Thursday, January 12, 2012

Zhao et al (Tianhe) Publish Successful Phase-I Results (in non-honeymoon diabetics)

In my opinion, this is big news.
It's the result of a phase-I study, published in BioMed Central's Medicine Journal (which is peer reviewed) by a group of researchers working at the University of Illinois at Chicago and in China.

What Did These Guys Do?

This trial was done on people with established type-1 diabetes.  Each person had a blood draw, and then a particular kind of immune cell was separated from the blood and specially processed.  The processing phase used umbilical cord stem cells, but not the patient's own umbilical cord.  (This was generic umbilical cord stem cells, not from the exact person being treated.)  The immune cells were then put back in the person.  The stem cells did not go into the person; they were only used for the external processing.

The goal was to teach the body's immune system to stop attacking beta cells.  The researchers refer to this as "education", and refer to the processing device used as an "Stem Cell Educator".

The treatment was done once and I think it took about 10 hours.  Patients were in the hospital for 2 days, but it's not clear to me if that was due to an over abundance of caution (this was a phase-I study, after all), or if it was really needed.  This trial was done at the General Hospital of Jinan Military Command (Jinan, Shandong, China).  The lead author of the paper is Yong Zhao, is an Assistant Professor at the University of Illinois at Chicago.

The patients averaged about 29 years old, and had had type-1 for an average of about 8.5 years.  Patients were followed for a total of 40 weeks, but most of the results data was gathered at 4, 12, and 24 weeks after the procedure.

The researchers divided their patients into three groups.  Group A (6 people) had some insulin production before treatment. Group B (6 people) had no measurable insulin production before treatment, and Group C (3 people) also had some insulin production  before treatment, but they got a "sham" (or placebo) treatment. 


What Results Did They Get?

There were no significant safety issues during the trial.

Average Daily Insulin Usage:
Group A's insulin requirement was down 38% at 12 weeks (from about 36 to 22 units/day).
Group B's insulin requirement was down 25% at 12 weeks (from about 48 to 36 units/day).
Group C's insulin requirements didn't change.

Note: earlier version of this blog had a typo in Group B's starting insulin units/day.  Fixed here.

Average A1C levels:
Group A started at 8.73 and dropped to 7.67 at 4 weeks and to 6.82 at 12 weeks (almost 2 points overall).
Group B started at 12.2 and dropped to about 10.5 at 12 weeks.
Group C started at 9 and was at 8.7 at 12 weeks.
Note: I consider a drop of 1 to be important, although some researchers consider even a drop of 0.5 as important.  Here we have drops of over 1.9 and 1.7.

Fasting C-peptide (ie. Body's ability to generate "basal" insulin at background levels)
All these numbers are average ng/ml, and are very approximate based on graphs in the paper.
Group A: Starts at about 0.35 and ends at about 0.8 at 24 weeks.
Group B: Starts at about 0 and ends at about 0.5 at 25 weeks.
Group C: Stays at about 0.4 at 4, 12, and 24 weeks.
Note: Non type-1 diabetics generally have a fasting C-peptide level between about 0.5 and 2.0.  The paper's authors felt that 0.6 was the lower bound of normal C-peptide in the population being studied.  So it is possible that Group A has moved into the bottom of the normal (for non-type-1 diabetics) range.

OGTT C-peptide (ie. Body's ability to generate "bolus" insulin in response to food)
All these numbers are average ng/ml, and are very approximate based on graphs in the paper.
Group A: Starts out generating 1 after a meal, at 4 weeks generates about 1.6, and at 12 weeks about 1.7.
Group B: Starts out generating about 0 after a meal, at 4 weeks generates about .05, at 12 weeks about 0.35, and at 40 weeks about 0.6.
Note: I don't know what "normal" is for this test, so can not compare either group to non type-1 diabetics.

The paper also contains data on immune system changes which the researchers felt showed significant improvement in autoimmunity.    I can not evaluate those results.

Also interesting, the researchers are very specific in saying that they think this study shows that beta cells do regrow, in people, if the immune system stops attacking them:
Notably, our clinical data provide powerful evidence that reversal of autoimmunity leads to regeneration of islet β cells and improvement of metabolic control in long-standing T1D subjects.
My take on all this data is that there is no question that the body is generating more of it's own insulin after this treatment than before.  And that happens in people who have had diabetes for a long time, and who are not generating any of their own insulin before treatment.  That's huge.  The results are large enough so that type-1 diabetics would see the improvement in their insulin usage and A1C numbers.

Discussion

Obviously, there is a lot of issues to discuss here:

Possible Conflict of Interest

I hate to start off with discussion of a conflict of interest, but in this case, the situation makes me nervous, so I'm discussing it first.  In the paper's pre-publication version, it says:
Competing interests 
The authors declare that they have no competing interests.
However, the unique and specialized equipment that they used in their clinical trial was manufactured by Tianhe Stem Cells Biotechnology.  This equipment was central to the clinical trial.  However, that company is connected to three of the authors (including both first and last authors).  Here is a quote from the University of Illinois web page:
Tianhe is a stem cell biotechnology company commercializing the inventions emanating from the labs of Drs. Zhao, Mazzone and Holterman within the Departments of Medicine and Surgery at the University of Illinois at Chicago. With operations in both Illinois and overseas, the Company is pursuing the application of stem cells for the treatment of autoimmune diseases.  Tianhe is initially pursuing the treatment of Type 1 diabetes through a clinical system which extracts the patient own stem cells and utilizes them to re-educate the patient’s faulty immune cells to prevent future immune response to the patient’s own insulin producing cell.    [from http://otm.illinois.edu/sites/all/files/files/otm-annual-reportseptember-1final.pdf]

Obviously, I don't know the exact financial details involving the University, Tianhe, and the three researchers, but I would like to see more details before I accepted the claim that the authors had no competing interests!  It certainly sounds like the researchers are testing equipment that they will make money off of, if it works.  On the other hand, if this relationship gets this research to market quicker, and the research helps people with type-1 diabetes, then I'm all in favor of it. :-)

Missing Data

There are a couple of obviously missing data points.  For example, Group A's 40 week post-meal C-peptide numbers are not reported.  And 40 week fasting C-peptide data is not reported for any group.  The trial design only collected insulin use and A1C data at 12 weeks, which is too bad.  I would have like to see it at 24 or even 40 weeks as well.

There are also a few other odditites.  For example: in Groups A and B (treated), about 2/3 of the patients are women, but Group C (placebo) is all male.  Also, the Group B A1C before treatment averaged 12.2, which is a lot higher than you would see in the US (I hope!)

None of this is particularly unusual for a phase-I trial; and none of it makes me nervous about the results.  It just makes me want to see data from a larger phase-II study.

Next Steps To Market

Getting a cure to market requires three things:
1. Scientific success.
2. Engineering and corporate success.
3. Regulatory approval.

This study is a solid, successful phase-I clinical trial.  No doubt (in my mind) about that.
Plus, it is the first time this has been used in people, as far as I know, and there are obvious ways to improve it.  More blood could be put through the machine.  The blood could spend more time in the machine.  It could be used repeatedly, etc.  The classic goal of a phase-II trial is to figure out the best dosing, and I think these guys are well positioned to do that.

There is a clear engineering path to market.  The "Educator" equipment is produced by Tianhe corporation, and I would expect that once the equipment is for sale, many doctors would be able to use it.  It sounds to me like there is a clear way to make money off this, and so I would expect that (if it works scientifically) Tianhe will have no problems getting funding and getting the corporate structure required to build a business around using their equipment to treat/cure type-1 diabetes.

As for regulatory approval, I think there are two paths forward.  The normal path to approval is a phase-II trial, and then two phase-III trials.  The already completed phase-I trial took about a year, I would expect the phase-II to be about that long, maybe a little longer, and phase-III to be still longer.  However, if they are successful and well funded, these guys could get to market in less than 10 years.  Of course, the next question is, what will they make it to market with?  Will the thing available be a treatment?  A cure?  A temporary cure?  Fewer long term complications?

There is a second, much faster, path to approval, called the "surgical procedure exemption".  I do not know all the details, but the FDA does not require that surgical procedures be proven "safe and effective" before a surgeon uses them.  Under this exception the FDA does allow some treatments to be sold without full approval, if those treatments involve taking something out of the body, processing it in some simple ways, and then putting it back in.  I don't know if this "educator" process would qualify or not.

I know some people are nervous about research done in China, and especially at a Chinese military hospital.  I think this is my first detailed blog post on research done in China.  I do want to point out that this trial has ethical approval from the review board at the University of Illinois at Chicago, and that it looks to me like the researchers followed US FDA standards in the trial, and international standards where applicable.  I don't have detailed knowledge of FDA requirements, but it does look to me like, even at this early stage, these guys are working to eventual US FDA approval.

News Coverage: http://www.medscape.com/viewarticle/756691?src=emailthis
Clinical Trials Record: http://clinicaltrials.gov/ct2/show/NCT01350219
Full Paper: http://www.biomedcentral.com/content/pdf/1741-7015-10-3.pdf

Some general information on C-peptide values:
http://www.diabeteshealth.com/read/2000/09/01/2020/interpreting-your-c-peptide-values/

A Personal Note
2011 was an awful year for following clinical trials aimed a curing type-1 diabetes.  We lost three phase-III clinical trials, and started zero new ones.  In phase-I and phase-II trials, the successes seemed small; the failures, great.   These results are a wonderful way to start 2012.

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.
Blog: http://cureresearch4type1diabetes.blogspot.com/

15 comments:

Papa Carlitos said...

Thanks Josh, I was very excited when the news broke a couple of days ago and was really looking forward to reading your comments on this.

I agree it is big, if this education happens merely by exposing rogue T-cells to a third party stem cell it would be huge news not only for Type 1 Diabetes but for medicine in general. Other than the significance of the breakthrough, the most exciting part is that it is a very concrete thing, and apparently readily available.

By reading the paper in its entirety, I'm not sure if this is just a draw of blood or that all of the blood is processed to extract all of the body's lymphocytes and then expose them through the "educator" for re-insertion into the patient's body.

QUOTE
A 16-gauge IV needle was placed in the left (or right) median cubital vein, and the patient’s blood was passed through a Blood Cell Separator MCS+ (Haemonetics®, Braintree, MA, US) at 35 mL/min for 6 to 7 hours to isolate lymphocytes in accordance with the manufacturer’s recommended protocol. The collected lymphocytes were transferred into the device for exposure to allogeneic CB-SCs (or process control without CB-SCs), and other blood components were returned to the patient. After 2 to 3 hours in the device, lymphocytes were returned to the patient’s circulation via a dorsal
vein in the hand under gravity flow control (2 to 3 mL/min) with physiological saline. Approximately 10,000 mL of blood was processed during the procedure resulting in approximately two repeated educations for the lymphocyte fraction. Patients were hospitalized for two days to monitor temperature and conduct routine laboratory blood tests for adverse reactions following treatment.
UNQUOTE

On the Phase II versus "surgical procedure exemption", it is a very relevant issue as it may be the difference between having this available "today" versus several years for Phase II/III/Marketing. If we take the Regenerative Sciences case as a precedent (not identical, but conceptually applicable), the FDA may go the conservative route and demand full phase II/III cycle. made it abundantly clear that any processing of internal body material will be considered to be a drug.

Definitely to be continued...

pdx_dc said...

Thanks Joshua! I am glad you reviewed this quickly! was holding my breath :-)

This clearly proves "regeneration" concept. Also umblical cord blood should be available easily without controversies.

I have a doubt about whether these cord stem cells simply clean up the bad T-cells - or - whether they fix the bone-marrow to stop making the bad T-cells in the first place...

I am thinking its the latter.. do you agree? is that why they call it "education"? Hurry up with Phase-11 please!!!! Also the A1C dropping substantially in 3 months is BIG PROOF that regeneration has taken place and susbtantial C-peptide has been generated and substantial Insulin has been generated....isn't that awesome? (even if I can't still personally understand or appreciate the actual C-peptide figures) JDRF will fund this? wouldn't that be nice to see accelerated results..

Bennet said...

I read paper this and am left with far more questions than I am comfortable with.

In part due to other news this week identified CD8 T cells as the source of the autoimmune response that causes type 1.*1 There is a quote from ViaCyte on Diabetes Mine that spoke to the difficulty of getting stem cells to differentiate into beta cells.*2 For that I presume that getting a stem cell to differentiate into any specific cell is an involved proposition.

The lymphocytes reprogramed here are already differentiated cells. If the autoimmune process is stopped it is due to a modification or reeducation of these CD8 T cells. There are a myriad of CD8 cells and they are created in the lymph nodes to recognize specific antigens on the cells the are programmed to kill.

So we are to believe that exposure to stem cells changes the antigen receptors? If that is true then why don’t the processor stem cell to the lymphocytes in our bone marrow have the same effect. I also fail to see a mechanism to explain how this erase the memory of the adaptive immune system.

All that said I would love to see a cure. I get excited by headlines just like everyone else. I hope this is repeatable. I have come to be suspicious of reports of apparatus that seem to good to be true.

1 La Jolla Institute researchers identify pivotal immune cell in Type 1 diabetes in humans, http://www.eurekalert.org/pub_releases/2012-01/ljif-lji011112.php

2 http://www.diabetesmine.com/2012/01/whats-up-with-diabetes-stem-cell-research-firm-viacyte.html

Anonymous said...

Thanks so much for your blog. Saves hours of research on my part, and I must confess I wouldn't even know where to begin. An A1c of 12 may not be at all rare in Third World Countries; and Type 1s are in dire need of a cure in places where they do not always have access to insulin, let alone the newer analogs. I can see why it might be easier to get volunteers for clinical trials. Our DD was cured in vitro in a study done at Naomie Berrie Diabetes Center recently; and I don't believe they have conducted Phase 1 trials. Of the nine patients tested, 7 were cured in vitro. Granted the cure only worked in the petri dish but if it works in vivo this would be a simple, safe cure for a high percentage of Type 1s (not all). I believe more studies may be out there with promising results. I have hope, but I also think with the complexity of the autoimmune process, the cure is decades away. Perhaps the cure will come sooner than planned,from an accidental discovery. It's happened before.

Joshua Levy said...

Papa C: I agree with your comments, and I don't really know if they put some blood through or all of it. I don't think this is going to be available really soon in any case.

Joshua Levy said...

pdx_dc: I don't have an opinion about why it works, or exactly how it works. I cover research "from the outside" meaning that I look at the results. These results are good. As to what is happening on the inside? That is for someone else to discuss. Someone with a lot more knowledge of the immune system, than I have.

As for funding: JDRF already funded this phase-1 trial, so I assume there will not be any problems having them fund follow on work.

Papa Carlitos said...

Josh and all, I wrote to the researcher and got some details. It seems indeed that he processes all of the body's blood. See below:


QUOTE
Question: is all of the blood from the body processed for lymphocyte separation or just one draw?

Answer: There is a holding needle in the patient’s arm for blood draw. Every time, the blood cell separator automatically draws a small amount of blood for isolation of lymphocytes, plasma and red blood cells are returned automatically to the patient blood circulation. This is continuing process for 10 cycles.

Question: was there further improvement in the A group after 12/24 weeks? would you suggest, i.e. to do a second round to target full remission?

Answer: That is the goal in our next trial. We will try additional treatment to improve the therapeutic potential.

Question: is this supposed to be permanent or will patients need to be treated on a frequent basis? sorry again if this is a silly question from a non scientist!

Answer: Based on our research data, cord blood stem cells can radically modulate and correct the autoimmune cells. You know that T1D is very complicated with different causes, including environmental factors, food, life style, and etc. These potential factors may affect the effectiveness after treatment with Educator therapy. Additional treatments may be necessary to strengthen the effectiveness.

Papa Carlitos said...

By the way, it is available. The researcher told me we can participate in the trial without problems, in China.

Peace said...

These results are encouraging because they suggest that immune suppression alone can induce beta cell regeneration. But the stem cells likely educate Tregs with a wide variety of antigen-specificities, so it may be like systemic immunosuppression, which has side effects. Perhaps the approach could be used as inducer therapy and combined with something more antigen-specific to sustain the effect.

Robert B said...

This is pretty exciting stuff. My wife is T1D and has been been since she was 10 1/2 months old. She has been pretty down about the prospects of a cure lately and I wanted to show her that progress is being made, it is just slow.

To Papa C: Did the researcher indicate if they would be doing any trials here? I am not sure if she would be up for it, but I would like to suggest to my wife to get involved. No chance she would go to China to try something experimental though.

Thanks

Papa Carlitos said...

Hello Robert. I asked him specifically about other locations and he said it is only available in China at this time.

Kathy said...

I am excited to see the increased C-peptides in this study. That says that this intervention shows real promise. I hope to see results of the clinical trials soon.

Anonymous said...

I fear big pharma will buy out the researchers on this research since it is so promising. ALso, shouldn't this be big news. I consider this a hugh breakthrough. Why is it no where in the news, unless I missed it. It's not even on JDRF website???

Papa Carlitos said...

Anonymous, I agree this should deserve breakthrough treatment in the news. If there's anything we can do as parent/patient community, I'm on!

Juan Carlos Huarte said...

In Asturias, Spain, in the Hospital Central de Asturias (HUCA) Dr. Jesús Otero will start a trial after Summer with Zhao technique.

More info (in spanish)
http://www.hayalternativas.org/noticias/?p=1015