Sunday, December 28, 2008

Burt's Brazilian Research

I've gotten a couple of questions about Burt's research, which is being done in Brazil. Below is my update on this research, together with some thoughts on it.

What is he trying to do, and what is the current status of the Research?

The basic plan is a two pronged attack [r1]: First, drugs are given to shut down (or almost shut down) the immune system. Second, the patient is given drugs to stimulate adult stem cells, which are then removed from his or her blood, treated, and reinjected into the patient. [d1]

In some ways, this research is similar to Trucco's [r7] and also Gitelman's [r6].
Gitelman is using ATG in his research, and that is one of the drugs used in Burt's research as well.

What is the good news?

The good news, is that it works. Burt's results -- in term of curing people for months and even years at a time -- are amazing. Much better than any other research that I know of. More than half of the people treated stopped requiring insulin for the entire time they were followed: a period of months, in some cases years! The rest of the people (except one) required much less insulin after the treatment than before it. That's huge, and no other treatment has come close.

To be specific, one year after treatment, of the 15 patients treated, only two were using injected insulin at the end of the first year after treatment, and 11 of the patients had never (or almost never) had to use injected insulin after the treatment [r8]. The [r1] reference also contains A1C data for these patients, which is also very good.

In a later follow up [r5] the results were also good. Out of 21 patients (and excluding one who had DKA), 13 patients were permanently free of insulin for as long as the study followed them. Some of these people were followed for more than 3 years!. 6 more patients were insulin free for some months after treatment. Just eye-balling that data, it looks to me like those 6 were insulin free for about 66% of the months after treatment. Only 2 patients from the 21 treated were never insulin free.

What is the bad news?

The bad news, is that it might be dangerous; even deadly. This treatment is quite complex. High doses of immunosuppressive drugs are given, and then different drugs are given to create stem cells, and then those are treated with other drugs. Finally, another bunch of drugs are given to lessen the severity of various side effects of the primary drugs. So there is a lot going on. In particular, the immunosuppressive drugs have serious short term and long term side effects. Some of the patients in the clinical trials were hit by some bad short term side effects of these drugs (although nothing permanent). There are also long term dangers of these drugs. In some cases, drugs in this class raise your chance of getting rare cancers even years after they were used.

Now, all of the drugs given as part of this study are approved for human use (for other treatments), but they are also well known to have dangerous side effects. In many cases, these drugs are approved to treat deadly cancers where the general tolerance for side effects, and even the chance of death is much higher than for a child with type-1 diabetes. My biggest single problem in getting excited about this research, that I don't know exactly how dangerous these drugs are, in the doses given here.

An interesting digression on "honeymoon" only clinical trials.

This study is a classic "honeymoon only" clinical trial. Only people who had been diagnosed for less than six weeks were admitted into the study. On the other hand, if a person's body can regenerate new insulin producing beta cells (as many researchers now believe), then this cure could work on established diabetics, too. Burt and his team believe that giving the immunospressive drugs early (when the body still has some working beta-cells) is important. However, if the body naturally regenerates these cells, it may turn out not to matter so much.

Some discussion of stem cell research issues.

This work uses stem cells, and it is being done in Brazil, even though it is based on research done in the US. This has led some people to jump to the conclusion that it uses embryonic stem cells, and was forced out of the US by right wing Christian objections to embryonic stem cells. However, I do not think this is what happened to this particular research. Not only are these guys using adult stem cells, they're using the patient's own stem cells. So only the most wacko religious loony is going to object to that.

On the other hand, there are other ethical issues involved in this research, which you can read about [r2,r3]. Basically, they involve using children in the initial clinical trial. There is no doubt that this trial followed all the proper legal and ethical rules for Brazil; but doing phase-I research on children when the drugs given are known to have serious side effects does raise ethical issues.

If I had more time....

If I had more time, I would certainly spend some of it researching the safety profiles of the various drugs used in this research. After all, if the drugs are safe, then this research is showing the highest cure rate of anything out there. Conversely, if the drugs are dangerous, then they will need to do a lot of research to find safer alternatives or lower doses, before I will personally be interested in this treatment.

Another project, if I had more time, would be to create a simple table comparing the most recent results of different clinical trials. For each trial include data points like: % drop in insulin use (average and standard deviation), % drop in A1C, % chance that a patient will go a month without using insulin, % chance that a patient will go a year without using insulin, etc.

If I had a spare 10 million (US$) lying around....

If I had a spare 10 million to spend, I would try duplicating this research on non-honeymoon diabetics, and I'd do it in the US. After all, since these would be people who had type-1 for years, so it could be done on adults, and so it could be done in the US.

A few random thoughts.

One interesting complexity in this research, is that it failed on the first person it was tried on. That person had DKA. After that, people who had DKA were excluded from the study, and everyone had much better results. Almost all diabetics, at some point, get DKA for some period of time. So if this is to become a widespread treatment for type-1, then the role of DKA will need to be better understood.

This sort of treatment might already be a competitor of islet cell transplant therapies. After all, those people must be on immunosuppressives for their whole lives (although at low dose). It might turn out that Burt's short term, high does treatment is overall safer than the long term, low dose that they get now.

Extra Notes and References

[d1] this is the exact quote, which I have a hard time translating into English. If anyone knows more specifically what it means, here it is, from [r1]:
Hematopoietic stem cells were mobilized with cyclophosphamide (2.0 g/m2) and granulocyte colony-stimulating factor (10 µg/kg per day) and then collected from peripheral blood by leukapheresis and cryopreserved. The cells were injected intravenously after conditioning with cyclophosphamide (200 mg/kg) and rabbit antithymocyte globulin (4.5 mg/kg).
[r1] Abstract of the JAMA article published in 2007



[r4] Some results and discussion:

[r5] A different report:

[r6] Gitelmans work is described here, on my web page:

[r7] Trucco's work is described here, on my web page:

[r8] See the graphs here:

Monday, December 15, 2008

LCT's Research

Someone asked me (in personal email) to give a summary of LCT's research [r1] in much the same way I summarized Faustman's research. Unfortunately, I just don't have the time to do that detailed a job. That Faustman post took me hours of research to put together. However, here is a summary of LCT's research, but with fewer details and fewer references. I'm sorry that I can't put more time into it.

The Pre-History of LCT's Research

In the 1970s and 1980s, it was commonly thought that type-1 diabetic's beta cells had been destroyed, and if they could just be replaced, their diabetes would be cured! This led to several attempts a cures, especially whole pancreas transplants, beta cell transplants, and drug treatments designed to get beta cells to regrow (such as human growth hormone). Of course, none of these worked very well, because the body's immunology attack on itself simply killed off the new beta cells. (Although if you gave immune suppressing drugs, you could get it to work a little bit, and you needed those drugs to prevent organ rejection of the new tissue, anyway.) This whole area of transplants is still being pursued, but it is no where near as successful as it was hoped to be decades ago.

When it became clear that the body's immunology attack kept going, some researchers tried the following approach: they encapsulated beta cells inside a wrapper and then implanted the bundle it in a person. The wrapper would need to be a very high-tech material that would allow nutrients and oxygen to flow in, and wastes to flow out, and insulin to flow out, and the chemicals which triggered insulin production to flow in. But if they succeeded, it would be like having a natural pancreas inside you, but protected from the immune system.

It's a great solution if you can do it, but very hard to do. In the last 20 years or so, there have been at least half a dozen companies that have tired this. Many have gone through several bankruptcies, name changes, and purchases by other companies. So far, none have been successful. In general, these companies try solutions from a "Chinese menu" one from column A and one from column B. Column A is the material inside the wrapper. The source of insulin. Column A has things like "human beta cells from cadavers", "human beta cells from live doners", "pig cells", "cloned embryonic stem cells", "cloned adult stem cells", etc. Column B is the wrapper material. Almost every company in this area has developed their own wrapper, and they all claim their wrapper is the best (and most of them try to incorporate good ideas from other's work, as much as they can).

One of these companies is LCT [r2]. From column A they selected pig beta cells, but from a special population of pigs that had lived for decades without contact with any other mammals on an island in the middle of nowhere. From column B they developed their own wrapper technology.

LCT's Research in the late 1990s
By the mid 1990s, LCT was ready to start human trials. These trials were underway in about 1998 when disaster struck. The disaster had nothing to do with their experiment. It had to do with the British food supply. Really! Mad cow disease hit, and it was caused by a previously unknown class of organisms called prions, which can be passed from animals to humans. Since LCT's work was basically transplanting pig tissue to humans, there was some concern about this, especially since at the time, there was no testing for prions either in the pigs or in the tissues being transplanted.

New Zealand reacted to all this by stopping the LCT phase-I clinical trial immediately. So LCT's most important task became to get their clinical trials started again.

LCT's Research in the 2000s
LCT then did several studies to show the safety of their technique. They showed that their pigs did not have a prion disease, that they were not likely to get a prion disease, that the technique was not likely to transfer it to people. that no one had ever gotten a prion disease from pigs, etc. Also, they improved their encapsulation technique. But all this was to no avail. New Zealand would not authorize any clinical trials. [d1]

This caused a lot of delay, and eventually LCT decided to run a phase-I trial in Russia (see below).

Meanwhile, almost all of the other companies working with encapsulated beta cells went out of business, or abandoned that line of research. In particular, pig cells turned out to be a better line of research than human cells (and that include all types of stem cells). Some companies that had been trying to use human beta cells (of various types) tried to switch to pig cells, when it became obvious that pig cells were working better, but this just emphasized the fact that LCT was way ahead of them, since they had always been using pig cells.

LCT's Current Clinical Trials
LCT ran their phase-I clinical trial in Russia. They hired an American company to oversee it and make sure that it was up to US FDA standards, but the trial was run in Russia.

They were going to just implant about 4 people in Russia (and about 4 more in New Zealand), but when they could not get approval in NZ, they did 2 extra people in Russia. One with a higher dose of islet cells. The results of this phase-I test in Russia were pretty good [r3]:

1 (out of 6) patients went 5 months without needing to inject insulin, but then needed to restart
4 patients required much less insulin before the treatment than after (some 40% less, some 20% etc.)
1 patient was not successful, requiring more insulin after the transplant, than before it

At about the same time, LCT released results of testing one of the people involved in their mid-1990s clinical trial [r4]. Basically, what they found from that exercise, is that the implanted cells were still there and still working (at least a little). But there was no way to know if this person's implants (now 10+ years old) were generating enough insulin to have any real effect on his BG, A1C, or insulin requirements. Even so, this was good news.

The most recent news from LCT is two fold: they have finally gotten permission to run a clinical trial in New Zealand [r6], and are working tords getting approval for a clinical trial in Denver (USA) [r5]. The New Zealand clinical trial they are about to start they are calling a phase-II trial. This makes sense, since it is after the Russian phase-I trial, but it doesn't make sense from a headcount point of view. They are only enrolling 8 people, so that is phase-I sized. I don't know if they will up the dose from their earlier trial; I certainly hope so.

I don't have a reference in front of me, but I thought that the Denver trial was going to be a standard phase-II trial: 50-100 people, etc. However, since they are calling their NZ trial a phase-II, maybe they will call this one a phase-III or add more people to it? I don't know.

The Future of LCT's Research
LCT has some really good results, but they are based on less than 8 people, and only about 6 months of treatment. So the future of their research needs to show better results, for longer periods of time, on more people.

Show better results: This is what I worry about the least. Most of the people in their phase-I trial were given the absolute minimum dose of new islets, and yet they had large drops in their insulin needs. One person used no insulin for a period of time! Since actual transplants can use 2x, 4x, or many more times the number of islets, I think it is very reasonable to assume that higher doses will result in less insulin needed. In many cases, no insulin needed.

For longer periods of time: For me, this is the biggest worry. How long will these new islets last? Or, how often will they need to be replaced? There are two potential problems here. The first is that islet cells may have natural lifespans, which cause them to stop working after a certain number of years. There has been some research suggesting this (sorry: no references for this), but the exact lifespan is not known. Secondly, and more importantly, the encapsulation or transplantation of the cells may cause them to start to die off. This could kill of the transplanted islets much more quickly. For example, if the wrapper is not "good enough" islet cells may start to run out of oxygen, and very slowly die off over weeks or months. This has been a very real problem with other company's encapsulating technologies.

On more people: Because so few people have been given these islet transplants, there is always the possibility that there is some major problem that we just don't know about, because not enough people have gotten the transplant. I don't think that is very likely, but as more people are treated, we'll develop more certainty that it is safe.

My Opinion of this Research
My personal option of this research is mixed. I think that it is very likely to work, eventually. But I'm not sure how long it will take for them to tweak out all the problems. Also, it requires surgery. And I suspect that the early people to get it may need follow up surgeries every 5 or 10 years. On the other hand, I think that there are lots of people who, if you tell them "we can cure diabetes for 10 years for $50k and a three day hospital stay", many will do it. And that is a very reasonable goal for this technology within the next 5 to 10 years. And in 10 or more years, it may be cheaper or last longer, or both.

If you want to follow LCT, I recommend their web site:, which is very glossy.

There is another source, which I recommend only with serious reservations, and that is This forum is run by an LCT cheerleader. He aggressively censors people who say bad things about LCT, or ask awkward questions. (And yes: I've been banned from the group several times.) I also believe that the forum owner makes many posts under many different names, to create a sort of false consensus on how wonderful LCT is doing. I have definitely seen the list owner post under multiple different names, I'm just not sure how many of the names on the board are real, and how many are fake. My best guess is about half are fake, but I'm really not sure.

More Discussion

[d1] Obviously there is a huge political saga here, which I will not get into.

Some References

[r1] My tracking of LCT is available here:

[r2] LCT home web page is here:

This is a news article with selected data from the first 6 months of the Russian phase-I trial.

[r4] Results of some tests on a guy who had this done 10 year previously:


[r6] Press reports on the New Zealand approval:

Friday, December 5, 2008

New to Me: Phase-I Clinical Trial of Polyclonal Anti-T-Cell (ATG)

This clinical trial treats honeymoon diabetes (during first 6 weeks) with ATG. The hope is for some beta cell preservation. This is a prelude to Gitelman's phase-II ATG trial, described here:, except that this trial is still ongoing. However, they have published interrum results (on their first 17 patients) here:

My eyeballing of the interrum results looks like the ATG group used about 60% as much insulin as the untreated group after about 12 months, and this seemed pretty stable. It did not look to me like the effect was "wearing off". This was good enough to motivate a follow-on, phase-II clinical trial, which is currently underway. I'm also very interested in what happens to these 17 patients after 2 years, 3 years etc. If the lower insulin requirement gradually goes away, that's too bad. If it stays stable, then that is very promising. If it gets even better slowly over time, that suggests that the body is growing new beta cells, and would be good news both for ATG treatments and for many others.

US Government Clinical Trial Record:

Estimated Enrollment: 28
Study Start Date: November 2000
Estimated Study Completion Date: December 2007

This work was sponsored by the Ministry of Health, Czech Republic, and is being done in Prague.

Monday, December 1, 2008

New Phase-I Clinical Trial: IL-2 and sirolimus

This trial is open to people diagnosed between 3 months and 4 years ago, so it's not a classic "honeymoon only" study, but it is limited. Patients will be given two drugs over a three month period. The hope is to preserve some beta cells. This is a classic phase-I trial, looking only at safety in a small number of patients.

US Government Clinical Trials Record: (NCT00525889)
Immune Tolerance Network Trial Record: (ITN018AI)
Info for patients:
General info on Sirolimus:
General info on IL-2:

Estimated Enrollment: 10
Study Start Date: August 2007
Estimated Study Completion Date: January 2012
Estimated Primary Completion Date: January 2010 (Final data collection date for primary outcome measure)

This study is being done in Seattle Washington, and is sponsored by NIAID.


Monday, November 24, 2008

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:
Wikipedia has general article on Abatacept:
TrialNet's record for this trial is here:

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.


Monday, November 17, 2008

Understanding the Research Funnel

I know that a lot of people are frustrated by the progress being made to cure type-1 diabetes. This posting is my attempt to explain the research process. Hopefully this will lead to less frustration with it, or at least more informed criticism of it.

The mental picture to have in your mind is a large funnel, with the big end to the left, and the small end to the right. The goal is to have a cure for type-1 diabetes come out of the right side, and the funnel shape represents the number of possible cures active at each stage in the process. In order to be approved for widespread human use, a medicine needs to go through five levels of testing:
  • animal testing ("pre-clinical")
  • safety testing on a very small group of people ("phase I clinical trials")
  • effectiveness testing on a slightly bigger group ("phase II clinical trials")
  • wide spread testing on a larger group of people ("phase III clinical trials")
  • approval to mass-produce and market
This is the system used for new drugs, devices and implants in the USA.

The key thing to remember, is that no cure for type-1 diabetes is going to be a surprise. Because every cure is going to slowly go through all five steps listed above. Nothing comes out of left field. They slowly progress through each step. So if you pay attention to what research is completing each step, you will know what is going on now, and what will be happening in the future.

Now the first question about this funnel is, how long does it take? How long does it take a possible cure to go through all the required research and testing, and get an actual cure out the other end. Obviously, we don't know for sure, because no cure has come out the end. But the length has got to be more than 10 years, because the Phase III research that we see now, is all a little less than 10 years old already.

So that is one valuable thing learned already. When someone says "I just cured type-1 in mice, so a cure in humans is 3-5 years away" we know that person is full of crap. The cure is at least 10 years away, even after mice have been cured. Remember that. I'll speak about it more, later. My basic rule of thumb is that the first step above (animal testing), can take a very long time. Many years, even decades. The three "phase" steps (human or clinical trials) each take 1-3 years if the research moves forward smoothly. Mass production and marketing is a little quicker, maybe 1/2 to 2 years.

So a second valuable thing learned is that if someone says "I will have a cure ready for you in 2 years", you just ask if it has completed phase III trials now. If the answer is no, then it surely will not be ready for the mass market in two years.

I'm not exactly sure how big the wide end of the funnel is. Basically, how many times per year researchers find a cure for type-1 diabetes in mice. My gut feeling is that it is happening at a rate of about 4 times per year, right now. (Although in the past I think it might have been only 2 or 3 per year.) Those possible cures are the "raw material" that the funnel works on.

Another thing to remember is this: don't get excited about cures in mice, because they hardly ever lead to cures in people. That's the whole funnel idea. The mice side is big, but the human side is small. Based on my estimates, it appears that only about half of the mice cures even enter human testing.

I do have a pretty good idea of how many possible cures are at different points within the funnel:
(As of Nov 2008)
  • There are 15 possible cures preparing for Phase I trials now.
  • There are 10 possible cures in Phase I trials now.
  • There are 5 possible cures in Phase II trials now.
  • There are 3 possible cures in Phase III trials now.
  • There are none waiting for marketing approval now.
See the funnel shape? From 15 down to 9 down to 5 down to 3 to 0.

Why are newspaper articles, bloggers, and researchers always saying that a cure is 3-5 years away? Why are they always wrong?

This is easy to explain, but also very galling. It boils down to over-optimism coupled with inexperience. So, some researchers have been working for years, maybe decades, to find a cure for type-1 diabetes in mice, and they finally do it! They are ecstatically happy, and they publish a press release.

So the first thing to notice, is that most reporters just rephrase the press release. They don't have a deep enough science background to understand it or know about similar research. Most bloggers don't even do that: they just cut-n-paste the press release. So the press release is the news. (Except for a few science reporters who really do know what is going on.)

Back to the researchers, who are writing their press release. First off, it is totally optimistic. It doesn't mention any possible problems or complexities. Also, they know the research needs to go through three phases of testing before it is generally available, and they know that each phase might only take a year, if all goes perfectly. (They always forget about the FDA production and marketing approvals.) So therefore, they say "It will be ready in as soon as 3 years" or "it will be ready in 3-5 years" or something very much like that.

But this is never true! For one thing, almost all phases take more than a year. Some take three years. For another, it assumes they start human trials the next day, and they never do. For a third, it ignores the time to get approval for manufacturing and marketing. And finally, it assumes that Phase II starts the day after Phase I ends, and Phase III the day after Phase II ends, and so on. And this is never true either. Often after the end of one phase, there is a delay while investors are found, the FDA is consulted, results are analyzed, and new trial subjects are found. So the result of all this is that these predictions of 3 years are never even close to right. The real number is 10 to 15 years.

So, why is this exact same mistake made with every new mouse cure? There are three reasons. First, it is usually the researcher's first time in curing diabetes in mice. It's not like they have done it before, so they don't realize the trap they have fallen into. Second, there is no "downside" to being wrong. Let's say they tell the reporters that the cure will be available in 3 years, and they are wrong. What bad thing will happen to them? Nothing. There is no reason for them to try to be accurate, because it just doesn't matter. No one is going to come back to them years later and stop a grant because they were wrong about this! Third, and most important, there are good reasons for the researchers to be over optimistic. At this point they are either trying to get grant money to do their human trials, or they are trying to get venture capital money to start a company to do their human trials. In either case, it is much better for them to say "we can cure it in 3-5 years" rather than "we can cure it in 10-15 years", even if the first is true and the second is not.

Some extra Information on the Phases

The goal of this phase is to prove safety; showing that the treatment works is a secondary goal. Therefore, phase-I trials usually involve only a few people (usually around 10), and usually use the lowest dosage possible of the treatment.

One thing to remember about these trials, is that they are rarely successful in terms of the treatment they are trying. Because the smallest possible dosage is used (for safety reasons), the results are often partial. So for type-1 cures, in phase-I you might temporarily cure type-1 diabetes, but have it come back later. Or maybe you use less insulin, but you still need to use some. Or your A1Cs get better, but still not good enough. These are all partial successes, which should be expected in phase-I trials.

The goal of this phase is to prove effectiveness: that the treatment actually works. Another goal is to show that it is safe in a larger segment of people. The doses used are often higher than phase-I. Sometimes different doses are used in different groups of people. These trials usually involve more people (often between 50 and 100).

At this point, you really should be seeing something close to what you want. The doses are higher and more people are involved.

The goal of this phase is to make sure that the treatment works in a larger group of people, and as sort of a "dress rehearsal" for actual use. The doses used here are generally the same as the doses that will be used in the general market. These tests usually involve hundreds of people.

At this point, the results seen in trial are pretty much the same as the results you should expect in the mass market. So no more wishful thinking: what the study shows is likely what will be available when the treatment is mass marketed.

I have sometimes seen this term used for clinical trials that use a treatment that is already approved for one purpose, to test to see if it will work for other purposes. For example, you might have a drug that curred one form of cancer, and test it to see if it will cure diabetes, also. I think of these more like phase-II trials.

Thursday, October 30, 2008

Faustman's Research (Part 1: History)

Before I describe the history of Faustman's research into curing type-1 diabetes, I wanted to say a little bit about my own history. In the past I have donated money to JDRF and also JLN; the first does not fund Dr. Faustman, the second does. I have never worked for either group. I'm not a diabetes researcher; I'm interested because my family is touched by type-1 diabetes. I've been tracking research into human trials to cure type-1 diabetes for years: both Dr. Faustman and others.

I have tried very hard to present facts and avoid opinions in this posting. However, that is sometimes hard to do. Especially with Dr. Faustman. When there are differences of opinion, I have tried to provide enough background so you can see why these differences exist. Different people evaluate research differently, so you may not agree with some of the things I say below.

This posting is still a work in progress. So if you see problems with it, or parts of it don't make sense, please tell me about them, so I can improve it.

As I write this one of the problems I have is how much detail to put in, and how many references. So I have tried to make it relatively short, but also added many end-notes (like [d1]) which contain more discussion of the points in the main text. You can just read the main text to get a nice flow, or read the end-notes to get a lot more information. References are shown like this: [r1]. So with that:

The Pre-History to Dr. Faustman's Work

In the 1990s immunology was the hot field in type-1 diabetes research. Several researchers were able to prevent diabetes in NOD mice [d1], by giving them a drug called CFA [d25] [r4,r5]. Others were able use CPA to stop the immune attack on insulin producing cells, even in mice with established type-1 diabetes [r26]. Obviously, a lot of excitement ensued, but also a problem: CFA is too toxic to give to people[r3]. However, BCG [d26] acts in people like CFA acts in mice. Also, BCG is known to be safe in people, and has been in some vaccines for decades, so it is cheap and well understood. Several studies were done on people given BCG specifically to try to prevent diabetes [r21,r24,r28], and other studies were done on people who had been given BCG for other reasons, such as part of a vaccine [r20,r22,r23]. Unfortunately, in both cases, no benefit was seen. CFA prevented type-1 diabetes in mice, but BCG did not prevent it in humans.

Dr. Faustman's Mice Research

At this time, Dr. Faustman set up an experiment to try to cure diabetes in mice who already had it [d4]. To do this she used a two treatment plan. The first treatment was CFA, which she hoped would stop the immune attack and the second was a transplant of spleen cells, which she hoped would help regrow insulin producing cells (previously destroyed by the immune attack). Spleen cells had previously [r4] been used to help prevent diabetes in NOD mice. This experiment on mice worked [r6,r2]: some were cured of type-1 diabetes! Again, a lot of excitement ensued.

The obvious next step was to run this CFA+spleen cell experiment in people. Faustman asked for research funding from the JDRF (Juvenile Diabetes Research Foundation) for exactly that human trial [d17, r27]. JDRF rejected this request. The exact reason why is not known [d5].

When scientists test two treatments together, there are several different designs they can use: Two groups of mice (one doesn't get either treatment, one gets both). Or three groups of mice (one gets no treatment, one gets one treatment, and the third gets both treatments). Or four groups of mice (no treatment, one treatment, other treatment, both treatments). The last design is the best, because it tells you exactly how each treatment interacts to give you the final results. The first design is the worst, because it doesn't tell you if one treatment is useless or not. Using a 3 or 4 group design is especially important if one of the treatments is known to affect the outcome by itself. Dr. Faustman used the first design in her mice study, which is the weakest design. Furthermore, it was an especially bad choice because it was known that CFA impacted type-1 diabetes in mice when used alone. So with her experimental design, it would be impossible to tell if the CFA alown impacted the mice's type-1 diabetes, or if the CFA and spleen cells together cause the impact. [d6]

Dr. Faustman was funded by JLN (Join Lee Now). However, it took them several years to raise the money and give it to Dr. Faustman. During that time no clinical trials were done.

Other Mice Research

However, with all the excitement (and the funding controversy) generated by Dr. Faustman's research, several other groups wanted to replicate it. In the end, three different groups attempted a similar experiment, but with a different design: three groups of NOD mice. One group got nothing, one group got CFA only, and the final group got CFA and the spleen cells. Furthermore, each group tested seperately if the transplanted spleen cells were contributing insulin to the mice, and each used a different scientific method to check this. JDRF did fund these experiments. All three of these researchers came up with the same basic results: many mice given CFA maintained normal blood glucose control, and many mice given CFA and spleen cells also maintained normal blood glucose, but at the same rate as the mice given CFA alone [r7], and the spleen cells did nothing to help maintain normal blood glucose levels [r8]. In all three cases they found that the transplanted spleen cells were not the source of the new insulin producing cells. So that is a second way to verify that the transplanted spleen cells were not functional to controlling the mice's BG levels. A study by Mezey [r25] is sometime sited as independant confirmation of the importance of spleen cells, but that is a mistake. This study was not independent, and did not show any insulin production from spleen cells [d7]

Understanding what these studies found, and what it means, is absolutely central to understanding why some people think Dr. Faustman is brilliant, while others think she has already failed.

The studies's conclusion can be described in two ways:
1. Dr. Faustman was right about CFA causing mice to have normal blood glucose control.
2. Dr. Faustman was wrong about the spleen cells being part of this process.

Dr. Faustman and her supporters describe what happened as "Three independent groups confirmed Dr. Faustman's results", emphasizing point 1. However it is equally true to say that all three independent groups, found that Faustman was wrong about spleen cells. However, from the point of view of curing type-1 diabetes, point 2 is much more important than point 1. CFA was already known to cure and prevent diabetes in mice, and this had not led to a human cure or prevention. Also, at the time of the original experiment, Faustman thought the spleen cells were the more important part of her experiment, and that was the part that later turned out to be wrong [d18, r2, r27]

The success of point 1 leads to a path of using CFA to cure diabetes, but that path had already been traveled down, and found not to work on people [r20,r21,r22,r23,r24]. But see also the discussion in [d19]. While point 2 closes off the new path that Faustman was hoping to follow to a human cure for diabetes. Basically, point 2 puts an end to the human trials that Faustman had asked JDRF (and later JLN) to fund.

Faustman has found that CFA cures type-1 diabetes in NOD mice, but that was already known [r26]. But since BCG has already been tested in humans, that is a less interesting finding. However, one guy used this information in a unique way.

Dr. Orban's Human Research

Another researcher, Dr. Orban, looked at all the mice research above, and tried a different approach from Dr. Faustman. Since CFA worked in mice, but BCG did not work in people, he tried curing type-1 diabetes with a different drug which was similar to CFA, but that you could give people and was not BCG [r10]. His work is based on Dr. Faustman's foundation, but he went in a different direction than she did. Orban's phase-I trial ended a year ago. I haven't seen the published results; last I heard they were still analysing the data. [d3]

Dr. Faustman's Human Research

Faustman looked at her own research and the other similar research, and tried this approach: she assumed that previous BCG human trials has failed because either they were not using the right dosing, or they did not have a sensitive enough machine to measure small improvements to the patient's immune response.

So, she stopped working with spleen cells and instead put the money from JLN into a super sensitive blood tester which could identify the difference between good immune cells and bad ones [d8]. She hoped that this machine would solve both problems with previous BCG experiments: it would detect tiny improvements in immune response, and this information could be used to find the right dosing.

Dr. Faustman's actions at this point show that JDRF was correct in not funding her original human trials. Once Faustman got the money to do trials, she herself did not do the trial that she had asked JDRF to fund. Instead she did a completely different one. The earlier one used BCG and spleen cells to cure diabetes in people. The current trial uses BCG alone to see if it affects the immune system (even a tiny amount) so that it can be used in future treatments. No cure is attempted in the current clinical trial. [d9]

This trial started in early 2008 and is expected to run to mid 2009. Any diabetic can take part: it is not limited to honeymoon diabetics. Basically, diabetics are treated with BCG, the same dose in certain vaccines, and then blood is taken over the next year to see how good and bad T-cells [d10] are affected.

The Future of Faustman's Work

The future of Dr. Faustman's work is an interesting question. Usually, getting funding for Phase-II clinical trials is easier than getting funding for Phase-I trials, even though you need more money. That's because, most of the time, you cured some people in your phase-I trial, so you can take that data to a funding source, and get more money.

However, Dr. Faustman's phase-I study isn't going to cure anyone [r15], and isn't even going to improve BG or A1C levels in anyone. The only evidence for improvement will be from Faustman's custom made, one of a kind, super sensitive machine [d12]. And no one will be able to double check her results. So even though the phase-I trial is still underway, it is clear that it will not provide strong information to help get funding for a phase-II trial. There is an alternate plan which would be to do a second phase-I trial, this one aimed at curing diabetes in people. If that panned out, then getting funding for a phase-II trial would be straight forward, but it would delay things.

If the current human trials are successful (meaning that BCG stops the immune attack), then Faustman might still have trouble getting funding for the next round of human trials (no matter if they are phase-I or phase-II). Remember, the last time she did a big experiment (the CFA+spleen test in mice) she was wrong about a major part of the results (the spleen part). This was discovered when other groups did the same experiment. However, no other group can replicate her current experiment, because no one else has her custom made, multi-million dollar equipment.

JLN has already announced that they will not fundraise for Faustman's next round of human trials. This is an important development. JLN knows more about Faustman's work than anybody except Faustman herself. They have been strong supporters since at least 2003, and have already sunk in millions of dollars. For them to cut her off at this point should be very troubling. Faustman and her supporters point out -- correctly -- that JLN said years ago that they would not fund a phase-II trial, so this is not new information. [d15] However it does seem unusual that Faustman's biggest supporters would cut off funding right at the end of a supposedly successful clinical trial. It does not send a good message to the rest of the funding community.

Level of Excitement

In a private email, someone asked me "Why aren't you excited about Dr. Faustman's research?" In a sense, this entire post answer that question. A more specific answer to this question is that I am excited about all research aimed at curing type-1 diabetes. I have faith that science will one day cure type-1 diabetes, and I am excited about all research progress in this area. The difference between me and most Dr. Faustman supporters, is that I look at her work as being much like any other research. She's at a very early stage of phase-I human trials, so I group her with all the other phase-Is out there. And behind the phase-IIs and phase-IIIs.

This is quite different than most of her supporters, who view her work as uniquely wonderful; much different and much better than most of the other work out there. To my mind, that is unwarranted. It is not that I'm unexcited about her work. It's that I have the same level of excitement for her work, as for any other research which is (a) in very early phase-I experiment, and (b) is testing a treatment which has previously failed -- in six previous experiments [r20,r21,r22,r23,r24,r28] -- when tested on people. Dr. Faustman supporters claim that these studies were quite different from Dr. Faustman's current work. This is further discussed in [d19].

Extra Discussion

Notes that start with a 'd' contain more discussion on an issue.

[d1] NOD mice are "non-obese diabetic mice". They are research mice specially bred to have diabetes, and widely used in type-1 diabetes experiments. All (or almost all) of these mice will get type-1 diabetes as they grow up, so the are good "animal models" to try to prevent or cure type-1 diabetes. However, it is also true that many things which have prevented or cured diabetes in NOD mice, have failed to work in people. NOD mice are generally considered the best animal model available, but it is still unclear how good they are.

[d] Any experiment involves risk, but transplants generally involve more risk than drugs. So a human trial at this point would have subjected the people to the extra risk of transplantation which could have been eliminated by doing a better mice experiment ahead of time. The better design used by the non-Faustman researchers proved conclusively that the spleen cell injection was worthless to the cure.

[d3] My experience is that if you need to spend a year analysing your data, the results are not going to be good. Good results are more obvious and are found faster.

[d4] Some people have claimed that Faustman was the first to stop the immune attack on insulin producing cells in mice with established type-1 diabetes, but this is incorrect. Faustman's own 2001 paper [r6] says that such cures were rare, but did exist, and she provided references to at least two previous such cures. These are listed here under [r26]

[d5] JDRF has a two phase system for evaluating requests for funding. One phase involves a review committee composed of researchers, scientists, and doctors expert in type-1 diabetes. The second phase involves a separate review committee composed of laypeople, mostly people who have type-1 diabetes, and the parents of children with type-1 diabetes. Approval of both committees is required to get money from JDRF.

[d6] I want to stress that I have no special insight into why Faustman's request for money was rejected. This discussion is based on my opinions about the research, not anything that I know happened inside of JDRF. I have no visibility inside JDRF or it's review process.

[d7] This study has never been published (or peer reviewed) on it's own. Rather, it was published as a "technical comment". The study was not independant because Denise Faustman was an author. In fact, she was the first listed author, and was listed as one of two authors to whom correspondence should be sent. As for what was found, consider their conclusion: "We show that islet regeneration predominately originates from endogenous cells but that introduced spleen cells can also contribute to islet recovery." They not claiming that the spleen cells did contribute to the cure, mearly that they could have contributed to the cure. They are also up front about the fact that any contribution from the spleen cells is -- at most -- a minor effect. However, if you read the entire report, they note they never looked for insulin produced by the spleen cells. Their optimism that the spleen cells are producing insulin is based on the fact that they exist at all. They claim to have measured the existance of spleen cells: not that they were active in any way.

[d8] The immune cells in question were T-cells that were mis-programmed to attack the beta cells in the pancrease which generate insulin. T-cells that attack beta cells are bad, and cause diabetes. Those that don't are good, and attack disease cells, as they should.

[d9] Symbolicly, the experiment Faustman asked JDRF to fund was this:
BCG + spleen cells = normal blood glucose control in patient
however the experiment that she actually ran with JLN's funding was this:
BCG = slight changes in patient's immunology
So there is a major difference in inputs and a major differences in results!

[d10] T-cells are part of the immune system. Bad T-cells cause the immune system to attack the body's own insulin producing cells, which starts type-1 diabetes.

[d12] A blogger who is very supportive of Faustman visted her lab and reported in his blog ( that:
They can't do trials in multiple centers because the equipment they've developed for testing results is not portable. In one case they moved a piece of equipment across the lab. It took 9 MONTHS to recalibrate it and get it working again.

We saw the equipment (no photos allowed). It's complex and large. The size of a full sized fridge on its side. To take a blood sample and extract the T cells takes an entire day.
(Bold and all-caps for "months" are in the original quote.)

[d15] At the time Faustman was planning a conventional phase-I clinical trial and everyone thought that she would have plenty of data showing lower BG numbers, lower A1C, and/or lower insulin requirements, so none of this would have been a problem. Faustman's phase-II research would have been funded based on her success with phase-I. However, when Faustman changed the type of experiment she was doing, it ment that her phase-I would not generate that kind of positive data.

[d16] Here is a quote from a Iacocca Foundation letter about stopping their funding of Faustman:
Now that we have reached this important milestone we have made the decision to stop actively fundraising through what has become The Iacocca Foundation/ for type 1 diabetes - a public charity. We will be accepting donations through December 31, 2008 when we will make our final committed payment to Dr. Faustman.

As we look to the future we remain committed as always to being part of a cure for type 1diabetes. The Iacocca family will continue to fund the brightest and best who are dedicated to ending this disease. And we hope you will turn your time and resources to continue to support Dr. Faustman directly as she and her team at Massachusetts General Hospital prepare to launch a campaign to raise funding for the Phase II BCG clinical trials.
[d17] Some people have claimed that Faustman never intended to do a CFA and spleen cell experiment. This is contradicted both by information available at the time, and by common sense. For example, the Mass General Hospital where Faustman worked (and still works) issues a press release saying specifically that "Mass. General's Diabetes Center has received approval from the US Food and Drug Administration to try the techniques pioneered by Faustman in humans. " [r27] So there is no doubt that she was planning on doing the same experiment in her human trial. From a common sense point of view, it makes no sense to run one test on mice, and then run a different test on people (unless the mice test is too dangerious to run on people). The whole point of doing mice studies to to prepare for human studies. So it only makes sense to run the same experiment in mice, that you are planning on people, if you possibly can.

[d18] For example, in the abstract to her own 2003 paper [r2] Faustman lists the spleen cells first, and CFA second: "Treatment of NOD mice with end-stage disease by injection of donor splenocytes and complete Freund's adjuvant..." In that same abstract, CFA is mentioned only once, while the spleen cells are mentioned three times. The official press release from MGH (where Faustman did the experiments) [r27] is even more clear: CFA is not mentioned at all, while the spleen cells are mentioned many times, and are the focus of the reporting: "Massachusetts General Hospital researchers have harnessed newly discovered cells from an unexpected source, the spleen, to cure juvenile diabetes in mice, a surprising breakthrough that could soon be tested in local patients and open a new chapter in diabetes research."

[d19] Naturually, Faustman's supporters object to comparisons between her current experiment [r15] which uses BCG, and the six previous experiments [r20,r21,r22,r23,r24] which used BCG and found that it did not effect type-1 diabetes. One paper [r28] found a slight improvement, but it was not statistically significant in a study of only 25 people. For example "kumquat79" says: "Those studies cited are not identical to the treatment Dr. Faustman is working on. Those were one-time vaccinations". While it is true that Faustman's experiment is slightly different than the six previous experiments (after all, experiments are almost never repeated exactly identically: what would be the point?) However, the experiments are very similar. Faustman's experiment uses 2 doses of BCG. The others either use 1 dose [r21,r22,r24,r28], or an unknown number, but probably just 1 dose [r20,r23]. Obviously the difference between 1 dose doing nothing, and 2 doses being a cure for type-1 seems a little farfetched! Furthermore, Faustman's has never previously claimed that the differences between her current 2 dose regimen, and the 1 dose previously given is important; her previous mice studies used only a single dose of adjuvant.

[d20] Honeymoon refers to the time period when a type-1 diabetic is first diagnosed, when they are are still generating some of their own insulin. This generally lasts for first few months after diagnosis. Researches use many different terms for "non-honeymoon", such as "established", "long standing", etc. A mouse with established diabetes is one that is not in the honeymoon phase.

[d25] CFA is Complete Freund's Adjuvant which is an adjuvant which can only be used in animals. In general, adjuvant increase immunological response. More information on adjuvants in general is here:

[d26] BCG is Bacille Calmette-Guerin which is an adjuvant which can be used in people. More information on adjuvants in general is here:
This adjuvant has been commonly used in TB immunizations, and others.

References and Sources

[r2] This is Faustman's 2003 publication:;302/5648/1223

[r3] For example, this book: contains this quote: "(CFA) is quite toxic and cannot be used in humans."
A general safety data sheet on CFA can be found here: Including this quote: "The undesirable side effects attributed to CFA use include increased pain and suffering and morbidity in inoculated test animals".

[r4] This study, published in 1992, researched both CFA and spleen cells in preventing type-1 diabetes (but not curing it):

[r5] This study was published in 1990:

[r6] This is Faustman's 2001 publication:

[r7] The best description of these studies and their results that I have found, is here:

[r8] Here are the three experiments that came to the same conclusion (no spleen cells required) in 2006:

[r10] Orban's experiment:

[r15] The Nathan/Faustman human trials are described here:


This study treated honeymoon diabetics with BCG and saw no improvement, compared with an untreated group. From the abstract: "Vaccination with BCG at the time of onset of type 1 diabetes does not increase the remission rate or preserve beta-cell". The full paper is here:

Neonatel vaccination with BCG has no good effect on type-1 diabetes rates: " The cumulative risks for developing islet autoantibodies by age 2 or 5 years were unaffected by BCG vaccination in the first 3 months of life" and "Progression to type 1 diabetes in BCG-vaccinated autoantibody-positive children was significantly faster than in nonvaccinated children" and " No evidence was found that BCG vaccination could prevent against ß-cell–damaging processes leading to type 1 diabetes in genetically at-risk children. The findings do not suggest that BCG vaccination will affect the overall incidence of type 1 diabetes"

Retrospective study on people who had been vaccinated with BCG.
"However, as a whole, results from these analyses fail to support a protective role of BCG vaccination against juvenile-onset IDDM."

This study was published in 1998:
"BCG vaccination in children who have been recently diagnosed with IDDM does not affect the progressive decline in C-peptide levels or alter the clinical course of the disease."

[r25] The Mezey/Faustman paper is here
See the discussion under [d7].

[r26] is a report from 1992 showing that CPA stopped the immune attack in mice with established type-1 diabetes. These same guys later went on to confirm their finding with BCG, previewing Faustman's research by five years:


[r28] Abstract is here:
Full paper: (in Korean)
Here is their conclusion from their abstract, in it's entirety:
BCG vaccine is safe and convenient to use, however, a large study is warranted for the use of BCG as a therapy of type 1 DM.
Note that there is no claim of any improvement to the patient. Here is the key sentence from their results section:
During follow-up, there was no significant difference in fasting and postprandial 2 hour C-peptides.
They then go on to list various good things they did see, in particular there were slight differences in C-peptide and insulin usages, and temporary remission in two patients, but these were not statistically significant. (And remember: this study was of honeymoon diabetics.)

Their paper is in Korean, which I can not read, however the tables are presented in English, and each table says very clearly "The differences between the two groups were not significant."

Sunday, October 19, 2008

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

Tuesday, September 2, 2008

Discussion of recent press reports of type 1 cures

Over the last two weeks or so, there have been several press reports about various research into cures for type 1 diabetes. Since I often get asked about these, I thought I would post my thoughts on them. Note that none of these are human (or clinical) trails. They are all animal research.

There are two things to remember about all animal based research:
  1. Very few cures that work in animals, work in people. It is not possible to know the exact number, but my gut feel is that for most treatments, only 1% or 2% of the cures that work in animals end up being used in people. And the number for type-1 diabetes might be lower than that!
  2. It takes 10 years or more for a cure that works in animals to be fully tested in people and get all the approvals needed to be mass marketed for people.

With that in mind, here is the recent research:

This sounds like the perfect cure. Inject a drug (Leptin) into a type-1 diabetic, even a non-honeymoon diabetic, and then they are cured. And it worked in mice! Since this is being funded by JDRF, they should have no trouble getting funding for phase-I trials on people, if this really is as good as it sounds. For my part, this sounds very interesting, but also very different than previous cures. So I'm hopeful, but also nervious. I do think that this will make for a great phase-I trial, and we will know a lot more about it when that first human trial is done.

Direct Reprogramming
This is a very powerful idea, that basically allows you to reprogram a cell that is already in the pancrease to create insulin. You convert already existing cells into beta-cells. It has all the advantages of stem cells, but you don't need stem cells, instead you reprogram the cells that are already there. Obviously, to be a cure, you would have to stop the immune systems attack on these new beta-cells; either that or generate so many new ones, that you kept ahead of the destruction. So this might need to be combined with one of the "honeymoon" cures currently in phase-III trials, to be a complete cure. I discussed this more in a previous post. As above, since this is being funded by JDRF, they should have no trouble getting funding for phase-I trials, if this really is as good as it sounds, and it turns out we need beta cells in order to cure type-1.

Making Beta Cells
This guy is experimenting with making new beta cells outside of a body; sort of like a beta cell factory. Ideally, these can later be implanted back in a person. Has many of the same issues as "Direct Reprogramming" described above. You still need to stop the immune attack, and so on.

The National Acadamy of Sciences just published some of Faustman's pre-clinical studies in mice. Faustman is already doing a human trial based on this same research, and results are expected next year. The current human trials do not even measure BG or A1C levels, so no one's diabetes is going to be cured, or even improved, by the clinical trial currently underway. They are hoping to learn enough to effect BG and/or A1C in the next set of clinical trials.

Gastric Bypass for Type-1
Basically gastric bypass is a type of surgery used for type-2 diabetics. It shortens the digestive track so that you can eat the same amount of stuff, but still loose wait. For people who's type-2 diabetes is fueled by being overweight, this can be a viable treatment option. However, one particular doctor has this theory that the digestive system is involved in type-1 diabetes, and that this surgery will cure type-1 diabetics! It seems pretty nuts to me. He sees evidence that the type-2s he works on get good BG control "too fast" and "too well" for it to be caused just be losing weight, and so he thinks there must be a direct effect (which would work on type-1s) as well.

Because this is a surgery (and not a drug, implant, or device) he doesn't need to get any FDA approvals. He can try this surgery on anyone he wants. So he is currently looking for non-overweight type-1 diabetes to operate on.

Inflamation Based Cures
Last year there was some surprizing research pointing to inflamation as being a possible cause of type-1 diabetes (not a symptom of it, as previously thought). This suggested the possiblity that stopping inflamation would actually stop type-1 diabetes. However, I know of no human trials currently underway which are based on this theory. The closest would be DiaKine's research

But remember for all the research described above and any research which is not being done on people: it has only a 1% or 2% chance of working in people, and will take 10 years (or more!) to become generally available. And that is why I don't track these "cured type-1 in animals" press releases very closely. I've got 10 years to see if they get anywhere, and most of them never do. Even the really well thought out ones that sounds like a really good idea have a 98%+ failure rate.

Most of the research discussed above is not described on my web page ( because that page only covers clinical trials: trials being done on people.


Wednesday, August 27, 2008

Disappointing News on DiaPep 227

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

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

Finally, in June 2008 the released interim results of their phase-III trials. You can read about them here, but you'll notice there are no numbers. No actual data results; they basically just said "did as well as phase-II testing" (although that is not an exact quote). Then one of their investors, who had seen the actual data dropped the following bombshell in a press release:
The reason is that the interim result does not provide statistically significant results about the effectiveness of DiaPep 277
Basically, what they are saying is that -- so far -- the people treated with DiaPep 227 and the people who were not had about the same outcomes. That is the worst news you can get our of a clinical trial. Now all is not lost, maybe the end part of the phase-III trial will show great improvement. Maybe a future clinical trial will have success. However, right now, things look pretty grim.

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

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

As always you can get updated on all the potential cures for type-1 diabetes on my web page: and read these updates on my blog:

Monday, July 21, 2008

LCT Reports Good Results from Phase-I Trials

LCT has just posted results from their Phase-I human trials. They are transplanting encapsulated pig islet cells. If successful, their cure will work on all type-1 diabetics. Even those who have been diabetic for years.

You can read the report here: my summary of it is below.

The Good News
No safety problems.
80% of people's A1c went down, average went from 8.5 to 6.8 (the one who went up was just .3)
All people's average insulin usage went down, on average by about 24% at end of study.
One person used no injected insulin at all for a time.

The Bad News
Study is very small, only six people.
Study is very short, a maximum of 12 months, most people were followed much less than that.
Study was done in Russia.

When you look at these results (and the more detailed results in the PDF paper linked above) remember that this is a Phase-I trial. That means it is designed to test safety, not effectiveness, and that they usually give a very small dose during Phase-I trials. It is usual to only get partial effectiveness in these trials, because you are testing for safety. Phase-II is where you should see the higher effectiveness, because you can use higher doses.

So, with that in mind, I think it is clear that LCT's treatment can lower the use a of insulin quite a bit, and also lower A1c numbers, and that should lead to fewer complications. And this is all in a low dose Phase-I trial!

The big issue for me is: How long will it last? And the news here is not so good. The two patients who were followed for 12 and 11 months ended up with about half the insulin production that they started with. So after about 11 months they were only generating about 1/2 the insulin as when they were first implanted. The two patients who were followed for 5 and 4 months, one stayed the same, and the other dropped about 30%. I think it is going to be critical to find out what happens to the 6 patients over the next four or five years. (Plus any research LCT can do to see why less insulin is generated after 11 months.)

There is also an issue in making sure the patient generates all of their own insulin, so they don't need to inject any, but I'm assuming that just requires more islet cells, and I'm kind of assuming that is not a big deal. They can put in 4x as many islets, and get 4x as much insulin. I hope.

The obvious question is: What is the next step? Will LCT start a higher dose, Phase-II trail? Will they follow their Phase-I patients for longer? Will the do more patients as part of their Phase-I trial? Will they do all of these things? I don't know. But when I do know, you will know.

Friday, June 27, 2008

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:

Tuesday, June 10, 2008

More Data on Bayhill's Phase I trial

I just poked around the Bayhill's web site a little. They are in the middle of a Phase-I trial aimed at curing type-1 diabetes. I noticed two pieces of very good news, and added both to my status page on cure research.

First, they have some data from the clinical trial that is on going right now, and that data looks very promising. This is the exact quote from their web page:
In the BHT-3021 phase I/II trial, nine patients have been randomized to the 1 mg dose cohort to date. BHT-3021 has demonstrated safety and tolerability, with no increase in adverse events among the first nine patients relative to placebo. Preliminary data also indicated that after the initiation of dosing with 1 mg of BHT-3021, there was a rapid reduction of approximately 50% in titers of anti-insulin antibodies that was sustained throughout the dosing period. In contrast, the anti-insulin antibody titers were unchanged with placebo dosing. Autoimmune T cell data from these initial patients are pending at this time.
Second, this trial is open to people who have had type-1 diabetes for any length of time. It is not "honeymoon" only, as so many are.

Check out the status of this, and all the other type-1 cure research that I track by clicking on the "Status of Research Discussed" to the right.

Friday, June 6, 2008

Hopeful Comments on Honeymoon Cures Becoming Cures for Everyone

Most research aimed a curing type-1 diabetes is focused on people in the "honeymoon" phase. People who have had type-1 for 3 months or less (or sometimes out to 6 months). In the past (before 2007) I was very nervious about these cures. I was afraid that if they worked, research into curing long term diabetes would stop, since there would not be a new pool of customers. However, recently I have come to a different conclusion. I now think that it is very likely that cures for type-1 diabetes will start out working on "honeymoon" diabetics, but end up being refined or augmented to work for all diabetics. Why?
  • Some recent research suggests that the pancrease is always making new cells, and the immune system is always killing them. If so, then even long term diabetics will slowly be cured with these treatments.
  • There are several research areas trying to make the pancrease grow new cells. Currently, these are not considered promising, because the immune system would just kill the new cells. But if any of these cures work for honeymooners, then they could be paired with a cell growth treatment for a cure for long term type-1 diabetics. Such growth factors include human growth hormone, INGAP, etc.
Remember that once a drug is approved for any one purpose, that drug can be proscribed by a doctor for any other purpose. This is called "off label" prescription. If if any of these cures are approved even just for honeymooners, then some doctor, somewhere is going to prescribe it to non-honeymooners, and we will all quickly learn what happens.

New Phase III Trial Starts: Otelixizumab from Tolerx

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

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

Press Release Reporting this (see the last paragraph)