Possible Cures for Type-1 in the News (January-2012).

Osiris's Prochymal fails in a Phase-2 Clinical Trial
For background, please read my previous blogging on Osiris: http://cureresearch4type1diabetes.blogspot.com/search/label/Osiris

The PROCHYMAL treatment has been shown safe in several phase-I, II, and even III trials for several immune diseases, so they are trying it with type-1 diabetes. This is an adult (actually self) stem cell treatment. Since safety is established, they went straight to phase-II clinical trials. The company's description is this: "Prochymal is a preparation of mesenchymal stem cells specially formulated for intravenous infusion. The stem cells are obtained from the bone marrow of healthy adult donors."

The results were a total failure: no change in the primary end point (C-peptide after a meal), or in any of the secondary end points.   No safety issues turned up.  This was after 1 year, and they will continue to follow the patients for another year.


News coverage: http://www.thestreet.com/story/11362832/1/osiris-stem-cell-therapy-fails-diabetes-trial.html
BTW: most news coverage of type-1 research is superficial.  They just repackage the press release, occasionally adding a quote or two from the company; sometimes not even that much.  But this article in "The Street" is much better than that, and is fun to read.

Background on mesenchymal stem cells:  http://en.wikipedia.org/wiki/Mesenchymal

Should We Give Up On Adult Stem Cells?

The short answer is "no".  But the full answer is a lot more interesting, but will need to wait for another blog posting.  The short version of my opinion is this: based on all the studies done so far, including this one, I don't think that just dumping a bunch of bone marrow stem cells into the body is likely to cure type-1 diabetes.  But that does not apply to stem cells specifically tailored for insulin production, because they are quite different, and so far we have no experience with them in people.  Remember that there are many different types of stem cells, and many different ways of differentiating stem cells, and many different uses of stem cells.  So while there is considerable bad news for the simple minded idea of dumping in a bunch of bone marrow stem cells and expecting a cure, there are many other avenues still open.   That is why I think I will need a whole blog entry to sort out possible stem cell cures.

Dr. Taback et al in Winnipeg Hope for Funding for Vitamin D Prevention Study

As part of my recent policy change to cover treatments designed to prevent type-1 diabetes, I'm starting to cover this potential clinical trial of Vitamin D.  I previously blogged once on Vitamin D, here:
http://cureresearch4type1diabetes.blogspot.com/2010/08/cinnamon-and-vitamin-d.html

Dr. Taback has put in the paperwork to ask for funding for a large, prospective study to see if giving people Vitamin D will lower the rate of type-1 diabetes.  The basic plan is to screen 60,000 babies to find about 5,000 at higher risk for type-1, and then give those babies about 2000 IU of Vitamin D per day (current suggested dose is 400 IU). And then follow them for years to see if fewer develop type-1.

Although no mechanism is known, a few studies [r3] have had promising results, so it makes a lot of sense to test this in a larger group.  Previous promising studies are summarized in [r1,r2].

An older study [r4] showed that Vitamin D consumption during pregnancy was NOT associated with  markers for type-1 diabetes.  Although this [r5] study just published recently suggests that it is associated with type-1 diabetes.  The newer study was of much higher quality than the older one for two reasons.  First, it measured actual cases of type-1, not markers.  Second, it measured actual Vitamin D levels in the person, while the older study had people fill out a questionnaire about diet (which is vastly less accurate).

News coverage: http://www.cbc.ca/news/health/story/2011/12/28/diabetes-type1-vitamin-d-chasing-cures.html

[r1] http://www.ncbi.nlm.nih.gov/pubmed/18339654
[r2] http://www.ncbi.nlm.nih.gov/pubmed/15671235
[r3] http://www.ncbi.nlm.nih.gov/pubmed/11705562
[r4] http://www.ncbi.nlm.nih.gov/pubmed/20369220 
[r5] News: http://www.foodconsumer.org/newsite/Nutrition/Vitamins/low_prenatal_vitamin_d_type_1_diabetes_0117120243.html
Study: http://diabetes.diabetesjournals.org/content/61/1/175.short


OmniBio Will Start another AAT Clinical Trial

OmniBio is testing AAT, an anti-inflammatory drug, which the body makes naturally, and which is already FDA approved for people who have a rare condition where a person don't make enough of it on their own.    They started with a 15 person, phase-I study, and about 11 months ago expanded to a 50 person study, which I would consider phase-II.  They just announced that they will start another study for type-1 diabetes and one for Graft-vs-Host disease.  That's good news, of course, but I'd be a little more excited if they announced the results from their initial 16 person study.

Previous blogging on AAT: http://cureresearch4type1diabetes.blogspot.com/search/label/AAT
Previous discussion of inflammation based cures: http://cureresearch4type1diabetes.blogspot.com/p/common-ideas-and-opinions.html
 
News article: http://www.marketwatch.com/story/omni-bio-to-conduct-new-human-clinical-trials-2012-01-13
Corporate web site: http://www.omnibiopharma.com/

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
Mice cures: http://t1dcuredinmice.blogspot.com/

Possible Cures for Type-1 in the News (March)

The first two lines of research discussed below involve treating inflammation, so here is a quick introduction to treating inflammation as a cure for type-1 diabetes:  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):

            /---> causes --> beta cells to die    

Autoimmunity

            \---> causes --> inflammation

However, some researchers believe that the underlying immune problem causes inflammation, and that this inflammation kills the beta cells, which then causes the symptoms of type-1:

Autoimmunity -causes-> inflammation -causes-> beta cells to die

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. 

OmniBio Starts a Phase-I Trial on Established Type-1 Diabetics and Expands their Honeymoon Phase-I Trial

Alpha-1 Antitrypsin (AAT) is an anti-inflammatory drug, which the body makes naturally, and which is already FDA approved for people who have a rare condition where a person don't make enough of it on their own. OmniBio had already started a phase-I trial for honeymoon diabetics, however they are now expanding in two important ways:

First, they are starting up a non-honeymoon phase-I clinical trial.  Obviously, this is very important to the majority of type-1 diabetics who have had the disease for a long time: 

The initiation of a late stage Type 1 diabetes trial.  Proposed Trial Site:  University of Basel, University Hospital-Basel, Basel, Switzerland.  Principal Investigator, Dr. Marc Donath, Professor of Endocrinology, Head of Clinic of Endocrinology, Diabetes & Metabolism.

Second, they are expanding their Honeymoon phase-I trial to 50 patients.  At that size, it really more of a phase-II trial.  Here is that part of the announcement:

The trial ... has seen improvement in the condition of the first enrolled patients.  Based on observations of the first enrolled patients..., Omni Bio intends to expand the patient enrollment to 50 patients, which may involve obtaining a second trial site.

That sounds like great news, but I'm very interesting in exactly what those results where.  (This is a case where "details matter" and a vague statement of improvement is not good enough by itself.)  Hopefully these guys will publish some details, soon.

Press release: http://www.prnewswire.com/news-releases/omni-bio-pharmaceutical-intends-to-expand-type-1-diabetes-trial-to-50-patients-117053528.html
clinical trials: http://www.clinicaltrials.gov/ct2/show/NCT01183468   http://www.clinicaltrials.gov/ct2/show/NCT01183455

Thanks to Cameron Donahue (who works with OmniBio) for providing some of the information used here.

Kamada Starts Paperwork for a Phase-I Trial of AAT

Kamada is a different pharmaceutical company that makes AAT.  They currently make an FDA and EMEA approved formulation which is used for people who naturally don't produced enough AAT of their own.  They are also working on an inhaled version of AAT, since the current product is intravenous, but that is still in clinical trials.  They are planning to test a different brand name of AAT (Glassia®), than Omni's (Aralast NP), but I don't think that is important.

The trial they are planning includes 24 people and will be completed around December 2012.  There will be no control (or "placebo") group, but three groups will each get different Glassia doses.  The primary outcome for this study is general safety, and the secondary outcomes are efficacy as measured by injected insulin and A1c numbers.  (There is also a mention of testing for "Pancreatic beta cell function" which I hope means C-peptide measurements, but the paperwork is not specific.)

This clinical trial is being done at two sites in Israel: Schneider Children's Medical Center (Petach Tikva) and Assaf Haroffeh Medical Center (Zerifin).  Contact is Mariana Rachmiel and her phone number is +972-8-9542007.

clinical trial: http://www.clinicaltrials.gov/ct2/show/NCT01304537
corporate site: http://www.kamada.com/

Personal Opinions on the Impact of this Research on Dr. Faustman's Research

The Alpha-1 Antitrypsin (AAT) research described above may also have huge impact on Dr. Faustman's research.  It could provide strong evidence that her theory is right or wrong.  Dr. Faustman's theory is that BCG will cause the body to generate more TNF which in turn will kill the autoreactive ("bad") T-cells and result in the body generating more of it's own insulin.   She announced that her phase-I trial had finished almost a year ago, but has not published results as yet.  (A very bad sign in itself.)  However, taking AAT lowers the amount of TNF in a person.  This is the opposite of BCG.  Especially for a honeymoon diabetic, this means that if Dr. Faustman's theory is correct, then giving AAT will cause a shorter honeymoon, and will generally result in a quicker onset and the body to generate less insulin.

So, if AAT results in a longer, stronger honeymoon, that suggests that Dr. Faustman's theory is wrong, even if she never publishes the results of her own clinical trail.  Conversely, if AAT results in a shorter, weaker honeymoon, that supports her theory. Again, independent of her own results.

Teplizumab Starts Phase-II to Prevent Type 1 Diabetes


Teplizumab was being developed by MacroGenics until late last year, when it failed it's phase-III clinical trials for honeymoon type 1 diabetics.  It is similar to Tolerx's Otelixizumab which also failed it's phase-III clinical trials.  Both target a specific type of cell in the immune system, called a CD3.  However, months before the phase-III trial failed, the paperwork had started on a clinical trial to give this drug to people at high risk for type-1 diabetes, but who had not yet come down with the disease.  These patients would be identified by having two or more auto-antibodies, a first degree relative with type-1, and already having an abnormal glucose tolerance test.  The idea would be to give these guys Teplizumab to see if it prevented or delayed or lessened the impact of type-1 diabetes.  TrialNet is moving forward with this clinical trial. 


It is easier to have a good effect on type-1 diabetics during the honeymoon phase than later on, after the disease is long established, so it makes sense that it should be easier still to prevent type-1 entirely than to treat it in the honeymoon phase.  So even though this drug did not improve honeymoon diabetics, there is still hope that it might still prevent the disease.


The study will enroll about 170 people, from many different clinical sites all over the US (for the locals: UCSF and Stanford are recruiting, but nothing in Sacramento).  Results in January 2016 if all goes according to plan.  Since the drug has already been through phase-I and II trials for honeymooners, they can start off at phase-II for their prevention trial.  If you're interested there is a recruiting web site and a lot of contact information in the clinical trial record (links below).

News: http://www.popsci.com/science/article/2011-03/experimental-drug-may-prevent-diabetes
Recruiting web site: http://www.diabetestrialnet.org/studies/ACD3.htm
Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT01030861
Note that the news article uses the term "Body Reboot" in it's title.  I think this is a poor choice of words.  The drug being tested does not reboot anything (in my opinion).  I think the term "reboot" is properly used to describe the cure being researched by Burt (and collaborators) in Brazil and Snarski in Poland.

(If this had been nearer to Halloween or nearer to April 1st, my lead paragraph would have been something like this:  

Zombie Drug, Left for Dead, Walks Again!  

Teplizumab which was last seen buried in a shallow grave, after having failed phase-III testing in honeymoon diabetics, has risen from the grave and is shambling towards a different use: preventing type-1 diabetes when given to at-risk people who have not yet been diagnosed with the disease.  It was heard mumbling to itself "Hungry for Ceeee Deeee Threees.  Must have Ceeee Deeeee Threees.  Give meeeee Ceee Deeee Threeees......  :-)

A Little Commentary


In addition to seeing if Teplizumab can prevent or minimize type-1 diabetes, this trial will also have a synergistic effect with TrialNet’s Natural History Study trial.  That trial tests relatives of type-1 diabetics for antibodies to help gather pre-diagnosis data on the disease.  I know some people don't participate, because even if they turn up positive for one or more antibodies, nothing can be done.  And they'd rather not know, if nothing can be done.  But now, something can be done: they can enroll in this Teplizumab trial, and maybe (emphasis on "maybe") get a benefit if the trial is successful.  So I think the very existence of this Teplizumab trial will help populate the Natural History Study trial.  And if you have not participated in  TrialNet’s Natural History Study, because you didn't think you could use what you learned, well now maybe you can.

Also, this trial simply could not be run without something like TrialNet’s Natural History Study trial.  The Teplizumab study is dependent on identifying a large group of people who don't yet have type-1, but have a high chance of having the initial onset in the next few years.  That's exactly the type of data that the Natural History Study produces.  Without a trial like Natural History Study it is almost impossible to even test a type-1 preventative drug, because you would need to give it to thousands of people, to even see even 10 or 20 people who would eventually become type-1 diabetic.  By starting with the Natural History Study data, you can run reasonably sized preventative trials, like the 170 for this one.

So this trial helps TrialNet’s Natural History Study, and TrialNet’s Natural History Study helps this trial.  I would expect that as we get more and more data from the Natural History Study these sorts of follow on, prevention studies will be come easier and easy to run (and cheaper), and therefor more common. 

Obviously, this trial is not research aimed at curing type-1 diabetes; it is aimed at preventing it.  So I'm not sure I will continue to follow this in the future.   I do include honeymoon trials.  Should I include prevention trials? 

Non-Type-1 Diabetes News (Learning from Other's Mistakes)
One of the major points I try to make in this blog, is that you can not make your medical decisions based on one study.  No matter how good, how important, how famous, or how much you like the results.  You must look at the whole area of research, and especially follow up studies, before you make a decision.  The Chronic Fatigue Syndrome community is learning this lesson the hard way, as a purported connection between a retrovirus (XMRV) and their disease is coming apart in a very painful and political way:

Editorial: http://newsblogs.chicagotribune.com/tribnation/2011/03/xmrv-chronic-fatigue-syndrome-and-a-fuller-picture-of-their-dubious-connections.html
News: http://www.chicagotribune.com/health/ct-met-chronic-fatigue-xmrv-20110317,0,6116823.story

This quote is from the editorial:

Our story today is about the danger of putting too much stock in one study and forgetting that scientific knowledge is hard won, proven over time, and borne out through many, many studies -- not just one.

Reminder About The Blog
There three ways you can help with this blog:
First, tell other people about it!  Heartfelt testimonials are the best advertising.
Second, tell me about any clinical trials you know about that are not already covered here.
Third, ask me questions that you have.  This tells me what I'm not explaining well, and where I need to put more information into my posts.

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. 
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news
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Possible Cures for Type-1 in the News (June)

AAT (Alpha-1 Antitrypsin) Starts Phase-I 
Omni Bio announced that the Barbara Davis Center for Childhood Diabetes has received IND (Investigational New Drug) regulatory clearance from the U.S. Food and Drug Administration (FDA) to start a Phase I clinical trial evaluating Alpha-1 Antitrypsin ("AAT") in patients with type I diabetes.

This is an anti-inflammatory drug, which the body makes naturally, and which is already FDA approved for people who have a rare condition where a person don't make enough of it on their own.  You can read my general comments about all inflammation based cures: http://joshualevy.pbworks.com/ConceptsAndBackground#Inflammation

There is not yet a clinical trials record for this,  but the press release says they will start out with 15 people in a phase-I trial, and will try to expand to a 50 person phase-II study.  This is all being done at the Barbara Davis Center in Denver.  People in the trial will get the drug for 8 weeks, and then be followed for 2 years.  It is not clear if this will be honeymoon only, or established diabetics only, or both.

Press release: http://www.omnibiopharma.com/admin/files/file/OMBP%20IND%20CLEARANCE_JEFFERIES_FINAL%206%208%202010.pdf
Corporate web site: http://www.omnibiopharma.com/

Welcome a new treatment and a new company to the world of clinical trials to cure type-1!

Some Discussion
One of the questions that I often get asked about mice cures is "how long until this is available for people".   My stock answer is "for a new drug, at least 10 years from the start of human testing (clinical trials)".  That's a true answer, but not a complete answer, because they are usually asking right after the announcement of a successful mouse trial, but before any human trials have started.  So part of the answer is how long does it take to go from the end of animal trials to the start of human trials.

This research has taken almost exactly 2 years to make that transition from animal testing to human testing.  So that is one solid data point on how long it takes.  But remember, this drug is already FDA approved for another disease, so it is probably quicker at making the transition, than a previously unapproved drug.

One Year Delay on Dr. Faustman's Results 

In May 2010, Faustman's Lab updated their FDA clinical trial record to reflect these two new dates:
Estimated Primary Completion Date: December 2010  (Previously it had been December 2009)
Estimated Study Completion Date:  February 2011  (Previously it had been Feburary 2010)
No other updates were made.

So this represents a one year delay in completing their phase-I study.  The first date is the "data complete" date, when they hope to have gathered all the data needed for the study.  The second date is the date when everything associated with the study will be completed.  I think it is fair to say that the second date is the earliest possible publication date for the results, although the actual publication date is likely to be months after that.  The only good part of this news, is that we have already waited through a couple months of the delay, so we only have about a year to wait.  (I"m assuming that if the study is complete in February, it will get published later than same year.) 

This is only the latest in a long line of delays for Faustman's phase-I study.  It was originally expected to take 7 months and be completed in July 2008.  After a series of four delays, it is now expected to take about 37 months (if it meets it's December 2010 date).  In late 2007, they thought they were about 7 months away from data completion, and now, in mid 2010, they still think they are about 7 months away from completion.  (Actually, that's closer to 3 years without forward progress.)  One way to look at this, is that they have made no visible progress in completing their phase-I trial in the last 2+ years.

Personal opinion: I think that for any research study where delays have been over four times longer than the original total length of the study (7 months of original length vs. 30 months of delay), that study is in real trouble.  And especially, this study, which only involves studying 25 people for 3 months each.  At it's heart, it is a small, simple study, using an already approved drug.  What could cause it to take 5 times it's original length, and still not be complete?  In a future blog entry I hope to write about what could cause such a delay.  But as a "teaser," I don't see how it could be just one problem.  The worst single problem you might have might double the length of your trial, because you would have to restart from the beginning.  But this trial is about 5 times longer than initially expected.  Also, at least once, the delay occurred after recruiting was complete.  The only way that could happen is there was a problem with the data gathered, so it had to be gathered again, or if the problem was found during data analysis.

Animal Research
The Lee Iacocca foundation is now funding Kineta.  Later this year, Kineta hopes to start human trials on SK-186, which is a inflammation based treatment for type-1 diabetes.   Here is the rational for this drug:

ShK-186 is a potent and highly specific Kv1.3 potassium channel blocker. It is designed to suppress activation of effector memory T cells, which are important mediators of inflammation and tissue damage in MS, type 1 diabetes mellitus and other autoimmune diseases. The drug candidate has been shown to significantly reverse disease in animal models of MS and rheumatoid arthritis. Animal models also have demonstrated that efficacy is achieved without the generalized immunosuppression that occurs with competing therapies.

You'll notice that they don't report any success for type-1 diabetes in animal models.  As above, remember my general comments about all inflammation based cures: http://joshualevy.pbworks.com/ConceptsAndBackground#Inflammation


There are currently four other inflammation based cures in clinical trials (including AAT, above).  Even a few years ago, there were none at all, so this is a growth area of research.


Press release: http://www.kinetabio.com/press_releases/PressRelease03292010.pdf
Corporate web site: http://www.kinetabio.com/
 

Request for Help
I'm trying to track down information on a clinical trial of NI-0401 by NovImmune, a Swiss company.  The company is very specific that a phase-I trial has started in the Netherlands, and I've seen other references to the trial as well.  But I can not find any official record of it.  No clinical trial record, and no registered trials record, either.  Does anyone know anything about this trial?  NI-0401 is supposed to be an anti-CD3 humanized monoclonal, so much like Otelixizumab and Teplizumab.

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. 
Blog: http://cureresearch4type1diabetes.blogspot.com
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials