Thursday, January 29, 2009

Stem Cell Updates for Type-1 Diabetes

Embryonic Stem Cells have been in the news recently, because of two recent events. First, ReNeuron has started a clinical trial to use embryonic stems cells to heal spinal injuries, and second Geron has gotten FDA approval to start a clinical trial in the US also to use embryonic stems cells to heal spinal injuries. Since embryonic stem cells have possible uses in curing (or helping to cure) type-1 diabetes, it is reasonable to review the current state of that research.

Summary of Embryonic Stem Cell Research in People to Cure Type-1 Diabetes

This is simple: there is none. To the best of my knowledge, there is not a single clinical trial, aimed at curing type-1 diabetes, that is based on embryonic stem cell research, that is being done anywhere in the world. Amcyte (now purchased by ReNeuron, see above) might have started such a study in either 2003 or 2006, but I can't find a current record of it, or any results.

Why might Embryonic Stem Cells Matter to Curing Type-1 Diabetes?

I don't talk much about direct transplants, because (so far) they all require immunosupressive drugs for the rest of your life, and they only function for a limited number of years. However, there are two ways of thinking about why these transplants fail. One group "camp A" says that they fail because the type-1 diabetes which killed the first pancreas, now kill the transplanted one. The other group "camp B" says that they fail because the body's normal immune system attacks them (properly) as foreign tissue, and that is what kills them.

Now, if any form of stem cells can be grown into transplantable beta cells (or whole pancreases) then using these cells would solve the immunospressive issues and the body's normal immune system would not attack these new cells. So if "camp B" is right, then transplants based on stem cells will cure type-1 diabetes outright. However, if "camp A" is right, then stem cells wont matter.

I think it is safe to say that most researchers are in "camp A", but not all. The guys who are doing transplantation work are probably in "camp B", and so are the guys researching inflammation. So while "camp A" is a strong majority, "camp B" is a reasonable minority opinion. (It's not a lunatic fringe.)

But there is another possible way that stem cells (especially embryonic ones) might help cure type-1 diabetes, which is basically transplants after immunsupression.

There are three "camps" when it comes to curing type-1 diabetes by ending the immune attack. One camp thinks that the human body naturally regrows beta cells quickly, so that if the immune attack on the beta cells could be stopped, people would naturally grow back their beta cells, and their diabetes would be cured. Another camp thinks that the human body does not naturally regrow beta cells once they have been destroyed (or does it very slowly). These researchers think that a cure will require stopping the immune attack, and getting the body new beta cells. A third camp thinks that the human body regrows beta cells, but very slowly. They fall in between the two other groups, and generally think that stopping the immune attack will not immediately cure diabetes, but that if you wait long enough, it might eventually.

So, camps 2 and 3 think that new beta cells will be required to cure type-1 diabetes. (But camp 1 doesn't think they will be needed.) Now there are several different sources of new beta cells. None of these work now, but any of them, or all of them, may be a source of new beta cells in the future: growing new beta cells "in place", transplanting embryonic stem cells, stimulating the patient's own stem cells, encapsulated translated beta cells from either people or pigs, etc. this is where stem cells (and particularly embryonic stem cells) come in. Example of getting the body to grow itself more beta cells are HGH (Human Growth Hormone), the HIP based research from CureDM, and INGAP. An example of stimulating the patient's own adult stem cells is Burt's work in Brazil. Transplanting embryonic stem cells is being worked on by several groups, but it is all pre-clinical trials. Encapsulated beta cells are led by LCT, but others are working on it as well.

So a summary of all this is as follows:
1. If beta cell transplants fail because the immune system attacks them, and not because of an underlying immune problem, then stem cells could be a complete cure for type-1 diabetes, but this is a minority opinion among researchers.
2. If the immune defect which leads to type-1 can be cured, and the body needs help regenerating beta cells, then stem cells could be part of a cure for type-1 diabetes.
3. There are many potential sources of beta cells out there, one of which is embryonic stem cells, which is behind other beta cell growing technologies, in terms of current status of human trials.

Science and Politics (and some personal opinions)

One of the interesting questions is, "why are there no embryonic stem cell cures in human trials right now? Is it because of problems with the science or problems with the politics? And in particular, has the 8 year Bush presidency impacted this? Obviously, we can never know an absolute answer to this question. But I must say that I'm struck by two things:

First, two days after the end of the Bush presidency the FDA approves the very first human embryonic stem cell human trial. Two days after! Sure the FDA and Geron both claim that politics had nothing to do with it. But I judge things based on actions, not words, and the timing of the approval makes it appear to me that the FDA under Bush did have a policy of not approving clinical trials that would promote embryonic stem cell research.

Second, one of the cornerstones of the anti-embryonic stem cell researchers, was that Bush only cut off money to certain embryonic stem cell work. Since some embryonic stem cell lines could still be used, and money raised from other sources, this would not by itself cut off embryonic stem cell research. So if that research was not going anywhere, that was because it was not good research, not because of government limitations. However, it seems clear now, that this was not true. That the FDA was artificially holding up approvals for embryonic stem cell clinical trials.

Such a policy would have four huge impacts on research: 1. clinical trials simply could not be done. 2. the biggest potential market for treatments (the USA) would never be open, because FDA approval for sale requires FDA approved clinical trials, 3. other markets around the world would be massively delayed or forbidden, because many local safety bureaucracies follow the FDA's lead. 4. anyone and everyone who wanted to fund embryonic stem cell research would need to factor in the denial of the USA market, and all the markets which followed the FDA, and also the delay for all the rest of the markets. And these impacts would effect all embryonic stem cell research, not just the ones explicitly banned by the Bush administration.

So it will be interesting to see what happens over the next 4-8 years.

Sunday, January 4, 2009

Best News of 2008 in Clinical Trials to Cure Type-1 Diabetes

Here is my list of Best News of 2008 in Clinical Trials to Cure Type-1 Diabetes. I've based this list on these simple rules:
  1. The best news is a cure, or a measurable improvement in BG, A1C, or insulin used.
  2. The bigger the drop (in BG, A1C, or insulin used) and the more people helped, the better.
  3. Results for non-honeymoon diabetics are better than the same results for honeymooners.
  4. Results from later phase trials are better than results from earlier phase trials.
So with that in mind, here are five "best news" and a few special mentions. Note that I have not parked one "best" another "second best" etc. They are all really good news in different ways:

The "Big 5"

LCT finishes a phase-I trial, and shows some results
This news had it all: shows improvements for type-1 diabetics, works for people who have had diabetes for a long time, and marks the end of a clinical trial, with data we can see. Insulin usage dropped 24%, and almost everyone's A1C number went down. One person was cured (used no insulin at all) for a period of months.
Hope for next year: The start of a bigger trial and to see longer term data from this trial. Publication in a peer reviewed journal would be nice, too!

More data here:
and here:

Burt Publishes 3+ year follow up data for their phase-I trials
This is the most amazing results seen yet: more than half of the patients where completely and permanently cured (low BG, A1C, and no more insulin needed). Some for over 3 years! Safety concerns linger, and it was honeymoon only.
Hope for next year: Start a phase-II trial for this, or better understand the safety issues.

More data is here:
and here:

Diamyd starts two large phase-III trials
These guys are the closest to mass marketing a type-1 cure for some people. Their treatment shows improvements (lower BG, A1C and insulin usage) for many people, and might cure some people. It has only been tested on honeymooners, but once it is approved for general use, anyone will be able to try it. Their phase-II trails suggested that Diamyd use doubled the amount of surviving insulin producing beta cells. This means they require less insulin, and are very likely to have far fewer complicatoins in later life.
Hope for next year: See some intermediate results from this phase-III trial, or test it on non-honeymooners, or both!

More data is here:
and here:

ToleRx starts a phase-III trial
These guys are also making steady progress on a treatment that may cure some people and improve the health of many more. It has been shown to lower BG, A1C, and insulin requirements, but has only been tested on honeymooners. People treated in phase-II trails required significantly less insulin even after 18 months, compared with untreated people. (Although they did not have a big milestone this year, MicroGenics is testing a similar CD3 based cure, and is only a half step behind ToleRx.)
Hope for next year: Maybe finish this phase-III trial, or test it on non-honeymooners, or both!

More data is here:
and here:

Gitelman and Osiris both started phase-II trails.
These are different immunology based cures, which are both at very similar point in their development. They are both being tested on honeymoon diabetics. Gitelman's research is based on previous phase-I research aimed a curing type-1 diabetes. The Osiris treatment has been tested in the past on several other immunological diseases, but this is the first time it has been tested as a cure for type-1 diabetes.
Hope for next year: probably nothing, but in 2010 good results from both!

More data is here:
and here:

More Generally

While the above paragraphs describe some specific research milestones of 2008, there are also more general good news out there. For example, I've been covering human trials aimed at curing type-1 diabetes for several years now, and every year I do it, there are more and more trials to keep track of. This year, for example, is the first year that there has been more than 1 phase-III clinical trial active. There were three of them at the end of the year. Will they all pan out? Probably not, but more trials means a bigger chance of one success. And we only need one success.

I'm also very intrigued by the new findings this year, about the importance of inflammation as a possible causative factor in type-1 diabetes. Although none of this research has yet led to clinical trials, it is clearly something new and different. As it is only a year old as a research direction, there is still lots of time for it to grow into something useful. Watch these guys: