The Future Cost of Type-1 Cures

Every now and then, someone will ask me how much I think a cure will cost, or they will complain that a cure that I take seriously will be too expensive (whatever that means), even if successful.  I have three thoughts that I always try to keep in my head when people talk about the cost of a cure:

First, it is a total waste of time, to discuss the cost of something that you can not buy.  No one really knows how much something will cost, if they can not sell it, and you can not buy it.  It's like discussing ghosts or fantasy football.

Second, "demand creates it's own supply" which is an economics phrase, that basically means that if people want something badly enough, then other people will find a way to make those things cheaper, which will change the basic economics of availability.  An example has to do with transplanting beta cells recovered from cadavers.  Right now, that doesn't result in a cure.  Some people say that could never result in a general cure, because there are not enough donated cadaver pancreases.  So such a cure is impossible, because even if it worked scientifically, there would not be enough cadaver pancreases.  But I don't agree with that logic.   For one thing, if cadaver pancreases could be used to cure type-1 diabetes, there would be a huge increase donated pancreases.  Groups like ADA and JDRF would launch public relations campaigns.  There would be scores of "feel good" local news articles about people cured with donated pancreases.   Suddenly, there would be many more pancreases donated.  At a minimum, every grandparent of a type-1 diabetic would be signing those forms. Furthermore, I would expect the technology to improve over time.  So if the first cure takes beta cells from three pancreases to cure one person, over time, it might take 2.5 and then 2, and maybe eventually 1.5 or even just 1.  That means that even thought the number of pancreases doesn't change, how many people they cure would change.  These are two examples of how "demand can create it's own supply".

Third, technology makes everything (high tech) cheaper.  Computers that cost over $100,000 dollars in 1970, cost $2000 in 1980, and so on. My daughter has a $400 iPad, which probably has a lot more computing power than an entire Apollo moon launch from the 1960s, and so on.  Many of the possible type-1 cures that people are afraid will be "too expensive" are very high tech, and we can expect them to get cheaper over time as we learn how to build them, and the general level of technology improves.

So my policy when thinking about cures myself, is not to worry about cost.  I know others do, and so I include that information when I have it.  But for myself: I only worry about availability, not cost.  Right now we have nothing.  So having a cure, even a really expensive cure, would be such a huge step forward, that I just can't bring myself to worry about the price.  I am sure that even if a cure starts out "too expensive" it will not stay that way for long. 

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

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

Stem Cell Research Checklist (and recent uterine stem cell news)

Whenever I see stem cell research published, I always ask myself the following questions, in order to evaluate it's importance:

• What animal was used in the research?
• Humans are the best animals to use, obviously.
• NOD mice, and other animals that have autoimmune diabetes are good to use.
• Animals that have artificially produced diabetes are not so good.
• Animals that don't have diabetes at all are the least promising.
• Were the cells created true beta cells?
• Sometimes people announce that they create "precursor" cells, or some other cell on the way to a beta cell, but not there yet.  
• Making a complete beta cell is good, but not enough.
• The best result, is making a beta cell that generates insulin in response to sugar in the blood.  That's what a real beta cell does.
• What sort of immune suppression (if any) was used.
• Any stem cell from another person (adult or embryonic) may trigger an immune response, so the first question is did they use the animal's own stem cells?
• What sort of drugs, treatments, or encapsulations were used to prevent rejection of the stem cells?
• Did it work in actual animals?
• Some research just measure what the cells do in petri dishes or cell cultures, but the true measure of a beta cell, is what it does in a real animal that needs insulin.
• Did the researchers measure C-peptides?
• Did they need less insulin, see lower A1c and lower BG (especially after meals)?
• The best would be no need for external insulin, and no bad side effects
• How long did it work?
• Obviously, longer is better (and remember to scale based on the lifespan of the animal involved).
• It's always better if the experiment ended before the effect ended, rather than the other way around.
• What's the plan for preventing the autoimmune attack from destroying the new beta cells?
• Many stem cell researchers have a "that's someone else's problem" attitude, which I don't think is a good one.
• A few stem cell options come with an integrated solution to the autoimmune attack, and those are a lot more interesting to me.

(As I look back over this list, I think most of it could be used for any research which claims to be curing type-1 diabetes.  First ask yourself: what animal?  And so on.) 

Applying the Checklist to a recent headline:

Uterine stem cells used to treat diabetes in mice

A press release is here: http://www.nih.gov/news/health/aug2011/nichd-30.htm

Here are the first few paragraphs (we've all read this stuff many times before):

Researchers funded by the National Institutes of Health have converted stem cells from the human endometrium into insulin-producing cells and transplanted them into mice to control the animals' diabetes.

 

The endometrium, or uterine lining, is a source of adult stem cells. Normally, these cells generate uterine tissue each month as part of the menstrual cycle. Like other stem cells, however, they can divide to form other kinds of cells.

The study's findings suggest the possibility that endometrial stem cells could be used to develop insulin-producing islet cells. These islet cells could then be used to advance the study of islet cells transplantation as a treatment for people with diabetes. If the transplantation of islet cells derived from endometrial cells is perfected, the study authors write that women with diabetes could provide their own endometrial tissue for such a transplant, sidestepping the chance of rejection posed by tissue from another person. Endometrial stem cells are readily available and can be collected easily during a simple outpatient procedure. Endometrial tissue could also be collected after hysterectomy, the surgical removal of the uterus.

How do I apply my checklist/questionnaire to that research?   Like this:

What animal was used in the research?
Two quotes from the abstract: "mice having a laboratory-induced form of diabetes" and "mice had few working beta cells. But the paper and in email from the author, things were a little more explicit: SCID mice were used, and their diabetes was triggered by giving them SZ toxin, which kills their beta cells.  SCID are "Severe Combined ImmunoDeficiency" mice.  These mice did not have autoimmune diabetes.  This creates some complexities, which I discuss below.

Were the cells created true beta cells?
Two quotes from the abstract: "The researchers found that some of these cells also produced insulin." and "the researchers exposed the mature stem cells to glucose and found that, like typical beta cells, the cultured cells responded by producing insulin." And the paper makes it crystal clear that the new beta cells did generate insulin in response to BG, and worked the way real beta cells are supposed to work.

What sort of immune suppression (if any) was used?
Nothing is mentioned in the abstract or paper.  SCID mice were used and they don't have a fully functioning immune system anyway.  In email, Dr. Taylor (lead author) said that he expects that a biopsy from one person would create enough stem cells to treat one person.  Discussion below about why that is important in terms of immune suppression, or lack of it.

Did it work in actual animals? 
Pretty well, but not perfectly.  The paper says that the mice had BG levels between 250-300, and were not given insulin.  This stayed pretty constant (my eye-balling of the data) during the weeks that the mice were followed. Obviously, the current standard of care is closer to 140, but remember that until the 1980s, BG levels around 300-400 were pretty standard.  So in this very first mouse experiment, they achieved better standard of care than the first 70+ years of human treatment.  And I expect they can refine their procedures to do much better.

How long did it work?
The abstract says "the animals continued to produce some insulin for six weeks, until the researchers ended the study." And the paper has more details on this.  The fact that they ended the study before the effect ended is promising as well.  It suggests that the effect will last longer.

What's the plan for preventing the autoimmune attack from destroying the new beta cells?
So far, there isn't one.  Since the mice in the experiment did not have autoimmune diabetes, the researchers didn't learn anything about what a type-1 diabetic's immune system would do to the new beta cells.  (Type-2 diabetics would not have this problem, of course.)  See below for some discussion about this.

What does all this mean?

My one sentence summary is: this is good research; very promising that it might be available in people in 15-20 years.

I know that a lot of people are staring at their screens right now screaming silently "how can it be good research yet still so far from general availability? Good research should give me a cure, quickly!"  And the answer is that if it were not good research, it would be even farther away.  Just because we want a cure quickly, does not mean we are going to get it that quickly.  Human research takes 10-12 years to make it from start to general availability, so I'm assuming that this research starts human trials in 3-10 years.  Because this research was done in severely immune compromised mice, I would expect that they would need to do some experiments in NOD mice or similar before trying it in type-1 diabetic people.

(Although the 10-12 year approval process is for drugs and devices, not surgical procedures, but this difference is too complex for me to describe here.  The much oversimplified version is: this research might take slightly less than the normal 10-12 years, but don't bet on it.)

Why is this research good?
Mostly because they made true beta cells that generated insulin in response to blood sugar and actually worked in real animals.  That's huge.  Even better, it continued to work for the length of the experiment.

What about this research needs more work?
It needs to run longer, for the whole life of the mouse.   It needs to be done on animals or people who have natural autoimmune diabetes.   Finally, it needs to be done in people.

What about this research is complex?
The type of mouse used combined with the lack of immunsuppression is the complex part of this research.  The mice used were SCID and these mice have seriously broken immune systems.  That's why they are used in transplant studies; they can't really reject foreign cells they way normal animal could.  So the researchers didn't have to give the mice an immunsuppresive drugs, because the mice were already immunsuppressed.  That all sounds pretty bad, in terms of applying this to people.

But maybe not.  Dr. Taylor has told me that he is hopeful that a single biopsy would provide enough uterine stem cells to treat one person.   If so, perhaps a person's own uterine stem cells could be used to treat themselves.  In that case, no immunespressives would be needed, because it would not be a foreign transplant.  Finding doners would not be a problem, either.  At least not for female diabetics.

The only issue remaining, and it is a big one, is this: would the body's own autoimmune attack kill of the new beta cells same as the old ones?  I would think they would.   However, the stem cell harvest / implanting process is simple (could be done in a clinic), so even if the new beta cells were attacked by the autoimmune process, maybe they could be replenished at every endo visit?  Or maybe every couple of endo visits?  That is why the researchers chose these particular stem cells to use: they are plentiful relatively easy to get, and are naturally replenished every month in women.

I'd like to thank Dr. Hugh Taylor (lead author), for his information., and for giving me a copy of the paper.

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

Results from a Phase-II Trial of Abatacept (Orencia)

Results from a Phase-II Trial of Abatacept (Orencia)

Abatacept is a treatment that prevents T-cells from becoming activated.  Presumably, for type-1 diabetes, it works by blocking the "bad" killer T-cells from activating.  This drug is already approved for use in rheumatoid arthritis when other treatments have failed, and is marketed as Orencia.  It was just recently approved for home use via under skin injections (similar to insulin).  Previously it required an infusion, and this study used the infused form.  It regulates (or modulates) T-cells, rather than depleting them, so the hope is that it will have less side effects than other immunosuppressives.

This study attempts to preserve beta cells during the honeymoon phase by giving newly diagnosed patients Abatacept.  This was a placebo controlled, double blind trial with 112 patients. About 2/3s (77 people) got the treatment and 1/3 (35 people) did not.  Three infusions the first month, and monthly thereafter for two years.  C-peptide production in response to a meal was the measured after two years.  The results where clearly better in the treated group.  Basically they produced 60% more of their own insulin at each point in the trial.  (Remember: C-peptide is a marker for insulin production.)  Also, the treated group had better A1c numbers.  The researchers estimate that this is similar to a 6-9 month delay in beta cell loss of type-1 diabetics at diagnosis.

Since Abatacept blocks some T-cell activation, infection was a worry, but the infection rates were the same in treated and placebo groups, as were injection site issues.  There were more mild side effects (things like headaches and nausea) in the treated group.

The researchers are going to continue to follow the patients to see what happens in the months after they stop getting regular doses of the drug.  They will see if the dosed patients stay ahead of the placebo group or not.

Next Steps

I'm not exactly sure what the next steps are in this line of research.  Are these results "good enough" so that you'd just move the same dosing into phase-III trials and then into the market?   Would you change the dose to try to get a better result?  (It looks like the researchers used the standard rheumatoid arthritis dosing for the trial.)  Would collecting data for a longer period of time, help planning the next move?  Belatacept is a follow on drug to Abatacept which was just approved in June 2011 (but not for type-1 diabetes), so would you move forward with Abatacept,  Belatacept, or both?

Another whole set of options involves combining Abatacept with another treatment.  The study chair for this trial is Dr. Tihamer Orban, who is also working on a B-chain insulin treatment (which already completed a phase-I trial, and which I've blogged on in the past), and he is interested in combining these two approaches. 

Abstract: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60886-6/abstract
News: http://www.medpagetoday.com/MeetingCoverage/ADA/27312
Previous blogging: http://cureresearch4type1diabetes.blogspot.com/search/label/Abatacept
Clinical trial record: http://clinicaltrials.gov/ct2/show/NCT00505375 
More News: http://www.marketwire.com/press-release/new-hope-immune-therapy-children-young-adults-with-type-1-diabetes-founder-orban-biotechs-1546447.htm
Related news: http://www.medicalnewstoday.com/articles/232194.php
Wikipedia: http://en.wikipedia.org/wiki/Abatacept

This study was run by TrialNet.  Thanks to Dr. Tihamer Orban for providing me we a pre-print of the Lancet article.  And thanks to everyone who provided help and information for this posting.

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
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