Atorvastatin (Lipitor), One down, one to go

In the mid-2000s, two different groups started clinical trials which gave honeymoon type-1 diabetics Atorvastatin (Lipitor®).  One of these trials was at  Children's Hospital of Philadelphia (fondly known as "CHOP") and the other in Germany.  Lipitor is one of the most prescribed drugs in the world, and is used for long periods of time, so safety should not be an issue.  On the other hand, I could never understand exactly why anyone thought it would help cure type-1 diabetes.  Earlier this year, the German group posted their results.  Here is their conclusion:

Atorvastatin [Lipitor] treatment did not significantly preserve beta cell function although there may have been a slower decline of beta-cell function which merits further study.

Which I translate to "It didn't work."

The CHOP study is a little overdue as well.  They were expected to finish collecting data in July 2010, so they've had about 15+ months to publish, but have not as yet.   Since that is the last Lipitor clinical trial that I know of, when we get the results from it, Lipitor is done.
 
My Previous Blogging: http://cureresearch4type1diabetes.blogspot.com/search/label/Lipitor
Abstract: http://www.ncbi.nlm.nih.gov/pubmed/21412424?dopt=Abstract
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT00529191
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT00974740

A Little Discussion: What was the FDA's Orphan Products group thinking?

One question you might have is do researchers think it would work?  After all, Lipitor is aimed a lowering cholesterol, which doesn't have any obvious connection to type-1 diabetes.  The basic answer is two fold.  First Lipitor is a immune modulator, so it might stop the immune system's attack on self.   Also, studies have shown that atorvastatin (Lipitor), and other statins, preserve beta cell function in a mouse model of type 1 diabetes.  But other studies have show that it did not work on NOD mice specifically.  So it was a known immune modulator, with conflicting results in animals.

But it has two things going for it, separate from the question of "does it work".  First, it is known safe and widely used.  So that makes it very easy to work with and get approvals for.  The second thing is that it has a big company behind it.  (And for that company, it's a big deal drug.)  So they have a strong interest in finding new markets to sell it to, especially if they can somehow get patent coverage over a new use.  Anyway, that was good enough to get two clinical trials started.

But there was one humorous note about this research:  The funders of the two trials.  The first trial was funded by Pfizer, which is just as you would expect.  They are the big pharma company that makes the drug.  But the second trial was funded by the FDA's Office of Orphan Products Development.  So here you have the biggest selling drug, from a huge drug company, and research is being funded by the office of orphan productions.  Both groups are funding research at about the same time, while the drug was still under patent.   It makes no sense to me.

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
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

Two Summaries of Clinical Trials Aimed at Curing Type-1 Diabetes

I keep two different summaries of the status of clinical trials aimed at curing type-1 diabetes, and I've just updated both of them.  So if you want a summary of the whole field, you might try looking at one or both of these:

Summary Table
This is a PDF file (so you can view it on the web), which is a table of all clinical trials aimed at curing type-1 diabetes.  From left to right it is organized by phase of clinical trial, so phase-I is on the left, and phase-III on the right.  Within each phase are three milestones: Has the trial started?  Is it fully enrolled? And have results been reported?  From top to bottom are different rows representing different techniques being tried to cure type-1.  So there is a row for immunology, a row for encapsulation, a row for inflammation, etc.

This table contains one entry for each treatment which is currently being tested, and is designed to be printed out in black and white on a 3 foot by 4 foot poster.  It is very plain, with no graphics at all.

This file is stored on www.box.com, but anyone should be able to see it, here:
http://www.box.net/shared/3i4hl9o2iuoqde3h1vup
or look here:
http://www.box.net/shared/4dlxsj9vshd2ghn9zil4
for the whole directory of material. 

Next Expected Milestone
This is a list of all clinical trials currently or recently running aimed at curing type-1 diabetes.  My goal with this page is to make it easy, for each clinical trial, to see what research milestones are expected to be completed and when.   It can also serve as an TLOD ("too long over due") list of research that isn't reporting the expected results.  It also contains the last milestone that a trial reached, so you can see where everyone last was.

This list contains one entry for each clinical trial which is currently underway, or recently was underway.  If many trials are being run on the same treatment, then there will be several entries in this list.  It is designed to be viewed on a computer monitor, so color is important.

This file is part of my blog, and you can see it here:
http://cureresearch4type1diabetes.blogspot.com/p/next-expected-milestone.html

I update these files at least once a year.  (I try to do it once a quarter.)  If you see a mistake or something is missing, please tell me.  Thanks.

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
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

Antibiotics and Type-1 Diabetes

I occasionally get asked about a link between antibiotics and type-1 diabetes.  Basically, people want to know if our expanding use of antibiotics is causing cases of type-1 diabetes.

The following study looked at this issue specifically (use of antibiotics causing type-1 diabetes) and found that it did not happen:

http://aje.oxfordjournals.org/cgi/content/abstract/kwp038v1

Denmark has a centralized records medical system, so it is possible to do studies where you look at all children in the country, and compare their antibiotics usage to their type-1 diabetes status.  We could never do something like that here in the USA, but we can benefit from the studies done in other countries.  This study was based on about 600,000 patients, and was just published recently (in 2009).

Here is about half of their abstract.  I've removed the numbers, so that it reads better:

Use of any antibiotic was not associated with type 1 diabetes. Evaluation of type 1 diabetes risk according to number of courses of any antibiotic yielded no association between antibiotic use and type 1 diabetes. No specific class of antibiotics was associated with type 1 diabetes, no specific age of use was associated with type 1 diabetes, and no specific age at onset of type 1 diabetes was associated with antibiotics. In a large nationwide prospective study, no association between antibiotic use and type 1 diabetes was found among Danish children.

I have not found any controlled clinical (human) studies which show that increased antibiotic use increases the chance of type-1 diabetes.

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 2011

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: 59% of the treatments currently in human trials have been funded by JDRF. (And the number is 76% for the later phase trials) This is an strong impact; one that any non-profit should be proud of.

As you read the list below, please remember that it is a list of possible treatments, not a list of trials. Some of the treatments below have several different trials on-going right now.  Also remember that I give an organization credit for funding a treatment if they funded it any any point in development; I don't limit it to the current trial.  For example, JDRF is not funding the current trials for DiaPep277, but they did fund much of the early research into it, which allowed it to grow into human trials.

Cures in Phase-III Human Trials
Summary: there is only one treatment in phase-III right now, and it has been funded by JDRF.

• Andromedia's DiaPep227 

This treatment has more than one study active right now.

Cures in Phase-II Human Trials
Summary: there are 16, and 12 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    (Established)
• Diamyd's GAD65 and lansoprazole and sitagliptin
• Exsulin (previously INGAP) by Exsulin    (Established)
• Kineret / Anakinra by Mandrup-Poulsen at Steno Diabetes Center
• Liraglutide at Hvidovre University Hospital   (Established)
• PROCHYMAL by Osiris Therapeutics
  
• Rituximab by Pescovitz at Indiana
• 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  (Established)

Not funded by JDRF:

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

Cures in Phase-I Human Trials
Summary: there are 20, and 11 of the are funded by JDRF and 9 are not. Here is the list funded by JDRF:

• Alefacept by TrialNet
• AAT or Alpha-1 antitrypsin by OmniBio and also Kamada
• ATG and GCSF by Haller at University of Florida    (Established)
• BHT 3021 by Bayhill Theraputics   (Established)
• CGSF by Haller at University of Florida
• Trucco at Children’s Hospital of Pittsburgh    (Established)
• IBC-VS01 by Orban at Joslin Diabetes Center
• Leptin by Garg at University of Texas
• Polyclonal Tregs 
• Proleukin and Rapamune by Greenbaum at Benaroya Research Institute    (Established)
• Lisofylline by DiaKine
  

Not funded by JDRF:

• ATG and autotransplant by Burt at University of Sao Paulo
• BCG by Faustman at MGH (Established)
• CGSF and autotransplant by Esmatjes at Hospital Clinic of Barcelona  (Established)
• Encapsulated Islets at University clinical Hospital Saint-Luc    (Established)
• Etanercept (ENBREL) by Quattrin at University at Buffalo School of Medicine
• Monolayer Cellular Device (Established)
• Rilonacept by White at University of Texas
• The Sydney Project, Encapsulated Stem Cells (Established) 
• Pioglitazone by Wilson at Stony Brook 

This summary does not include Artificial Pancreas research or stem cell trials, which I discuss separately.  The list above is a list of treatments, not a list of trials.  For example, the "ATG and autotransplant" treatment is actually running two trials (that I know of) one by Burt and another by Snarski, but since they are testing the same treatment, it is only one item in the list.  DiaPep277 is running several trials, Rituximab has two, and so on.  Each treatment gets one entry in the list, not each trial.  Finally, those treatments marked "(Established)" have at least one trial which is open to people who have had type-1 diabetes for over a year.  So those are open to non-honeymoon diabetics.

Summary of all Trials
37 in total
22 funded by JDRF
So 59% 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.

Just Looking at Trials on Established Type-1 Diabetics
13 in total (35% of all trials)
8 funded by JDRF (61%)
So 61% of the trials recruiting established type-1 diabetics, are funded by JDRF.

Compared to Last Year
In 2010 there were 33 treatments in clinical trials, in 2011 there are 37 (growth of 12%)
In 2010 there were 4 treatments in Phase-III trials, in 2011 there is 1 (major drop: -75%).
In 2010 there were 16 treatments in Phase-II trials, in 2011 there are still 16 (no change).
In 2010 there were 13 treatments in Phase-I trials, in 2010 there are 20 (big growth: 54%).

The big change this year is that 3 out of 4 phase-III trials have ended in failure.  That big, bad news.  The other side of the coin is that there are 7 new phase-I trials, but it's still a loosing trade off. The basic trade off is that -- on average -- starting 4.5 phase-I trials will eventually result in 1 phase-III trial.  So we gained the equivalent of about 1.5 phase-III studies, but lost 3. 

The following two drugs might turn out to be treatments rather that cures, but right now it's not know how they will turn out, so I'm still tracking them as possible cures:

• Liraglutide at Hvidovre University Hospital
• Sitagliptin and Lansoprazole at Sanford Health 

And finally, the Sitagliptin-only trial which I was covering as a possible cure last year, I now think is a treatment, so I'm removing it from the list of possible cures.

How I Count Trials for This Comparison

• I give an organization credit for funding a cure if it funded that cure at any point in it's development cycle.
• I mark the start of a research trial when the researchers start recruiting patients (and if there is any uncertainty, when the first patient is dosed).  Some researchers talk about starting a trial when they submit the paper work, which is usually months earlier.
• For trials which use combinations of two or more different treatments, 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.
• 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 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.)
• I don't work for the US Gov, JDRF, or any of the other organizations discussed here. I'm 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 three years:
http://cureresearch4type1diabetes.blogspot.com/2010/09/jdrf-funding-research-for-cure-2010.html
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!

Finally, if you see any mistakes or oversights in this posting, please tell me!  There is a lot of information packed into this small posting, and I've made mistakes in the past.

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
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news