Two DiaPep277 Papers Retracted

I had previously reported here:
http://cureresearch4type1diabetes.blogspot.com/2014/09/diapep277-development-canceled-due-to.html
that DiaPep277 development had been canceled due to serious allegations of misconduct.
The "second shoe" has now dropped.  A key paper on DiaPep277 has been retracted.  You can read about it here:
http://care.diabetesjournals.org/content/38/1/178.full

Additionally, a second paper has also been retracted:
http://care.diabetesjournals.org/content/38/1/179.full
This paper reported on an unexpected difference in two different C-peptide measurement schemes, during the DiaPep277 testing.  Since it used the same data which now is in question, it is retracted.

The paper's authors don't have any new information, but are retracting the paper based on the already published allegations.  For me, the interesting part of the retraction, is that only the authors not employed by Andromeda Biotech took part. The authors who worked for (or still work for) Andromeda Biotech were "unavailable for comment and therefore are not part of this retraction process".

This story include a sort of "collateral damage" warning about the impact of fraud in science.  The alleged manipulation was all targeted at the first paper.  The goal of it was to make the drug look more effective than it actually was, and that was what the first paper reported.  However, the second paper represents a dangerous side effect.  Because the data was manipulated (allegedly), the second paper gave an unexpected result.  If the alleged manipulation had not been discovered, then the second paper might have caused unnecessary research to try to explain it's results.  Even more worrisome, perfectly good research that used the measurement schemes discussed in the second paper might have been cast into doubt.  Luckily, none of that will happen now.

I encourage you to read my previous blogging on DiaPep277.
Unfortunately, science that turns out to be wrong is going to be a mini-theme, as I'm putting the finishing touches on a blog posting describing another incorrect paper which was also important to type-1 diabetes research.  That blog should go out in early January.


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 or JDCA 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.

DiaPep277 Development Canceled Due To Alleged Misconduct

This is the first paragraph from yesterday's press release from Hyperion:

Hyperion Therapeutics, Inc. (HPTX) today announced it is terminating development of DiaPep277 for newly diagnosed Type 1 diabetes. The company has uncovered evidence that certain employees of Andromeda Biotech, Ltd., which Hyperion acquired in June 2014, engaged in serious misconduct, including collusion with a third-party biostatistics firm in Israel to improperly receive un-blinded DIA-AID 1 trial data and to use such data in order to manipulate the analyses to obtain a favorable result. Additional evidence indicates that the biostatistics firm and certain Andromeda employees continued the improper practice of sharing and examining un-blinded data from the ongoing DIA-AID 2 trial. All of these acts were concealed from Hyperion and others. The Company has suspended the Andromeda employees known to be involved, is notifying relevant regulatory authorities, and continues to investigate in order to explore its legal options. Hyperion employees were not involved in any of the improper conduct.

A note on terminology:  Hyperion did not use the term "fraud" in describing what happened, although Globe News did, and another news service said "falsified data".  Instead, in their conference call and press release, Hyperion used terms like "serious misconduct and deceit", "collusion", "extensive measures to conceal their wrong doing", "actively and consistently lied", "dishonesty and deceit", "deception was extraordinarily serious", and so on.  Based on all that, I do think that "fraud" is the right term, but it is important to remember that I mean this word in the English dictionary meaning [d1], not the legal meaning.  No one has been convicted of any crime, not even charged, and I doubt anyone ever will be.

The sound track for this posting is here:
http://grooveshark.com/#!/s/Saturday+Night+s+Alright+for+Fighting/2UTbqy
(Note this is The Who's version, because I can hear the words better in it than in Elton John's.)

As usual [d] notes are at the bottom of the posting, and provide more details.

Background on DiaPep277

DiaPep277 is a peptide (a part of a protein).  It is a small part of a naturally occurring protein called "heat shock protein 60".  The hope was that it would cause the immune system to stop attacking beta cells.  Development was done by Andromeda (either as a separate company or a division within another company), and no other company is doing work in this area.  It is one of the potential cures for type-1 diabetes that I have followed from the very beginning of my research.  It had already finished phase-II trials when my daughter was diagnosed in 2003.  I have made more postings on DiaPep277 than any other potential cure, except for Diamyd.  You can read them here:
http://cureresearch4type1diabetes.blogspot.com/search/label/DiaPep%20277

In 2008 I published a blog based on DiaPep277's earliest data from a phase-III trial and I felt the results were so small it was unlikely to be successful.  You can read that here:
http://cureresearch4type1diabetes.blogspot.com/2008/08/disappointing-news-on-diapep-227.html
However, in 2011 I published this slightly more upbeat blog:
http://cureresearch4type1diabetes.blogspot.com/2011/11/andromedas-diapep277-succeeds-in-phase.html
I continued to follow it until 2013 when I "threw in the towel" stating that the results seen so far were so small that they could not lead to a cure (although I still held out hope they could lead to a new treatment).
http://cureresearch4type1diabetes.blogspot.com/2013/06/possible-cures-for-type-1-in-news-june.html

What Happened?

As you read my description of what happened, it is important to remember that all my information comes from Hyperion (except for a tiny bit from Evotech), and none of it comes from Andromeda, or any of the specific employees who are alleged to have participated in the dishonesty.  If Andromeda or the people involved publicize their side of the story, I will likely need to update this, based on that new information.

It is normal practice to run two large clinical trials to get the data required by the FDA and the EMEA, and Andromeda had started two: DIA-AID-1 and DIA-AID-2.  They were designed to be twin studies and have 450 people each [d2].  Just last June, DiaPep277 was sold to Hyperion.  This sale included all rights to the new drug, and the transfer of some Andromeda employees who were working on it.  At that point DIA-AID-1 was complete and had been published, but DIA-AID-2 was not quite finished.  The completion date is early 2015.  So the Hyperion statistics team were evaluating the entire DIA-AID-1 data set, as a sort of practice run to get ready to analyse the DIA-AID-2 data, when it was ready.

You can read the DIA-AID-1 results in this paper:
http://care.diabetesjournals.org/content/37/5/1392.full.pdf+html
Thanks very much to Diabetes Care, published by the ADA, for making the whole paper available on line.

When the Hyperion statisticians looked at the full data set for DIA-AID-1, they noticed something very odd.  If they analyzed the entire data set, then DiaPep277 did not have a statistically significant good effect in the primary outcome measurement.  The clinical trial had failed.  However, Andromeda had excluded 30+ patients from the analysis because they had violated the rules about who should be signed up [d3].  With those exclusions, the data showed a statistically significant good effect in the primary outcome [d4].  The study had succeeded. That's unusual, because the exclusions are supposed to be made "blind" (not knowing if the drug worked for those people, or even if they got the drug), and excluding people randomly from a trial, should not change the outcome.  These exclusions were done by an outside company which was involved in the clinical trial, and that company was not supposed to know who got the drug and who got the placebo.

Except Hyperion's investigation found (according to Hyperion) that some of the Andromeda employees passed data to the outside company, and people at that company used that data to selectively remove patients from the study to bias the results.  Also, Andromeda employees changed the primary end point of the study [d5], so that it would be successful. In both cases, the decision was made "unblinded" (i.e. knowing who received DiaPep277, and who received placebo), when the decision should have been made "blind". This completely undercuts the results of the clinical trial.  Hyperion said that this did happen in the DIA-AID-1 trials results, and was also in process of happening in the DIA-AID-2 trial [d6]

Although Hyperion was careful not to name the company that did the statistical analysis for Andromeda (they always referred to it as an Israeli Biostatistics company), nor did they name any of the people involved.   However, on page 1399 of the DIA-AID-1 paper, there is discussion of what companies did statistical analysis as well as describing what each author did in running the study and writing the paper.  (In the future, I'll be checking to see if this company or these researchers are involved in any research I report on.)

Impact

Hyperion has said that there is no way to move forward with regulatory approval for DiaPep277, and they will not attempt it.  So DiaPep277 is dead.  That's the short term impact.  I suppose they could try to sell it to someone else, but who would want to buy it now?

The medium-term impact has three questions:

1. Will the paper describing the results from the DIA-AID-1 trial be retracted?  It was published in Diabetes Care (a journal of the American Diabetes Association), so it will be interesting if the authors retract it, or if the editors/publishers retract it [d7].

2. Will there be a civil lawsuit?  Will anyone face a criminal charge?  Remember that Hyperion paid tens of millions of dollars for DiaPep277 based largely on results which were invalid.  Andromeda and the nameless Biostatistics company are Israeli, while Hyperion is American, and I'm sure that will complicate both civil and criminal legal matters.

3. In addition to the results paper, Andromeda employees also published a research paper comparing the primary end points (new and old) of their study.  If Hyperion's can show that this data was manipulated, then this study should be retracted as well.

The abstract of the paper is here:
http://www.ncbi.nlm.nih.gov/pubmed/24408401
and says specifically that the findings were "unexpected", which Hyperion claims is untrue.

The long term impact is less predictable, but could be much wider.  How many other studies used the same biostatistics company?  Some of the researchers involved in this study are very big names, and have published many other papers, and worked with other companies, including some companies doing clinical trials.

Some Personal Notes

I gave up on DiaPep277 long ago, so in that sense, it was dead to me even before this came up.  But it is still deeply shocking.  (A statistician that looked at this situation described it as "staggering".)  At the end of the day, new drug safety and effectiveness are supposed to be shown via scientific testing. There is a lot of good statistics used to show that results are meaningful, and not due to chance, accident or mistake.  But all those statistics assume that the people running the study are not liars or cheats.  Detecting people who are willing to commit serious misconduct in their scientific studies is not easy.  Implementing the procedures necessary to detect active deceit in all scientific studies would be horribly expensive.  Currently, the FDA uses statistical methods, to find "honest" mistakes, rather than do the sort of investigations and surveillance required to find premeditated fraud.  That's part of the reason why I think it's important to the scientific process to see what consequences the people and corporations face in this case.   Because if other people and other corporations see that they don't face huge consequences, then they will be more willing to risk the same kind of misconduct that is alleged here.

In general, this blog does not report on financial transactions.   That is specifically because of Andromeda and DiaPep277.  Whenever a company buys a new drug, there are always very positive press releases, and early on I thought about reporting those in the blog.  But I noticed that DiaPep277, in particular, was getting passed around to a lot of different companies, and for no good reason that I could see.  I don't remember now all the moves (this was years ago), but I'm pretty sure that Andromeda sold it, got it back, sold it to someone else, and got it back again.  All the companies were Israeli, and as I remember it, some of them were partial owners of each other [d8].  I did not understand it.  That's a lot of moving around in a small market.  It convinced me not to report on company-to-company movement in my blog; that it didn't mean anything, or at least I didn't know the meaning.  But now, in retrospect, I wonder if it was a sign of trouble.  

Finally, I want to personally urge Hyperion to make public the researchers involved, and the evidence about each one's involvement in this alleged misconduct.  There are 21 named authors of the DIA-AID-1 study, and 6 named authors of the change-of-primary-endpoint paper (with much overlap).   Right now, all of these researchers are "under a cloud"  but it is likely that many of them did nothing wrong.  Maybe none of them did anything wrong, and the misconduct was done by others, or never happened at all.  But in any case, the whole type-1 world deserves to know who did what, and the supporting evidence.

Extra Discussion

[d1] For example (from dictionary.com): "deceit, trickery, sharp practice, or breach of confidence, perpetrated for profit or to gain some unfair or dishonest advantage."

[d2] This is a quirk of the American approval process.  It is law that there must be two studies to confirm the results.  Therefore, you can not run one 600 person study, you must run two 300 people studies, even if they are otherwise identical.

[d3] It is common for some patients enrolled in a clinical trial to be excluded from the results for a variety of reasons.  The most common is that someone drops out, and complete data for that person is not available.  However, people are sometimes enrolled by mistake in violation of the study's rules. For example, a trial might require first treatment within 100 days of diagnosis, but a review of paperwork, after the study completes might determine that the patient signed the paperwork within 100 days, but didn't actually get the drug until later.  Data for that patient would be (properly) dropped from the study results.

[d4] If you look at the patient flow diagram on page 1394 of the paper, you can see that a total of 34 patients were excluded from analysis.  It is the two boxes just below the "allocated" boxes, and these changes impacted both the "mITT" data and the "PP" data.  The claim Hyperion made was that these exclusions were made "unblinded" and were specifically tailored to bias the results.

[d5] The primary end point is the most important result of a clinical trial.  Usually, there is one primary end point, and several (less important) secondary end points.  If the primary end point shows a statistically significant good effect, then the trial is successful.  If this is not seen, then the trial is unsuccessful.  The FDA generally determines effectiveness of new drugs based on primary end points.  So therefore, changing the primary end point of a study, in the middle of the study is very unusual, and if it was done "unblinded" (ie. with knowledge that the current primary end point is failing, or the new one succeeding) that is scientific fraud (in my opinion).  Its the moral equivalent of moving the goal posts to the ball's location, rather than putting the ball through the (stationary) goal posts.

In the case of DIA-AID-1, both the original primary end point, and the new primary end point involved measuring C-peptide, but the two end points measured it in different ways.  The details are described in the comparison paper.  Abstract is here: http://www.ncbi.nlm.nih.gov/pubmed/24408401

Remember that although Hyperion has said that this happened in the DIA-AID-1 study, I have not seen their supporting evidence, and so have no way of knowing if this is correct or not.

[d6] As part of this research the DIA-AID-2 data collected to date was unblinded, and Hyperion said that there is almost no chance that it would end up showing a good effect in the primary end point.  (Remember that most of the DIA-AID-2 data has already been collected, even as they are still waiting for the last few patients to get the last few data points.)

[d7] To be blunt, the paper contains the following two quotes (pages 1393 and 1394), which Hyperion now claims are untrue:  "Participants, investigator site staff, persons performing the assessments, and data analysts were blinded to patient allocation from the time of randomization until database lock" and "The study protocol was amended, and the statistical analysis plan was planned and finalized before the study was unblinded, with the GST clearly defined as the primary end point."

[d8] Even now, I don't have a complete list, but here is a partial list of companies involved in DiaPep277 development: Andromeda, Clal Biotechnologies, Teva, Peptor, DeveloGen, and Evotek.

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 (February)

DiaVacs Starts a Phase-II Trial of Dendritic Cells (DV-0100)

DiaVacs is a newly created company with a goal of further developing the Dendritic Cell research done in Dr. Trucco's lab.  You can read my previous blog posting on this research here:
http://cureresearch4type1diabetes.blogspot.com/2011/11/results-from-truccos-phase-i-dendritic.html

The idea behind this research is to remove dendritic cells from a person, grow them out, and then put them back in.  The hope is that they will then regulate the immune system and cut down on the autoimmune attack.  Dendritic cells are part of the immune system which find foreign cells and "present" them to T-cells (another part of the immune system) so that they know what to attack.  You can read more about them here: http://en.wikipedia.org/wiki/Dendritic_cells  The goal of this therapy is to interrupt the immune system's internal communications so as to stop the immune attack on beta cells, without stopping immune attack on foreign cells.

The goal is to enroll 90 people, eventually.  The first 10 will need to be adults, and then the hope is that the safety record from those first patients will be used to get the FDA to approve children.  Since this is a honeymoon trial (within 6 months of diagnosis), limiting recruiting to adults will slow everything down, but the FDA will not approve a trial on children without some safety data from adults, if they can possibly avoid it.

Treatment is expected to last 3 months, and then patients will be followed for another year. Primary goal is safety, secondary goal is C-peptide production (as a stand-in for insulin production) 12 months after treatment.  C-peptides are measured because they are created naturally when insulin is generated by the body.  So they are a measure of natural insulin production.  Insulin measurements can't be used, because there is no way to tell if the insulin was injected or created naturally.  So all modern research measures C-peptide to determine insulin production.

A Little Discussion

When I heard this group was doing a phase-II trial, I was a little surprised.  If you look at my summary of their phase-I trial, I did not see a clear success in their Phase-I results.  There were some results that the researchers viewed positively, but there was no improvement to insulin generation (for example).  However, that first study was done on established type-1 diabetics.  My understanding is that they expect this treatment to stop the immune attack, but not automatically regrow beta cells, so it should be much more effective in the honeymoon phase, because there are still some beta cells at that time.

Put another way, the researchers did not expect this treatment -- by itself -- to cure established type-1 diabetes.  They did expect it to have some impact on the immune system, and think that it did, and think that the impact of these changes will be seen when used on honeymooners.

In some ways, this treatment is similar to the "Polyclonal Tregs" treatment, which is in phase-I trials for honeymooners.  One difference is that different immunology cells are being amplified  (a specific type of T-reg cell vs. a dendric cell).

News: http://www.news-medical.net/news/20140106/FDA-grants-orphan-drug-designation-for-DiaVacs-type-1-diabetes-mellitus-therapy.aspx
http://www.post-gazette.com/news/health/2014/02/10/Type-1-Diabetes-A-treatment-s-in-sight-but-where-s-the-funding
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01947569
Corporate Site: http://www.diavacs.com/
Facebook: https://www.facebook.com/DiavacsTheCureForJuvenileDiabetes

DiaPep277 Starts an Extension to Their Phase-III DIA-AID2 Study

In the past I have thought that DiaPep277 might result in a cure, but I no longer think that is likely, but it still maybe be used as a treatment or a honeymoon extender.  In case people are still interested, you can read my previous blogging here:
http://cureresearch4type1diabetes.blogspot.com/search/label/DiaPep%20277

The recent news, is that they have started treating their first patient in an extension to their phase-III clinical trial.  That means the main part of the phase-III study is done, and this is the second such trial.  So they have the option of starting the process of getting marketing approval (so they could actually sell it, and we could buy it).  I don't think any truly new treatment for type-1 diabetes has ever entered the FDA's marketing approval phase before.  (Not counting different versions of insulin.)

Opinion

It will be interesting to see if these guys try to get it approved, and if so, will the FDA approve it, and will insurers pay for it?  My take is that the impact of the treatment is pretty small.  The safety profile is good, however, so the FDA could approve it as a small impact, small risk treatment.  But they could decide the impact is so small that it should not be approved.   Even if the FDA approves it, some insurance companies might not pay for it, arguing that it does not give a large enough benefit, or does not give a cost effective benefit.

Here are some recent news stories:
http://online.wsj.com/article/PR-CO-20140112-900596.html
http://www.pharmabiz.com/NewsDetails.aspx?aid=79410&sid=2

Abatacept

Abatacept is a treatment that prevents T-cells from becoming activated. Presumably, for type-1 diabetes, it works by blocking the "bad" killer T-cells from activating. ("Bad" killer T-cells are those which target the body's own beta cells rather than the foriegn invaders they are supposed to target).  This drug is already approved for use in rheumatoid arthritis when other treatments have failed, and is marketed as Orencia. It regulates (or modulates) T-cells, rather than depleting them, so the hope is that it will have fewer side effects than other immunosuppressives.

This was a honeymoon study. It was a placebo controlled, double blind trial with 112 patients. About 2/3s (77 people) got the treatment and 1/3 (35 people) did not. The treatment consists of three infusions the first month, and one a month thereafter for two years. C-peptide production in response to a meal was measured after two years.  Those results were discussed in a previous blog:
http://cureresearch4type1diabetes.blogspot.com/2011/09/results-from-phase-ii-trial-of.html

Now, the researchers have published a follow-on paper, which contains data for a C-peptide production a year later.  So this is one year after the last dose of Abatacept, and three years after diagnosis (approximately).

Results

People treated with Abatacept continued to generate about 50% more of their own insulin, than those not treated.   The amount of insulin generated years after diagnosis is pretty small, so the actual difference is half of a tiny number.  One way to view these results was that Abatacept delayed the "end of insulin generation" by 9.5 months.  Someone who got the drug generated the same amount of insulin 36 months after diagnosis as someone who did not get the drug generated 27 months after diagnosis.

Discussion

My view of this drug is very similar to my view of Rituximab in a blog posting last month. (Which makes sense, since the results were similar.)  By itself, it's not a big step towards a cure.  I used to hope that by combining drugs or changing doses, researchers would take so-so results like these, and create a cure or a preventative.  However, I have yet to see many clinical trials where these sorts of drugs are combined, or doses changed significantly, or any other way of improving on these results.  And these results, as reported here, are not going to lead to a cure.

Abstract: http://care.diabetesjournals.org/content/early/2013/11/22/dc13-0604.abstract?papetoc

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 (June)

Aldesleukin (Proleukin) Starts a Phase-II Clinical Trial

Called DILD1T, this is a 40 person clinical trial.  It started in March 2013, and is expected to finish in January 2015.  It is enrolling adults who have had type-1 diabetes for 3-24 months (so not just honeymooners) in Addenbrooke’s Hospital, Cambridge, UK.  Currently, it is only 12% enrolled, so they have a ways to go.  I'm treating this as a phase-II trial, because of it's size and because Proleukin has already been tested twice in type-1 diabetics (that I know of).

I think that this study involves only one subcutaneous injection (like an insulin injection).

Here is the justification for the study.  The quote is from the researchers, but I've removed some of the medical language:

The vast majority of genes that contribute to susceptibility to type 1 diabetes [are related to] immune regulation and function. In particular, ... the interleukin 2 (IL-2) pathway that regulates T cell activation .... Aldesleukin (Proleukin) is a human recombinant IL-2 product .... There is substantial [research data in tissues/petri dishes, animals, and humans] that ultra low dose IL-2 (aldesleukin) therapy can arrest the autoimmune mediated destruction of pancreatic beta cells by [encouraging] functional T regulatory cells.

The researchers view this study as looking for the optimal dose as a prelude to doing a large phase-III trial.  This is a classic goal of many phase-II trials.  This trial is funded by the Welcome Trust (a big UK operation), JDRF, and the NHS Foundation Trust (which I think is the UK government).

Here are links for this new research:
Web sites: http://www.clinical-trials-type1-diabetes.com  http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=13846
News: http://www.wellcome.ac.uk/News/Media-office/Press-releases/2013/WTP052844.htm
Facebook: https://www.facebook.com/ClinicalTrialsType1Diabetes
Twitter: https://twitter.com/t1diabetestrial
WHO Registration: http://www.controlled-trials.com/ISRCTN27852285/
US Registration: http://www.clinicaltrials.gov/ct2/show/NCT01827735
Wikipedia on IL-2: http://en.wikipedia.org/wiki/Interleukin_2

I also think it is important to remember that IL-2 has been tested in humans twice before, and has failed both times.  I previously blogged on those trials:
http://cureresearch4type1diabetes.blogspot.com/search/label/IL-2
Clinical Trial Records:
    http://www.clinicaltrials.gov/ct2/show/NCT00336674
    http://www.clinicaltrials.gov/ct2/show/NCT00525889


DiaPep 277's Results from an Extended Phase-III Trial:
No Longer a Cure?

I've been following DiaPep 277 for as long as I've been following type-1 diabetes cures.  When I started, it was already in phase-II trials.  Recently Andromeda Biotech Ltd, the company developing it, has published some phase-III results, and (most recently) some extended phase-III results.  These extended results are from people who were in the phase-III trial for two years, and then continued with the treatment for an additional two years.  The two year extension was "open label", meaning that the patients and doctors knew they were getting the treatment; it was not blinded.

Unfortunately, the results are decidedly mild.  People's A1C numbers dropped by 0.6 (from an average of 7.6 to an average of 7.0.  In terms of improvement of treatment, that's not bad.  I think there is a market for a drug that would lower A1C numbers that amount, but it is not a cure.  There is always hope that future improvements in the treatment will lead to even better A1C improvements (which I think is likely), or even improvements so great they lead to a cure (which I think is very unlikely).  But currently, this is an adjunct treatment, not a cure.  So I expect to stop covering DiaPep 277, unless I see results much larger than are seen here.

news: http://www.globenewswire.com/news-release/2013/06/05/552188/10035325/en/Andromeda-Announces-the-Results-of-an-Extension-to-Its-Phase-III-Study.html

The previously announced results from one of their phase-III trials, which I blogged about here:
http://cureresearch4type1diabetes.blogspot.com/2011/11/andromedas-diapep277-succeeds-in-phase.html
were similarly mild, and much more like a treatment than like a cure. 

Phase-I Trial Resets the Immune System in MS Patients

This news comes from a human trial in multiple sclerosis (MS) patients.  Basically, researchers were able to "reset" the body's immune system, to lower the autoimmunity reaction (the body's attacking it's own cells) by  50%.-75%.  This was in a 9 person phase-I trial in Germany.

To understand why that is important, a little background is needed.  Most researchers believe that MS and Type-1 are related diseases.  In both cases the immune system mistakenly attacks the body's own cells.  In Type-1, it attacks beta cells in the pancreas, and in MS it attacks the myelin sheaths of nerve cells, however the underlying autoimmunity reaction is similar.

Prior to testing on people, this method was tested in mice who had MS and in mice who had type-1 diabetes, and worked on both groups of mice.  However, the human trials were MS only.  But obviously, trials in type-1 diabetic people could be done as well.  In my opinion, should be done.

The idea of resetting (or rebooting) the body's immune system has been tried on type-1 diabetics, and it was successful.  Some of the treated type-1 diabetics did not have to inject insulin for years afterwards.  However, the risk involved is high enough, that these treatments have never moved forward.  At least three different teams (in Brazil, Poland, and China) have run similar trials and gotten similar results.  I have blogged about them before:
http://cureresearch4type1diabetes.blogspot.com/search/label/Burt

Although it is hard to draw a direct comparison, it sounds like the procedure being tested here is much safer, but slightly less effective than the procedure used by Burt, Snarski, Li, etc.  Of course, it might be refined over time to make it more effective or safer, or both.

news: http://scienceblog.com/63715/big-multiple-sclerosis-breakthrough/

Personal Note

In the past, I've posted on my blog what I call a "non-conflict of interest statement" which is this:

• I don't work for a company involved in medical research; I never have.
• I don't get paid in any way by any company doing medical research; I never have. And that includes free samples, free travel, or free anything.
• None of the hours that I have put into my blog, or the posts that I make to any web site, has ever been paid for, nor have I gotten anything free.  (Except for some very nice and heart felt thank-you emails, and those are worth more than money.)

I'm now adding a fourth bullet point:

• My daughter has type-1 diabetes and participates in clinical trials.  She usually gets some money for participating. I sometimes report on trials that she participates in.  For several reasons, I don't generally reveal what studies she enrolled in (or tried to enroll).  

Why not, you ask?  A couple of reasons.  First  of all, her participation is a two step process.  My wife and I decide the research is safe and that she can participate, and then she decides if she wants to participate.  Therefore, she selects different studies than I would select.  For example, she prefers studies in the summer, and studies that pay well.  I don't want people coming back to me and saying why did she participate in study X rather than study Y?  Second, I get important information from researchers.  I don't want researchers thinking, "his daughter was in Dr. X's trial, but not mine, why is that?"  (Truthfully, the answer is usually, Dr. X paid better, or required less time, or was more convenient, but I don't want to be explaining that.)  Thirdly, I don't want readers of this blog to be thinking "Joshua's daughter isn't in trial X, why should my child be in that one?" or the reverse "Josh's daughter is in trial X, I should get my kid in there, also!"  Our kids are different, and participating in a trial should always be personal decision.  And finally, even participating in a trial might make public health information about my daughter that I don't want public.  For example, enrollment might only be open to people who have a particular side effect, or don't have that side effect, or who are still generating some insulin, or whatever. 

In the last 5 years, I have only blogged on one study that my daughter participated in.  I would expect to blog on only a couple in the next 5 years, so this is a rare thing. 

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 daughter has type-1 diabetes and participates in clinical trials.  My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog. 
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

Possible Cures for Type-1 in the News (late Sept-2012)

Prochymal Failed Phase-II Trials

I missed this, when it was published back in May, but luckily Kelly Close (of Close Concerns, who publishes DiaTribe) reported on it:

At 1 year, intravenous infusions of Prochymal were reportedly well tolerated, with no differences in adverse event rates between the Prochymal and placebo groups. 

With regard to efficacy, no significant differences in stimulated C-peptide levels were observed between the two arms (the primary efficacy endpoint), although a trend towards fewer hypoglycemic events in the Prochymal arm was observed. 

A full analysis will be performed following an additional year of follow-up (for a total of 24 months)

My translation is this:

• The trial failed its primary endpoint.
• The researchers are trying to be optimistic about a small, vague result in one of the secondary endpoints.
• The study will get more data after another year, and they are hoping for better news.

Obviously, I'm hoping for better news next year, too.  But I'm not expecting it.

Scientific Press Coverage: http://onlinelibrary.wiley.com/doi/10.1111/j.1753-0407.2012.00197.x/full

DiaTribe is a free on line newsletter (http://www.diatribe.us/), which is is a great source of info on diabetes research, technology, etc.

NI-0401 by NovImmune Failed a Long Time Ago

Years ago a company called NovImmune started a phase-II trial for their drug NI-0401 aimed at type-1 diabetes.    After that, no news.  This drug was targeted at CD3, and all the other CD3 drugs failed, so I always assumed this one had, as well.  But there never was any news, and I never saw an official announcement.  However, NovImmune updated their entire web site, and NI-0401 is still there, but diabetes is not listed as a target at all.  Also, I found a European clinical trial registry, which showed that the long ago study had been canceled just months after it started.

So NI-0401 is dead, as far as I'm concerned, until I hear otherwise.

European clinical trials registry:
http://apps.who.int/trialsearch/trial.aspx?trialid=EUCTR2009-012988-34-AT
https://www.clinicaltrialsregister.eu/ctr-search/trial/2009-012988-34/AT

Corporate web site:
http://www.novimmune.com/products/ni-0401.html

DiaPep277 by Andromida is Fully Enrolled

This is the only treatment that I'm following that is currently in phase-III trials.  The results from previous work suggest it might be a "longer, strong honeymoon" type treatment, rather than a cure. they have already finished one phase-III trial, and this is their second.  The FDA requires two, so when this one completes, if it is successful, they will be ready to move into "marketing approval" phase, which takes a year or two.

Why is this important? For two reasons.  First, because it is now possible to predict when they will finish collecting data.  (Since this study gathers data for 2 years, it will finish about Sept 2014.) Second, because much of the uncertainty that surrounds clinical trials, is involved with recruiting participants.  It is often unclear how hard it will be to recruit people, and long it will take.   But that this point, all that cunertainty is behind the researchers.  From now on, it is just gather data, then analyze data, and then publish data.  Researchers have a lot more control over those later stages, then over recruiting people in the first place.

News: http://www.marketwatch.com/story/andromeda-biotech-successfully-completes-patient-recruitment-in-phase-iii-confirmatory-trial-for-its-lead-drug-diapep277-for-type-1-diabetes-2012-09-12

How Doctors Weigh Clinical Trial Funding

This was a very interesting study of doctors.  Basically, the researchers gave doctors summaries of research results.  These summaries breifly described a study's results, methodology, and source of funding.    The doctor was then asked questions to determine how much they trusted the results, and how willing they were to proscribe the medicine being tested, based on the trial.  (The research described was fictional, so the doctors did not have any prior knowledge of the drugs in question.)

Here is a summary of the results:

The study found that physicians weighted their assessment of the rigor of a trial based on pharma funding, and that they were half as willing to prescribe those disclosing industry sponsorship as they were those disclosing NIH funding, regardless of methodological rigor.

Discussion

I think these results are good in two separate (but related) ways.  First, they suggest to me that doctors properly "discount" clinical trials funded by industry.  Second, it suggests to me that when a doctor recommends a treatment, they are already taking into account who funded the studies suggesting its use.  The recent problems with pharma PR guys "ghost writing" research articles, and withholding placebos from some researchers has made some people nervous about the accuracy of studies they do fund.  I think it is proper that doctors are also nervous, and I feel good that the average doctor in the study took into account the funding source of clinical trials they read about.

Interestingly, the researchers who ran this particular trial are a little unhappy about their own results.  They seem to think that when comparing two studies, if the methodologies are equally rigorous, that the results should be weighted the same, no matter who did the funding.  They are specifically worried about doctors undervaluing what the researchers consider large scale, well designed, industry funded studies.   I disagree.  I think the prescribing doctors are doing the right thing by undervaluing (or "discounting") equally rigorous studies that are funded by industry.  I view the attitude of these researchers as being very "old school" (and in this case, out of date).  Sure, in the 1950s the idea was that rigorous trial methodology and peer review together were all that was needed to ensure accurate results.  The idea was that the scientific method was so good that who funded the trial was not critical to the quality of the results.  But 60 years later, I don't think that's the consensus opinion.   Now we know that quality starts with good methodology and peer review, but those alone are not enough.

News coverage: http://www.mmm-online.com/docs-downgrade-results-of-pharma-funded-clinical-trials/article/259981/

Symlin as a Treatment

Not for a cure, but of interest, are the results of two studies testing symlin in type-1 diabetics.  Only one was placebo controled, and it found:

analysis of 248 patients from a 29-week, placebo-controlled study, measurements in the normal range based on ADA criteria increased from 37.3 percent to 43.9 percent for SYMLIN-treated patients (n=115), compared to an increase from 38.2 percent to 40.9 percent in those receiving placebo (n=133). The percent of measurements in the normal range based on AACE criteria increased from 22.6 percent to 27.8 percent for SYMLIN-treated patients compared to an increase from 24.1 to 25.0 in those receiving placebo. The percentage of readings in the hypoglycemic range remained relatively stable.

Discussion

I'm not sure I'd take a second injection with meals (or a first injection for pump users) for that level of improvement, but it's still interesting.  I also think that A1c improvements would be a better measure of goodness than % inside of guidelines.   But you gotta start somewhere.

Maybe we'll end up with a tri-treatment artificial pancreas.  It will dose insulin for highs, glucagon for lows, and symlin with meal boluses.

Press Release: http://www.businesswire.com/news/home/20120609005027/en/SYMLIN%C2%AE-Helped-Patients-Type-2-Type-1

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 (July-2012)

Status of DiaPep277

The good news: DiaPep277 has finished one successful phase-III clinical trial, and is expected to finish enrollment of the second (and last) one in the next few weeks.  Once that second one is fully enrolled, there is a two year wait for it to complete, and then (if it is also successful) another year or two for marketing approval, and then (with a lot of luck and good results) DiaPep277 will be generally available in the US.  The EU timeline would be similar.

The bad news: The results from their first phase-III clinical trial are no where near a cure.  The results so far have been a statistically significant, longer and stronger honeymoon phase. Something like 25% more insulin production in the year after diagnosis.

Discussion: So, if we assume that DiaPep is successful from here on, and gets approved,  and works as well in actual use, as it worked in this first phase-III trial, how good is that news?

If you are a glass is half full kind of guy, then you can say things like this: DiaPep is the first treatment that actually changes the path of type-1 diabetes.  In addition to lengthening and straightening the honeymoon period, it may result in fewer lows and fewer highs, which means fewer long term complications of the disease.  Plus, future research may well make it better than it is now.

If you are a glass is half empty kind of guy, then you can say things like this: DiaPep's impact is only for a year in the honeymoon phase, and it's not even clear that it's good effect will have any impact at all in the long term complications of the disease.

But in any case, I think we are still 4+ years away from general availability.

Zhao in Spain

Drs. Delgado and Otero at Hospital Universitario Central de Asturias (in Spain) are going to start a clinical trial of the Zhao research. (Previous blogging here: http://cureresearch4type1diabetes.blogspot.com/search/label/Zhao)  They expect to treat 30 people, and to start in the fall.  


News: http://www.hayalternativas.org/noticias/?p=1015 (in Spanish)

Non-Cure Trial to Reduce Hypoglycaemia

I thought this study was interesting, even if it is not aimed at curing type-1 diabetes.  The goal here is preserve alpha cell function.  Alpha cells are cells in the pancreas that generate various hormones, but not insulin.  Almost all of the current research on type-1 diabetes is focused on beta cells (which generate insulin), but type-1 also effects alpha cells.  So this research is aimed at trying to preserve the body's natural glucagon response to low blood sugar events.

The news here is that this trial completed enrollment on 7-March-2012, and since it takes 3 months to gather the data, they should have it all by now.  So we just need to wait for them to publish the results.

Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT01272583

Great Blog (by Riva) on Meter Accuracy

This is a great posting on meter accuracy:
http://www.huffingtonpost.com/riva-greenberg/glucose-meters_b_1624263.html

Compares different meters to each other.  Compares the same meter used at different times.  Compares household meters to blood lab readings.  What more could you want?

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 (June-2012)

News About Diabetes News

The biggest diabetes research meeting in the world is the American Diabetes Assoication (ADA) Science Sessions, which are in June (this year: June 8-12).  It is followed by the big European Association for the Study of Diabetes (EASD) Annual Meeting (this year: Oct 1-5).  So expect a lot of news over the next few months.  We are already seeing press releases from companies publicizing what they will report at these large meetings.

Phase-II Results from Autologous Hematopoietic Stem Cell Transplants by Li at Nanjing University

This is the third group to do a Burt-like cure for type-1 diabetes, and get similar results.
You can read my previous blogging here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Burt

But the basic summary is this: for recently diagnosed type-1 diabetics, this is the closest to a cure there is.  People have gone years after this treatment without needing to inject insulin.  This result has been reproduced in both Poland and China, after originally being done in Brazil.  The down side?  Safety.  This treatment requires a full immune reboot.  Very approximately: They kill off your old immune system, and you regrow a new one, so for a few days (or a few weeks) you are very susceptible to infections and you stay in a special isolation ward in a hospital.  As far as I know, no one has died, but the risk is there.  Plus, there are long term risks.

From the abstract:

After [treatment], 11 of 13 patients required significantly reduced doses of insulin for adequate glycemic control, accompanied by reduced levels of glycosylated hemoglobin but increased C-peptide concentrations. Three patients achieved exogenous insulin independence for 7-54 months. [Meaning one person was functionally cured for 4 1/2 years.]

Abstract: http://www.ncbi.nlm.nih.gov/pubmed/22419704
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01341899

Alefacept Finishes Enrolling a phase-II Clinical Trial

This study is also called "T1DAL", which I'm sure is pronounced "tidal".  This trial is being run by the Immune Tolerance Network, and they finished enrolling people in the trial on 30-April-2012.


This drug targets the immune system's T cells, and is already approved for treating "plaque psoriasis" which is an autoimmune disease similar to type-1 diabetes.  It has a good safety profile there. The hope is that by giving it to honeymoon type-1 diabetics, beta cells will be preserved.


Why is finishing enrollment important? For two reasons.  First, because it is now possible to predict when they will finish collecting data.  (This study collects data for 2 years, so they should have it done by May-2014.)  Second, because much of the uncertainty that surrounds clinical trials, is involved with recruiting participants.  It is often unclear how hard it will be to recruite people, and how long it will take.   But at this point, all that uncertainty is behind the researchers.  From now on, it is just gather data, then analize data, and then publish data.  Researchers have a lot more control over those later stages, then over recruiting people in the first place.


Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT00965458


Company X Gets Orphan Drug Status for Drug Y

I often see headlines like the one above.  The most recent was "Andromeda Announces FDA Orphan Drug Designation for DiaPep277". I don't report that as news in this blog, because I don't consider it scientific progress.  Orphan Drug is a designation used by the USA and the EU.  Companies with such drugs have the legal right to sell them for a longer period of time without competition.  The idea is that the drugs target rare conditions, and companies could not profitably develop them, if they only got the benefit of "normal" legal protection, because the market would be too small.  So, if the condition is rare enough, then the government says it is an orphan drug, and then the company gets a longer period of time before others can manufacture the drug.  Now, type-1 diabetes is a very common disease (over 1 million people in the US alone, by most estimates).  So a type-1 diabetes drug would not qualify as orphan.  But drugs that only work in the honeymoon phase can get orphan drug status, because only a couple of tens of thousands people are in the honeymoon phase in the US at any time.  I'm not sure that was a result the people who originally wrote the law would have approved, but that is how the law has been implemented.

But in any case: this is good news for the company, because it mean bigger revenues (or longer revenues) if the drug is successful.  But it does not say anything about the chances of success for the drug.  It says more about the disease being treated, than the drug with the status.

Wikipedia: http://en.wikipedia.org/wiki/Orphan_drug

Omni Announces Some Phase-I Results for AAT

AAT is an anti-inflammatory drug, which the body makes naturally, and which is already FDA approved for people who have a rare condition where a person don't make enough of it on their own. This treatment is based on the idea that treating inflammation can cure/prevent/treat type-1 diabetes.

There are several trials currently underway with AAT.    Omni recently announced some information about the first 12 people treated as part of their trial.  This trial is continuing to enroll more people.  This is a intermediate report of progress.  I'm hoping there will be more information published at ADA or EASD, but this is from their press release.  Note that they are reporting on 12 patients (all treated, no untreated comparison group), and that 7 of the patients were in their honeymoon phase, and 5 were not.

The treatment has been very safe and well tolerated by all the study subjects. 

Six months following the initial screening four of the seven [honeymoon] patients showed increased C-peptide levels, whereas most Type 1 diabetics progressively lose their ability to produce endogenous insulin, and, therefore, demonstrate progressively decreasing levels of C-peptide. 

Three of the seven [honeymoon] patients displayed decreased dependence on insulin during the 3-6 month period following the start of their eight week AAT therapy.

My interpretations (opinions) of the results:

• They don't provide any numbers:  no c-peptide numbers and no insulin number.  I've come to believe this is a bad sign.  I hope they publish this data soon.
• For established type-1 diabetics, it looks like AAT had no positive effect at all, in this small sample. 
• For honeymoon type-1 diabetics, Omni is trying to be optimistic, and it does look like the treated group did better in some ways than average untreated people.  However, the reporting is vague, no numbers are provided, few patients were treated, and things are naturally unsettled in the honeymoon phase, that it is very hard to see the data described so far as a successful result.  So I would not get excited about AAT yet. 

Press Release: http://www.omnibiopharma.com/_literature_136822/Omni_Bio_Diabetes_Trial_Data_-_May_30,_2012

A Personal Note

Several months ago my wife and I started looking for a new house.  That takes a lot of time, and actually buying one, even more so.  I'm happy to say that we were successful, and are in the middle of moving from one Silicon Valley town to another.  That is why I have not had the time to publish any blogs for a while.  It now looks like I will move into the new house in mid-June  (wooo-hooo!).  I hope to return to my normal blogging sometime in late July or August.

I know there are more things going on in the world of research aimed at curing type-1 diabetes than I have included in this blog, and I'm sorry it will take a while to get through the backlog.  I'm sure there will be a land side of new information from the upcoming scientific conferences, as well.

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/

Andromeda's DiaPep277 Succeeds In Phase-III Trial

... but what does that mean? 

Good News First

This was a big (450+ people) study, and phase-III, so late in the processes of commercialization.  The treatment was DiaPep277, which is a peptide (a short protein) which is related to a naturally occurring protein called "heat shock protein 60" or hsp60.  The treatment is one under-skin injection every 3 months.  People were followed for 2 years.  The study was blind, random assignment; half got the treatment, half the placebo.


DiaPep277 works by increasing the activity of regulatory T cells (especially Th2 cells), which serve to control the autoimmune attack on beta cells in the pancreas.  Earlier research described the mechanism this way: hsp60 is a protein found in the pancreas and very similar to hsp65, which is found in microorganisms.  Your autoimmune system gets mixed up between hsp65 (sign of foreign invasion) and hsp60 (naturally there), and attacks the beta cells in your pancreas.  DiaPep277 is part of the larger hsp60 molecule and teaches your immune system not to attack.  The idea is similar to giving people tiny amounts of peanut protein to wean them off of peanut allergies. [r3,r4]



The important pieces of news from this study are:

1. The primary outcome for this was C-peptide production.  Measuring C-peptide is the same as measuring the body's production of insulin[d1].  The people who got the treatment generated (on average) 0.949 nmol/L/20 minutes more, which is 23.4% more than the untreated group. That was statistically significant.  But remember that type-1 diabetics generate very little insulin, so even a tiny bit more will cause a big percentage change.  
2. Untreated honeymoon diabetics loose their ability to generate insulin as the disease progresses.  People treated with DiaPep277 also lost this ability, but it happened more slowly, so that at each point in time, the treated group generated more of their own insulin as compared to the untreated group.  Some of the news coverage refers to "preserving insulin production" but it is important to remember that insulin production was not preserved at the same level as when treatment started.  Instead, production was higher in treated people then in untreated people. It's a big difference.
3. A secondary outcome was lower A1c numbers in the treated group.  The company did not report average A1c numbers [d2], but they did say that 45.5% of the treated group was below 7, but only 35.7% of the untreated group was that low.  This suggests that the extra insulin produced was useful, and was lowering A1c, and was having a positive effect on the body. 
   
4. The "initial safety data also indicate that DiaPep277 was well tolerated", which means no serious side effects, which is always a good thing, and consistent with earlier testing.  This drug never had a hint of safety issues, that I know of.
5. Shlomo Dagan, CEO of Andromeda (the developer of the drug) said "I estimate that that the drug will be on the shelf by the end of 2014" (but this was quoted in Hebrew, which I don't understand, so I'm relying on a translation into English).  But I think he's wrong about that.  To get approved, a drug needs two trials.   The second phase-III trial is supposed to finish enrollment in 2012, and it's a 2 year treatment program, so that study finishes in 2014.   Then there is a year or two for marketing approval, so I'd estimate approval in 2015 or 2016, assuming further analysis of this trial is successful, and the second phase-III trial is also successful.

You can read more about Andromeda here: http://www.andromedabio.com/
 

Now the Bad News

1. This is not a cure, in it's current form. This drug has only been tested on honeymoon diabetics and only been found to extend the honeymoon duration. 
2. I'm not sure how big the effect really is, in terms of how much it would improve the life of a type-1 diabetic [d3]. 

However, right now we have nothing that effects the body's immune system to help a type-1 diabetic.  Nothing at all.  If this treatment gets approved, then we will have one thing.  And we must start somewhere, so I do think getting this approved and available is a big step forward no matter what it's limitations.

Comparison with Other Results

Dr. Faustman's BCG results showed spikes of  .004 to .005 nmols of C-peptide [d4], so the DiaPep277 results are about 200 times bigger an effect than her results [d5], although her results were in established type-1 diabetics, not honeymooners.

Dr. Orban's Abatacept (Orencia) results showed improvements of 60% in C-peptide production, as compared to 23.4% seen in DiaPep277 [d5].  However, Abatacept was in a phase-II trial, so it was smaller, and farther away from approval for type-1 diabetes.  But it is already approved for use for another disease.

Dr. Pescovitz's Rituximab results showed improvements of about 20% in C-peptide production as compare to 23.4% seen in DiaPep277 [d5].  However, Rituximab was in a phase-II trial, so it was smaller, and farther away from approval for type-1 diabetes.  But it is already approved for use for another disease.

More Data; Future Results
There were a couple of data points that I wish were in the press release, but aren't.  I'll certainly be looking for them in the published paper.  First, a comparison of A1c numbers in treated vs. untreated.  See [d2] for details of what I'd like to see.  Second, a time based comparison: if an untreated type-1 reaches the end of their honeymoon N months after diagnosis (on average), how many months will it take someone with this treatment to get to the end of their honeymoon?  Third, some details on safety.  It's great to say "well tolerated", but I'd like to see the details.


In terms of future work: obviously, these guys need to complete their analysis of this trial, complete their second phase-III trial, and get marketing approval from the FDA and EMEA.  That's just to get it widely available in the market.


In addition there are several expansion paths which I hope they will take now, but might need to wait until after the treatment get approval.  (Once a drug is approved for any use, it is a lot easier to run a trial for other uses.)  Interesting lines of research would include:

1. Trying it on patients before they were diagnosed with type-1 diabetes.  Many believe that anything that works in honeymooners will work better in people who have not yet been diagnosed at all.  Even a few years ago, however, we could not find those "not yet diagnosed" people, so we could not design a trial around them.  Now however, thanks to the "natural history" trial run by TrialNet [r2], we can find people who have not yet been diagnosed, and recruit them for pre-diagnosis trials.  So running a trial on people more likely to be diagnosed in the future, but not yet diagnosed, is an obvious thing to do.
2. Combining it with other drugs.  Testing multiple drugs is becoming a common technique when there is no one drug that is completely effective.  For this drug, there are two ways to attack the problem.  One is try a combination of drugs all aimed at extending the honeymoon.  See if all of them together can actually stop the beta cell destruction and permanently preserve the beta cell function which is present at diagnosis.  Another track is to combine this drug with another drug which grows beta cells. 
3. Trying it on established type-1 diabetes.  Majority consensus is that stopping type-1 diabetes when in starts (during the honeymoon) is easier than stopping it later (once established).  However, I'm still in favor of trying a drug that works on honeymooners, on established type-1 diabetics as well, especially when the side effects are very small or nonexistent.  Especially researchers who believe that beta cells continue to grow back slowly throughout a person's life, they might be particularly interested in a drug that lowers the autoimmune attack, even if given late in life.  Also, to put it bluntly, at this point established type-1 diabetics have little to loose, and few good options to try.

Press release:
http://www.andromedabio.com/page.php?pageID=69

News coverage:
http://www.marketwatch.com/story/andromeda-announces-phase-iii-clinical-study-with-diapep277r-a-novel-immunotherapeutic-agent-for-type-1-diabetes-met-primary-endpoint-2011-11-22
http://www.globes.co.il/serveen/globes/docview.asp?did=1000699926&fid=1725
http://www.rttnews.com/Content/BiotechStory.aspx?Id=1766892&Category=ClinicalTrial


Extra Discussion and References

[d1] Researchers can not measure insulin directly, because that would just measure how much insulin was being injected.  Measuring C-peptide tells them how much insulin the body is producing itself.  C-peptide is the official (by FDA) marker for approval of drugs to help type-1 diabetes, so it is the right thing to look at for trials like this.

[d2] My personal requirement, is that changing A1c numbers by 0.5 is interesting and worth looking at, but that changing them by 1 is important, and obviously good without any further discussion.  My understanding is that most diabetes researchers are happy with 0.5, and consider even smaller changes interesting.

[d3] Primarily, I'm not sure how much improvement there would be in terms of fewer side effects, less dangerous lows, etc.  I think the most important point here is duration of effect.  If the effect is long lasting, then it is reasonable to assume fewer long term side effects, but I have not seen any duration information.  Separately, there is also some debate about the benefit of having a longer, stronger honeymoon.  Some people hold that this just makes it tougher to treat type-1 diabetes: easier to have hypoglycemic events and harder to control BG and A1c numbers.  From a cure point of view, however, generating more of your own insulin is clearly the path to a cure, so I consider a longer, stronger honeymoon to be a good thing.

[d4] Different research report C-peptide results in different units.  Dr. Faustman reports [r1] her results in terms of pmols / liter, and a pmol is 1/1000th of an nmol, so 5 pmols is the same as .005 nmols / liter.  On the other hand, Dr. Pescovitz reports in pmol / milliliter (which happens to be the same as nmol / liter). 

[d5] Because there are several different ways to measure C-peptide production, I don't think this is a direct "apples to apples" comparison.  However, it is the closest to a direct comparison that I can make.  C-peptides can be measured in response to a meal, or while fasting.  The exact mechanism of measurement can vary as well.

[r1] http://www.solvingdiabetes.org/2011/07/04/highlights-of-ada-scientific-sessions-i-bgc-trial/
[r2] http://www.diabetestrialnet.org/studies/natural-history.htm
[r3] How it works in NOD mice: http://www.ncbi.nlm.nih.gov/pubmed/9133541
[r4] How it works in BB rats: http://www.diabetes-mellitus.org/p277_idf.htm


Thanks to Abush at CWD for posting the first news of this, including the English translation.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement. 
Blog: http://cureresearch4type1diabetes.blogspot.com

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

More News on Rituximab

Background on the drug: Rituximab targets the CD20 part of the immune system's B cells (different from the pancreas's beta cells) to try to prevent the autoimmune attack. B cells are part of the body's immune system and communicate with the T cells, which actually attack the body's beta cells in the pancreas. By targeting the B cells, it is hoped this treatment will stop or lower the attack of the T cells. Rituximab showed some effectiveness in preserving the beta cell function of honeymoon type-1 diabetes in a phase-II trial, and there is a second trial underway. Rituximab is a monoclonal antibody, a product of Genetech (now a division of Roche), and already approved by the US FDA for rheumatoid arthritis and several cancers (and used off label for several other diseases).

Background on antibodies: Type-1 diabetes is triggered when the body's own immune system attacks it's own beta cells in the pancreas, which create insulin. Autoantibodies are part of the process of this self-attack. In type-1 diabetes four different types of autoantibodies have been measured: GAD, Insulin, IA2, and ZnT8. There might be a few more autoantibodies that we don't yet know about. People with type-1 diabetes usually have one or more autoantibodies in their system, and this starts before they are diagnosed. I think that GAD is the most common, and IAA is second, but I'm not up on the details.

For this study, 49 patients where given four doses of Rituximab, while 29 got the placebo.  For all patients, measurements were made for each different type of autoantibody.  What they found was that  Rituximab was very good at lowering IAA autoantibodies, but much less effective on the other three known types of autoantibodies.  This was the biggest finding:

A total of 40% (19 of 48) of rituximab-treated patients who were IAA positive became IAA negative versus 0 of 29 placebo-treated patients.

So that means that Rituximab was highly selective as to what antibodies it shut down. This is a very interesting finding, at least for me.  In terms of impact on patients, we need to see the C-peptide numbers, which were not in the abstract.

Next Steps?

In light of these results, one obvious clinical trial to run would be to treat honeymoon type-1 diabetics, who only have autoantibodies to IAA, with Rituximab, and see what happens.  The results above imply that over a third of these patients would end up having no autoantibodies remaining, and it would be very interesting to see what happens to these patients.  What effect will it have on their insulin production?  Will they still have type-1 diabetes?  Will their pancreases regrow?  If so, how quickly?  These are critical questions.

Another interesting clinical trial to run would involve patients that did not have type-1 diabetes, but were being tracked by TrialNet's Natural History Study, and are known to only have IAA autoantibodies.  Basically, does treating these specific people with Rituximab delay or reduce the onset of type-1 diabetes?

And finally, there is a potential study for established type-1 diabetics who only have IAA antibodies.  Would giving them this drug have good effects?

I have no idea if any studies like these are feasible, or are being planned, but I hope so!

Abstract: http://diabetes.diabetesjournals.org/content/early/2011/08/05/db11-0674.abstract
News article: http://www.doctorslounge.com/index.php/news/pb/22439
Wikipedia: http://en.wikipedia.org/wiki/Rituximab
More on Autoantibodies: http://www.msdlatinamerica.com/diabetes/sid683880.html


News about News on DiaPep277

DiaPep277 is the longest running phase-III study aimed at curing type-1 diabetes.  It is a honeymoon only treatment. Results from the phase-II study were (in my opinion) "mixed".  (I know that doesn't sound very definitive and I really should go back and review their phase-II results in more depth, but I haven't had time.)  My most detailed discussion of their phase-II results is here, but it's not much:
http://cureresearch4type1diabetes.blogspot.com/2009/11/possible-cures-for-type-1-in-news-nov.html
and all of my blogging on DiaPep277 (hsp60) is here:
http://cureresearch4type1diabetes.blogspot.com/search/label/DiaPep%20277

The following quote is from a news article on them, and is the most recent news I have heard about when they might have some phase-III results.  The key news is that the study should be done late this year, which is not very far away.  With a little luck, we'll see results in 2012.

In the first Phase III studies being conducted at 40 medical centers in Europe, South Africa and Israel, diabetes patients aged 16 to 45 have been receiving DiaPep277 injections once every three months. The study began in 2005 and is ending late this year.

They have a second phase-III study already underway, and expected to finish in 2014.  (Remember, you need two in order to get FDA or EU approval.)

News coverage: http://www.shalomlife.com/health/15810/promising-treatment-for-diabetes/

Rilonacept is Recruiting for a Phase-I Trial

I know there is a lot of frustration about  studies that are targeted at "honeymoon" diabetics.  And it is certainly true that most current trials are aimed at honeymooners.  However, "most" does not mean "all".  Dr. White is running a study on Rilonacept that is open to people within 5 years of diagnosis.  Also, this study has no placebo group, so if you are in the study, you know you are getting the treatment.

I have previously blogged on this clinical trial, which you can read here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Rilonacept

This drug is already approved in the US under the trade name "Arcalyst", but not for type-1 diabetes.  In addition to this approval, it is currently being used in about 12 other clinical trials for a variety of inflammation related diseases.  Dr. White has told me (via email) that there have been "no untoward effects thus far".  The trial is being run in Dallas, Texas.  Contact information is in my previous blogging (link above).

Trial web site: http://www.childrens.com/specialties/endocrinology/rilonacept-study/
Clinical Trial Site: http://www.clinicaltrials.gov/ct2/show/NCT00962026

Some Background Reading

Below is a link to a short interview with Dr. Arthur Caplan, a bioethicist at University of Pennsylvania, which makes for some interesting reading.  It is about the ethics of overseas medical research.  Something that we are seeing a lot of in type-1 diabetes research.  Dr. Caplan is an interesting guy and a good speaker.  UPenn is my alma mater:
http://www.pbs.org/newshour/rundown/2011/08/sending-us-drug-research-overseas.html

The following Wikipedia article covers accuracy of home glucose monitors.  Many people are shocked to learn that they are only accurate to within 20%.  So you might get 310, 340, or even 360 at the same time: http://en.wikipedia.org/wiki/Clarke_Error_Grid
Thanks to swellman at CWD for pointing this out to me and many others.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement. 
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

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

I didn't quite get this out by the end of May, but it is the May update.....


Andromedia Starts DIA-AID2: Second phase-III Trial of DiaPep 277
Andromedia just (in April 2010) started their second phase-III trial, which will enroll 450 people and is planned to last until March 2014.  Both the EU and the US require two large scale trials for approval of new drugs, so if this study and their earlier DIA-AID trial both work well, then the approval process can start mid-2014.  It usually takes a year or two for marketing approval, so 2015 or 2016.  This treatment has only been tested on honeymoon diabetics.  

Neither this treatment nor ToleRx's (described below) will cure people by themselves.  They are both attempts to preserve some beta cells and so either extend the honeymoon or make the continuing diabetes "less brittle" in terms of fewer quick BG drops.  In both cases, I need to put together a blog posting on exactly how effective they were in their phase-II and early phase-III results.

Andromedia's DIA-AID2 page: http://www.andromedabio.com/clinical_trials.php
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01103284


ToleRx Starts DEFEND-2: Second phase-III trial of Otelixizumab
This must be the month for starting second (sometimes called "confirmatory") phase-III trials, since ToleRx is also starting one of these.  The news is just as good as Andromedia.  Actually better, since ToleRx hopes to finish their second phase-III by May 2013.  The study will have 396 people.  The same market approval math works here, so 2014 or 2015, but only if they finish their second phase-III as expected, and with the results they expect.  Both of their phase-III trials are limited to honeymooners only (so any approval would only be for newly diagnosed).  Their phase-II clinical trial (called "TTEDD") did enroll non-honeymooners.  However, it looks like good results were only seen for honeymooners (but I don't have the details handy).  That would explain why their phase-III trials are all honeymooners only.


TolerRx's DEFEND-2 page: http://www.clinicaltrials.gov/ct2/show/NCT01123083
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01123083
 

Data from XOMA Phase-I on Behcet's Disease
Previous blogging on XOMA 052: http://cureresearch4type1diabetes.blogspot.com/search/label/Xoma
Current Status on XOMA 052: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials#Xoma052byXoma

Behcet's Disease is an auto-inflammatory condition, which is rare in the US, but more common in Turkey.  Since XOMA 052 is an anti inflammatory, it is a natural drug to test on the disease.  It's of interest to people with type-1 diabetes because XOMA 052 is also being tested for both type-1 and type-2 diabetes (in separate phase-II trials).  Link to why inflammation might be a cause of diabetes:
http://joshualevy.pbworks.com/ConceptsAndBackground#Inflammation
(but remember that this is a minority opinion).

So, with all that a background, their results are very good (but on a very small group of people).  This trial only included 4 people.  However each person involved showed real improvement to their Behect's symptoms.

My take on this research is as follows: It shows that XOMA 052 has a major impact on inflammation in a situation similar to (but not identical with) type-1 diabetes.  So, if inflammation is a causative factor, or if reducing inflammation allows the pancreas to regrow, then XOMA 052 has a good chance of being successful.

Also, there is news about Xoma's phase-II trial in type-1 diabetics.  They have changed it considerably from the last time I looked.  It is a 24 person study, which started in Feb 2009 and is expected to finish in July 2011.  Since it lasts a year, if they finish enrollment in July 2010, then they will be on track to finish the study a year later.  This trial is open to non-honeymoon diabetics only, but there is only one site: Zurich, Switzerland.

So there are now at least two phase-II trials aimed a curing diabetes via anti-inflammatories, and they will both have results in 2011, so that might be a pivotal year for the whole idea of cures based on anti-inflammatories.

News: http://www.marketwatch.com/story/abstract-published-on-initial-results-from-xoma-052-clinical-trial-in-behcets-disease-2010-05-12?reflink=MW_news_stmp
Abstract: https://b-com.mci-group.com/Abstract/Statistics/AbstractStatisticsViewPage.aspx?AbstractID=19942&ItemsPerPage=20&AppliedFilter=[SubmitterFullName]%20Like%20%27Ahmet%20%%27&ShowOnlyInFinalAcceptance=true


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.