Possible Cures for Type-1 in the News (Mid Oct)

Here is another collection of news from the last few weeks.


Teplizumab (by MacroGenics / Eli Lilly) Fails in phase-III Trials


It appears that MacroGenics lead phase-III trial of Teplizumab has failed.  Here are some quotes from their press release:

The Data Monitoring Committee concluded that the primary efficacy endpoint of the study, a composite of a patient’s total daily insulin usage and HbA1c level at 12 months, was not met 

Following careful evaluation of the Data Monitoring Committee’s recommendations for [this clinical trial], based on the lack of efficacy, [MacroGenics and Eli Lilly] have decided to suspend further enrollment and dosing of patients in two other ongoing clinical trials of teplizumab in type 1 diabetes: the Protégé Encore Trial, a second Phase 3 trial of the same design as Protégé, and the SUBCUE trial, a Phase 1b trial that is exploring the subcutaneous administration in patients with type 1 diabetes.

Discussion

Obviously, this is a huge blow to this drug as a possible cure for type-1.  MacroGenics might try to salvage this drug by reanalyzing the data from this experiment to see if there was a subpopulation which was helped.  But it is a long shot.

Another ominous question is what about similar drugs also under development?  Teplizumab is a monoclonal antibody targeting CD3 T-cells.  There are two other drugs in that category currently in clinical trials: Otelixizumab and NI-0401.  I don't know if Teplizumab failed because attacking CD3 is the wrong technique, or there was a problem specific to that one drug.  I hope the latter, because if it is the former, all three of these drugs will fail.  


The President and CEO of ToleRx (developers of Otelixizumab) has a blog ("The Green Chair") which you can read here:
http://www.tolerx.com/index.php?page=greenchair
His whole blog entry on this is worth reading. Here is his quote on this particular issue:

Next, I’d like to underscore some of the reasons why we continue to have a strong belief in our lead product candidate, otelixizumab. Otelixizumab’s biochemical structure is fundamentally different from other anti-CD3 monoclonal antibodies, such as teplizumab.  We believe this unique molecular structure is inherently important in mediating or delivering the “right” signals to T cells, and it is these signals, we believe, that are responsible for the effects, both in efficacy and tolerability, that were observed in our previous clinical trials. 

ToleRx expects to publish their phase-III results in the second quarter of 2011.

I haven't found any comment by Novimmune (makers of NI-0401).

Prior to this news, there were four treatments in phase-III of clinical trials aimed at curing type-1 diabetes.  And phase-III is the last stage before market approval. Teplizumab was one of these, and Otelixizumab is another.  NI-0401 is in phase-II clinical trials.    If you're a "glass is half empty" kind of person, you can say that this news has lowered the number of phase-III possibilities by 25%, and cast a pall over another 25%.  If you're a "glass is half full" kind of person, you can say that 5 years ago he had only one drug in phase-III trials, and even after this news, we still have three.  For myself, I would point out that over 30% of treatments in phase-III trials end up failing for one reason or other.  So of the four we had, we should expect 1 or 2 to fail.  And now, 1 has.

News article: http://www.reuters.com/article/idUSN2024945620101021
Press release: http://www.macrogenics.com/press_releases-284.html
Biz news article: http://www.bioworld.com/servlet/com.accumedia.web.Dispatcher?next=bioWorldHeadlines_article&forceid=56170

Sitagliptin and Lansoprazole Start a Phase-II Clinical Trial
I had previously blogged about this trial here:
http://cureresearch4type1diabetes.blogspot.com/2010/08/possible-cures-for-type-1-in-news-mid.html
but at the time they were planning the trial, but now they have started it:
http://www.clinicaltrials.gov/ct2/show/NCT01155284
These are two drugs currently used for type-2 diabetes, but this trial is aimed at using them on people who have type-1 diabetes.

Another Encapsulated Beta Cell Cure in Human Trials
I've been following LCT (encapsulated pig beta cells) for years, and just last month I found a second encapsulated beta cell trial (that one using human cells).  Now this month I found a third group doing encapsulated beta cell trials in people. Thanks to kisiliz (of CWD) for pointing this out to me:
http://www.lifescientist.com.au/article/222165/2010_sydney_project/?
http://care.diabetesjournals.org/content/32/10/1887.full

Unfortunately, the results of this phase-I study of about 14 people. (4 of whom were actually treated) were not good.  C-peptides were detected only immediately after the implantation.  Although slight amounts of generated insulin could be detected years later, Insulin usage and BG numbers did not change.  Basically, it was a proof of concept, but no practical impact.  However, this study was just published in 2009, so they might well improve things, and move forward.

This makes for a total of three encapsulated beta cell research teams active right now, and that's a good sign.


Below is Animal Research, so Years Away from Human Trials
I don't usually blog about research that has not started human trials, but I thought the following two research areas were particularly interesting.  Remember that anything that has not yet started clinical trials is well over 10 years away from general availability, and has a less than 50/50 chance of ever even starting human trials:

Alternate Artificial Pancreas Design
I would describe this as a "cool hack" (which is a software engineering way of saying "a really elegant design, which solves a complex problem in a simple way").  You can think of it as a hybrid of self dosing insulin and an implanted device.  If you prefer, you can think of it as an artificial pancreas with no moving parts or computer software.

The trick is as follows: you create an artificial pancreas, which is nothing more than an insulin reservoir, a chemical barrier, and a tube so the insulin (once it gets past the barrier) goes directly into the liver.  The barrier is key.  It reacts to the BG levels in blood to either let more insulin out, or less insulin.  This is very much like the "self dosing" insulins being researched by SmartInsulin and others, but it is different in that the "self dosing" chemistry is in a barrier which is separate from the insulin itself.  I don't know if this is a better or worse approach (than combining the self dosing chemistry into the insulin), but it is different.  And I believe that in early research, different is good,  because we don't care how many fail, just that one succeeds.  Sending the insulin straight to the liver is an interesting refinement as well.  Naturally generated insulin goes to the liver very quickly, before it circulates through the blood or is deposited in the fat cells under the skin.  So dripping the insulin into the liver should result in faster response, and in a sense is a more natural flow.  Injecting insulin in the fat just below the skin is very easy to do, with almost no training, which is why we do it, but that does not mean it is the best from a biological point of view, just that it is the most practical.

Since there are no batteries, moving parts, electronics, etc, this type of artificial pancreas should be much easier to care for as an implanted device, and have fewer parts that can break or need to be replaced.   Only insulin will need to be added.  Unfortunately, I have not found any published animal research on this device, but I haven't looked very hard (and I'm not so familiar with the tools to search for animal trials, as I am for human trials.) 

http://www.medicalnewstoday.com/articles/201455.php
http://onlinelibrary.wiley.com/doi/10.1002/jps.22138/abstract

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

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.  


http://www.clinicaltrials.gov/ct2/show/NCT00260234

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:
http://cureresearch4type1diabetes.blogspot.com/2009/09/two-possible-cures-go-to-boneyard.html
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):
http://cureresearch4type1diabetes.blogspot.com/search/label/Rituximab
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

News from MacroGenics on Teplizumab

Two pieces of news from MacroGenics:
First, their phase-II human trial of teplizumab (called PROTEGE) is fully enrolled.
Second, they are starting a follow on phase-III study called PROTEGE ENCORE.

Teplizumab is a "humanized monoclonal antibody" which targets the CD3 part of the immune system in order to lower (or stop) the body's autoimmune response. This drug tries to prevent type-1, or lessen it's severity, by "turning down" the immune system's attack on the body's own pancreas cells. This basic approach has resulted in treatments (but not cures) for other autoimmune diseases. It does carry the risk that the body's immune system will not properly attack a real threat.

Fully enrolling a study (especially one this large: 530 people) is important because the major reason that studies are delayed, is trouble enrolling people in them. Especially a study like this where only "honeymoon" diabetics can participate, getting 530 often takes longer than planned. But once it is fully enrolled, that source of delay is removed.

The new study is a sign that MacroGenics is looking to productize this drug. The new study is focused on "clinical responses". That's research-speak to mean "does it help patients" or "do real people benefit in a useful way from this treatment". This is the kind of trial you do just prior to putting it on the market. The new study is 400 people and is scheduled from June 2009 to June 2012.

There is also a third PROTEGE trial which is ongoing, called PROTEGE Extension, which follows patients from the PROTEGE trial for an extended length of time.

If you view the path to a cure as a race, then with this announcement MacroGenics has pulled even with ToleRx which also has a CD3 targeted humanized monoclonal antibody in phase-III human trials. (That's the DEFEND trial of Otelixizumab.) It is interesting, to me at least, to see the dance of small companies and big companies. The PROTEGE trial is sponsored by MacroGenics. The PROTEGE Extended trial by MacroGenics / Eli Lilly, and the PROTEGE Encore trial by Eli Lilly, so you can see how Eli Lilly taking over the Teplizumab treatment from MacroGenics. Similarly, ToleRx has a partnership with GlaxoSmithKline for their Otelixizumab treatment.

(Note: MacroGenics/Eli Lilly calls PROTEGE a "phase-II/III trial", and the Encore trial a phase-III. But I considered PROTEGE a phase-II and Encore a phase-III.)

You can read more about it here:
http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials#MacroGenics
(although I really need to update this)

Read the press release here:
http://sev.prnewswire.com/health-care-hospitals/20090616/PH3265516062009-1.html

The web page home of this trial is here:
http://www.protegediabetes.org/

Here are the US Clinical Trial entries for all three studies:
http://www.clinicaltrials.gov/ct2/show/NCT00385697 (Protege)
http://www.clinicaltrials.gov/ct2/show/NCT00870818 (Extension)
http://www.clinicaltrials.gov/ct2/show/NCT00920582 (Encore)

Joshua Levy