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

Exsulin's Phase-II Trial is Data Complete 

The exact update I got on the Exsulin phase-II trial is this: "We have finished recruitment for this trial. We are still in the process of finalizing the results".  I interpret this to mean, not only have the finished recruting all their patients, but they have all their data, and are now working on the data analysis / paper writing part of the research.  This is great news, because I'm hopeful that we will hear the results in a few months.

Rituximab Starts another Phase-II Trial

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.

Comment: Most treatments aimed at stopping the autoimmune attack are very focused on stopping the "bad" T cells which directly attack the beta cells in the pancreas. This treatment (if successful) opens up a whole 'nother way to stop the attack: by targeting the immune systems communication and support system, the B cells.

The current research (which I consider phase-II, although the researchers list it as phase-IV) is very similar to the a previous trial which I blogged on before (link below).  The current trial has already started enrolling 50 people at First Affiliated Hospital, Nanjing Medical University (Nanjing, Jiangsu, China). If you are interested in enrolling, contact Tao Yang, PhD at phone 86-25-83718836 ext 6466 or email yangt@njmu.edu.cn.  There is no placebo group in this trial: everyone is treated.  They started in July 2010, and hope to complete it by December 2013.  This is for people with type-1 diabetes for less than one year.

clinical trial record: http://www.clinicaltrials.gov/ct2/show/NCT01280682

A Sad Note to the Previous CD20 Research
The previous Rituximab research was led by Dr. Mark Pescovitz who died in a car crash at the end of last year.  That work was published by the prestigious New England Journal of Medicine, and was just one part of a distinguished research career.
http://www.boingboing.net/2010/12/13/mark-pescovitz-1955-.html
http://www.jdrf.org/index.cfm?page_id=114825

My previous blogging on Rituximab is here: http://cureresearch4type1diabetes.blogspot.com/search/label/Rituximab

Sitagliptin Completes Enrollment on a Phase-II Trail (as a Treatment)

This is a large (140 person) trial which started in late 2010 and is the follow on to a trial which I've blogged about before.  The goal of this is to lower A1Cs for type-1 diabetics by about 0.3, by lowering BG levels more quickly after a mean than is done now.  The 0.3 number is pretty close to what they did in an earlier, smaller trial. Sitagliptin is already approved for type-2 diabetes.  It's trade name is Januvia.

They completed enrollment in February 2011, I think.  The record is not 100% clear, and it might have been earlier.  If they did complete enrollment in February, then they will finish collecting data about June.  The clinical record says the trial will complete in July 2011, so I think it is reasonable to see results by the end of this year for this research.  This same group published their previous results very quickly after the study was done.

Clinical trial: http://www.clinicaltrials.gov/ct2/show/NCT01227460
Previous trial: http://www.clinicaltrials.gov/ct2/show/NCT00978796
Results from related trial: http://cureresearch4type1diabetes.blogspot.com/2011/02/possible-cures-for-type-1-in-news-late.html (but this was combining this drug with another)

Extra Reading

Dr. Skyler has written a wonderful summary of some of the more interesting clinical trials in type-1 diabetes done between June 2009 and July 2010:
http://onlinelibrary.wiley.com/doi/10.1111/j.1742-1241.2010.02580.x/full
One of the things I particularly liked about this paper, is that for each clinical trial, there is a summary of the abstract and then Dr. Skyler's comments.  These comments often put the research into context, discuss next steps, or give his opinions on it.  That perspective is missing from the raw scientific papers.  (Although he wrote this before the two anti-CD3 treatments had failed in phase-III trials, so those are discussed here, although they are already dead as cures.)

Here is part of his summary of the whole year:

That negative studies continue to dominate the field, and that the positive ones still show decline in β-cell function over time, has led to more calls for combination approaches. When I [Dr. Skyler] have advanced such prospects at meetings of paediatric diabetologists, I hear groans. Yet when I have advanced these prospects at meetings of immunologists and transplant surgeons, I hear cheers.

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

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

Canakinumab Completes Enrollment
Canakinumab is a monoclonal antibody, which is designed to lower inflammation.  It targets IL-1β (interleukin-1 beta) which causes inflammation.  The drug was approved in 2009 (both US FDA and EU EMEA) for a collection of rare autoimmune based inflammatory diseases.  (And type-1 is an autoimmune disease which causes inflammation, but it is not clear how important the inflammation is to the symptoms of the disease.)  Good results have been seen in people with type-2 diabetes, and it has been used in children as young as 3.

They have completed enrollment of their phase-II clinical trial (66 people) as of March 2011. Because this drug is already FDA approved, there was not a phase-I trial in people with type-1 diabetes.  So the results from this trial will be the first type-1 results that we see.

Why is completing enrollment important? For two reasons.  First, because it is now possible to predict when they will finish collecting data.  This study runs for 2-4 years, so they should have data collected by March 2015 at the absolute latest, and might have some early data by March 2013.  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 uncertainty 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.

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

Xoma 052 Fails (Mostly) in Phase-II for Type-2

Xoma 052 is a monoclonal antibody which is a broad anti-inflammatory, and works by blocking the IL-1 inflammation pathway.  The news is that Xoma announced that their Xoma 52 phase-II trial for type-2 diabetes had missed it's primary end point (which was better BG control).  They are still hopeful that it will lower bad cholesterol and be marketable for that purpose.  But that's a big come-down: they were hoping to lower BGs which is a big, sweeping treatment for type-2, but now they are hoping to help one particular symptom.  Plus, there are already other drugs that lower bad cholesterol.

Why is this important? Xoma is also testing this drug on type-1 diabetics.  That trial is ongoing and results are not expected until around October 2011.  But obviously, this is not good news.  However, since the mechanisms behind type-1 and type-2 are very different, we really need to wait and see what happens in their type-1 clinical trial.

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, mergers and acquisitions ("M&A"), director or C-level resignations, 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

New Resource: Next Expected Milestone

I have the first draft of a new on-line resource for tracking research aimed at curing type-1 diabetes.  It is not in a "polished" form as yet.  I'm releasing it now partly because I think it will be very helpful, and partly so you can give me feedback on it.

I call it the Next Expected Milestone page.  It's permanent home is here:
http://cureresearch4type1diabetes.blogspot.com/p/next-expected-milestone.html
But I've included the important part below.

My goal with this page is to make it easy, for each clinical trial, to see what research milestones are expected to be completed in the next month, season, year, etc.   On the one hand, this page can serve as an TLOD ("too long over due") list of research that isn't reporting the expected results.  On the other hand, it can tell you what announcements to especially look for in the next few months.

In the table below, the the important column is the last one.  It contains the next expected milestone the researchers should make.  So "Jun-2011 III Results !" means that in June of 2011, that trial should release their results, and the ! means they have publicly said they will do this.  "April-2012 II Started" means they will start a phase-II trial in April 2012, and so on.  Red dates are long over due.  Orange dates are slightly over due. and BoldGreen dates are coming up in the next few months.  All the columns in the table, and all the abbreviations and acronyms, are described in a section below the table.

Name          Id/Developer           Notes            Date Last Milestone        Date Next Milestone

Lisofylline   DiaKine                Inflam           May-2009 I Started         Dec-2009 I Complete

BCG           Faustman               Estab Comm       Jun-2010 I GotData         Oct-2010 I Results

Anakinra      NCT00645840            Inflam (Kineret) Jun-2010 I Completed       Dec-2010 I Results
Exsulin       Exsulin                Beta             Sep-2009 II Started        Nov-2010 II Complete

Atorvastatin  NCT00529191            (Lipitor)        Feb-2010 II Enrolled       Feb-2011 GotData

Etanercept    NCT00730392            (ENBREL)         Apr-2009 I Results         Apr-2011 II Start

GAD65*        NCT00723411 - EU                        Nov-2009 III Enrolled      Jun-2011 III Results!
Dendritics    NCT00445913            Estab            Feb-2011 I Enrolled[*]     Jun-2011 Results
Liraglutide   Hvidovre Univ Hosp     Estab            Jan-2011 II Complete       Jul-2011 II Results

AAT           Kamada                 Inflam           Mar-2011 I Paperwork       Aug-2011 I Starts

Anakinra      AIDA                   Inflam (Kineret) Jan-2009 I Starts          Sep-2011 I Complete 

BHT-3021      NCT00453375            Estab            Nov-2010 I Enrolled        Oct-2011 I Complete?

Xoma 52       Xoma Corp              Estab Inflam     Jul-2010 II Enrolled       Oct-2011 II Results
GAD65         NCT00751842 DIAPREVENT                  Nov-2010 III Enrolled     Oct-2011 III Complete 
DiaPep227*    DIA-AID1 NCT00615264                    Sep-2009 III Enrolled      Dec-2011 III Complete

Rituximab     Pescovitz at Indiana                    Dec-2009 II Publication?   Dec-2011 III Start?

Cord Blood    Haller                                  Mar-2009 II Started        Mar-2012 II Complete?
PROCHYMAL     Osiris                                  Jan-2010 II Enrolled       Apr-2012 II Results
Pioglitazone  NCT00545857                             Oct-2009 I HalfEnrolled    Jun-2012 I Complete
GCSF          NCT01102699            Estab            May-2010 I Started         Jun-2012 I Complete 
IBC-VS01      NCT00057499 Orban                       Jun-2010 I Published       Jun-2012 II Start

GAD65 [1]     NCT00837759            Estab            Jan-2011 II Enrolled       Oct-2012 II Complete 
GAD           NCT00529399                             Apr-2010 II Enrolled       Dec-2012 II Complete 
Sitagliptin   Garg                   Estab            Feb-2011 I Results         Feb-2013 II Start
GCSF          Haller                                  Apr-2008 I Start           Apr-2013 I Complete
ATG GCSF      Haller                 Estab            Apr-2010 I Started ?Aug    Apr-2013 I Complete
AAT           NCT01319331            Estab Inflam     Mar-2011 I Started         Sep-2013 II Complete 

Abatacept     Orban at Joslin                         Feb-2008 II Started        Sep-2013 Results
Proleukin Rapamune  NCT00525889      Estab            Nov-2010 I Enrolled        Sep-2013 I Complete?

NI-0401       NovImmune                               Aug-2010 II Started        Aug-2013 II Results ?
Rituximab     NCT01280682                             July-2010 II Started       Dec-2013 II Completed
DiaPep 277    DIA-AID2 NCT01103284                    May-2010 III Started       Mar-2014 III Complete
AAT*          RETAIN-1 NCT01183468   Inflam           Oct-2010 II FirstDose      Nov-2014 II Complete
Canakinumab   TrialNet               Inflam           Mar-2011 I Enrolled        Dec-2014 I Complete 
ATG           START NCT00515099                       Aug-2007 II Started        June-2015 II Results

Poly Tregs    Gitelman               Estab            Jan-2011 I Started         2016 I Results

[1] Combo trial including GAD65, lansoprazole, and sitagliptin

Understanding The Table

Each line is a separate clinical trial (so drugs/treatments with more than one trial active may have more than one line). 

Name

The most common name of the drug or treatment.  Only one is included.  For drugs that have trade names and generic names, I usually use the generic name if there is space for it.  A * means this is the leading (farthest along) clinical trial for this drug or treatment in type-1 diabetes,  for treatments with many studies going on at the same time.

Id/Developer
Should be an identifying number or trial name, or both.  However, I started out putting the name of the researcher here, and I'm only slowly replacing that with the US government's clinical trial number, or a similar number from another governmental organization.  Developer is the organization creating the treatment or testing it.  Only one is included.

Notes

Here are the notations in this field:

• Appr: Drug or treatment already approved in the US or EU or both.
  
• Beta: Drug or treatment aimed at increasing beta cell mass or efficiency.
• Comm: A commonly used drug, so widely prescribed or not prescription at all.
• Estab: A trial on established (non-honeymoon) type-1 diabetics.  Generally over 1 year.
• Inflam: A drug or treatment based on preventing or lowering inflammation.
• Prev: A trial aimed at preventing type-1, not curing it.
• Treat: A drug aimed at treating type-1, not curing it. 
• (...): A trade name of the drug in the trial, these drugs are usually "Appr".

Milestone Columns
The last two columns in the table are both milestones, and are very similar.  Here are the types of milestones listed in these columns: 

• Paperwork: Filed the paperwork required to start a trial.  Usually either the clinical trial record, or the IND application, if in the USA.
  
• Start: Started trying to enrolling patients in the trial.  Recruitment has started.
  
• First Dose: The first patient actually enrolled and dosed.
  
• Enrolled: Finished enrolling patients in the trial.  Trial is full.
  
• Complete: The completion date from the clinical trial record.
  
• GotData: Finished gathering data.
  
• Results:  Important results published in some form (paper, symposia, abstract,etc.)
  
• Published: Important Results published in a peer reviewed journal.

Also, these marks are used in both milestone columns:

• "I", "II", and "III" refers to phases of clinical trials, and trials which the researchers consider phase-IV, are considered phase-II here.
• A "?" means I need to recheck that date.
• A "!" means the researcher or organization has publicly listed that date.

 
Last Milestone 
This column contains the date and content of this research's last milestone.

Next Milestone 
This column contains the date and content of this research's next expected milestone.

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

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

The first two lines of research discussed below involve treating inflammation, so here is a quick introduction to treating inflammation as a cure for type-1 diabetes:  Everyone knows that type-1 diabetics have a lot of inflammation in their pancreas and especially around their beta cells. Most researchers believe that inflammation is a result of the body's immune attack on it's own cells. That is, the underlying immune problem causes inflammation and also causes beta cells to die (which causes the symptoms of type-1 diabetes):

            /---> causes --> beta cells to die    

Autoimmunity

            \---> causes --> inflammation

However, some researchers believe that the underlying immune problem causes inflammation, and that this inflammation kills the beta cells, which then causes the symptoms of type-1:

Autoimmunity -causes-> inflammation -causes-> beta cells to die

The difference is that, in the second model, if you stop the inflammation you can stop the symptoms of type-1 diabetes (the high BG numbers and the low numbers). And that is a big difference. But this second model is still a minority opinion. 

OmniBio Starts a Phase-I Trial on Established Type-1 Diabetics and Expands their Honeymoon Phase-I Trial

Alpha-1 Antitrypsin (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. OmniBio had already started a phase-I trial for honeymoon diabetics, however they are now expanding in two important ways:

First, they are starting up a non-honeymoon phase-I clinical trial.  Obviously, this is very important to the majority of type-1 diabetics who have had the disease for a long time: 

The initiation of a late stage Type 1 diabetes trial.  Proposed Trial Site:  University of Basel, University Hospital-Basel, Basel, Switzerland.  Principal Investigator, Dr. Marc Donath, Professor of Endocrinology, Head of Clinic of Endocrinology, Diabetes & Metabolism.

Second, they are expanding their Honeymoon phase-I trial to 50 patients.  At that size, it really more of a phase-II trial.  Here is that part of the announcement:

The trial ... has seen improvement in the condition of the first enrolled patients.  Based on observations of the first enrolled patients..., Omni Bio intends to expand the patient enrollment to 50 patients, which may involve obtaining a second trial site.

That sounds like great news, but I'm very interesting in exactly what those results where.  (This is a case where "details matter" and a vague statement of improvement is not good enough by itself.)  Hopefully these guys will publish some details, soon.

Press release: http://www.prnewswire.com/news-releases/omni-bio-pharmaceutical-intends-to-expand-type-1-diabetes-trial-to-50-patients-117053528.html
clinical trials: http://www.clinicaltrials.gov/ct2/show/NCT01183468   http://www.clinicaltrials.gov/ct2/show/NCT01183455

Thanks to Cameron Donahue (who works with OmniBio) for providing some of the information used here.

Kamada Starts Paperwork for a Phase-I Trial of AAT

Kamada is a different pharmaceutical company that makes AAT.  They currently make an FDA and EMEA approved formulation which is used for people who naturally don't produced enough AAT of their own.  They are also working on an inhaled version of AAT, since the current product is intravenous, but that is still in clinical trials.  They are planning to test a different brand name of AAT (Glassia®), than Omni's (Aralast NP), but I don't think that is important.

The trial they are planning includes 24 people and will be completed around December 2012.  There will be no control (or "placebo") group, but three groups will each get different Glassia doses.  The primary outcome for this study is general safety, and the secondary outcomes are efficacy as measured by injected insulin and A1c numbers.  (There is also a mention of testing for "Pancreatic beta cell function" which I hope means C-peptide measurements, but the paperwork is not specific.)

This clinical trial is being done at two sites in Israel: Schneider Children's Medical Center (Petach Tikva) and Assaf Haroffeh Medical Center (Zerifin).  Contact is Mariana Rachmiel and her phone number is +972-8-9542007.

clinical trial: http://www.clinicaltrials.gov/ct2/show/NCT01304537
corporate site: http://www.kamada.com/

Personal Opinions on the Impact of this Research on Dr. Faustman's Research

The Alpha-1 Antitrypsin (AAT) research described above may also have huge impact on Dr. Faustman's research.  It could provide strong evidence that her theory is right or wrong.  Dr. Faustman's theory is that BCG will cause the body to generate more TNF which in turn will kill the autoreactive ("bad") T-cells and result in the body generating more of it's own insulin.   She announced that her phase-I trial had finished almost a year ago, but has not published results as yet.  (A very bad sign in itself.)  However, taking AAT lowers the amount of TNF in a person.  This is the opposite of BCG.  Especially for a honeymoon diabetic, this means that if Dr. Faustman's theory is correct, then giving AAT will cause a shorter honeymoon, and will generally result in a quicker onset and the body to generate less insulin.

So, if AAT results in a longer, stronger honeymoon, that suggests that Dr. Faustman's theory is wrong, even if she never publishes the results of her own clinical trail.  Conversely, if AAT results in a shorter, weaker honeymoon, that supports her theory. Again, independent of her own results.

Teplizumab Starts Phase-II to Prevent Type 1 Diabetes


Teplizumab was being developed by MacroGenics until late last year, when it failed it's phase-III clinical trials for honeymoon type 1 diabetics.  It is similar to Tolerx's Otelixizumab which also failed it's phase-III clinical trials.  Both target a specific type of cell in the immune system, called a CD3.  However, months before the phase-III trial failed, the paperwork had started on a clinical trial to give this drug to people at high risk for type-1 diabetes, but who had not yet come down with the disease.  These patients would be identified by having two or more auto-antibodies, a first degree relative with type-1, and already having an abnormal glucose tolerance test.  The idea would be to give these guys Teplizumab to see if it prevented or delayed or lessened the impact of type-1 diabetes.  TrialNet is moving forward with this clinical trial. 


It is easier to have a good effect on type-1 diabetics during the honeymoon phase than later on, after the disease is long established, so it makes sense that it should be easier still to prevent type-1 entirely than to treat it in the honeymoon phase.  So even though this drug did not improve honeymoon diabetics, there is still hope that it might still prevent the disease.


The study will enroll about 170 people, from many different clinical sites all over the US (for the locals: UCSF and Stanford are recruiting, but nothing in Sacramento).  Results in January 2016 if all goes according to plan.  Since the drug has already been through phase-I and II trials for honeymooners, they can start off at phase-II for their prevention trial.  If you're interested there is a recruiting web site and a lot of contact information in the clinical trial record (links below).

News: http://www.popsci.com/science/article/2011-03/experimental-drug-may-prevent-diabetes
Recruiting web site: http://www.diabetestrialnet.org/studies/ACD3.htm
Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT01030861
Note that the news article uses the term "Body Reboot" in it's title.  I think this is a poor choice of words.  The drug being tested does not reboot anything (in my opinion).  I think the term "reboot" is properly used to describe the cure being researched by Burt (and collaborators) in Brazil and Snarski in Poland.

(If this had been nearer to Halloween or nearer to April 1st, my lead paragraph would have been something like this:  

Zombie Drug, Left for Dead, Walks Again!  

Teplizumab which was last seen buried in a shallow grave, after having failed phase-III testing in honeymoon diabetics, has risen from the grave and is shambling towards a different use: preventing type-1 diabetes when given to at-risk people who have not yet been diagnosed with the disease.  It was heard mumbling to itself "Hungry for Ceeee Deeee Threees.  Must have Ceeee Deeeee Threees.  Give meeeee Ceee Deeee Threeees......  :-)

A Little Commentary


In addition to seeing if Teplizumab can prevent or minimize type-1 diabetes, this trial will also have a synergistic effect with TrialNet’s Natural History Study trial.  That trial tests relatives of type-1 diabetics for antibodies to help gather pre-diagnosis data on the disease.  I know some people don't participate, because even if they turn up positive for one or more antibodies, nothing can be done.  And they'd rather not know, if nothing can be done.  But now, something can be done: they can enroll in this Teplizumab trial, and maybe (emphasis on "maybe") get a benefit if the trial is successful.  So I think the very existence of this Teplizumab trial will help populate the Natural History Study trial.  And if you have not participated in  TrialNet’s Natural History Study, because you didn't think you could use what you learned, well now maybe you can.

Also, this trial simply could not be run without something like TrialNet’s Natural History Study trial.  The Teplizumab study is dependent on identifying a large group of people who don't yet have type-1, but have a high chance of having the initial onset in the next few years.  That's exactly the type of data that the Natural History Study produces.  Without a trial like Natural History Study it is almost impossible to even test a type-1 preventative drug, because you would need to give it to thousands of people, to even see even 10 or 20 people who would eventually become type-1 diabetic.  By starting with the Natural History Study data, you can run reasonably sized preventative trials, like the 170 for this one.

So this trial helps TrialNet’s Natural History Study, and TrialNet’s Natural History Study helps this trial.  I would expect that as we get more and more data from the Natural History Study these sorts of follow on, prevention studies will be come easier and easy to run (and cheaper), and therefor more common. 

Obviously, this trial is not research aimed at curing type-1 diabetes; it is aimed at preventing it.  So I'm not sure I will continue to follow this in the future.   I do include honeymoon trials.  Should I include prevention trials? 

Non-Type-1 Diabetes News (Learning from Other's Mistakes)
One of the major points I try to make in this blog, is that you can not make your medical decisions based on one study.  No matter how good, how important, how famous, or how much you like the results.  You must look at the whole area of research, and especially follow up studies, before you make a decision.  The Chronic Fatigue Syndrome community is learning this lesson the hard way, as a purported connection between a retrovirus (XMRV) and their disease is coming apart in a very painful and political way:

Editorial: http://newsblogs.chicagotribune.com/tribnation/2011/03/xmrv-chronic-fatigue-syndrome-and-a-fuller-picture-of-their-dubious-connections.html
News: http://www.chicagotribune.com/health/ct-met-chronic-fatigue-xmrv-20110317,0,6116823.story

This quote is from the editorial:

Our story today is about the danger of putting too much stock in one study and forgetting that scientific knowledge is hard won, proven over time, and borne out through many, many studies -- not just one.

Reminder About The Blog
There three ways you can help with this blog:
First, tell other people about it!  Heartfelt testimonials are the best advertising.
Second, tell me about any clinical trials you know about that are not already covered here.
Third, ask me questions that you have.  This tells me what I'm not explaining well, and where I need to put more information into my posts.

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
Old Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials

Tolerx's Otelixizumab Fails in Phase-III Trial

Otelixizumab (Tolerx / GlaxoSmithKline) Fails Phase-III Trial

The official quote is "did not meet the primary efficacy endpoint".  Basically, the the people who got the drug did not do better than those who did not, in the the most important  measurement of success.  The primary endpoint for this experiment was C-peptide generation, which is a marker for natural insulin production.  Basically, they were hoping that giving this drug would help honeymoon type-1 diabetics generate more of their own insulin, but it did not.

In terms of actions: they have stopped enrollment in their second phase-III trial (DEFEND-2), which shows that they think that there is little to no hope of moving forward with this drug at this time.

So that is about as dead as a phase-III trial can get.  

Press release: http://classic.cnbc.com/id/42028160
Tolerx blog: http://tolerx.com/index.php?page=greenchair&entry=committed-to-the-promise-of-our-normalization-immunotherapy-platform
DEFEND-1: http://www.clinicaltrials.gov/ct2/show/NCT00678886
DEFEND-2: http://www.clinicaltrials.gov/ct2/show/NCT01123083

A Little Discussion

This is not completely unexpected, because there was another similar drug (Teplizumab), which was also an anti-CD3 monoclonal antibody which was also in phase-III clinical trials and just a few months ago, it failed as well.   And for the same reason: did not cure/improve people.  Neither trial had any safety problems.

There is still one anti-CD3 monoclonal antibody out there.  It is NI-0401 by NovImmune, and is in phase-II clinical trials.  Unfortunately, I've never been able to find results for their phase-I study, so I don't hold out much hope.  If you know anything about NovImmune's NI-0401 results, or where they were published, then please tell me.

Previous blogging on Teplizumab:
http://cureresearch4type1diabetes.blogspot.com/search/label/Teplizumab
Previous blogging on NI-0401:
http://cureresearch4type1diabetes.blogspot.com/search/label/NI-0401

So where are we now?

Years ago, there was only one treatment in phase-III trials: DiaPep277.  Last year, there were four.  Since then, two have failed and none have entered, so we are down to two: GAD65 and DiaPep277.  GAD65 is expected to announce their first phase-III results in the next 3 months, but DiaPep277 results are much farther away.

The official musical accompaniment for this blog entry is "River of No Return" from The Jeff Healey Band's album "See the Light".  
      It's a cold hard lesson, that you're gonna learn, on the river of no return....

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 (late Feb)

Results from a phase-I Clinical Trial

Back in Sept 2009, Dr. Garg started a small pilot trial of Sitagliptin and Lansoprazole. These are two drugs currently used for type-2 diabetes, but this trial is aimed at using them on people who have type-1 diabetes.  The study was supposed to last about three months, and now they have published some results.

Summary:

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

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

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

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

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

Sources:

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

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

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

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

DiaPep277 Fully Enrolls a Small Phase-III Trial

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

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

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

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

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

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


Random Reading / Listening

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

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

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

Reminder About The Blog

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

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. 
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials

Chance of FDA Approval

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

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


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


Major findings about the process right now:

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

Major findings about changes in the process:

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

Commentary

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

But with two serious limitations:

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

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

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

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

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


Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. 
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials