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

Alefacept Starts a phase-II Clinical Trial
This study is also called "T1DAL", which I'm sure is pronounced "tidal".

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.


Because this is an ITN trial, there is a long list of sites where you can participate. For the locals: UCSF is the only California location.  They expect enrollment to take 2 years, but (of course) I hope it fills up sooner than that.  The sooner they finish recruiting, the sooner we learn the results.  The trial is for people within 100 days of diagnosis, and requires weekly injections for 12 weeks, followed by 12 weeks "off", followed by another 12 weeks of injections.

Estimated Enrollment:  66

Study Start Date:  March 2011

Estimated Study Completion Date:  August 2014

Estimated Primary Completion Date:  August 2013 (Final data collection date primary outcome)

Web page: http://www.immunetolerance.org/news/2011/04/itn-announces-enrollment-first-participant-t1dal-trial-people-recently-diagnosed-type-1
Recruiting web site: http://www.t1dal.org/
Clinical Trial: http://www.clinicaltrials.gov/ct2/show/study/NCT00965458

Artificial Pancreas Trial Handles Dinner and Night

Hovorka's team at Cambridge University continues to make progress on testing their AP. These most recent results are aimed at showing that their AP can deal with dinner and the night after dinner. They tested with both a simulated "at home" dinner (fewer carbs, earlier in the evening) and an "out" dinner (more carbs, alcohol, and later in the evening).  The study was small (12 people) and "cross over" meaning that half used a pump and half used an AP for the "eat in" dinner, and then they switch (previously pumpers do AP, previous AP use their pumps), and have another "eat in" dinner, and then do again for the "eat out" dinner.  Each person was in the test group once, and in the untreated group once, for each meal scenario.

"For the eating-in scenario, overnight closed loop delivery increased the time plasma glucose levels were in target by a median 15 percent," said Hovorka. For the eating out scenario, the average time good blood sugar control was increased was 28 percent on average. And, when combined, the average increase in blood sugar control was 22 percent, according to the study.

Remember, the goal for FDA approval for something like this is as good control as a pump, so 22% better than a pump is more than good enough.  Now, to get insurance to pay for it, it will need to do better than a pump, but this trial shows that it is.  My reading of the study, is that they did tell the pump the number of carbs eaten at the meal, so this is what the JDRF would call a stage 4 AP.  (A stage 5 AP would not need to be told ahead of time about carbs in food.)  You can read my general background for AP research (including stages) here:
http://cureresearch4type1diabetes.blogspot.com/2009/09/background-for-artifical-pancreas.html

I know there has been some interest in how accurate CGMs really are.  This is what the study found:

The accuracy of the sensor, evaluated as the median relative absolute difference between sensor glucose levels and paired plasma glucose levels divided by plasma glucose levels, was 8.0% (4.5-19.3%) in the eating in scenario and 12.0% (6.8-17.2%) in the eating out scenario.

News coverage: http://www.businessweek.com/lifestyle/content/healthday/651955.html
Full paper: http://www.bmj.com/content/342/bmj.d1855.full   (Thank you BMJ!)

Team Brazil Rolls
In the past, I have blogged about what I call the "Burt" research, which you can read here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Burt
but it was done in Brazil, so maybe that is a better term for it.  This research uses the patient's own hematopoietic stem cells. (remember that)

In any case, it is by far the most successful research aimed at curing honeymoon type-1 diabetics.  Most of the people treated were insulin free for months, many for years.  Some for five years or longer.  These are much better results than anyone else.  But those results came at a cost of safety.  Although no one died or suffered serious side effects, the treatment involves significant risk.  At least one researcher (not part of this team) has estimated that the chance of dying would be "less than 1%" (personal communications with me), but that is way too high for most people to accept.

So the question is, how does this research move forward?  There have been several different answers, as you might expect:

1. Haller's CSGF+ATG studies are trying a similar treatment, but without the most dangerous drug.
2. Snarski is replicating the Brazilian trial, and getting similar results (and no serious side effects so far).
3. Now in this paper: a Chinese group is replicating their work.  University of Naijing (2006) found that of 5 patients treated within 3 months of dx, 4 of them used no injected insulin for a time.  However, of 11 patients treated after 3 months of diagnosis, none became free of injected insulin.  So the good news here is that the replicated the results.  The bad news is that it looks very honeymoon dependent.  In the past, I had hoped that this treatment might also work for established type-1 diabetics, but this trial shows that isn't true.
4. And also in this paper: the original group is trying to use mesenchymal stem cells (a different type of stem cell than used previously.  This protocol is significantly safer than the current one.  The following paragraph from the paper describes the new protocol:

The protocol includes bone marrow biopsy under general anesthesia in first-degree relatives for the collection of mesenchymal cells. These cells are sent to a laboratory to be stimulated to proliferate for a month and are later infused into the patient ...; there is no need for chemotherapy. The patient is hospitalized for 1 day but only as a precaution. After 1 month, the patient receives another infusion. ... Inclusion criteria are age 12 to 35 years, diagnosis of T1DM less than 4 weeks prior to treatment without ketoacidosis and positive serum levels of anti-GAD. So far [in 2008] , two patients have been included in this protocol and, as soon as we have a proper follow-up, the results will be published.

The paper below is an overview written by this research team.  It describes the background for their original research, the results they got, and continue to get, and (new to me) extentions of their work (items 3 and 4 above).

Full paper: http://www.springerlink.com/content/hq7882r31162332t/fulltext.pdf  (Thank you Diabetology & Metabolic Syndrome!)

Another Overview Paper

This is a readable overview paper by Jay S. Skyler and Camillo Ricordi, both very big names in type-1 diabetes research.  The title is "Stopping Type 1 Diabetes: Attempts to Prevent or Cure Type 1 Diabetes in Man".  Thanks to Ellen at CWD for pointing out this paper to me.
http://diabetes.diabetesjournals.org/content/60/1/1.long


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

Roadmap To Curing Type-1 Diabetes

This posting is a draft.  But I've been working on it for so long that I decided to publish what I have while continuing to refine it.  It's not perfect as-is, but I've decided that it is good enough to publish.

I've been posting a lot of narrow updates recently.  By narrow, I mean "treatment X passed milestone Y" kind of thing: a lot of detail on a very specific treatment.  This posting is the opposite, it is my attempt to put all those narrow postings into context. It is an overview of how we can cure type-1 diabetes using the research that is going on right now.  That cure is still a long way off, but this posting describes the possible paths between here and there.

Please remember that this is a posting about possibilities!  By listing a line of research here, I'm not saying that I think it will work.  All I'm saying is that researchers are actively working on it.  I'm sure that in the end most of the research listed here will fail.  That doesn't matter.  If one succeeds, then it doesn't matter how many fail.  Also, I fully understand that not everyone thinks that all the "cures" listed below are legitimate cures for type-1 diabetes.  Feel free to ignore the ones that you don't consider cures.

First, A little terminology:
Pancreas is the organ that contains specific structures called islets.  Islets contain beta cells, which are the exact cells that generate insulin. 

When the immune system mistakenly attacks cells of it's own body, that is called autoimmunity.  If the attacked cells are beta cells, that creates a disease called type-1 diabetes.  Autoimmunity can target other cells, in which case the disease will have different names and different symptoms.

The immune system attacks beta cells with killer T-cells.  Those specific killer T-cells which attack beta cells are often called "bad" killer T-cells or autoreactive killer T-cells.  Killer T-cells in general are held in check by regulatory T-cells, which are often called T-regs.  Also within the immune system are B-cells (not to be confused with beta cells, which are in the pancreas), and those cells communicate between T cells to encourage them to attack certain cells.

There are many different types of T-cells and B-cells, and they are often identified by CD numbers.  So a T-cells might be described as a CD3 T-cell or a CD8 T-cell.  B-cells might be CD20.  A cell is not limited to one CD number, you could have CD4+CD25+ T regulatory cells (for example).

How to Cure Type-1: Overview

Type-1 diabetes is caused by the body's own immune system mistakenly destroying beta cells in the pancreas.  These beta cells would normally create the insulin the body needs.  Current research is following five basic paths to try to cure it (labeled A-F below) and many of those basic paths have different sub-paths, which I've numbered. 

A. Replace the Beta Cells
Replace the patient's beta cells with ones that can not be attacked by the immune system, so the are not effected by autoimmunity.   Simply replacing beta cells is not likely to be a cure, since the autoimmune attack will destroy the new ones same as the old ones.

1. Encapsulated islet cells.  Wrap the cells in a membrane which allows nourishment and sugars in, waste products and insulin out, and also prevents immune cells from attacking the beta cells on the inside.  LCT is in phase-II trials and has permission to sell this in Russia but the current results are not a cure, and there are separate phase-I trials in Belgium and Australia.
2. Elecro-mechanical pancreas (Artificial Pancreas).  Build a pump and sensor replacement pancreas that can measure blood glucose and dose insulin.  The term "Artificial Pancreas" usually refers to using current pump and current CGM sensor technology, so both of these things use external hardware, and the sensors measure BG levels just below the skin, not in blood veins.  There are at least three groups in phase-I or phase-II trials.
3. Sertoli cells.  There are cells in a human body which are not genetically the same as the rest of the cells, and yet are not attacked by the body's immune system.  An example are sperm cells; which only contain half the genetic material as regular body cells.  They are quite different than regular cells, yet are not attacked as foreign by the immune system.   This is because there are special cells, called Sertoli cells, which block the immune system.  A possible cure for type-1 diabetes it to combine beta cells and Sertoli cells in a transplant that would not need immune suppressive drugs.  Not in clinical trials, although has been in the past. Sernova is doing animal trials in Canada.
4. Implanted elecro-mechanical.  Similar to the artificial pancreas described above, except that implantation means that the blood glucose sensor can be put directly into a blood vein, and resupplying with insulin and new batteries is more of a problem.  Also, this is internal, so not visible outside of a person.  At least one was in phase-I trials in the past; not sure if any are now.  (Dr. Rennard's work in France is with an implanted pump, not an implanted artificial pancreas.  So is headed in this direction, but not quite here, yet.)
5. Non-pancreatic beta cells.  In the last decade we have learned a little bit on how to take adult stem cells and program them to become other types of cells.  So a possible cure for type-1 diabetes would be to take adult stem cells or even just normal cells from the liver, and program them to produce insulin in response to glucose.  The hope is that since they started out as liver cells, the autoimmune attack would not target them, but they would still generate insulin in response to blood glucose.  Not in clinical trials.
6. No Moving Parts Artificial Pancreas.  This is similar to "self dosing insulin" (described below), except that there is a chemical barrier that is sugar sensitive, and the insulin is stored behind the barrier.  If the sugar level in the blood is too high, the barrier becomes more permeable and more insulin leaves the reservoir.  Conversely, if the sugar level goes low, the barrier becomes less permeable and less insulin gets out.  Not in human trials; may not even be in animal trials.

I don't consider a classic pancreas transplant or beta cell transplant a cure, because they will require a lifetime of immune suppressive drugs and related complications and side effects. But there is a lot of research going on to improve these procedures.

B. Stop the Autoimmune Attack
Stopping the body's immune attack on it's own pancreas is another way to cure diabetes.   Some refer to this as curing the underlying cause of type-1 diabetes, as opposed to replacing the pancreas which they view as curing the symptoms.

I divide this research into different groups based on how they attempt to stop the autoimmune attack.  Since the immune system is very complex, there are many ways to try to get it to stop, and so many different ways to categorize this research.  The division below is my personal taste.  Different researchers do it differently.

Any treatment that stops the immune attack on beta cells needs to be focused, so that it does not stop the immune attack on foreign cells.  A "cure" that hobbled the immune system's beneficial functions would be worse than than type-1 (in my opinion), and I would not consider it a cure at all.

1. Antigen specific targeting. 
• GAD65.  GAD65 is one of the proteins on a beta cell which is (mistakenly) attacked by the immune system, and this treatment is an attempt to teach the immune system not to attack that exact protien.  In phase-III trials.
• Insulin B chain.  Finished phase-I trial.
• Insulin.
2. Targeting specific "killer" T-Cells. Modern technology can create monoclonal antibodies which specifically target specific T-cells. 
• Anti-CD3s.  CD3 are a type of immune cells which are involved in the attack on beta cells.  These treatments target that cell type.  There is currently one (NI-0401) in phase-II trials.  (Two more just failed phase-III trials.)
3. Targeting communications cells.  Monoclonal antibodies have also been created to target CD20.  Finished phase-II trials. 
4. Heat Shock Protein 60 (HSP60) is a small protein that might help teach the immune system not to attack it's own body.  Diapep277 is based on this, and in phase-III trials.
5. Polyclonals.  
• ATG.   **need more info here**  In phase-II trials.
6. Raising the level of TNF.  BCG.  TNF is a naturally occurring substance that kills of certain types of cells (especially tumor cells).  If TNF kills off "bad" killer T-cells specifically, then raising TNF levels might put type-1 diabetes into remission or even cure it.  Since BCG is known to raise TNF levels, it is a possible cure for type-1 diabetes.  No results from a phase-I trial.
7. Reinforcing T regulator cells.
• Dendric cells. **need more info here** In phase-I trials.
• T-regs.  **need more info here**  In phase-I trials.

Note that this path may require that we replace the lost beta cells (see section C), or those cells may regrow without outside help, once the autoimmune attack is stopped.

C. Create new beta cells to replace those that were lost.
If the autoimmune attack is stopped by a cure from group B, then it may still be required to regrow, improve, or replace beta cells in order to have a cure.  

1. Drugs that trigger regrowth.  There are several drugs which might trigger regrowth of beta cells.  These include Human Growth Hormone and Exsulin, which have done some clinical trials, and CureDM, which has not yet.  Exsulin is in phase-II trials.
2. Stem Cells could be used to grow new beta cells.  Many different techniques, some you can get in a clinic now, some in phase-I, and others still doing animal experiments.
3. Temporary beta cell replacement.  Any of the cures in group A could also be used to provide new insulin, especially if only needed temporarily while the body's beta cells naturally regrew.
4. Type-2 drugs. Many of the drugs given to type-2 diabetics work by getting more insulin out of existing beta cells, or having that insulin used more efficiently by cells, so any of them might be helpful here as well.  Several in phase-II trials.

D. Stop inflammation to stop type-1.
Most researchers believe that as the immune system attacks the beta cells, it causes inflammation:
        Autoimmunity -> Kills Beta Cells -> Causes Inflammation
But some researchers believe that the inflammation itself kills the beta cells.
        Autoimmunity -> Causes Inflammation -> Kills Beta Cells
This difference is important because the second group of researchers believe that if you could stop the inflammation, you could stop type-1 diabetes.  There are a large number of anti-inflammation drugs out there, and new ones are being worked on all the time, so I'm only listing those that are being tested on type-1 diabetes specifically: Anakinra is in phase-II, Lisofylline and Xoma 052 are in phase-I. **need more info here**

E. Self Dosing Insulin.
Create a substance that contains insulin, but only makes that insulin available when the blood glucose level is too high.  SmartInsulin, SIA-II, and BIOD Smart Basal are examples of research into this type of cure. Smart insulin is probably in clinical trials now.  (I'm trying to confirm this.)  The other two are not.  **need more info here**

F. Gut Permeability
Most researchers believe that gut permeability has nothing to do with diabetes.  But some researchers believe that heightened gut permeability causes the autoimmune response that causes type-1 diabetes.  When more and larger molicules move out of the intestine and into the bloodstream, that over activates the immune system which attacks the cell of the body.   These researchers believe that if you could lower gut permeability, you could prevent or stop type-1 diabetes.  Right now, there are no drugs based on this theory in clinical trials, although in the past Alba Therapeutics talked about testing their AT-1001 drug on type-1 diabetes.  (It is currently only being tested for Celiac disease.)

Combining Therapies

Basically A, D, E, and F cures are "one step" if they work, we're done.  But B and C are a little more complex.  B might require C to be a cure, or maybe not, or maybe B will work by itself, but take a very long time, so a practicle cure would still require both B and C.  In any case, it seems unlikely that C alone could cure type-1.  Certainly, we have tried Exsulin, Human Growth Hormone, and many types of beta cell transplants, and none of those have led to a cure.

Please do remember that this posting is a work in progress, and I do hope to improve it over time.  Please email me with specific parts that are hard to understand, or need more explanation.  This is a case where I think publishing this information now, is better than waiting for perfect, refined information to be ready in the unknown future.

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

History of Exsulin and AAT

Based on my last couple of posts, I got the two following questions:

How is the phase-II Exsulin study that is currently underway, different from the phase-II Exsulin study that was reported on in 2009?

The first trial gave one day's dose in one injection.  In the current trial, one day's dose is spread over three injections over the course of the day.  On one hand, the researchers think this will lead to better results, because they think that Exsulin does not stay in the system very long, so putting it in repeatedly over the day should lead to better results.  The drug will be more consistently in the system the whole day through.  On the other hand, they also think this will lead to fewer "injection site side effects".  In the earlier trial, some patients complained about pain, redness, itching, and other problems right around the injection site.  Since the second trial will only be injecting 1/3 of the dose at once, they are hoping there will be far fewer of these side effects.  They are also changing the exact formulation to try to minimize this discomfort.

Also, the first study lists the doses as 600 and 300, while the second lists them as 200 and 100.  I'm assuming that is per injection, and the daily dose was the same for each study.  But it is possible that is not true and the second trial is using a much lower dose.  If so, this would be another big difference.

The purpose of most phase-II studies is to find the best dose, the best format for that dose, and to test the treatment on a larger population than in phase-I.  So this study is testing improvements to the dosing and formulation; just what you would expect in phase-II studies.

What is AAT used for today?  Is that disease like type-1 diabetes?

AAT (Alpha 1-antitrypsin) which is also sometimes called A1AT, is approved for treating Alpha 1-antitrypsin deficiency.  Makes sense: your body doesn't produce enough AAT, so AAT is approved as a treatment.  This disease is not an autoimmune disease, and is nothing like type-1 diabetes.  It is genetic, and comes in different severities depending on if you have one or two of the bad genes .  It is estimated to affects 1 out every 2,500 people in the US, although only about 10% of the people affected are actually diagnosed.  Here is a note on the most common symptoms from the Alpha-1 Association:

The most common indicators of Alpha-1 include shortness of breath, a chronic cough, and abnormal liver test results. If you have any of these symptoms there is a simple blood test that can detect alpha-1 antitrypsin levels. This test is also recommended if you have relatives, especially siblings, who have been diagnosed with alpha-1, or if there is a family history of early emphysema, with or without smoking.

You can read about it here:
http://en.wikipedia.org/wiki/Alpha_1-antitrypsin_deficiency

And here are some support groups:
http://www.alpha1.org
http://www.alpha-1foundation.org


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 (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
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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