Three Unsuccessful Trials

This blog posting summarizes several clinical trials aimed at curing type-1 diabetes which have failed.  These are never fun, happy blog postings, but they are important.  One of the big problems with trying to understand research based on mass media reporting is that failures are rarely covered at all.  The soundtrack for this posting is "Down" by Melissa Lambert:
http://grooveshark.com/#!/s/Down/4BHhwn

Sitagliptin and Lansoprazole Unsuccessful in Phase-II Trial

This was a combination therapy.  The researchers were attempting to combine a drug to stop the autoimmune attack and another drug to trigger beta cell growth.  Both drugs were approved for other purposes, and commonly used.  Unfortunately, it didn't work.  Summary from abstract:

At 12 months, the mean change in C-peptide area under curve was −229 pmol/L for the treatment group and −253 pmol/L for the placebo group; this difference was not significant (p=0·77).

Abstract: http://www.sciencedirect.com/science/article/pii/S2213858714701159
Blog at start of trial: http://cureresearch4type1diabetes.blogspot.com/2010/08/possible-cures-for-type-1-in-news-mid.html

Pioglitazone Unsuccessful in Phase-I Trial

Pioglitazone has been approved for use in type-2 diabetes for over 10 years. It is part of a larger drug family called thiazolidinediones which have been shown to preserve beta cells in animals with type-1 diabetes, and to reduce death of beta cells in petri dishes.  It was being tested as a honeymoon cure, but did not pan out:

Conclusion: In this pilot study, pioglitazone did not preserve β cell function when compared to placebo.

Article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890222/
Previous blogging: http://cureresearch4type1diabetes.blogspot.com/search/label/Pioglitazone

Stop Covering Lisofylline

As far as I can tell, no one has done human trials of this treatment for over two years, so I'm going to stop considering it as a possible cure, unless something new comes to light.  Lisofylline is an anti-inflammatory.

Previous coverage (one blog posting) is here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Lisofylline


Joshua Levy
http://cureresearch4type1diabetes.blogspot.com 
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF, JDCA, or Tidepool news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Possible Cures for Type-1 in the News (Early Feburary)

These two news updates are both interesting, and each probably deserves it's own blog entry.  However, since I'm backlogged, I'm putting them together in one posting (together with a Zhao update).  Even after this posting, I'm still a month or more behind.

Results from a Polish Trial of Polyclonal Tregs

What is being tested?  I call this technique "Polyclonal Tregs", but I'm not sure if it has a more official name.  Basically, the researchers remove one specific type of T regulator cell (called a "CD3(+)CD4(+)CD25(high)CD127(-)" T regulator) from a person with type-1 diabetes.  They use these cells to grow a lot more of these cells outside of the body, and then put them back in the body.  Since regulatory T cells naturally regulate the body's immune system, the hope is that they will prevent the autoimmune attack which causes type-1 diabetes.  Previous research in both animals and people has supported the idea that increasing regulator T cells may be a path to a cure.  

The Polish group tested this technique on 10 recently diagnosed (within 2 months) type-1 patients and compared them to 10 patients who did not get the treatment.  4 people got a lower dose (10 × 10^6 Tregs/kg) and 6 people got a high dose (twice as much).  In my opinion, they packed a lot of research into a small trial.  However there were no differences between the lower dose group and the higher dose group.  

Because it was an early trial, safety was an important consideration, and there were no safety related issues.  So that was good.  The publication had effectiveness data from a short (four month) follow up.  Basically:

• The treated patients generated about 50% more C-peptide than untreated.
• The treated patients used about half the injected insulin as untreated.
• A1c levels were about the same.

You can see that here:
http://care.diabetesjournals.org/content/35/9/1817/F1.large.jpg
Remember: grey bars are untreated and white bars are treated.

But remember, these people were within 2 months of diagnosis, and even at the end of the data presented here, were within 7 months of diagnosis, so well within the common honeymoon timeframe.  So I think longer follow on is critical to understanding how important these results are.  If these patients are still using half the insulin that untreated patients are using after 2 years, that would be wonderful.

The good news right now is that they already have one year follow up data, and expect to get it published later in 2013.  Beyond that, they have some improvements to the protocol, and hope to start a follow on trial with an updated protocol soon.  

The Other Polyclonal Treg Study ...

This is not the only study using this "Polyclonal Treg" method.  About two years ago a very similar study started in San Francisco.  Dr. Gitelman is running it, and results are expected in 2016.   I've blogged in the past about this trial here:
http://cureresearch4type1diabetes.blogspot.com/2011/01/possible-cures-for-type-1-in-news-jan.html

This trial has now enrolled its first two groups (out of four total).  I'm told all subjects are doing well with stable pancreas function. The researchers are currently in the middle of the 3rd group, and they anticipate completing the full study enrollment this year.  Each group gets 8 times as large a dose as the previous group so the last group will get about 500 times as much as the first.

... and the Ethics of Experimenting on Children

There is an obvious question here: If both studies started at about the same time, why does one have results 4 years sooner than the other?  I think there are two answers to this question.  The first is pretty simple: the Polish researchers published data covering 4 months after treatment.  The American researchers are gathering data for years.  But that only explains about 20 months of difference.

The second reason might be more important: The American researchers are only enrolling adults, people over 18 years old.  The Polish researchers enrolled children, 5-18 years old.  Obviously, when you are looking for recently diagnosed type-1 diabetics, there are a lot more to be found in the 5-18 year range than the 18+ year range.  By limiting recruitment to adults, the Americans have a much smaller pool of people, and it will therefore take them much longer to fully populate their trial.

But why are the American researchers only enrolling adults?  That answer is a combination of ethics and previous experience.  There is a general ethical principal (enshrined in various FDA rules, and international guidelines) that research should be done on adults first, before it is done on children, if that is feasible.  That makes a lot of sense, of course, but here we see the impact.  For a disease like type-1 diabetes, it is possible to recruit recently diagnosed adults, but it is far harder and slower.  So if we insist that the first bunch of patients are adults, it serves to slow down research disproportionately.

The Polish group had previously run a similar clinical trial in adults with a different disease (graft vs. host disease).  Now measuring safety in adults with one disease is not exactly the same as measuring safety in adults with a different disease, but it is similar.  Therefore, they could recruit children based on the safety profile with adults in the previous study.  Also, they could test different doses more quickly, again based on the previous experience.

Abstract: http://www.ncbi.nlm.nih.gov/pubmed/22723342
Full paper: http://care.diabetesjournals.org/content/35/9/1817.long (Thanks to ADA's DiabetesCare.)

Clinical trial record for the American study: http://clinicaltrials.gov/show/nct01210664

More Details on This Treatment

One way to view the immune system is a balancing act.  We want aggressive immune cells to attack foreign cells, but overly aggressive cells might attack our own beta cells and cause type-1 diabetes.  So we also want regulatory immune cells to keep the aggressive cells in line.  But we don't want those cells too strong, because then they would prevent an attack on the foreign cells.  In this view, type-1 diabetes can be seen as a too aggressive immune system, and therefor boosting the regulatory side might be a cure.

The regulatory cells which are been grown out (or "amplified" might be a better word) are general purpose regulatory cells.  That's a good place to start, but it would be even better if the researchers could multiply a regulatory cell that specifically targeted autoimmune cells (the "bad" cells that are attacking the wrong target).  Unfortunately, the technology is not there yet, although people are working on it.  But in any case, we need to start somewhere.

Below is a link to a study that suggests that newly diagnosed type-1 diabetic children have lower levels of these T regulator cells, than children who do not have type-1 diabetes.  (Although it was a small group.)  http://www.ncbi.nlm.nih.gov/pubmed/19454187

A Note About "Remission"

Some type-1 researchers use the term "remission".  Specifically, they use it to mean "Uses less than 1/2 a unit of insulin per kg of body weight per day".   Don't be confused.  Non-researchers think of "remission" as meaning "doesn't use insulin", but that is NOT how researchers use the term.   If your child weighs 40 kg (about 88 pounds), and uses 20 units of insulin, or less, then they are "in remission", and this does happen to some people during the honeymoon.


Perle Bioscience Starts two Phase-III Clinical Trials of Cyclosporine and Lansoprazole ("Prevacid")

Dr. Claresa Levetan at Perl Bioscience has filed the paperwork to start two very interesting studies.   Both studies are looking at a combination of Cyclosporine and Lansoprazole (commonly known as "Prevacid") as a cure for type-1 diabetes.  The two studies are identical, but one recruits honeymooners and the other established type-1 diabetics.  These are combo clinical trials exactly like many people have been hoping for, for years:  Cyclosporine is known to stop the autoimmune attack and Lansoprazole is known to encourage the natural regrowth of pancreatic beta cells.  Both are approved drugs (for other diseases).  Lansoprazole (as "Prevacid") is over the counter, so has a very good safety profile.  Cyclosporine has a more complex safety profile.  I'm sure if this study pans out, the relative safety of Cyclosporine is going to be an important topic of discussion.

Both studies are expected to enroll 200 people (half getting the treatment and half getting placebo).  They plan to start in September 2013 and end by March 2014 (so very quick).   There will be four groups: one group getting both drugs, one just getting Cyclosporine, one just getting Lansoprazole, and one getting neither.  This is good experimental design for a two drug combination. They will measure C-peptide in response to eating, A1c, and insulin usage.

Note on phases: The researchers running this trial have described it as a "phase-III trial", however I consider it a phase-II trial.  Why the difference?  For me, size is the most important issue.  At 200 people, it is right on the border between what I consider phase-II and phase-III for clinical trials aimed at curing type-1 diabetes.  (For comparison, all eight recent phase-III trials have involved 300 people.  That seems to be the magic number for FDA approval as a pivotal trial in type-1 diabetes.)  Also, this combination of drugs has never (to my knowledge) been tested on type-1 diabetics before.  Since both drugs are approved for other things, I'm willing to call it phase-II (rather than phase-I), but with zero experience with the combination, I'm not willing to call it a phase-III.

Of course, the important question is not what I consider the trial, or even what the researchers consider the trial, the real question is how will the FDA consider the trial?  That remains to be seen, but remember: since both drugs are already approved for other uses, your doctor can prescribe this combination right now.  It would be an off label use.

The researcher working on this, Dr. Claresa Levetan, previously worked on CureDM, and sold that to Sanofi-Aventis two years ago.  My understanding is that they are developing the CureDM technology (a peptide which stimulates beta cell development) for the type-2 market.

Wikipedia on Lansoprazole: http://en.wikipedia.org/wiki/Lansoprazole
Wikipedia on Cyclosporine: http://en.wikipedia.org/wiki/Cyclosporine
Clinical Trial Record (Honeymoon): http://www.clinicaltrials.gov/ct2/show/NCT01762644
Clinical Trial Record (Established): http://www.clinicaltrials.gov/ct2/show/NCT01762657

More Background on
http://www.ncbi.nlm.nih.gov/pubmed?term=3125434

Zhao Updates from Spain 

Previous blogging on Zhao's "Stem Educator" is here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Zhao

These two links go to Spanish language news reports on people getting treated with the Stem Educator in Spain.  I found that using Chrome to translate them into English worked pretty well for me:
http://www.rtpa.es/ciencia:El-HUCA-busca-financiacion-para-un-proyecto-pionero-en-el-tratamiento-de-la-diabetes_111357993752.html
http://diabetesmadrid.org/2012/12/05/el-huca-lidera-la-lucha-contra-la-diabetes/

The basic summary is that the clinical trial in Spain has started.  Two patients had their first session of stem cell educator therapy in December 2012.  The plan is to treat a total of 30 people.  (Not sure how many are placebo and how many will get the real treatment.)  The two treated so far have had type-1 for over 10 years.  This trial is expected to end in September 2014, but we will not know with certainty until it is fully enrolled.

JDCA State of the Cure 2012


The JDCA (Juvenile Diabetes Cure Alliance) is trying to focus more research dollars into cure research (as opposed to treatment research, cause research, etc.)  They publish research papers, which are often quite interesting.  They use my blog as a source, and we sometimes discuss various research issues.

The article below is their year end summary, and well worth a read.  Although I certainly don't agree with everything in it, it is a rich source of information.  (I especially object to their not including Dr. Zhao's research as a possible cure, and JDCA did cover Zhao in a report after this one.)

http://www.thejdca.org/wp-content/uploads/2012/11/State-of-the-Cure-report.pdf

A Final Note

In the past, I have included a specific "thank you" when people reviewed a blog posting, provided information for it, or pointed out the news to me (when only one person did so).  Unfortunately, keeping track of who helped with what, and also making sure it was OK to thank them by name, has become too much of a burden.
So I'm going to stop doing that.

I'm very sorry I will not be able to thank people individually for their help in writing this blog.  But I do want to thank:

• My wife, who improves my English, and puts up with the hours I spend yelling at the computer when I should be talking with her.
• All the researchers who have answered my questions and provided extra information.
• Everyone who emails me when they see news that I should cover.

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. 
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

Possible Cures for Type-1 in the News (early Aug-2012)

Prologue: Why Completing Enrollment is an Important Milestone for Clinical Trials

For two reasons.  First, because at that point it is possible to predict when the researchers will eventually finish collecting data.  The experimental design will say how long data will be collected for each person, so you can just add that duration to the date they finished enrollment, and that tells you when the final data will be collected.  Second, because much of the uncertainty that surrounds clinical trials involves recruiting participants, it is often unclear how hard it will be to get people, and long it will take.   But at this point, all that cunertainty is behind the researchers.  Once enrollment is complete, it is just gathering data, then analyzing data, and then publishing the data.  Researchers have a lot more control over those later stages, than over recruiting people in the first place.

Put another way, a clinical trial is made up of five tasks:
1. Do research to figure out what clinical trial should be done.  During this phase, the researchers are at the mercy of the science.  If they science doesn't pan out, then the experiment never gets done.
2. Get FDA approval for the clinical trial.  During this phase, the researchers are at the mercy of the FDA (or similar regulatory agency).  If they don't get approval, the experiment never gets done.
3. Recruiting patients.  During this phase, the researchers are at the mercy of the patients (or their parents).  If they can't get enough people to enroll, the experiment fails.
4.  Gathering the data.  During this phase, the researchers pretty much control their own destiny, unless a huge number of people drop out, or there is some unexpected safety issue.
5. Writing and publishing the results.  During this phase, the researchers are subject to editors and peer review (to some degree).  However, there are so many journals and web sites, that the researchers have many choices; they can even self publish, if all else fails.  They are not at the mercy of any one person or committee.

Completing enrollment is the end of phase 3 / start of phase 4, and you can see that researchers have a lot more control of their own destiny in phases 4 and 5, then in 1, 2, or 3.  

"REPAIR-T1D" (Lansoprazole and Sitagliptin) phase-II Study Completes Enrollment

This study finished enrolling in May 2012 and they plan to gather data for two years, so we should have results soon after May 2014.  This trail gives two currently approved drugs (Januvia and Prevacid) to type-1 diabetics within six months of diagnosis.  The hope is that it will restore or at least preserve beta cell function.

Press Release: http://www.newswise.com/articles/the-sanford-project-reaches-milestone-in-quest-to-cure-type-1-diabetes
Clinical trial record: http://www.clinicaltrials.gov/ct2/show/NCT01155284

GCSF/Neulasta phase-II Study Completes Enrollment

Previous blogging here: http://cureresearch4type1diabetes.blogspot.com/search/label/Haller

This study finished enrolling in March 2012, and they plan to gather data for two years, so we should have results soon after March 2014.  (Their clinical trial record says December 2014.) GCSF, also known as Neulasta or Pegfilgrastim, causes the body to generate it's own stem cells from bone marrow. These might rebalence the immune system or they might retrain it, but in any case, the hope is they will help cure type-1.

Burt's trial (the most successful so far) uses GCSF, ATG, and CZ. CZ is, by far, the most toxic of the three, so this trial can be viewed as "Burt ultra-lite". GCSF and ATG together would be "Burt lite" and there is a trial for that also ongoing.
Clinical Trial Record:   http://www.clinicaltrials.gov/ct2/show/NCT00662519

Thymoglobulin (ATG) Phase-II Study Completes Enrollment

Please read about Thymoglobulin (ATG) here: http://cureresearch4type1diabetes.blogspot.com/p/drugs-and-treatments-in-clinical-trials.html (scroll down the page until you see the section on ATG)

This phase-II study of ATG has completed enrollment.   It took them about 2 years longer than expected, so that's not good, but we can expect data collection to be complete in 2 years, and hopefully results will be published soon there after.  The ATG link about has complete information on why the researchers hope ATG might cure type-1 diabetes or be part of a cure.

Clinical Trial Record:  http://www.clinicaltrials.gov/ct2/show/NCT00515099
Previous blogging here: http://cureresearch4type1diabetes.blogspot.com/search/label/Gitelman

Combo (Diamyd, Lansoprazole and Sitagliptin) Trial Fails

This trial has a long and not so good history, which you can read in my previous blogging here: http://cureresearch4type1diabetes.blogspot.com/search/label/Combo

This Phase II study combined regenerative agents (lansoprazole and sitagliptin) and also Diamyd. The regenerative agents are both marketed drugs in the US. Diamyd is a vaccine like drug which trains the body's autoimmune system not to attack it's own cells.

This study's clinical trial record updated to show that it was terminated on 20 March 2012, although I think it had actually ended earlier.  Dr. Harlan, who started this study, had left the NIH, and the phase-III studies of Diamyd alone had failed or been canceled, so they decided not to pursue it.  

Obviously, it's too bad that it was canceled.  This was the first study that I knew of that attempted to combine a drug to stop the autoimmune attack and drugs to encourage the regrowth of beta cells.      I think that combining treatments like that is still a good thing to try, even if this specific combination did not work out.

Clinical Trial Record:  http://www.clinicaltrials.gov/ct2/show/NCT00837759

More Stable Glucagon

This is only vaguely related to a cure, but I thought I'd mention it.  Xeris is trying to create a form of glucagon which can be stored at room temperature for long periods of time.  From a cure point of view this is useful for an artificial pancreas (if you consider that a cure).  Simple APs are based on insulin alone.  However, there are more complex APs, which are based on insulin and glucagon.  Having a glucagon which was approved to sit in the pump for days, maybe weeks, would be important to these "bihormonal" APs.

As a nice side effect, it would mean that emergency glucagon needles could be preloaded, just like insulin pens, which would make them much easier to actually use in an emergency.  It also would make mini-glucagon doses much easier to administer, for those who use them.

You can think of an insulin only AP sort of like a car with a break but no accelerator.  The engine "revs high" and you run along.  You use the break to slow up.  A bihormonal AP (insulin and glucagon) is more like a car with a break and an accelerator.  More control.  The analogy is not perfect, but that's the basic idea.

Press Release: http://www.marketwatch.com/story/xeris-pharmaceuticals-awarded-phase-i-ii-nih-sbir-fast-track-grant-to-advance-stable-non-aqueous-glucagon-for-bi-hormonal-artificial-pancreas-2012-07-31

Why Pharma/Med Device Co's Apply for Approval in Europe FIRST

If you haven't read this blog posting by Scott Strumello, you should!  It compares the approval process for medical devices in the EU to the same process in the US:
http://blog.sstrumello.com/2012/08/why-pharmamed-device-cos-apply-for.html

Next Up: Results from Dr. Faustman's Phase-I BCG Trial

She published in PLoS last week, so I hope to blog about it in a week or two.

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.
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

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

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

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


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


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

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

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

Discussion

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

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


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

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

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

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

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

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

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

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

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

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


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

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

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

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

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

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. 
Blog: http://cureresearch4type1diabetes.blogspot.com
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials

Possible Cures for Type-1 in the News (mid-Aug)

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

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

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

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

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

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

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

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

So this is basically a one year slip.

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

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

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

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

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

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

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

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


Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. 
Blog: http://cureresearch4type1diabetes.blogspot.com
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials