Tuesday, September 28, 2010

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

An Encapsulated Human Islet Transplant Cure in Phase-I
For the last many years, I have thought that LCT was the only company actively doing clinical trials on an encapsulated islet cell cure for type-1 diabetes.  However, I recently found this clinical trial record: http://www.clinicaltrials.gov/ct2/show/NCT00790257

These guys are testing human encapsulated islet cells (so not pig cells, as LCT is using).  They started in November 2008 and ending in December 2013, and includes 15 people.  They're doing this one trial in two phases, the first phase is only open to people who have already had an organ transplant (which I'm sure is delaying the study, since it takes a long time to recruit people like that). They call their device a "Monolayer Cellular Device", and the work is being done in Belgium

News on Otelixizumab by Tolerx
I have two tidbits on Tolerx's Otelixizumab.  The first is from news article which was discussing the start of their DEFEND-2 clinical trial, which is a confirmatory phase-III trial.  So that is the last stage before FDA approval.  So, as the quote shows below, Tolerx is starting to look to eventual approval:
If the trial [DEFEND-2] is successful, the company plans to send the drug candidate to the U.S. Food and Drug Administration in 2012.
Obviously that is good news.  For comparison, Diamyd was talking about starting the approval process in 2011, and LCT at one time was 2011, but more recently was 2013.  To the best of my knowledge we have never started the marketing approval process for a non-insulin drug to target type-1 diabetes.  So having three possible starts in the next 3 years is great.  Although that is tempered by the fact that only one of these treatments has been tested on established diabetics, and none of them represents a cure so far.

The other piece of news is a little more technical.  Here is the key quote:
The new research findings support existing data suggesting that otelixizumab may work in patients with new-onset type 1 diabetes by blocking the function of T killer/effector cells that mistakenly attack and destroy insulin-producing beta cells, while simultaneously stimulating T regulatory cells that are thought to protect against future T killer/effector destruction. Clinical data from the recently completed DEFEND-1 Phase 3 study and the ongoing DEFEND-2 confirmatory Phase 3 study will be evaluated in light of these new findings to determine whether this dual effect of otelixizumab is consistent with results from patients who have received otelixizumab.
 Press release: http://www.prnewswire.com/news-releases/tolerx-presents-research-at-european-diabetes-meeting-and-enrolls-first-patient-in-europe-in-the-defend-2-phase-3-clinical-study-in-type-1-diabetes-103610664.html

What this means is that they believe that their experiments show that Otelixizumab works in two different ways.  First, it blocks the bad killer T-cells.  The cells that are directly attacking the pancreas.  Second it increases the actions of the regulatory T-cells, which are cells designed to control killer T-cells.  That is potentially a powerful combination (although it will be interesting to see how long it lasts).  Another interesting piece of data is how selective is it?  Attacking the bad killer T cells is one thing, but it would be even better to NOT attack the good killer T cells.  The press release implies that it is selective, (which would be great) but this is a case where we need to see the numbers, to see exactly how selective it is. 

Both Tolerx (Otelixizumab) and MacroGenics (Teplizumab) Start Separate Subcutaneous Trials
Both Tolerx and MacroGenics are starting clinical trials designed to test their respective drugs when given subcutaniously.   The current clinical trials for both drugs require an IV (drip into a blood vein).  Those can not be done at home.  However, these studies are checking to see if the respective drugs can be injected just under the skin (called Subcutaneously, or SubQ).  That is how insulin is injected.  So if these clinical trials are successful, that means people would be able to inject themselves at home, rather than go to a clinic and have a nurse do it.

These are both phase-I studies and both are still recruiting new patients.
The Teplizumab study has 71 people, and should complete in July 2012, and is honeymoon only.  You must be within 1 year of diagnosis.
The Otelixizumab study has 28 people, and should complete was supposed to finish in July 2010. This study is not limited to honeymoon diabetics, but you must have A1C numbers above 9%, you must generate a little C-peptide.  If the study shows that the drug has the same (or similar) effect when injected like just under the skin as they see with IV drips, then I would love to see how it effects long established diabetics. 

Clinical trial record: http://www.clinicaltrials.gov/ct2/show/NCT01189422 Teplizumab
Clinical trial record: http://www.clinicaltrials.gov/ct2/show/NCT00946257 Otelixizumab

Testing C-Peptides: Fasting as good as Stimulated?
A little background: When your body makes insulin, it also makes a small molecule called C-Peptide.  This is very important to diabetes research, because if a researcher sees insulin in a person's blood, there is no way to know if that insulin came from an injection or from internal production.  However, C-peptide only comes from internal insulin production.  So when someone measures if a drug helps insulin production, what they really do is measure C-peptide.  Years ago the US FDA adopted this standard, so that in order to get a new drug approved to help a diabetic produce more insulin, the drug company must show evidence that the new drug increases C-peptide levels.  (Paradoxically, measuring insulin is considered a second rate way to testing insulin production, because the type-1 diabetic might have injected more insulin for any number of reasons.)  C-peptide is the gold standard of measuring insulin production.

But there are two ways to measure C-peptide: fasting and after a meal (which is sometimes called a "challenge" or "stimulated").  The fasting one is quicker and easier to do (at least for the researchers, the patient may prefer a meal :-) )  But the meal one is considered a better measure of effectiveness.   Basically, a fasting C-peptide measure tells you how well your body creates "basil"  (ie. no food) insulin.  While the meal test tells you how well your body creates "bolus" insulin (in response to food).  The meal one is considered better, but the fasting one is easier.  

The summary of this poster session is that the results of the two different tests are linked.  So that doing a fasting test predicts what will happen for a meal test, and doing a meal test predicts what will happen for a fasting test.  If confirmed by other trials, this will make it cheaper and easier to do clinical trials in the future (especially for large numbers of people) since you will only need to do a fasting test.

Press release: http://www.sys-con.com/node/1544442

Novocell Terminates Encapsulated Islet Transplant Clinical Trial
Years ago, Novocell was developing an encapsulated islet cell transplant cure, similar to LCT, although my memory was that they were using human islet cells, not pig cells.  In any case, the research did not move forward.  They started a phase-I clinical trial in 2005, but in 2006 they stopped recruiting for it.  I think that it has been moribund ever since, but they just (April 2010) officially terminated it.

The company recently changed it's name to ViaCyte, and is working on an encapsulated islet cure called "Pro-Islet".  They are doing animal ("pre-clinical") studies, so I'm not following it as yet.  


Final End of TT-223
A few days ago, Transition Therapeutics announced the end of clinical research for TT-223:
Transition Therapeutics announced today [17 Sept 2010] that a clinical study of gastrin analogue TT-223 in combination with a Lilly proprietary GLP-1 analogue in patients with type 2 diabetes did not meet its efficacy endpoints. Given these findings, there will be no further development of TT-223.
Press release: http://www.transitiontherapeutics.com/media/news.php

My translation: Even when we mixed it with another drug, it still did not work well enough to move forward.

So that's about as dead as you can get.  (Although INGAP went through this same process and was later "reborn" by the original developers who thought it had a future even though their big pharma backers did not.  Those guys are still doing clinical trials of INGAP (renamed Exsulin) and who knows what will happen?)

A little history:
TT-223 was one of the possible cures in existence when I started tracking them on my original web status page.  They were initially funded by JDRF, but then Eli Lily took over development from Transition Therapeutics, the small company that JDRF had funded.  JDRF got it's money back at this point because their funding was no longer needed, and they then reinvested it in something else.  But Eli only continued the type-2 testing, not the type-1 testing.  So almost exactly a year ago I blogged about this, and said that TT-223 was dead as far as a cure for type-1 (at least until someone started testing it again in type-1 diabetics).  You can read that post here:
At that point I stopped following TT-223.  However, an alert reader continued to follow them, and so when they issued the press release above, that reader forwarded it to me.  Thanks!  You know who you are.

Rituximab in the Real World
I have previously blogged on Rituximab (sold as Rituxan):
This drug is already approved for use in the US for certain diseases, and there was a recently published article on it's safety as applied to rheumatoid arthritis, which is an autoimmune disease of the same general family as type-1 diabetes.  You can read that here:

News coverage: http://www.medpagetoday.com/Rheumatology/Arthritis/22038
Abstract: http://onlinelibrary.wiley.com/doi/10.1002/art.27555/abstract

This study was based on a registry of over a thousand French citizens who were treated with Rituximab and who were followed up for at least a year.  So this is a much bigger study than the Phase-I study for type-1 diabetics, which was less than 90 people for 1 year. 

There were two interesting results, from my point of view:

First, the overall rate of serious infection was about the same in this trial as it had been in the trials that were used to get approval for the drug in the first place.  That's good news, because those approval trials generally exclude patients who have "co-morbidities" (that is: something else wrong with them).  On the other hand, real world use include patients who have several different diseases.  (Especially rheumatoid arthritis.)  And having more than one disease raises the chance of serious infection, and that is exactly what this study was looking at.  So it is good news that the side effects were no worse for real world use as for experimental use.

Second, the serious infection rate was much higher (about 5 times as high) for people who had "low IgG levels".  So the authors of the study suggest that people getting Rituximab get tested for that before each dosing.  Other co-morbidities that were associated with a higher chance of serious infection included chronic lung disease and/or cardiac insufficiency and extraarticular involvement. (Which are not common in type-1 diabetics, and especially not young ones.)

I think this is good safety news for this drug. Both because it shows it is safe when used "as-is", but also because it provides a clear path to even higher levels of safety via a simple screening process. 

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

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