rights to it after P&G didn't like the phase-II results. Their analysis of the results convinced them that INGAP was helping grow new beta cells, but that those new cells were being killed off too quickly to help the patient. (Maybe because of the body's immune system, or maybe because of inflammation, or maybe for some other reason.) So it is natural for them to pair Exsulin with another drug to treat the other problem, and see if both together can cure type-1 diabetes. But the research they are starting now is just Exsulin, not paired with anything.

Joshua Levy

Wednesday, May 27, 2009

DiaKine starts Phase-I clinical trials on Lisofylline (LSF)

DiaKine is about to start it's first clinical trial in a research program aimed at curing type-1 diabetes. Their treatment is Lisofylline (LSF), an anti-inflammatory drug that (in NOD mice) has prevented type-1 diabetes and (when given with exendin-4) cured existing type-1 diabetes.

Previously (in May 2008) DiaKine has formed a joint project with Kinexum Metabolics, to run a human trial (phase-II) using both of their drugs together (LSF and INGAP). The combination had already given good results in NOD mice. That trial was supposed to start in "late 2008". Kinexum Metabolics has since changed it's name to Exsulin (not INsulin, but EXsulin. Get it?) I can't find any record of the LSF+INGAP trial starting, but each company is testing it's own stuff seperately, so maybe after that, they'll test them together. I know a lot of people are interested in an anti-inflammatory and a beta-cell growing combination therapy, and obviously these two companies are interested in that, also. In any case, this trial is LSF only, not the combo they talked about earlier.

The current trial involves 8 people, and is supposed to start in May 2009 and be done by December 2009.

This research is being done in New Jersey.

You can read a news article here:,821004.shtml

The US FDA's clinical trial record is here:

And the official press release is here (and is better than most):

The press release talking about LSF+INGAP together is here:

I want to thank the Wainscoat family for bringing this to my attention.

Joshua Levy

Monday, May 25, 2009

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:

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) :

More information on MacroGenics (Teplizumab):

Joshua Levy

Thursday, May 21, 2009

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: Nice summary Phase-I Results Abstract Phase-I Results Whole Paper 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: 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 for pointing the phase-II trial out to me.

Joshua Levy

Wednesday, May 6, 2009

Quick Updates: Faustman, Diamyd, and LCT

Quick Update on Faustman
This is a very fluffy TV news segment on Faustman, with no new information in it, except that results of her human trials should be published "by 2010". Previously, the target was mid-2009, and before that, late 2008.

Discussion on Faustman
There is no way to know if this is bad news for the research or not, because there is no way of knowing the cause of the delay. Human trials are often delayed because it takes longer than expected to recruit people (a good reason), but sometimes they are delayed for more complex analysis required to see a small benefit, not seen in the quicker data analysis (a bad reason).

Quick Update on Diamyd{16C4F628-8E2A-4E83-B0FB-0A514E053449}&dist=msr_2
This is a five year follow up on Diamyd's phase-II clinical trial of their GAD65 treatment on LADA patients. Sometimes called "type 1.5" LADA is immunity based diabetes that effects older people. So the results seen here are likely to be relevant to type 1 diabetics. The results were good, especially in avoiding insulin use. The 47 patients got several different doses. The best dose seemed to be 20ug. At the start of the trial, none of the patients required insulin. For the 20ug dose, only 14% of the people required insulin after 5 years. For the no-dose group, 64% required insulin. Put another way, of the 11 people who did not get GAD65, 7 of them required insulin at the end of the study. Of the 7 people who got 20ug, only 1 did. The 20ug group, had very slightly better C-peptide numbers at the end of the trial than at the beginning, while the no-dose group had worse C-peptide numbers at the end. That suggests that the GAD65 prevented the destruction of beta cells.

Discussion on Diamyd
One of the big issues in type-1 cure research is this: If the immune system stops attacking it's own beta cells, will the body's beta cells naturally regrow without further help? This research suggests to me that the answer is no. C-peptide is created when the body makes insulin. If you look at the patient's C-peptide numbers, the no GAD group's declined, which is what you'd expect from an immune system continuing to attack the beta cells. However, in the groups that got the treatment, the C-peptide numbers basically stayed the same, not going up or down. That suggests that the beta cell attack stopped, but that no new beta cells were regenerated by the body.

Quick Update on LCT
LCT now has two patients who don't require external insulin right now.

Discussion on LCT
This is basically the same news we've heard before from LCT. Some people given their treatment do not require insulin for a few weeks or a few months. This is good news, to be sure, but it is the same news we already knew of their work. In my mind, the big issue with their cure is how long the implanted cells last, and I don' t think the data announced here addresses that issue.

A personal note: I'm in the middle of an internal transfer at work. This is something that I've wanted for a long time, but in the short term, it means less time to read and comment on research. When I first started this blog, I was hoping for about 2 postings per month, but April was much busier than that. But I doubt I'll have time to make as many postings in May and through the summer.


Monday, April 27, 2009

Etanercept (ENBREL) Completes a phase-I Trial in New Onset Type 1 Diabetes

This is a "new to me" phase-I study of
Etanercept (ENBREL) , which just published it's results last week: and you can read the abstract of the results here:

This is "give a drug quickly after diagnosis of type-1 diabetes to preserve some beta cell function" type treatment. The drug,
Etanercept (ENBREL), is a product of Amgen, who sponsored the research, and is US FDA approved for several self-immunity related conditions including Rheumatoid Arthritis and Psoriasis. You can read more about it here:
Note that although the name is similar, this not Efalizumab which I reported on recently.

The results were solidly good, after 24 weeks:
  • HbA1c was lower in the etanercept (5.91 +/- 0.5%) compared to placebo group (6.98 +/- 1.2%)
  • The percent change in c-peptide AUC showed a 39% increase in the etanercept group and a 20% decrease in the placebo group
  • Insulin dose decreased 18% in the etanercept group compared to 23% increase in the placebo group
So the result in plain English is that the treated patients had, on average, A1C measures 1 lower than the non-treated group. They were generating about 60% more of their own insulin (as measured by c-peptide), and used about 40% less insulin. Overall, very nice results for a phase-I trial.

And before you ask: I don't know if they are planning a phase-II study, and I don't know if this will work on non-honeymooners. I did find two interesting papers that reported that people who had type-2 diabetes and who were treated with Etanercept for rheumatoid arthritis had large drops in their BG numbers. How that maps to people with established type-1 diabetes, I'm not sure. Lastly, although this drug is approved by the US FDA different people may well have different opinions about it's safety. It does carry a black-box warning due to higher rates of infection. (Black-box warnings are the strongest warnings that the US FDA requires on prescription medicines to warn people of potential dangers.)

TNF: Friend or Foe?

This research brings up an interesting conflict in research to cure type-1 diabetes: is TNF a friend or a foe? TNF (tumor necrosis factor) also called TNF-alpha is a protein that kills tumors. It also kills other cells in the body. Several treatments currently in clinical trials for various self-immune diseases are based on interfering with the TNF receptor, and Etanercept is one of these. On the other hand, Faustman holds the opposite theory. Her treatment is based on increasing levels of TNF. The drugs she used on NOD mice (CFA), and in people (BCG) are both expected to raise the level of TNF. Now these two beliefs are not exactly opposite, because Etanercept blocks a TNF receptor, while BCG (and CFA) stimulate the production of TNF itself. However, it is unclear how both Etanercept and BCG can both have a good impact on type-1 diabetes since they effect TNF in opposite ways. If one helps cure type-1 diabetes, the other should make it worse, and visa-versa (at least at first impression). So it is possible to interpret the success of Etanercept as bad news for Faustman. Of course it is also possible that the two work in completely different ways, and TNF is a "red herring" in terms of curing type-1 diabetes.

Here is a link to some discussion of Faustman and TNF:

Joshua Levy

Monday, April 20, 2009

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:
And a press release of the withdrawal:

Joshua Levy

Sunday, April 19, 2009

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:

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:
Of course, the studies are focused on different time frames, honeymoon vs. non-honeymoon so they may well come to different results.

Joshua Levy

Friday, April 17, 2009

Recent LCT Press Releases

LCT has recently had three news items on their progress. They have completed a phase-I clinical trial. Their basic technology is to take pig beta cells and encapsulate them in a wrapper which protects them from the body's own immune attack, but that the same time lets the cells generate insulin in response to BG levels. Background information on LCT is here:

Below is my discussion of the three recent news items:

Living Cell Technologies Gains Additional Benefit From DIABECELL

LCT recently finished a phase-I clinical trial of seven people. A few patients had short periods when they did not need to inject any insulin, others required less insulin, and some people were not helped at all. The very best result was that one person was insulin independent for two months. So they took that person, and gave her another implant. This time her insulin requirement dropped 50%. They waited a few more months and gave her a third transplant. After this third transplant, she is again insulin independent. They don't say how long after the third transplant it has been. The first transplant was 5 ku/kg, the second was also 5 ku/kg, and the third was 8 ku/kg. Two key quotes from the paper are:
reports insulin independence in a patient with insulin dependent type 1 diabetes
At this early stage of clinical trials, results show that insulin independence is potentially achievable at least in some patients and that repeat implants are safe.
My Thoughts on this Paper

It is important to remember that this press release discusses only a single person, so I'm very cautious about reading too much into it. Especially since this one person had the best results of all the people in the phase-I trial. She was the person who was insulin free for the longest period after the first transplant. So by publishing only her follow on results, they are really "cherry picking" their results. ("Cherry picking" refers to only including the people who had the best results, and ignoring the people who had other results. It can be a huge source of bias in scientific research.)

Keeping all that in mind, I think these results imply that the current LCT implant product is effective for less than 6 months, when given in the 5ku/kg dose. Here is my reasoning: for this patient, a dose of 8 ku/kg leads to insulin independence the one time it was used. But a dose of 5 ku/kg sometimes does and sometimes does not. But the second 5 ku/kg dose did not lead to insulin independence, which suggests that there was less than 2ku/kg cells still working from the first implantation. (Because if there was more than that, there would have been 8ku/kg total effective when he second operation was done: 3 left over from the first operation, and 5 new ones.) So that implies that the LCT implants don't last very long right now. That's not the end of the world, of course. LCT has years to improve these before they are approved for general use, but it does suggest that they have a long way to go, if people want a cure that only requires an operation every few years. Of course for those who will accept a cure that requires an operation every few months, that is much closer.

Put another way: This patient got a dose and went for 2 months without needing insulin, but then needed it again. Her second dose did not provide any insulin independence. If there were still some working cells from the first implantation, then they would have combined with the new cells to give insulin independence again. But that did not happen.

A note on the Politics of this Information

The most important thing about this press release, is that there is no new news here. The patient in question was "insulin independent" for two months, at the start of the phase-I trial (months ago), and is now "insulin independent" again (with no duration reported).

So why a press release now? My answer: Politics.

LCT has been working for almost a decade to get approval for human testing in New Zealand. Initially, they were questions about the safety of xenotransplantation (especially with respect to a particular pig disease called PERV). LCT did a lot of safety based research, and put those questions to rest years ago, but still New Zealand refused to allow clinical trials. Finally, LCT moved ahead with clinical trials in Russia, which were successful. New Zealand was finally shamed into approving the clinical trails "conditionally" on LCT getting some scientific safety approvals. That wasn't a problem, because LCT has had solid scientific safety studies done for years. They got the approvals, and the New Zealand political minister still has not approved their testing. Hence the press release.

The only good news is that LCT is (or was, see below) also working toward starting a phase-II trial in the US mid this year, and that should happen independently of New Zealand.

Living Cell Technologies Welcomes Report On Safety of Pig Cell Transplants

Here LCT publicizes research done by others. One of the fears of LCT's treatment is that a pig retrovirus might infect people via the transplant. This is especially true of very hard to detect retrovirus, such as PERV, which is similar to retroviruses which are known to cause incurable diseases in sheep, cows, and humans, and to jump from species to species.

LCT had previously done studies to show that the pigs in their flock did not have PERV, and that PERV could be detected prior to transplantation, and that PERV in the beta cells was unlikely to be transferred to people who got transplants, even if in the pigs. So they had already show a solid three barrier safety infrastructure.

Here they report on research were several types of non-human primates were injected with PERV and other viruses and non-virus pathogens found in pigs, after the primates had been injected with drugs specifically to weaken their immune system. None of the primates got sick. That is pretty much the ultimate safety testing. It shows that even if all the safety systems break down, and PERV go straight into a person, and the person has a very weak immune system, then they still will not get sick.

This is good news, and should put to rest any lingering worries about PERV safety in LCT"s treatment.

From the "Note from the CEO" column in the March 2009 LCT Newsletter:
LCT has been in discussions with advisors in Russia to outline a commercialisation route and business plan. To focus on this commercialisation plan, Dr Robert Caspari stepped down as CEO as activities in the United States are of lower priority. Dr Caspari remains a valued member of our board of directors.
Also, there is no mention in this newsletter of the previously proposed, larger scale, clinical trials to start at the Barbara Davis center in Denver, USA.

Some people have interpreted this to mean that the larger phase-II trial they had been talking about running in the US has been put on hold in favor of more work in Russia. Obviously that would be disappointing to people in the US who were hoping to take part in the trial.

Also, if they can not resolve their differences with the New Zealand minister, and can't get started in the US, that leaves only their Russian testing. I'm also worried about the impact of "all Russian" clinical trial data on future US FDA approval. Officially, I think the FDA treats well done clinical trial data the same, no matter where it was done. But I'm a little worried that unofficially, having nothing but Russian data may delay things.

I hope that this entire interpretation is wrong (ie. they are getting rid of their American CEO, but that will not impact their American clinical trials). That would be the best news. They wanted to start that trial mid-2009, so we should know soon if there is a delay.

Joshua Levy