Wednesday, August 29, 2012

Summary of Dr.Faustman's Phase-I Results

This is a short summary of Dr. Faustman's research.  If you want the long, detailed version, that was yesterday's blog, and you can see it here:

Dr. Faustman has published the peer reviewed results of her phase-I clinical trial.
The trial was complex, and the results are complex, and I know there is a lot of interest in this particular research, so this post contains a quick summary of the results. 

If you want more explanation of anything I say here, please take a look at that detailed posting first.  If it doesn't answer your questions, then comment or email me.  Thanks.

I've blogged extensively on Dr. Faustman's research in the past, which you can read here:

Background to Dr. Faustman's Research

The essence of Dr. Faustman's theory on how to cure type-1 diabetes is:
  • Part 1: BCG causes the body to generate TNF
  • Part 2: TNF causes fewer autoreactive T-cells
  • Part 3: Fewer autoreactive T-cells results in beta cell regrowth and more insulin generation
  • Part 4: More insulin generation is the path to curing type-1
BCG (Bacillus Calmette–Guérin) is a biologic which has been given to over a billion people (in low dose) as a tuberculosis vaccine, and is also approved (in much higher doses) as a bladder cancer treatment.  It is a generic drug with a very long record of safety.  This trial focuses on parts 1-3 of the theory.  Part 4 is not controversial at all, and part 1 is widely believed as well, so it is parts 2 and 3 that really need testing.

TNF ("Tumor necrosis factor" or TNF-alpha) is a naturally occurring protein that can cause cells to die.  It is involved in the natural regulation of immune cells.

"Autoreactive" refers to immune cells which mistakenly attack the body's own beta cells.  The destruction of these beta cells leads to type-1 diabetes.  This is sometimes referred to as an "autoimmune attack" because the body's own immune system attacks the body itself.

Summary of Results

In this day of 10 second sound bytes and 140 character messages, everyone wants a short summary.  But this is a complex trial, and just about any quick summary will be an over simplification.   This is the best that I can do:

This trial was supposed to provide support for three parts of Dr. Faustman's theory, but:
1. It provided no data to support part 1 of Dr. Faustman's theory.
2. It provided data that part 2 was not happening (ie. it contradicted part 2 of Dr. Faustman's theory).  In particular, no change in live autoreactive T cells were reported.
3. The study shows a very small improvement to C-peptide numbers (but that was dependent on using a particular control group).  This improvement to C-peptide production supports part 3 of Dr. Faustman's theory.

Result 2 above, suggests that Dr. Faustman's theory about how BCG could help cure type one diabetes, was wrong.  But result 3 holds out a sliver of hope, that maybe in some different way BCG will be part of a cure.  Therefore, all discussions about the success or failure of this experiment are going to quickly boil down to the importance (and even existence) of the very small increase in C-peptide production in item 3 above.  This very small increase in C-peptide production was "brittle", meaning it was only seen with a particular control group.

Other important points:
4. There were no safety issues, although this was expected considering BCG's long safety history, and the fact that it was chosen specifically because it was known to be safe.
5. The improvement to C-peptide numbers, is much smaller than that seen in established type-1 diabetics enrolled in Dr. Zhao's or LCT's previously published phase-I clinical trials.
6. In this very small study, A1c numbers got worse for people given BCG.  For me, this was a worrisome effect, although the paper does not treat it as such.
7. Part of the paper described one patient who came down with Epstein Bar Virus (EBV) during the trial.  I consider that a single patient case study, not a clinical trial, so I'm not going over it in detail. If you're interested in that one patient, you should read those parts of the paper.

The Future of This Research

In one sense, the future of this research is easy to predict.  Dr. Faustman has already gathered $8 million for the follow-on phase-II trial, so I have every expectation that a follow-on clinical trial will be done.

But scientifically, the future is much more murky.   Moving this research forward is not going to be easy.  Because the current results are 100s of times too small for a cure, I don't think it is reasonable to just give "linear" higher doses or more frequent doses.  Certainly, not a dose 100s of times higher.  Often, it is the theory about why the treatment works that gives you clues about how to change doses between phase-I and phase-II.  If there is an important threshold, for example.  But in this case the theory about why the treatment works has not been supported by phase-I, so there is no help there.

Of course, research is always about the future: what can this grow into?  But if you are betting on future improvements, then it makes sense to start with a stronger base, and Dr. Zhao had much better results 6 months ago, and LCT for longer than that.

My opinion: Everyone wants to know if this clinical trial succeeded or failed.  This trial did not succeed, but did it fail?  Maybe, I would phrase it a little differently.  One way to phrase it is this: This trial succeeded in telling us that the previous theory was wrong.  Another way to phrase it is this: This trial is more indicative of a basic research result, than a path-to-product research result.  There were anomalies that might turn out to be interesting: the dead autoreactive T cells and also the change in GAD/TnT8A antibodies and regulatory T cells, but these represent basic research and there is no obvious path from these results to a cure.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
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