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

JDRF Funding Research for a Cure 2010

Note: I forgot one study in the original (Sept-13) version of this blog entry, but this updated (Sept-15) version includes that study and updates the counts and percentages.  I'm sorry for the oversight.

In the US, we are starting the "Walking Season" when JDRF asks us to walk to raise money for cure. So I'd like to do my part, by reminding you all how important JDRF is to the human trials of potential cures for type-1 diabetes, which I track. 

Let me give you the punch line up front: 73% of the treatments currently in human trials have been funded by JDRF. (And the number is 85% for the later phase trials!) This is an amazing impact; one that any non-profit should be proud of.

One new complication (which I am very happy to have!) is that there are now more studies which combine two different drugs into one treatment.  In general, I give funding credit, if the organization in the past funded any component of a combination treatment, or if they are funding the current combined treatment. Also, I list experiments separately if they use at least one different drug.  For example, There are currently about six different trials going on for Diamyd's GAD65, both phase-III and phase-II, however all of these are covered by the one listing in the phase-III section.  However, the clinical trial using Diamyd's GAD65 and lansoprazole and sitagliptin together gets it's own listing, in the phase-II section.

Last year, I didn't think there were enough  trials aimed at established (non-honeymoon) diabetics, to mark them separately, but this year, I think there are.  The trials marked E/NH below include patients who have had type-1 diabetes for more than one year, and so are out of the honeymoon period.  Other treatments might end up helping established diabetics, but these are the ones being actively tested right now. I was surprised at how many there are.  There is a general belief that all the current clinical trials are for honeymoon diabetics, or that JDRF's funding is somehow only going to curing honeymooners.  It is true that none of the phase-III studies are aimed at established type-1 diabetes, but phase-II contains 37% non-honeymoon trials, and phase-I contains 50% (with JDRF funding 81% of the non-honeymoon trials).

Cures in Phase-III Human Trials
Summary: there are 4, and all of the treatments have been funded by JDRF.

• Diamyd's GAD65
• TolerRx's CD3
• MacroGenics's CD3
• Andromedia's DiaPep227 

All of these treatments have more than one study active right now.

Cures in Phase-II Human Trials
Summary: there are 16, and 13 of them have been funded by JDRF, either directly or indirectly through ITN. Here are the treatments that have been funded by JDRF:

• Abatacept by Orban at Joslin Diabetes Center
• Diabecell by Living Cell Technologies    (E/NH)
• Diamyd's GAD65 and lansoprazole and sitagliptin
• Exsulin (previously INGAP) by Exsulin    (E/NH)
• Kineret / Anakinra by Mandrup-Poulsen at Steno Diabetes Center
• Liraglutide at Hvidovre University Hospital   (E/NH)
• PROCHYMAL by Osiris Therapeutics
  
• Rituximab by Pescovitz at Indiana
• Sitagliptin by Garg    (E/NH)
• Sitagliptin and Lansoprazole at Sanford Health
• Thymoglobulin (also known as ATG) by Gitelman
  
• Umbilical Cord Blood Infusion by Haller at University of Florida
• Xoma 52 by Xoma Corp  (E/NH)

Not funded by JDRF:

• Atorvastatin (Lipitor) by Willi at Children's Hospital of Philadelphia
  
• Brod at University of Texas-Health Science Center
• NI-0401 by NovImmune

Cures in Phase-I Human Trials
Summary: there are 13, and 7 of the are funded by JDRF and 6 are not. Here is the list funded by JDRF:

• ATG and GCSF by Haller at University of Florida    (E/NH)
• BHT 3021 by Bayhill Theraputics    (E/NH)
• CGSF by Haller at University of Florida
• Trucco at Children’s Hospital of Pittsburgh    (E/NH)
• IBC-VS01 by Orban at Joslin Diabetes Center
  
• Proleukin and Rapamune by Greenbaum at Benaroya Research Institute    (E/NH)
  
• Lisofylline by DiaKine
  

Not funded by JDRF:

• ATG and autotransplant by Burt at University of Sao Paulo
• BCG by Faustman at MGH
• CGSF and autotransplant by Esmatjes at Hospital Clinic of Barcelona  (E/NH)
• Encapsulated Islets at University clinical Hospital Saint-Luc    (E/NH)
• Etanercept (ENBREL) by Quattrin at University at Buffalo School of Medicine
• Pioglitazone by Wilson at Stony Brook 

This summary does not include Artificial Pancreas research, which I discuss separately.
Nor does it include the last group of eight stem cell trials.

Summary of all Trials
33 in total
9 not funded by JDRF
So 73% of the human trials currently underway are funded (either directly or indirectly) by JDRF. Everyone who donates to JDRF should be proud of this huge impact; and everyone who works for JDRF or volunteers for it, should be doubly proud.

It is important to remember, however, that although there are four treatments in Phase-III trials, we are not close to a cure for established type-1 diabetes.  None of the treatments in Phase-III trials resulted in cures during their Phase-II trials. They all extended or increased the honeymoon phase in some way.

We have a long way to go, and that is where JDRF comes in.

Compared to Last Year

In 2009 there were 4 treatments in Phase-III trials, in 2010 there are 4 (no growth).
In 2009 there were 10 treatments in Phase-II trials, in 2010 there are 16 (growth of 60%, but see the discussion below).
In 2009 there were 13 treatments in Phase-I trials, in 2010 there are 13 (no growth).

Obviously, there is not the same level of growth as there was last year.  I'm not sure if that is because last year had unusually large growth, or if this year has unusually small growth, or if we are hitting "equilibrium" in our clinical trials of possible cures.   I'll discuss that in more detail in a future post, as time permits.

Another issue, is that the growth in phase-II trials is partly due to my including several clinical trials of drugs which are used to treat type-2 diabetes and are being tested on type-1 diabetes.  Some of these drugs have shown success at lowering insulin requirements for type-1 diabetics, but I'm not sure if they are possible paths to a cure.  They may just be better treatments.  My plan on these is to wait about 9 more months and make a decision at that time if they are possible cures or just possible treatments.  If they are not cures, I'll remove them from my comparison.  The studies in this group include:

• Liraglutide at Hvidovre University Hospital
• Sitagliptin by Garg    (E/NH)
• Sitagliptin and Lansoprazole at Sanford Health 

Discussion

• I give an organization credit for funding a cure if it funded that cure at any point in it's development cycle.
• I use the term "US Gov" for all the different branches and organizations within the United States of America's federal govenment (so includes NIDDK, NIAID, NICHD, etc.)
• The ITN (Immune Tolerance Network) has JDRF as a major funder, so I count ITN as indirect JDRF funding.
• I have made no attempt to find out how much funding different organizations gave to different research. This would be next to impossible for long research programs, anyway.
• Funding of research is not my primary interest, so I don't spend a lot of time tracking down details in this area. I might be wrong on details.
  
• I don't work for the US Gov, JDRF, or any of the other organizations discussed here. I'm on the Research Information Committee of the San Francisco Bay Area chapter of the of JDRF and an adviser to JDCA. I also own stock in several of the companies discussed here.

This is an update and extension to blog postings that I've made for the last two years:
http://cureresearch4type1diabetes.blogspot.com/2009/09/jdrf-funding-research-for-cure.html
http://cureresearch4type1diabetes.blogspot.com/2008/10/jdrf-funding-of-cure-research-phases-ii.html

Please think of this posting as being my personal  "thank you" note to all the JDRF staff, volunteers, and everyone who donates money to research a cure for type-1 diabetes:  Thank You!

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 (late-Aug)

 
GCSF (Neulasta/Pegfilgrastim) Starts a Phase-I Clinical Trial
This is straight forward trial where GCSF is given to people in the honeymoon phase of type-1 diabetes.  It is interesting for many of the same reasons that the ATG+GCSF trial is interesting (see older post on ATG+GCSF).  Both of these trials are being done at the University of Florida, and Dr. Michael J. Haller is involved in both.

Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT00662519

There is a second GCSF clinical trial being done at the University of Padova (Padova, Padua, Italy), but it is not aimed directly a curing type-1 diabetes.  Although I don't understand it fully, it appears to be more basic research into GCSF effects on people with type-1 diabetes.  Clinical trial record is here: http://www.clinicaltrials.gov/ct2/show/NCT01102699

A Little Discussion: Why a GCSF only Trial?
One obvious question that came to mind when I saw this GCSF only clinical trial, done at the same place and time, and by the same researcher as doing the ATG and GCSF trial, was: why do both?  I mean, if GCSF works, then certainly ATG and GCSF will work, and clinical trials are a lot of work and expense.

The answer to this question (for me) has to do with with three separate, but related goals:

1. We want to cure type-1 diabetes. (Cure Product Development.)
2. We want to learn how drugs effect type-1 diabetes, so we can find a cure.  (Basic research.)
3. We want the FDA to approve clinical trials which lead to points 1 and 2.

If you only look at point 1, then a GCSF-only trial (when a GCSF+ATG trial is also ongoing) might sound like a waste of time.  As a parent of a child with type-1 diabetes, I often focus only on point 1.  However, product development flows out of basic research, so points 2 and 3 are also important.  It may turn out that studying GCSF alone will help create a cure in the future, or that the FDA might require more knowledge of GCSF alone before it will approve some future clinical trial, which leads to finding a cure.

In the past I have blogged about not understanding how  Sitagliptin alone, or Sitagliptin and Lansoprozole combined, could cure type-1 diabetes.  However, it may be that these clinical trials will be valuable, because of points 2 or 3 above.  They might be the basic research or FDA required background that eventually leads to a cure, even if they are not the cure themselves.

LCT Announces Completion/Extension of their Phase-II Trial
LCT has announced these things in August:

1. Their phase-II trial has been extended with 4 new patients who will get dose 20k u/kg dose.  The phase-II study now includes 4 who got 10k u/kg, 4 who got 15k u/kg and these 4.  This is a 50% expansion of their study, at 33% higher dose.
2. The first four patients have seen a benefit of fewer (or elimination) of low BG episodes.  Only two such events, compared to nineteen, so almost a 90% drop.
3. They plan "commercial launch" in 2013, and "global reach though partnership".  They seem to be assuming that the operation will cost about $150k (I think this is US$, but not sure.)
4. They have also laid out the following time line for getting to commercial availability, which is the most detailed that I've seen:

• 2011: Continue phase-II trials, get approval for phase-III trial (They use the term "pivotal".)
• 2012: Complete phase-III, report on results.
• 2013: "Approval and revenue"

That's their plan, and I hope they make it.  I see the following issues for them to overcome.  First, they need to have a cure.  Right now, the longest they have had anyone insulin-free is 32 weeks, and only two people (out of twelve) have been insulin free for any number of weeks.    Obviously they need to improve both of these numbers.  (Although, if you view them as a treatment to help brittle diabetics, then their results might be good enough already - depending on how long they last - but that wouldn't be a cure.) Second, they need to treat enough people to get their approvals.  Right now, they have treated a total of 16, with 4 more on the way.  That is far fewer patients than any other phase-II trial that I know of.  A more common count is 20-30 in the phase-I trial, 80-120 in phase-II, and 300 in a phase-III "pivotal" trial, and then a second phase-III trial for confirmation.  (Basically all the drugs in phase-III trials have followed that path.)  LCT is running at about 1/3 the size in their phase-I trial, and 1/10 the size in their phase-II.


Press release: http://www.blogger.com/post-edit.g?blogID=5472921328078253036&postID=548554300707664816
Corporate Overview: http://www.lct.com.au/downloads/cms_latest_news/2010-08-26-Presentation%20August%2010.pdf
This corporate presentation contains a lot of information on where they are, what they plan to do in the future, and how they plan to make money.  It is targeted at investors, after all.


NovImmune has started a phase-II for NI-0401
This company is very hard for me to follow, because they don't issue many press releases, don't have the clinical trial records, that most other researchers have, and it is just generally hard to find information on them.  The  are a small, relatively new company and their lead product (the one farthest along is the drug development process) is NI-0401 which is and anti-CD3 drug, generally similar to the Teplizumab and Otelixizumab. 

Their recent corporate literature makes it clear that NI-0401 has started a phase-II clinical trial for type-1 diabetes.  Unfortunately, I have not been able to find clinical trial records for either the phase-I or phase-II trials, so I have no ideas how many patients are involved, if they are honeymoon or not, or any other of the most basic information about the study.  Even worse, I can not find any published results for the phase-I study in type-1 diabetics.  (I did find results for their phase-I trial on Crohn's disease, but not tyoe-1.)


Corp presentation: http://www.swissequitybiotechday.ch/media/biotechday/downloads/novimmune.pdf


AP News: Faster Insulin
Below is a link to a JDRF press release on their project to created faster acting insulin (mostly to help their Artificial Pancreas project):
http://www.eurekalert.org/pub_releases/2010-08/jdrf-jlr081610.php
I normally would not cover it, because it doesn't talk much about results or progress, however I did want to mention it because it is much broader and contains more context than your usual press release.

Most press releases just cover one piece of news for one line of research, but this press release gives a lot more useful context to the search for faster acting insulin.  Basically, it starts out with a goal.  The goal is to get faster acting insulin, mostly because it will make creating an artificial pancreas easier, and make the resulting pancreas better.  (Obviously,  it will also help everyone who uses insulin with meals, which is basically all type-1s.)  The simplest way to speed up insulin (and the way done in the past) is to create a new form of insuilin which is faster than the currently available forms.  And JDRF is funding Dr. Buckingham at Stanford to test one of those.  Another way is to find a faster pathway into the body.  So JDRF is funding Dr. Zisser testing of AFREZZA, which is inhaled insulin; the hope is that inhaled equals faster.  A third idea is to use microneedles to deliver insulin faster (JDRF is working with BD on this one).  A fourth is a port-system which puts insulin from a standard pump directly into a person's liver.  Since insulin mostly effects the liver, this could speed up the effectiveness of pumped insulin.  (JDRF is working with Roche on this.)  Finally, there is a post-pump insulin warmer which might also speed up insulin effectiveness.  (JDRF is funding Dr. Tamborlane of Yale to test this for InsuPatch.)

My Opinions.....
The whole point of research is that you don't know which projects are going to pan out and which are not.  This press release shows how JDRF is trying many different possible paths to faster insulin.  Some of those paths seem like good ideas to me.  Others seem very inventive, if a little strange.  Others don't strike me as unlikely to succeed.  I'm sure other people looking at the same list will expect different research to fail and succeed than I do.  That is why JDRF is funding all of them.  No one knows which will pan out.  I believe that this whole project is part of JDRF's "glucose control" research area, and that whole section includes about 6% of their funding.  So even though it sounds like a lot of different research projects in different areas (and it is!), all together it is only a few percentages of JDRF's total investment.   It doesn't even begin to touch the 33%+ aimed at immune therapies or the 40% aimed a regrowing beta cells.

JDRF Page on Spending: http://www.jdrf.org/index.cfm?fuseaction=home.viewPage&page_id=0B36CA86-9128-4C49-B7D8F55955507931




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 (mid-Aug)

Sitagliptin and Lansoprazole Preparing for a Phase-II Clinical Trial
This trial is giving two drugs (both of which are already in use) to people with type-1 diabetes in their honeymoon phase.  The hope is that it will preserve some beta cell function.  This study is not yet recruiting patients.  They hope to recruit 54 patients and finish in April 2014. Sitagliptin is the generic name for Januvia, and Lansoprozole is the generic name for Prevacid.

A Little Discussion: I still don't understand why this is supposed to preserve beta cells.
When I blogged about the Sitagliptin only clinical trial, I said that I didn't understand why it might help type-1 diabetics; and I still don't.  With this trial, I don't understand why adding a antacid like Lansoprozole would help type-1 diabetics, either.  On the other hand, Januvia is available now for type-2 diabetes with a prescription, and Prevacid is available "over the counter" and as a generic.  So if this pans out, you will be able to get this as an "off label" use without waiting for further FDA approvals.

For me, a far more interesting trial, which I have blogged about before, is being run by the NIH, and which uses Diamyd plus Sitagliptin and Lansoprozole.  That one I understand: Diamyd stops the autoimmune attack by retraining it, and the other two drugs reverse beta cell damage or develop new beta cells.  You can read about that study here:
http://cureresearch4type1diabetes.blogspot.com/2010/02/diamyd-combo-phase-ii-trial-scaled-back.html
and I think they have upped the enrollment to 7 since I wrote that blog entry.  On the other hand, if this Sitagliptin and Lansoprozole only study lays a scientific foundation for more studies where they pair it with something to stop the autoimmune attack, that would be valuable.

News article: http://www.argusleader.com/article/20100811/NEWS/8110318/1001
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01155284

Other Phase-II trial of Sitagliptin: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials#SitagliptinbyGarg
Blogging on Sitagliptin: http://cureresearch4type1diabetes.blogspot.com/search/label/Sitagliptin
Wikipedia for Sitagliptin: http://en.wikipedia.org/wiki/Sitagliptin
Wikipedia for Lansoprazole: http://en.wikipedia.org/wiki/Lansoprazole

Delay in Trucco's Phase-I Trial
Trucco's clinical trial is one of the first ones that I ever followed in my "status" web page.  That was years before I started my blog.  I've never blogged on it, because there has never been news.  Basically, they remove dentric cells, which are part of the immune system, treat those cells, and then put them back in the patient (the same patient where they came from).  This trial only enrolls people who have had diabetes for more than five years, so honeymooners are excluded.  It is a safety only study: they are not measuring any BG, A1C, insuline usage or C-peptide numbers.  If it turns out safe, then they plan to start a honeymooner only study to see if it improves any of those things. 

Now, finally, there is news.  In June 2010, Trucco's group updated their clinical trials record as follows:

Estimated Enrollment:	15
Study Start Date:	March 2007
Estimated Study Completion Date:	June 2011 (previously had been mid-2010)
Estimated Primary Completion Date:	December 2010 (previously had been mid-2009)

So this is basically a one year slip.

Web status page: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials#TruccoatChildren%E2%80%99sHospitalofPittsburgh 
Year old newspaper article: http://durangoherald.com/sections/Features/Health/2009/08/24/Experiment_seeks_way_to_head_off_Type_1_diabetes_found_in_children/
Scientific Overview: http://www.mcgowan.pitt.edu/news/images/Trucco_PediatricDiabetes_2008.pdf
(Includes a nice diagram on page 8, even if the rest is highly technical.)

One Possible Cure, but not yet in Clinical Trials.
Some researchers in India are working with a "release as needed" injected insulin.  This is broadly similar to SmartInsulin.  A single injection of this new insulin, called Supramolecular Insulin Assembly II (SIA-II) resulted in good blood glucose levels (which they call "physiologic glucose levels") for over 100 days in animals.  I'm very much looking forward to what this does in people.  But remember: drugs generally take 10+ years to go through human trials, and less than half of the drugs successful in animals ever go on to human trials.  (Since this is an Insulin it might be slightly faster than 10 years, but not much.)

Abstract: http://www.pnas.org/content/107/30/13246.abstract
News report: http://www.dnaindia.com/india/report_india-develops-single-shot-insulin-for-diabetics_1409481

Another benefit of this drug, is that it puts pressure on the SmartInsulin developers.  In turn the SmartInsulin developers put pressure on the SIA-II developers.  I'm a firm believer that competition pushes both groups of developers to move faster, so I'm all for it.  It sounds to me like both SmartInsulin and SIA-II are close to starting human trials, but SmartInsulin is closer.

Discussion: What is a Cure?  Is this a Cure?
This drug (and also Smart Insulin) can start off an interesting parlor conversation about what is a cure?  Are treatments like SmartInsulin or SIA-II cures?   Obviously, each of us must make up their own mind about what is and is not a cure.  But in my mind, a treatment that required one injection every 3 months, and no blood glucose checks, no dietary limitations (no counting carbs), with no long term side effects and a normal life expectancy.  Personally, I would call that a cure, even though it requires an injection every 3 months, and even though you would have type-1 "on the inside".  It would be a functional cure.  Your opinion may differ.

News from Cerco Medical
I don't really cover Cerco Medical, because they have not yet started human trials for their "islet sheet", which is an encapsulated beta cell cure generally similar to LCT's  Diabcell.  However I know people are interested in it, and this is the most specific news I've heard about when they are hoping to start a clinical trial:

His [Scott R. King, president of Cerco Medical] company is planning to begin human testing in 2012 or 2013.  

This comes from a newspaper article, which is mostly about Artificial Pancreas work in Oregon:  http://www.oregonlive.com/health/index.ssf/2010/08/putting_blood-sugar_control_on.html


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

Eight New Stem Cell Clinical Trials For Type-1 Diabetes

I hate putting out half-digested information, but I'm convinced that I will never have time to fully digest all of these studies, so I'm putting out what I have, on the basis that something is better than nothing.

This is a list of eight studies, which are pretty similar.  They all involve using stem cells to treat or cure type-1 diabetes.  Some of these studies use adult stem cells, others embryonic, and others cord, although I think the most common is the patient's own bone marrow stem cells.

I consider stem cells to be one possible way to regenerate beta cells.  My opinion of beta cell regeneration in general, is that it is not going to cure type-1 diabetes by itself (because the autoimmune attack will kill the new beta cells same as the old ones) but that it might be an important part of the cure.  It's importance depends on how fast beta cells regrow after the autoimmune attack is stopped.  If they grow back quickly, then no form of beta regeneration will be needed, but if they grow back slowly or not at all, then some form of beta regeneration will be needed.  Stem cells are one form of beta cell regeneration, but there are others.  Exsulin and human growth hormone have been tested in people, and CureDM's drug in animals, and there are many more.

The good news here, is that there is a lot going on with stem cells, so if we do end up needing new beta cells to cure type-1 diabetes, here are 8 or more reasons why we are likely to have them.  And that is not even counting all the non-stem cell technologies out there.  But (in my opinion) the "gating factor" (what we in the software industry call the "critical path") to curing type-1 on this path is stopping the autoimmune response, not regenerating the beta cells.

As you read these, you will notice that some of them have end dates in the past, but are still active today.  Others have start dates in the past, but have not actually started recruiting patients.  These are signs that the researchers have not updated the clinical trial records, and need to.  This is quite common.  "Primary Completion" is when they finish collecting the data from the patients.

Uppsala University Hospital Stem Cell phase-I Trial
Treatment of Patients With Newly Onset of Type 1 Diabetes With Mesenchymal Stem Cells

Estimated Enrollment:	20
Study Start Date:	March 2010
Estimated Study Completion Date:	January 2012
Estimated Primary Completion Date:	January 2011

Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT01068951


Armed Police General Hospital
Stem Cell Therapy for Type 1 Diabetes Mellitus
Cellonis Biotechnology Co. Ltd.

Estimated Enrollment:	24
Study Start Date:	August 2010
Estimated Study Completion Date:	December 2011
Estimated Primary Completion Date:	August 2011

Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT01143168

Hospital Universitario Dr. Jose E. Gonzalez
Hematopoietic Stem Cell Transplantation in Type 1 Diabetes Mellitus

Estimated Enrollment:	15
Study Start Date:	May 2010
Estimated Study Completion Date:	March 2011
Estimated Primary Completion Date:	December 2010

Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT01143168

Shanghai Jiao Tong University School of Medicine 
Autologous Hematopoietic Stem Cell Transplantation for Early Onset Type 1 Diabetes

Estimated Enrollment:	30
Study Start Date:	February 2008
Estimated Study Completion Date:	February 2013
Estimated Primary Completion Date:	January 2013

Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT00807651

Veterens Memorial Medical Centre
Safety and Efficacy of Autologous Adipose-Derived Stem Cell Transplantation in Patients With Type 1 Diabetes
Adistem Ltd

Estimated Enrollment:	30
Study Start Date:	November 2007
Estimated Study Completion Date:	December 2009
Estimated Primary Completion Date:	November 2009

Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT00703599

Shandong University
Autologous Bone Marrow Mononuclear Cells Transplantation in Treating Diabetes Patients

Estimated Enrollment:	200
Study Start Date:	March 2006
Estimated Study Completion Date:	March 2014

Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT00465478

Technische Universität München
Cord Blood Infusion for Type 1 Diabetes Mellitus (T1DM)
23 patients, but no start or end dates provided
Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT00989547

University of Moron
Safety and Efficacy of Arterial Delivery of Autologous Bone Marrow Cells in the Treatment of Insulin-Dependent Diabetes
Stematix, Inc

Estimated Enrollment:	34
Study Start Date:	October 2009
Estimated Study Completion Date:	October 2014
Estimated Primary Completion Date:	October 2011

Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT00971503


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

ATG + GCSF Starts a Phase-I Clinical Trial

ATG + GCSF Starts a Phase-I Clinical Trial
This is a very interesting study, which is why I'm giving it, it's own blog posting.  The official title of this study says it all, optimistically: "Reversing Type 1 Diabetes After it is Established".  It builds on three separate lines of research: Burt's ATG/GCSF/cyclophosphamide trial, a separate line of ATG-only trials, and NOD mice trials on ATG and GCSF (all discussed more below).

The basic idea behind this research is that ATG modulates the body's immune system, while GCSG  causes the body to generate more t-cells directly from it's own bone marrow.

ATG is a mixture of different antibodies that target T cells, including the anti-CD3 antibody.  The hope is that this multi-faceted approach will be even more successful and have a longer lasting effect than with anti-CD3 alone, and may treat diabetes by several mechanisms. First, it lowers the number of T cells, so there are fewer to attack the beta cells. It also seems to alter the T cells remaining behind, rendering them less likely to be destructive. Following this depletion, the T cells that grow back in the following weeks may be reset and have a healthier balance (meaning that a special type of T cells, called regulatory T cells, will help keep the destructive T cells in check).

GCSG  is essentially a growth factor that helps the body repopulate the cells after ATG depletes them.  So, if ATG fixes the immune system by getting rid of the destructive cells, and the GCSG can cause the body to generate more t-cells afterwords, and presumably a healthier balance of these cells, then the two together could stop the autoimmune defect that causes type-1 diabetes.  (Regrowing new beta cells might still be required for some people.)  And, this process has already been used successfully to cure type-1 diabetes in mice, so that is always a good first step.

But the really positive thing about this research is it's relationship to previous research by Burt.  You can read my previous blog entries about Burt's research at the URL below, but the quick summary is this: Burt has -- by far -- the best results in people of any researcher.  That study used a combination of 3 drugs, ATG, GCSF, and cyclophosphamide.  Some patients went into remission (no need for injected insulin) for a period of years, others for months, and all of these people used much less insulin after the trial.  Only two patients in the study did not go insulin free for at least a few months.  This research also has a serious weakness, which is safety.  Although none of the people in Burt's had serious side effects, the process involves "rebooting" the immune system.  So while this is happening, the patients are in an isolation ward, because their immune system is highly compromised.  Also, there were "hints of toxicity" seen in the trial: a few people had unusual infections, and some of the males had reduced sperm counts afterward.  Burt's research was in honeymoon diabetics, only.

A second line of research that has been going for years uses ATG alone to try to preserve beta cell function in honeymoon type-1 diabetics.  This research has already completed a phase-I study, and a phase-II study is underway right now.  The phase-II study is called START and they hope to finish recruiting patients in 4-6 months.  ATG alone is very good in curing mice, but in combination with GCSF the success rate is nearly 90% for the mice, and hopefully that will translate to people.

Oversimplified a little: Burt's research involves using three drugs (ATG, GCSF, and cyclophosphamide), and reinjecting the patient's own precursor bone marrow cells (previously removed). Dosing with just ATG and GCSF can be viewed as a "kinder, gentler" Burt. Especially since the cyclophosphamide is the one that really hammers the immune system and requires the isolation ward. 

In the past, I've been asked who was following up Burt's research, and this is a pretty direct follow up. Most phase-I trials are aimed at minimum effect and maximum safety, so minimal doses are used.  The follow on research usually involves more drugs.  However, in this case the effectiveness is high, while the safety is the issue.  So the follow on research involves less drugs.  In this case it involves removing the most toxic drug from the treatment.

They are enrolling 25 people who have had type-1 diabetes for more than 4 months, but less than 2 years.  Planned completion date is April 2013.  They are recruiting at the University of Florida, which is in Gainsville.  UCSF (San Francisco, California, USA) and also the Davis Center (Denver, Colorado, USA) will be participating in this study, but they are not listed in the clinical trial record.  The coordination is through University of Florida by Dr. Michael Haller (who is running several other clinical trials aimed at type-1 as well).  The email contact is listed as hallemj@peds.ufl.edu, so I would start there if you are interested.


Previous blogging on Burt's research:  http://cureresearch4type1diabetes.blogspot.com/search/label/Burt
Previous blogging on ATG: http://cureresearch4type1diabetes.blogspot.com/search/label/ATG

Description of study: http://diabetes.ufl.edu/research/clinical-trials-and-studies/established-type-1-diabetes/atggcsf-clinical-trial/
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01106157
Abstract of animal study: http://www.ncbi.nlm.nih.gov/pubmed/19628781?dopt=Abstract
Wikipedia for GCSF: http://en.wikipedia.org/wiki/Neulasta
Wikipedia for ATG: http://en.wikipedia.org/wiki/Anti-thymocyte_globulin

I'd like to thank Dr. Steve Gitelman (who is a Principal Investigator in the ATG START study) for his thoughts on this research.  All mistakes here are my own.


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