Possible Cures for Type-1 in the News (late Feb)

Results from a phase-I Clinical Trial

Back in Sept 2009, Dr. Garg started a small pilot trial of Sitagliptin and Lansoprazole. 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.  The study was supposed to last about three months, and now they have published some results.

Summary:

The [treatment] lowered their mean blood glucose by about 12 mg/dL and their A1Cs by 0.27%, and they were able to cut their insulin dose by nearly 10 percent during the treatment period.

They are very happy with the results and plan to start a 120 person study.  You can see the government clinical trials registration here, although it hasn't started yet:

http://www.clinicaltrials.gov/ct2/show/NCT01227460

The improvement looks pretty small to me.  They are cheering about 12 BG points improvement?  A quarter point A1c?  10% less insulin?   So, for example, someone who is currently averages a BG of 150 might drop to 138.  An A1c might go from 7.5 to 7.25.  Instead of using 60 units of insulin a day, they might use 54.  I'm underwhelmed, and I hope they get bigger improvements in their phase-II studies.  On the other hand, Lansoprazole is a common antacid and is available over the counter, and while Sitagliptin is prescription, it is also very common.  I don't know the longest clinical trial run with either one of these drugs however.  I'm a little nervous that previous testing of Lansoprazole (the antacid) might just assume you take it once in a while.  I'd be real curious if anyone has seen what happened (even in animals) if you took it every day for a month, a year, 10 years, etc.  Since that is what is envisioned here.  I expect that is what will be learned from the phase-II and phase-III trials.

As far as this blog is concerned, I don't think I will continue following this research, because I think it looks like a treatment for diabetes, not a cure.  But I don't want to be too "down" on this research.  Up until now, different types of insulin has been the only treatment available for type-1s, so this might be the first step to having an array of drugs that help keep BGs more stable.  I know a lot of people would be very happy with a .75 or 1 unit change in A1c, and as a first test, this got 1/3 to 1/4 of the way there.  So maybe further development will get there.

Sources:

http://www.diabeteshealth.com/read/2011/01/07/7004/sitagliptin-januvia-lowers-blood-sugar-in-people-with-type-1-diabetes/

http://www.jdrftalk.org/2011/01/19/pilot-study-shows-popular-type-2-diabetes-drug-lowers-blood-sugar-levels-in-people-with-type-1-diabetes/

http://www.renalandurologynews.com/type-2-diabetes-drug-shows-promise-for-type-1/article/193749/

http://www.clinicaltrials.gov/ct2/show/NCT00978796

DiaPep277 Fully Enrolls a Small Phase-III Trial

DiaPep277 is a protein design to help train the body's immune system not to attack it's own beta cells.  It was the first treatment that I know of that started phase-III clinical trials, and has been in them for years.  There were two different phase-III studies underway, both about 300 people.  (Remember that for US or EU approval new treatments generally require two phase-III studies of about this size.)  However, the news story below is about a smaller "follow on" phase-III study with 40 people.  This study will follow people for 2 years after they were already part of the phase-II study.  It is looking at longer term safety/effectiveness issues.  Since it is fully enrolled, we "just" need to wait 2+ years for the results.  Of course the results from their mainline phase-III trials matter much more.

News: http://www.globes.co.il/serveen/globes/docview.asp?did=1000624744&fid=1725
Clinical trial: http://www.clinicaltrials.gov/ct2/show/NCT01281072

One Scam Cure and One Fringe Theory
Note that both of these guys cite Dr. Faustman's work, but are totally separate from it.  One of the "tricks" of scientific scams, is that it helps to cite real research, as part of your fraud.  So the fact that Drs. Arnim and Broxmeyer are citing Dr. Faustman says nothing about Dr. Faustman's work.

Ulrich von Arnim
If you ever wanted to know what a type-1 diabetes cure fraud would look like.  Here is your chance:
http://bva-tec.com/studien_en.php
And here is the news coverage.
http://www.theage.com.au/national/health-conman-strikes-again-20110209-1an2v.html
I'm not worried that this guy might have really cured type-1 diabetes: he's been in jail for two years for fraud, and has an arrest warrant waiting for him in Germany.  But it is interesting to look at his web site.  If that was your only source of information, you would think it was real.  The only tip-offs that I saw were these:

• If you look at the "clinical trial registration" number column, I can see that those are not European clinical trial numbers.  Nor are they American numbers.  I think they are European patent numbers (and patents are not the same as clinical trials!)  Also the first row that says "(pre-study)" so has no clinical trial number.  That's wrong: if they used people, they gotta have a clinical trial.  There are ethical and legal issues if they don't.  (It's possible that things were different in 1990-1992, but I don't think they were that different.)
• The second issue was the number of people "cured".  He claims to have cured about 14,000 people.  Now, there are about 1.5 million people with type-1 diabetes in the EU, so he has cured about 1% of them.  Already.  And we've never heard from even one of his patients.  Sounds nuts to me. (And he claims to have cured 1000s of people as long as 20 years ago, and no one has talked about this?)

Lawrence Broxmeyer
This guy has a fringe theory, or maybe a quack theory, that diabetes is caused by Tuberculosis (TB).  Actually, he has a lot of theories that a lot of different diseases are caused by TB.
http://lawrencebroxmeyer.wordpress.com/2011/01/26/diabetes-mellitus-tuberculosis-and-the-science-of-denial-by-dr-lawrence-broxmeyer/
If you believe this stuff, then it's obvious why a TB vaccine (like BCG) would cure type-1 diabetes.  He conveniently ignores the fact that giving BCG to people with type-1 diabetes does not cure them.  Nor does it prevent type-1 diabetes.  (In five or six previously completed studies.)


Random Reading / Listening

If you have a CD player in your car, I recommend a recorded lecture called "What is Wrong with Cloning?" by Dr. Arthur Caplan.  (The Sunnyvale, California, USA library has a copy.)  It is 1/3 a discussion of ethics, 1/3 the science of cloning and stem cells, and 1/3 stand-up comedy.  I have never laughed so hard while learning so much.  It's published by The Great Lecture Library.

This University PR piece:
http://www.ucsf.edu/news/2011/02/9428/type-1-diabetes-clinical-trials-aim-save-beta-cells-immunotherapies
describes three different clinical trials all being run out of UCSF by Dr. Steve Gitelman.
You can search my blog site for "Gitelman" to see previous coverage of these trials.

You might want to also look at this data, about longer life spans for type-1 diabetics dx recently vs. dx in the 1950s:
http://www.t1diabetes.nih.gov/Research_Accomp.pdf

Reminder About The Blog

This blog generally only covers research results.   Occasionally related topics are discussed.   However, I generally don't discuss funding issues, stock issues, new hires (such as presidents, new board of director members, etc.)  patient issues, etc.  These are all news worthy, but they are not the kind of news that I cover here.

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

Chance of FDA Approval

Long ago, one of my first blog postings described the "research funnel".  How a drug went from animal tests through three phases of clinical trials and was eventually approved (and how drugs could fail at each step in the process).  If you haven't read that posting, it contains a lot of useful background information on how drugs get approved in the USA:
http://cureresearch4type1diabetes.blogspot.com/2008/06/understanding-research-funnel.html

I used the best data I could find for that post, but I'm very happy to say that Biotechnology Industry Organization (an industry trade group) and BioMedTracker (a company which collects data on drugs in development) have published some much better data on success rates for US FDA approvals.  Their data set is much larger than what I had back then.  And it is interesting! At least to me :-)


The study was conducted from 2004 through 2010 reviewed more than 4,000 drugs from companies large and small and both publicly traded and private.  But NOT university or non-profit research.


Major findings about the process right now:

• The overall success rate (all the way through successful FDA approval) for drugs moving from early stage Phase I clinical trials is about 9%.  For phase-II it is 15%, for phase-III it is 44%.
• 63% of drugs in Phase I testing advanced to Phase II
• 33% of Phase II drugs made it to Phase III
• 55% of the drugs that made it to Phase III testing filed for approval applications.
• 80% of the drugs that filed for approval gained eventual approval (only about half were approved on their initial FDA review)
• Biologics had a 15% chance of going from Phase I through to FDA approval, compared with a 7% success rate for traditional small molecule chemical drugs. A biologic is more complex than a simple drug.  It is generally something derived from a living organism.  For example, a purified microorganism or specially treated or processed blood or tissue would be a biologic.  BCG, cord blood, and ATG are biologics that are being tested on type-1 diabetics.  
• The highest overall success rate from Phase 1 through likelihood of approval was for infectious diseases, such as hepatitis and HIV drugs, at 12%.  Next was endocrine system drugs, featuring [type-2] diabetes treatments, at 10.4%.  And then autoimmune diseases, such as rheumatoid arthritis, at 9.4%.
• Overall success rates from Phase I to FDA approval is nearly 9%. This number is comprised of lead and secondary indications. When separated, lead indications have close to a one in seven rate of approval and secondary indications have a rate of one in 30.  This was seen in all phases of clinical development as well as in all disease areas. 
• The study also shows that large molecule drugs are twice as successful in gaining approval than small molecule drugs.

Major findings about changes in the process:

• Overall success rate for drugs moving from early stage Phase I clinical trials to FDA approval is about 9%, down from one in five to one in six seen in reports involving earlier years.
• The 80% approval rate (for drugs that submitted applications), is down from 93% seen in early studies.

Commentary

Here are some very rough calculations:
There are currently about 15 phase-I trials with a 9% chance of eventual approval   (1.35 total)
There are currently about 10 phase-II trials with a 15% chance of eventual approval (1.50 total)
There are currently about 3 phase-III trials with a 44% chance of eventual approval (1.35 total)
So, a reasonable estimate is that out of the current crop,  4 drugs will eventually be approved.  It will be very interesting to see how this plays out over the next few years.

But with two serious limitations:

First, The study above only included commercial company's drugs.  it did not include drugs being researched at universities.  I would assume that university research is far less likely to eventually be approved than commercial research. (There are at least two reasons for this: first, universities should be more experimental and less worried about practicle applications, and second, they don't have the resources to push treatments and commercial companies do.)  Since several of the current clinical trials are university research, they are less likely to end up being approved.

Second, most of the current crop of treatments in clinical trials are not cures.  Indeed, only one (Burt) has kept people free of external insulin for 4 years.  That is a phase-I trial, so I think it is reasonable that we are going to need about 10 more treatments in phase-I that actually cure people (or get close) before such a cure will become generally available.

I know that many people want to spend a lot of time and resources investigating drugs that are already approved, for some other purpose, in the hopes that they will cure type-1.  This study shows the dangers of such a focus, since those are the secondary indications that have the much lower success rate.  It turns out that most treatments only work on one thing, so if you try to use them for something else, you chance of success goes way down.  (Even if it is cheaper and quicker.)

Also, it is interesting to me that more complex treatments have higher chances of eventual approval.  Biologics are more complex than drugs, but have a greater chance of approval.  More complex molecules are more likely to be approved than simple ones.  My guess is that because these are more expensive to develop, companies only push the very best of them.  Or maybe all the simple cures have already been productized, and only the more complex ones remain.

Handouts:
If you work in the pharma industry, or if it is important to you, I strongly suggest that you look at this PDF file.  It is thick with information:
http://insidebioia.files.wordpress.com/2011/02/bio-ceo-biomedtracker-bio-study-handout-final-2-15-2011.pdf
News reports:
http://news.yahoo.com/s/nm/20110214/hl_nm/us_pharmaceuticals_success;_ylt=AgsEciuYx.Hb5aUFo.oOX0gPLBIF;_ylu=X3oDMTJ2OGI2aGpzBGFzc2V0A25tLzIwMTEwMjE0L3VzX3BoYXJtYWNldXRpY2Fsc19zdWNjZXNzBHBvcwM4BHNlYwN5bl9hcnRpY2xlX3N1bW1hcnlfbGlzdARzbGsDc3VjY2Vzc3JhdGVz
http://www.bio.org/news/pressreleases/newsitem.asp?id=2011_0214_02


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

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

Rilonacept Starts a phase-I Clinical Trial

About six months ago, I blogged about three clinical trials which had not yet started, but were expected to start "soon".  Now the Rilonacept study is actually starting. 

This drug has not previously been tested on type-1 diabetes, but is already approved for other diseases (since 2008 to treat CAPS) under the name Arcalyst.  It is currently in use in about 12 phase-II and phase-III clinical trials for several different inflammation based diseases, especially Gout. It is an IL-1 inhibitor, and IL-1 is known to be involved in the destruction of beta cells in people with type-1 diabetes.  The hope is that this treatment will result in a longer, stronger honeymoon, and may result in long term improvements in A1c (such improvements might lead to fewer serious complications years or decades down the road).  This is the third treatment targeting IL-1 that I'm following. Others include Anakinra and Canakinumab.

The study will enroll 15 patients, all of who will be treated with Rilonacept (no placebo group).  To enroll you must be over 16 years old, within 5 years of diagnosis, and still producing some C-peptides (> 0.2 nmol/L) in response to food. These people will be followed for six months, involving five clinic visits, and it is hoped the trial will be complete by June 2012.  The treatment is weekly injections (under the skin, like insulin).  They will be looking for general safety issues, as well as effectiveness (A1c, C-peptides, and insulin dose).  This is NOT a honeymoon only trial, by my definition.

This is being run out of Children's Medical Center (Dallas, Texas, USA):
Principal Investigator: Perrin C White, MD    perrin.white@utsouthwestern.edu

If you are interested in participating, send Dr. White some email.  Don't worry about your C-peptide production.  If you meet the other criteria, they will test for that.

It is interesting to me how much the design of this clinical trial has changed in the last six months.  You can compare what I'm writing now, to what I wrote back then:
http://cureresearch4type1diabetes.blogspot.com/2010/06/three-new-treatments-preparing-to-enter.html
to see the differences.

Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT00962026

Thanks very much to Dr. White for providing information about this trial.

News on the Animas Artificial Pancreas

News article on Animas's Artificial Pancreas.  Obviously, I'll be a lot more interested when it actually starts a clinical trial:
http://www.bizjournals.com/philadelphia/print-edition/2011/01/21/artificial-pancreas-awaits-fda.html

Background reading on Artificial Pancreases in General

This paper is a little dry and a little dense, but it gives a good summary update of where we are, and the lead author (Hovorka) is actively involved in AP research:
http://www.touchendocrinology.com/articles/progress-closed-loop-systems-type-1-diabetes-0?page=0%2C0

Reminder About The Blog

I'm not a doctor or research professional of any kind.  I can not provide medical advice, because I lack the knowledge.  I don't recommend one clinical trial or another.  I think that any discussion about participating in a clinical trial must be held between you and your medical team.  I know not everyone has a doctor they trust, and I'm sorry about that, but I can't give you advice on which clinical trial you should be part of, or avoid. 

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

Glucagon / Leptin type-1 "Cure" in the News

This posting discusses research which has mostly been done on mice.  Please remember that anything that cures type-1 diabetes in mice is always years away from general availability in people.  I'm posting about this because it is making a big splash in the news, so I expect to get questions about this from friends and relations. I've already gotten questions from BBs.  Here is an example of one the better news articles:
http://www.sciencedaily.com/releases/2011/01/110126161835.htm

This research is quite different from other research aimed at curing type-1.

Drs. Unger and Lee Publish a Mouse Study Explaining Why Leptin Might Cure Type-1 Diabetes (or make it asymptomatic)

History

Several months ago, these researchers published a paper showing that giving Leptin to NOD mice was in some ways better than giving them Insulin.  Mice given Leptin had much better BG control than mice given Insulin, and that many mice given Leptin did not need to take Insulin at all.
Abstract: http://www.pnas.org/content/107/11/4813.abstract
Previous blog: http://cureresearch4type1diabetes.blogspot.com/2008/09/discussion-of-recent-press-reports-of.html
Related research: http://www.pnas.org/content/107/40/17391

Just recently, these researchers also started a clinical trial of Leptin, to see if people would have the same benefit seen in NOD mice, which I've covered a little bit.  But I did not cover it aggressively, because it was not clear if it was a cure for type-1 diabetes, or just a better treatment:
http://cureresearch4type1diabetes.blogspot.com/2010/12/possible-cures-for-type-1-in-news-late.html
http://www.clinicaltrials.gov/ct2/show/NCT01268644

Now, they have published another mouse study, which describes why they think Leptin helps type-1 mice so much.   And it is clear that they think they are on to a cure mechanism for type-1 diabetes.
Abstract: http://diabetes.diabetesjournals.org/content/60/2/391
Extract of commentary: http://diabetes.diabetesjournals.org/content/60/2/377.extract

What The Current Paper Means

This paper suggests a much different mechanism for type-1 diabetes than previously believed.
First, it suggests that mice can utilize the carbs in food without producing their own insulin.  That even animals with no beta-cells to produce insulin and no injected insulin, will still live long, happy lives if they are injected with Leptin.  Insulin is not the "key that lets sugars into cells" that we have been told that it is.
Second, The high blood glucose levels that are seen in type-1 diabetics who do not take insulin are actually caused by glucagon.  And these researchers believe that glucagon (in type-1 diabetics) is incorrectly over generated by the body, triggered by a lack of insulin.

Obviously, this suggests that type-1 diabetes can be treated by preventing (or lowering) the generation of glucagon.  In fact, from a functional point of view, it may be that preventing (or restricting) the body from making glucagon results in a "cure" where the person does not need to measure carbs, inject insulin, or suffer the long term side effects of type-1 diabetes.  This could "kick off" a long discussion of what is a cure, what is not a cure, and so on.  Different people have fundamentally different definitions of a cure, and this can lead to huge arguments.  My definition of a cure (which is on my blog) is "functional".  Others think you must stop the autoimmune attack for a real cure. I don't think it is a worthwhile argument to have now, but do remember: even in the absolute best case, this research is aimed at a functional cure.

Leptin is an example of a treatment which is known to restrict glucagon generation, but there may be others.  Some research showing Leptin's impact on glucagon:
http://www.ionchannels.org/showabstract.php?pmid=19401420

As this research progresses, it will be interesting to see if Leptin used in this way effects the use of emergency glucagon injections.  My guess is that it would not, there would be so much glucagon in the injection that a Leptin dose earlier in the day would make little to no impact.  But testing would be needed to make sure of this.

Some General Discussion

One comment I got about this research is this: "They cured mice.  So what.  Happens all the time, why care about these guys."  And that's true.  When someone announces a mouse cure, they are usually 2 years away from the start of a human trial, and often never get even that far.  But these researchers are in a different situation. They are NOT announcing a mouse cure.  They announced the mouse cure a year ago.  They have already started the human trial (3 out of 15 people already have started the treatment).  What they are announcing now is research into the mechanism that is curing these mice.

But notice how many times I used the word "mouse" in the previous paragraph.  One thing to keep in the front of your mind throughout this discussion, is that people are not mice, and mice are not people.  We know that type-1 diabetes is not the same in mice as in people.  We get mice cures at a rate of several per year.  We get people cures at a rate of zero so far.  Over 100 mouse cures have NOT worked in people.  One of my serious worries about this research is that it won't work on people at all.  That it is based on something in mice that is not there in people.  The only way to allay that fear is human trials, and that is why I'm excited that these guys have already started such a trial.

Also, it is important to remember that there were two studies, with two types of mice.  The first study, which used Leptin to cure type-1 diabetes used NOD mice.  The mice in the second ("mechanism") study were not NOD mice, and did not have autoimmunity. They were given a drug that killed their beta-cells, which induces diabetes, but not the autoimmunity part. In theory, for this research, that should not matter, but I'm always nervous about researching type-1 diabetes in mice that don't have autoimmunity.

One obvious issue is that this theory assumes that insulin is NOT actually needed to get the energy from carbs.  It assumes that if glucagon is removed, a type-1 diabetic will still be able to use all the energy in the carbs eaten.  However, this goes against mainstream medical theory that has lasted for decades.  It seems a little unlikely that no one has noticed -- even after decades of research -- that type-1 diabetics can process carbs without insulin.

Another issue is that some people have had their entire pancreases removed, and those people would not generate any insulin or glucagon.  However, they do have the classic symptoms of type-1 diabetes.  That doesn't fit in with this theory.  (Thanks to CWD's LantusFiend for pointing this out.)

I sometimes get asked "do you think it will work" (about a lot of research, not just this research).  I know that question is in the back of many people's minds.  But the question is meaningless.  It doesn't matter if I think it will work, for me or anyone else.  It only matters if it actually works, and that means data from clinical trials.  Not opinions.

How do we get from here to a cure?

I don't think we can replicate the recently announced mouse experiments in people.  These experiments used specially bred "glucagon knockout" mice.   These are mice which are a specific genetic defect that turns off their glucagon system.  I don't think there are people like that walking around.  Even if there were, we would need to find people who didn't have a glucagon system and did have type-1 diabetes.  And even if such people existed, according to these researchers, their type-1 diabetes might be asymptomatic.  They wouldn't even know they had it!  So they couldn't be recruited for a study.

So back in reality, the only way to test this in people is to find a safe way to turn down the glucagon system of someone who already has type-1 diabetes.  If this theory is right, their type-1 diabetes would become asymptomatic (or maybe they would require far less insulin than they do now).  But turning off a major hormone is not something done lightly.  Hormones are very important, and a little tricky: we often don't know all the functions that one hormone has.  Researchers are often surprised that a hormone that they thought just did X, also does Y, or stops Z from happening.  So shutting it down to help with X might cause problems in Y or Z.

So, with all that as background, these researchers know that Leptin lowers glucagon generation, so giving Leptin to type-1 diabetics is an obvious clinical trial to run, and they have already started such a trial.  However, there may be other ways to limit, control, or stop glucagon generation, and it might be interesting to run other clinical trials that use other method to turn down a type-1 diabetic's glucagon system (carefully).

An obvious question is: how safe is Leptin?  The current phase-I study in type-1 diabetics is not the first trial for Leptin.  It has already completed some phase-I studies in people who have type-2 diabetes and in people who are over weight.  However, the real question is, how safe is it when used on type-1 diabetics in the dose needed for them to get the good effects we want?  And also, do any safety issues surface in the larger phase-II and phase-III studies (for any indication)?  And those issues can only be resolved by going through the clinical trial process.

Finally, Amylin is a commercial company that is researching Leptin, and they are a collaborator in the clinical trial.  Amylin is a big name in the treatment of type-2 diabetes, but as far as I know, they do not have a drug aimed at type-1 (so no "conflict of revenue").  They are interested in Leptin as a combination weight loss treatment.  But obviously, good results in treating type-1 could open up a whole new market for them.

One Last Point

If these guys are right about glucagon and Leptin in people, and their study uses the right dose, then they are going to find out quickly.  Their current study is NOT blinded, and they believe the effect is not honeymoon dependent.  So even though their experiment is supposed to last until early-2013 (and may last longer), the researchers involved (and the patients involved) may know sooner.

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

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

Polyclonal Tregs Starts a Phase-I Clinical Trail

This one is a little complex.  The body's immune system includes T-regulatory cells, which help control the "killer" T-cells which (in type-1 diabetes) mistakenly attack the beta cells.  Some researchers have attempted to reduce the number of "killer" T-cells, while other researchers are trying to raise the number of T-regulatory cells.  This research is trying to raise the number of T-regulatory cells.  The basic technique is as follows: remove some of a patient's own T-regulatory cells, which is the same processes as giving blood.  Then separate and purify those T-reg cells, and grow them for about 2 weeks.  You can end up with 1000 times as many as you started with. Finally, put them back into the patient.  Since these cells naturally regulate (or control) the body's immune system, having more of them may result in the body stopping it's own autoimmune attack.   They've had good results in NOD mice.  Finally, some researchers believe that the previously seen good results in some other treatments (such as anti-CD3 and ATG) might be caused by these treatments stimulating T-reg production, rather than, or in addition to, lowering "killer" T-cell production.

This study involves 14 people, who have had type-1 diabetes for more than 3 months, but less than 2 years.  It is primarily a safety trial (to make sure the procedure is safe), but has secondary measures to also see if the treatment improves type-1 diabetes (for example: higher C-peptides, lower A1Cs, etc.).  It is a single site study, being done at UCSF (San Francisco, California, USA).  Dr. Gitelman  ("Dr. Steve", if you attend Bearskin Meadows camp) is running it.

Unfortunately, this study will not be quick.  It is expected to last until 2016.

Clinical trial record: http://www.clinicaltrials.gov/ct2/show/NCT01210664
UCSF's web page: http://www.diabetes.ucsf.edu/clinical-care-education/clinical-trials/type-1-diabetes/new-onset-type-1-diabetes-age-6-45-years-wit

Canakinumab Starts a Phase-II Clinical Trial

Canakinumab is a monoclonal antibody, which is designed to lower inflammation.  It was approved in 2009 (both US FDA and EU EMEA) for a collection of rare autoimmune based inflammatory diseases.  Good results have been seen in people with type-2 diabetes, and it has been used in children as young as 3. Therefore, it is known safe, and can start a phase-II trial for type-1 diabetes.  The trial is for 66 people who will be followed for 4 years.  It is honeymoon only (100 days from diagnosis).  The treatment is monthly injections for a year: 2/3 get treatment, 1/3 get placebo.  My general comments on inflammation based cures apply here: http://joshualevy.pbworks.com/w/page/24444346/ConceptsAndBackground#Inflammation

This is a large trial, recruiting in many locations in the US, which are listed in the clinical trial record below.  For locals: both UCSF and Stanford are participating.

Clinical trial record: http://www.clinicaltrials.gov/ct2/show/NCT00947427
Wikipedia entry: http://en.wikipedia.org/wiki/Canakinumab

Data Published from extended follow up to Diamyd Phase-II Trial

Diamyd as published some extended follow up up data from their phase-II trials, which I have not had time to review, but you can see it here:

Full Paper: http://www.springerlink.com/content/k7051252031r1671/fulltext.html
Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT00435981

Not Yet In Human Trials

There were several new types of artificial pancreas which I heard about in 2010, and this is the latest.  It is called a "Bionic Pancreas" and is basically a dual-hormone (insulin and glucagon) AP, but designed as a single, custom computer chip.  They hope to start human trials "this year [2011]".  These guys know about the dual-hormone work being done at Harvard, and the two groups are using some of the same ideas, but pushing different parts of the technology.  The Harvard guys are focused more on exact algorithms, and these guys (at Imperial Collage, in the UK) are focused more on a single chip package.

News report: http://spectrum.ieee.org/biomedical/devices/bionic-pancreas

Not Type-1 Diabetes Related

The following article describes the ethical issues of a chemist who works with brain chemicals in rats, and who's work is often used by black marketeers to create street drugs, which sometimes kill people.  It is an interesting read and an interesting moral dilemma.

http://news.yahoo.com/s/ap/20110105/ap_on_sc/us_sci_haunted_scientist;_ylt=Apj8w6un3xq9J8J_t4MMSEAPLBIF;_ylu=X3oDMTJwM2I5NnNlBGFzc2V0A2FwLzIwMTEwMTA1L3VzX3NjaV9oYXVudGVkX3NjaWVudGlzdARjcG9zAzEEcG9zAzIEc2VjA3luX3RvcF9zdG9yeQRzbGsDc2NpZW50aXN0aGF1

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

Symposium on Therapeutic and Preventive Vaccines for Autoimmune Diseases

I recently attended a Symposium on Therapeutic and Preventive Vaccines for Autoimmune Diseases as a guest of the JDRF.  This posting contains some information that I got there, and also some thoughts and opinions that bubbled up while I was there.  This is not a summary of the meeting, it's more "bits and pieces" motivated by the meeting.

But before I do that, I want to discuss the word "vaccine".  When I talk to parents or people who have type-1 diabetes, and ask them what the word "vaccine" means, they always say something like "something you give to a healthy person to prevent a disease".  And they wonder why anyone who already has type-1 diabetes would care about a vaccine.  But in the scientific world, the term "vaccine" means something that changes how the body responds to a specific substance (called an "antigen").  As researchers use the term, a vaccine can cause the body to respond more strongly or less strongly.  So from this point of view, a vaccine which causes the immune system to stop attacking it's own beta cells would be very important to cure research.

This symposium was jointly sponsored by JDRF and FastForward which is focused on finding a cure for multiple sclerosis.  Both of these are autoimmune diseases (ie. diseases caused by the body's immune system mistakenly attacking a working part of the body).  So the idea is to jointly research and promote cures for autoimmunity in general.

There was one piece of bad news about why companies do not invest in type-1 diabetes, and two pieces of good news about why they do:

The bad news:  If you've got 50 or 100 million dollars to invest in research, are you going to spend it on type-1 diabetes, or type-2 diabetes (which has about 10 times a big a market)?  You are going to spend that money to develop a type-2 drug.  Bigger market.

The first good news:  Curing type-1 is an "unmet need".  That means there is no competition.  You make more money if there is no competition, so that is motivating people to research type-1 even in the face of the larger type-2 market.  If you enter the type-2 market you have lots of competition (and some of it is really cheap, so it is hard for you to charge a lot for a new drug, if an old one is cheap).  However, if you enter the type-1 market, you own it.

The second good news: Type-1 is related to other autoimmune diseases (especially: rheumatoid arthritis, multiple sclerosis, and possibly lupus and others.)  So that means that money you put into curing type-1 diabetes might also lead to a cure for these other diseases, and that could be very profitable.  A sort of three for one deal on cures.  This also motivates companies to put more money into type-1 research.

This leads into discussion of the symposium's magic word: "platform".  You might think that a platform is a wooden box that you stand on.  I'm a software engineer, and we use "platform" to mean a bunch of software that helps develop new software and can be used over and over again for that purpose.  The pharma guys use the word in much the same way that software guys do.  A pharma "platform" is a way to speed the development of multiple drugs.  Everyone who is working on a drug, talks about their platform.  They hope that their development can be used again and again to develop multiple different cures for different diseases.   The word "platform" represents the unbridled optimism common to researchers; and the funding opportunity that every venture capitalist, pharma company, and non-profit is looking for.  They haven't even started a clinical trial, and are already talking about how they will cure multiple diseases in the future. "Platform" is the pot of gold at the end of the rainbow.

To be a little more specific, two types of platforms were discussed.  The first was a common collection of ingredients that you can customize to cure different diseases.  Consider this bread analogy: you have a recipe for pecan bread.  You try replacing the pecans with almonds, now you have almond bread.  You replace them with blueberries and now you have blueberry bread.  Your bread is what the pharma guys would call a "platform".  You drop in one new ingredient to create a new bread.  If your bread recipe is good at this sort of flexibility, then a commercial bakery would be very interested in it, as well as all the "specialty" bread recipes.

Bayhills has exactly this kind of platform:  it is a ring structure of several chemicals, one of which is specific to type-1 diabetes.  That drug is called BHT-3021 and is targeted at type-1 diabetes.  But if you take the same basic ring, and replace the type-1 chemical with a different one aimed at multiple sclerosis, then the drug is called BHT-3009 and is aimed at MS.  And so on....

Another kind of platform is a method to find drugs, which you can use again and again on different diseases.  Again, to use a cooking analogy, let's say you are looking for a dinner recipe and so you grab a can of chicken soup and pour it over chicken meat and bake it.  A week later you grab mushroom soup, pour it over beef and bake that.  You now have a "platform" for making recipes.  The platform is this: pour a can of soup over a meat and bake it.  None of the ingredients are reused (as they are above), but the basic technique is reused.    There were a couple of different researchers with this kind of platform at the meeting.  Including Apitope and Dr. Mannie (neither in clinical trials as yet).

The second most important word at the symposium was "bio-marker".  A bio-marker is a way to do an experiment for cheap.  For example, lets say you have a drug and you think it cures type-1 diabetes.  Running an experiment to see if it does will take years: you need to make sure type-1 doesn't come back.  However, if you had some blood test that told you the person no longer had type-1, then you would not need to follow them for years.  You would just need to do the blood test.  That blood test would be for a "bio-marker".  Something that showed you the drug had worked, but was cheaper, quicker, and easier than seeing if it had really worked.  Finding a bio-marker for a disease speeds up ALL research aimed at curing that disease, and it attracts research money to that disease, since research there is less risky.

C-peptide is such a bio-marker for type-1 diabetes, but the pharma guys are always wishing that there were more.  It makes research, cheaper, quicker, less risky, and less unknown.  It is especially important that the government regulators agree to the use of the bio-marker.  If they do, then you can get government approval that the drug is useful, based on the bio-marker: quicker, cheaper, less risky, and you know approval will be granted.

Type-1 diabetes is diagnosed in about 78 thousand people per year in the US and the EU.  That is your core market for any new, honeymoon treatment.  There are about 2.1 million people who have type-1 diabetes in the US and the EU, so that is your market for any new treatment.  At the time of diagnosis about 10%-20% of the beta cells are still working.

Since I focus on clinical trials, for me, the most important presenters were those who had clinical trials underway:

Diamyd (makers of GAD-Alum) expects to have results from the Euopean phase-III trial "this Spring, before the Summer".  This study has three branches (people who did not get Diamyd, people who got two injections and people who got four injections).  It only includes people within three months of diagnosis.  Their phase-II study included people from longer after diagnosis, but the results were not so good for those people, so the phase-III study cut off eligibility at 3 months post diagnosis.

There is also have a small prevention trial in Sweden: 50 kids aged 4-7 who already tested positive to 2 or more different antibodies associated with type-1 diabetes, including the GAD antibody.  This study will take years, since they need to wait and see how many of the patients actually come down with type-1 diabetes.  This is an example of a the type of trial that doesn't have a bio-marker to speed it along, so it takes a long time to do even a small study.

Bayhill is expecting to be ready to start their phase-II study on BHT-3021 "very soon".  They expect to publish the full data from their phase-I study "later this year".  They have already published interim phase-I results last Summer, and I'm trying to get a copy of that presentation.  Although the FDA did not allow them to enroll children in their phase-I trial, they do expect their phase-II trial to be open to patients under 18 years old.  Obviously, this make it easier to complete enrollment.  It is also a general sign of safety that the FDA will let you include children in your trial.

One of the interesting things about their phase-I trial is that everyone gets treated eventually.  When you enroll, half the people get the drug, and half get a placebo.  Each group is then followed for a year, and the research is based on this treated vs. untreated comparison.  But then, the people who previously got the placebo are given the drug.  The advantage to this (I think) is easier recruitment.   Because, in the end, everyone gets the drug.  In classic trials, some people don't what to participate, because they are afraid that they will be in the placebo group, and go through all the work, and not get the treatment.  This design ensures that: everyone gets the treatment.

Finally, ToleRx (makers of Otelixizumab) were there, but my understanding is that their drug is not antigen specific and therefore would not be considered a vaccine.  In any case, I did ask, and was told, that they expected to publish results mid this year from their first phase-III trial.  I know their second phase-III trial is about a year behind their first, and both need to be done before they can submit to the FDA for market approval.

Most of the research discussed at this meeting had been done on animals, not people, and I discuss some of it (not all of it), below:

I was reminded (yet again) how enticing animal research is.  There were at least three or four researchers at this one symposium who had cured type-1 diabetes in NOD mice.  Some of them had cured it in several different animals models, and had performed all sources of confirmatory tests to make sure the animals were permanently cured of type-1 diabetes.  It would have been so easy to latch one to one of these guys as the one-true-cure that will lead us all to the promised land.  Again and again I reminded myself: don't get too excited about animal cures: they are always a long time and an uncertain result away from a human cure.

The most interesting to me was Parvus.  They have licensed Dr. Santamaria's research, which is based on attaching proteins to nanomolecules.  He published mice research in April 2010, which made quite a splash.  The Parvus guys hope to start human trials in 18-24 months.  If the FDA requires them to do monkey trials before human trials, then it will be on the longer side of the time frame.  If not, then closer to the shorter time. Previous news:  http://www.diabetesincontrol.com/articles/did-you-know/9191-

I particularly liked this paragraph:

According to Teodora Staeva, Ph.D., JDRF Program Director of Immune Therapies, a key finding from [this research] is that only the immune cells specifically focused on aggressively destroying beta cells (or, alternatively, regulating these cells) responded to the antigen-specific nanoparticle vaccine.  That means the treatment did not compromise the rest of the immune system -- a key consideration for the treatment to be safe and effective in an otherwise healthy person with Type 1 diabetes. 

Another interesting piece of animal research was Dr. Daniell, who I've blogged on before:
http://cureresearch4type1diabetes.blogspot.com/search/label/Lettuce
Dr. Daniell is still looking for funding to start a human trial, and his presentation sounded like a funding pitch. Basically, he has genetically modified lettuce to contain proinsulin, and because proinsulin is wrapped in cellulose, it is not digested, but enters the system of whoever ate it.  Why is this important?  Because giving proinsulin to NOD mice prevents the development of type-1 diabetes.  However, previous researchers have tried to slip proinsulin past the digestive system in people, but this has not succeeded in preventing or curing type-1 diabetes.  (As I discuss in more detail in my previous blog entry.)   I asked Dr. Daniell about this specifically, and his reply was simple.  In previous proinsulin clinical trials the methods used to get the proinsulin past the digestive system were not very good, and he believes the experiments failed because they were not good enough.  However, generating proinsulin, naturally wrapped in lettuce cellulose is a much better system.  This proinsluiln will get past the digestive system, and therefore will be successful even in the face of the previous failures.

A third interesting research area was Dr. Mannie.  He has a platform which he used to create an MS drug, which he has successfully tested in animals.  He hopes to get IND paperwork (required to start a human trial) done by 2015 for that drug.  So far, he has spent $700,000 on the project.  He is confidant that his platform will work for type-1 diabetes as well, if someone gave him a few $100,000s for that project.  So, think about this: would developing another cure for type-1 diabetes in NOD mice, be worth $500,000?  Should JDRF (or anyone else) put in that money now?  Or wait about 6-7 years and see what happens to the MS drug in people?

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

LCT Gets Commercial Approval In Russia!

I had not planned to make another blog entry until Jan-2011, but I felt that the following news was important, so made an exception.   Happy Winter Solstice everyone!

The official sound track for this blog entry is The Blur's "Song 2":  Woooo-hooooo!
http://www.last.fm/music/Blur/+videos/+1-OSB3SUh3Xd8

LCT Gets Commercial Approval In Russia!

Background: LCT is developing an encapsulated pig beta cell cure for type-1 diabetes.
Called "Diabecell", it has pig beta cells encapsulated in a special coating.  The coating allows blood sugar in, and insulin out, but does not allow the body's immune system to attack the beta cells.  It also allows nutrients in and waste products out.  This allows the beta cells to naturally grow and to react to the body's sugar by generating insulin which goes into the body's blood system.  Meanwhile, the body's autoimmune attack can not target these beta cells, and you don't need to take any immunsuppression drugs (as you would for a normal beta cell transplantation).  Remember that for decades, diabetics injected pig and cow insulin every day, so the fact that they are transplanting pig beta cells instead of human beta cells should not make anyone nervous.  Different researchers have been working on this kind of system for decades, but LCT is the first group to get government approval for this sort of "bio-artificial" pancreas.

I completely understand that not everyone considers a bio-artificial pancreas to be a cure.  Some people think it is just a good treatment: a much better treatment that we have now.  I've written this blog entry from the point of view of someone who thinks that a bio-artificial pancreas that really works is a cure.  If you don't believe that, just replace the word "cure" with "better treatment" in your mind as you read this.

So What Does This News Mean: My understanding is this means LCT has approval to sell their Diabecells as a commercial medical treatment in Russia.  LCT already has a commercial presence in Russia, so I would expect that in the next few months we will see actual availability of the treatment there.  LCT has said that they are working with two different clinics in Russia. LCT thinks that in the second half of 2011, you will be able to fly to Russia (if you don't live there already) and get this treatment.

What can LCT's Diabecell Do Right Now: In my opinion, the current performance of Diabecell does not make it a cure.  They have reported on less than 16 people, and only 2 of them were insulin free for any length of time, and those two were insulin free for only a few months.  But don't underestimate LCT's Diabecell just because it is not a cure right now:  First, research is about doing more in the future than you are doing right now, and this may grow into a cure over time.  Second, this treatment almost eliminates very low blood glucose episodes, and that is a benefit even without being a cure.  For "brittle" type-1 diabetics, this might prove reason enough to get this treatment.

Discussion

Just about every one of these discussion points could be expanded to a full blog entry, all by themselves.  I'm just trying to "hit the high points" here.  As you read this discussion, don't forget the central point: these guys have gotten farther along the path of encapsulated beta cells as a future cure of type-1 diabetes than anyone else.  They are the first people to get government approval for something that might, in the future, with some more work, cure type-1 diabetes (at least by my definition of "cure").

Edmunton Protocol vs. Diabecell
In a previous blog I compared Diabecell with Burt's immune system reboot research, but that was unfair because Diabecell works on established diabetics, while the reboot research has only been tested on honeymoon diabetics.  However, a better comparison might be to compare the Edmunton protocol (for beta cell transplants) to Diabecell (for encapsulated beta cell transplants).  Both work on established type-1 diabetes.  Unfortunately, I don't know exactly how successful the Edmunton Protocol is, as used these days, so I can't compare it to Diabecell.  But it would be a great project: a useful head to head comparison of cure rates and durations of these two transplant techniques.

My best guess is that right now, the Edmunton protocol has a much higher success rate (in terms of % of people who don't need to use insulin for some period of time) and a much longer remission rate (length of time they don't need to use insulin).  However, it requires the person to take immune suppession drugs for the rest of their life.  Those drugs have serious side effects, and taking them for years or decades raises the chance of problems in the future (like cancer), and Diabecell doesn't have those side effects.

But I do think that the first commercial impact that Diabecell is going to have is on the Edmunton protocol clinics.  Right now, only a few diabetics get an Edmunton protocol beta cell transplant.  The ones who do are often "brittle" diabetics who experience seizures and are either worried about driving, or worried about "dead-in-bed" or both.  Those diabetics will now have an alternative to the Edmunton protocol, and we will see over the next few years how many of them take advantage of it.

From Here to a Cure
One obvious question is, if the current Diabecell is not a cure, can they make it into one?  And if so, how long will that take?  I think there are two steps needed for Diabecell to become a cure (by my definition):
First, it needs to work better.  Right now, about 90% of the people who get the treatment, continue to need to use insulin.  That's not a cure for me.  
Second, they need their treatment to last longer.  Since it requires an operation, I think it needs to last at least a couple of years.  Five or ten years (or longer) would be reasonable for a cure for me.

The big unknown for me is how hard will it be to improve Diabecell in these two ways.  If it is just an engineering issue, then that is great news: if they can just tinker with it and gradually improve both the success rate and the duration, that would be great.  They could tinker with it for 5 to 10 years and end up with a cure.  On the other hand, there might be a research issue in there that they need to solve.  That would require scientific research and a breakthrough of some kind to make it more successful and last longer.  Research breakthroughs are much harder to predict.  You might get it in a year, or maybe never.

Getting Approval Elsewhere
Another important question is, how quickly will LCT get approval in other places like the US and the EU?  I'm not an expert in government approval, and I know some of my readers know this area much better than I do.  However, I don't think getting approval in Russia is going to speed up the process for getting approval in the US.  I think they are still two or three large clinical trials away from US approval.  Remember, in the end, only 8 people have completed clinical trials with Diabecell, and that only lasted a year.  Eight or twelve more are in the middle of a second trial.  But even if you stretch this to the max, it is still just 20 people for a year or two each.  I'm not sure if that is enough data to even start a phase-III trial (as defined by the US FDA).

This is an important point: LCT got their approval in Russia, because the standards in Russia are much lower than the US and EU.  (I'm sure the LCT guys will have a much nicer way to phrase this.  And I'm sure they will be unhappy that I'm so blunt.)  But, my understanding is that the research they have done to date is no where near enough to get approval in the US or EU, and they are not trying to, right now.  (As I pointed out above, I'm not even sure it is enough to start a phase-III trial.)  Obviously, if you believe that the US FDA and the EU EMEA over regulate and are a bunch of "nervous Nellies" that tie up promising treatments in red tape, well here is your chance to get a treatment that hasn't yet gone though all that approval process.  To be a little crass: nothing bad happened in the first 20 people; your kid (or yourself) can be number 21.

The LCT press release talks about starting a pivotal study in New Zealand in 2011.  (Pivotal usually means the first phase-III study, designed to provide proof of efficiency and safety. Remember that even after this study, to get US approval they will need to do a second ("confirmatory") phase-III study and get marketing approval.)  So it still feels to me like they are 3-6 years away from approval in either the US or EU.  Although the Russian approval was quicker than I thought it would be, so maybe these guys are just faster than I expected.

Cost and Availability
Dr. Elliot at LCT estimated a cost of AU$ 150,000 per operation to start, which is pretty close to US$ 150,000.  There was no mention of exactly how soon the procedure would be started.  There are issues of training, and of transporting the cells from New Zealand to Russia.  At the start, there will be volume limitations, based on the size of LCT's herd of pigs. With that all said, I assume as more people get the procedure done, there will be economies of scale, and it will get cheaper.  An important part of the economic calculations is how long the implanted cells will work.  After all, $150k once is quite different than $150k every ten years, or every year!  And we don't know how long it will last. 

What's The Big Deal?
One way to look at this news is this: nothing has changed in the research.  The results LCT has today are the same as the results they had yesterday.  The only difference is Russian government approval.  So why is this important news?  I think that part of the answer involves the pace of progress in research vs. the commercial world.  Things happen more quickly in the commercial world.  Economic pressure and competition between companies do that.  This news marks part of the transition for LCT from the world of research to the world of commerce.  Not a complete, black and white conversion from one to the other, but a shifting of importance.  Another part of the answer involves availability.  Up until now, you could only get the treatment as part of a research study.  In the future, anyone with money and desire will be able to get it.  So availability will be controlled by the patients who choose to get the treatment, rather than researchers who choose to provide it. (That's over simplified a little, but you get the idea.)

Newspaper article: http://news.smh.com.au/breaking-news-national/animaltohuman-transplant-first-20101210-18sfk.html
Press release: http://www.lctglobal.com/html/blob.php/LCT%27s%20Diabecell%20Registered%20for%20Sale%20and%20Use%20in%20Russica_101210.pdf?attach=0&documentCode=2409&elementId=20084
Forum: http://islet.org/forum/messages/54131.htm
Previous blogging on LCT: http://cureresearch4type1diabetes.blogspot.com/search/label/LCT
Previous status on LCT: http://joshualevy.pbworks.com/w/page/13864073/DiabetesCureReadyForHumanTrials#DiabecellbyLivingCellTechnologies

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
Email:  To get these blog entries emailed to you join the Google Group:  http://groups.google.com/group/type-1-diabetes-clinical-trials-news