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

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:
http://ww2.aievolution.com/ada0901/index.cfm?do=abs.viewAbs&abs=5458

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:
http://www.bayhilltherapeutics.com/art/BHT_GNE_PartnershipReleaseFNL6-9-09.pdf

Joshua Levy

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

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:
http://www.exsulin.com/underway.html

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: http://www.clinicaltrials.gov/ct2/show/NCT00034255. The phase-II study is described here: http://www.clinicaltrials.gov/ct2/show/NCT00071409. 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

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:
http://www.earthtimes.org/articles/show/diakine-therapeutics-diabetes-immune-modulator-drug-set-for-human-clinical-trial,821004.shtml

The US FDA's clinical trial record is here:
http://clinicaltrials.gov/ct2/show/NCT00896077

And the official press release is here (and is better than most):
http://www.diakine.com/assets/news20090512.pdf

The press release talking about LSF+INGAP together is here:
http://www.diakine.com/assets/news20080506.pdf

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

Joshua Levy

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

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

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

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

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

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

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

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

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

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

Joshua Levy

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: http://www.clinicaltrials.gov/ct2/show/NCT00730392 and you can read the abstract of the results here: http://www.ncbi.nlm.nih.gov/pubmed/19366957

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: http://en.wikipedia.org/wiki/Etanercept
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:
http://www.faustmanlab.org/docs/mediacoverage/MedPageToday_8-25-08.pdf

Joshua Levy

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:
http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#DiabecellbyLivingCellTechnologies
http://cureresearch4type1diabetes.blogspot.com/search/label/LCT

Below is my discussion of the three recent news items:

Living Cell Technologies Gains Additional Benefit From DIABECELL
http://www.lctglobal.com/downloads/cms_latest_news/2009-04-05-Clinical%20Update%20Apr09.pdf

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
http://www.lctglobal.com/downloads/cms_media_resources/2009-04-08-Xeno%20Apr09.pdf

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

Two New Trials to Test Kineret / Anakinra

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

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

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

This is their description of the drug:

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

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

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

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

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

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

A Little Discussion

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

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

Joshua Levy

Peakman's Phase-I Results

Peakman's Phase-I Results

Years ago, when I first started tracking research to cure type-1 diabetes, Peakman's clinical trial was one of the first ones that I added to my list and started following. And it was very frustrating, because nothing happened. Years went by and nothing happened. But now something has happened. The phase-I clinical trial ended, and the results have been published.

This research is based on the idea of using a modified protein to teach the body's immune system to not attack it's own beta cells. The clinical trial gave some people no protein, some a little protein, and some a lot. The patients were all people with established type-1 diabetes.

You can see the abstract here. The full study is pay-for-view:
http://www3.interscience.wiley.com/journal/121536033/abstract
And JDRF (which helped to fund the work) has a good description of it here:
http://www.jdrf.org/index.cfm?fuseaction=home.viewPage&page_id=DD5ADF6D-110A-9BB5-F8684C43208F87D2
Here is a great quote from JDRF's description:

Peptide immunotherapy is a type of treatment that uses small proteins to "reset" the immune system to a healthy state, much like the common allergy shot. In the case of proinsulin peptide therapy, the goal is to train the immune system to tolerate the insulin-producing beta cells that are the target of the immune response that causes type 1 diabetes.

From a safety point of view, this study was completely successful: no safety issues were found. So they can move on to phase-II trials. They hope to start those in less than 6 months. (That will be interesting in itself. My experience is that the time between ending a phase-I and starting a phase-II is always more than 9 months, so it will be interesting to see if these guys can do it quicker.)

Safety is the official goal of every phase-I clinical trial. However, most of them also try to generate some data on effectiveness of the treatment. Since they are testing minimal doses (for safety), expectations are set low, but it is still common to see some improvement. But I don't see that for this trial. I don't see any record that they looked for or found lower BG rates, lower A1Cs or less insulin usage. They did see some small changes for a 6 month period in the patient's immune system, but it is not clear what impact those changes would have.

So my overall summary for the research right now, is that their results from phase-I definitely get them to phase-II testing, but there is no data to evaluate if it is working or not. We'll need to wait for the phase-II trial to finish for that.

Joshua Levy

Follow up to Phase-I: LCT Releases Longer Follow Up Data

LCT has released some more data on their Phase-I clinical trial. This includes longer term data on the first five people in the study, and some news on two later people. LCT encapsulates insulin generating cells from pigs in a special coating so that the body's immune system does not attack them, but nutrients can flow in and wastes and insulin can flow out. You can read their press release here:

http://www.lctglobal.com/downloads/cms_media_resources/2009-02-10-LCT%20Announcement%20Feb%2009%20ClinUpdate%20Final_110209.pdf

My quick review is that this data is more of the same, so my previous comments on LCT still apply:
http://cureresearch4type1diabetes.blogspot.com/2008/12/lcts-research.html (most recent comments)
http://cureresearch4type1diabetes.blogspot.com/search/label/LCT (all comments)
http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#DiabecellbyLivingCellTechnologies (general status, prior to this announcement)

The quick summary is this:
It can work on anyone (honeymoon and non-honeymoon patients).
The low doses used so far have worked for some people, but not for everyone, but higher doses are expected to work better for more people.
Some people have been temporarily cured (no BG checks or using insulin) for days or weeks as part of this phase-I trial.
The big unknown is how long the implants will work, or how often the new implants will need to be added.
Plus all the normal phase-I risks: only a small number of people have had this treatment and only at low doses, etc.

What I'd really like to see from these guys is a graph showing insulin usage over a 1-3 year period. Or, even more specifically: for people who had a big drop in insulin usage after getting the implants, how much of that drop stayed with them for 1, 2 or 3 years?

Overall, I think this is a strong research program, although this update doesn't have much meat on it.

Joshua Levy

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
http://jama.ama-assn.org/cgi/content/full/297/14/1568
http://jama.ama-assn.org/cgi/content/abstract/297/14/1568

[r2] http://jama.ama-assn.org/cgi/content/extract/298/3/285

[r3] http://jama.ama-assn.org/cgi/content/extract/298/3/285-a

[r4] Some results and discussion:
http://66.102.1.104/scholar?hl=en&lr=&q=cache:0B8eccFzyUUJ:www.scielo.br/scielo.php%3Fpid%3DS1516-84842008000600014%26script%3Dsci_abstract%26tlng%3Den+burt+diabetes+brazil

[r5] A different report:
http://www.scielo.br/pdf/rbhh/v30s2/14.pdf

[r6] Gitelmans work is described here, on my web page:
http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#NIAID/ITNGitelmanThymoglobulin/ATG

[r7] Trucco's work is described here, on my web page:
http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#Children%E2%80%99sHospitalofPittsburghTrucco

[r8] See the graphs here:
http://jama.ama-assn.org/cgi/content/full/297/14/1568/JPC70002F1

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: http://www.lctglobal.com/, which is very glossy.

There is another source, which I recommend only with serious reservations, and that is http://www.islet.org/forum/wwwboard.htm. 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: http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#LivingCellTechnologiesDiabecell

[r2] LCT home web page is here: http://www.lct.com.au/

[r3] http://www.scoop.co.nz/stories/SC0803/S00061.htm
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: http://www.diabetesincontrol.com/results.php?storyarticle=4688

[r5] http://www.cwdfoundation.org/Grants2008/LCTBDC.html

[r6] Press reports on the New Zealand approval:
http://www.fiercebiotech.com/press-releases/living-cell-technologies-receives-health-ministers-approval-start-leading-edge-live-c

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: http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#NIAID/ITNGitelmanThymoglobulin/ATG, except that this trial is still ongoing. However, they have published interrum results (on their first 17 patients) here: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1783538

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: http://clinicaltrials.gov/ct2/show/NCT00190502

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.

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: http://clinicaltrials.gov/ct2/show/NCT00525889 (NCT00525889)
Immune Tolerance Network Trial Record: http://www.immunetolerance.org/studies/a-phase-i-trial-il-2-and-sirolimus-recent-onset-type-1-diabetes-mellitus (ITN018AI)
Info for patients: http://www.benaroyaresearch.org/files/webfm/diabetes/web_il2_rapa_intervention.doc
General info on Sirolimus: http://en.wikipedia.org/wiki/Rapamycin
General info on IL-2: http://en.wikipedia.org/wiki/Interleukin_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.

Joshua

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 (http://www.bernardfarrell.com/blog/2008/05/meeting-with-dr-faustman-again.htm) 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: http://en.wikipedia.org/wiki/Immunologic_adjuvant

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

References and Sources

[r2] This is Faustman's 2003 publication: http://www.sciencemag.org/cgi/content/abstract/sci;302/5648/1223

[r3] For example, this book: http://books.google.com/books?id=TFoIXMe-UEEC&pg=PA403&lpg=PA403&dq=complete+Freund%27s+adjuvant+CFA+safety&source=web&ots=dYXKq2PcQ-&sig=zrlavn3Lmahle2DArr02aE1_Ib8&hl=en&sa=X&oi=book_result&resnum=10&ct=result contains this quote: "(CFA) is quite toxic and cannot be used in humans."
A general safety data sheet on CFA can be found here: http://www.vcu.edu/oehs/chemical/biosafe/CFAinfo.pdf. 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): http://www.pnas.org/content/89/9/3927.abstract

[r5] This study was published in 1990: http://diabetes.diabetesjournals.org/cgi/content/abstract/39/5/583

[r6] This is Faustman's 2001 publication: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=209340

[r7] The best description of these studies and their results that I have found, is here: http://www.joslin.org/1083_3312.asp

[r8] Here are the three experiments that came to the same conclusion (no spleen cells required) in 2006:
http://www.sciencemag.org/cgi/content/abstract/311/5768/1774
http://www.sciencemag.org/cgi/content/abstract/311/5768/1775
http://www.sciencemag.org/cgi/content/short/311/5768/1778

[r10] Orban's experiment: http://clinicaltrials.gov/ct2/show/NCT00057499

[r15] The Nathan/Faustman human trials are described here: http://www.clinicaltrial.gov/ct2/show/NCT00607230

[r20] http://cat.inist.fr/?aModele=afficheN&cpsidt=11111587
In English the article is entitled "THE CUMULATIVE INCIDENCE OF CHILDHOOD DIABETES MELLITUS IN SWEDEN UNAFFECTED BY BCG-VACCINATION"

[r21] http://care.diabetesjournals.org/cgi/content/abstract/22/10/1703
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: http://care.diabetesjournals.org/cgi/reprint/22/10/1703

[r22] http://care.diabetesjournals.org/cgi/content/full/28/5/1204
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"

[r23] http://care.diabetesjournals.org/cgi/content/abstract/20/5/767?ijkey=de477936685fbc95cfd98bc52cb120be655acd09&keytype2=tf_ipsecsha
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."

[r24] http://care.diabetesjournals.org/cgi/content/abstract/21/10/1691
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 http://www.sciencemag.org/cgi/content/full/314/5803/1243a
See the discussion under [d7].

[r26] http://www.ncbi.nlm.nih.gov/pubmed/1727730 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: http://www.ncbi.nlm.nih.gov/pubmed/8178349

[r27] http://www.diabetes-mellitus.org/mgh_tnf_nod.htm

[r28] Abstract is here: http://210.101.116.102/Diabetes/koreamad/JournalSearch_index.asp?year=2000&page=340&vol=24&iss=3
Full paper: ftp://210.101.116.17/kiss8/27203283.pdf (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."

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: http://www.lctglobal.com/news/LCTReportsClinicalBenefits.pdf 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.

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.