Introduction to the The Juvenile Diabetes Cure Alliance

At the bottom of my posts is the phrase "nothing here is official JDRF or JDCA news, views, policies or opinions".  Everyone knows what the JDRF is, but I do occasionally get asked what JDCA is.   In the past JDCA was in "start up, stealth mode" meaning they were deliberately staying out of view.  But they are now taking a more public stance, so I thought I'd say a few words about them:

Introduction to the JDCA: The Juvenile Diabetes Cure Alliance

JDCA is a relatively new organization, which I think is unique in the world of type-1 diabetes charities (and maybe unique in all of philanthropy).  I think of it as a hybrid of Consumer Reports and a Lobbying Organization, but focused on type-1 charities.  The Consumer Reports part of their goal is to shine a light into what various type-1 charities are spending money on.  The Lobbying part of their goal is to focus more of that money into projects directly aimed a curing type-1 diabetes in the next 15 years.  They want to lobby the charities to focus on this goal, and also help doners channel their money into this goal. 

Their tag line is "The Voice Of The Donor for a Cure" and their mission is to "direct donor contributions to the research opportunities that provide the best chance of curing Type 1 diabetes by 2025".

Obviously there are some strong synergies between what they want, and what I research.  We are both focused on the cure end of the process.  I look at human trials, which gives me a 10 year view.  They are looking at a slightly longer 15 year view.  But even 15 years is not very long in the world of research.

Culturally, they have a strong business / financial ethic.  The founder and the senior guys he's hired have business backgrounds.  They use the terminology, methodology, and mind set of business analysis.  It is my understanding that the key movers in the organization are parents of children with type-1 diabetes (at least right now).

They also feel that measurable progress and deadlines for results are critical to ensuring that funded research will lead to a cure, quickly.

As far as I know they don't accept donations for themselves, rather they are funded by one wealthy family which is recently effected by type-1 diabetes, and which thinks that this project is the most productive work they can do to cure type-1 diabetes.

Their web site is here: www.thejdca.com
Their first report is here: http://www.thejdca.org/uploads/JDCA_initial_report_2011.pdf
Their definition of a cure is here: http://www.thejdca.org/uploads/Defining_a_Practical_Cure.pdf
(Their "practical" cure is very similar to my "functional" cure.)

Non-conflict of interest statement: I don't work for the JDCA nor am I a member.  They've never paid me or given me any kind of gift or freebie.  They do read my blog and use the research they find there.  We discuss specific issues that they care about and they sometimes ask my opinions on research into cures.  Some of the information and opinions we discuss have not yet made their way into my blog.

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 (June)

LCT Starts A Phase-II Trial in Argentina

LCT is developing an encapsulated pig islet cell product.  The hope is by implanting these cells, people with type-1 diabetes will not need to measure their BG level or inject insulin, and the cells will keep their BG levels in normal range without an external help.

LCT has gotten government permission to start a phase-II trial in Argentina.  They expect to dose 8 people in the second half of 2011.  Each person will get to implants about 3 months apart.  LCT has already run a phase-I trial in Russia, and a phase-II trial in New Zealand.  But together, those trials have treated only 20 people.  This trial will bring the number up to 28.  Previous results were that one patient was did not need external insulin for a few months, and another was insulin free for a few weeks.  Several other patients used less insulin after the implantation, for weeks or months.  From my point of view, that's a long way from a cure, but LCT has been working to improve their encapsulation technology and their islet cell processing technology, and research is always about doing better in the future.

http://www.lctglobal.com/html/blob.php/974605%20(2).pdf?attach=0&documentCode=3453&elementId=20084


Are Pharma Companies Paying Your Doctor?

The guys over at Pro Publica have gotten a hold of several databases of doctors who are being paid by pharmaceutical companies, for various reasons.  The companies provided this information to the government, but Pro Publica has also taken it and made an easy to search database.  See if your doctor is getting paid for speaking, or for meals, or for any other reason.  (Look up names like "Smith" and "Jones" to get a feel for how much money is involved.)  I never thought a lunch or two really mattered, but some of these guys are getting more than $35,000 in one year, and that's enough to make you wonder.  Or at least make me wonder.

http://projects.propublica.org/docdollars/

Xcell (Adult Stem Cell Clinic) Shut Down in Germany

Every few months, I get asked about for-profit clinics that offer to cure various aliments (including type-1 diabetes) by injecting people with their own adult stem cells.  I'm working on a detailed posting about these clinics, but in the meantime, there is one less clinic to worry about:  Xcell, with two locations in Germany, has been shut down.

I definitely got more questions about Xcell then about similar clinics in Mexico, Argentina, Thailand, the Ukraine  China or anywhere else.  I think being located in Europe gave them an aura of respectability missing from other clinics.   Years ago, they announced that they were going to start a clinical trial on type-1 diabetes.  I searched diligently, but never found any evidence that the actually had started the study, and certainly no results.  But they always had great on-line testimonials from people with type-1 diabetes (and many other illnesses) who they had "helped".

News coverage:
http://www.bionews.org.uk/page_95103.asp
http://www.telegraph.co.uk/news/worldnews/europe/germany/8500233/Europes-largest-stem-cell-clinic-shut-down-after-death-of-baby.html

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

Diamyd Fails in Phase-III Trial

Diamyd Fails in Phase-III Trial

Diamyd's European phase-III trial has failed. 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.

(By the way: if that paragraph sounds familiar, it's because its the exact same paragraph that I used to describe Tolerx's Otelixizumab failure a few weeks ago, and could have been used to describe MacroGenics's Teplizumab failure a few weeks before that. It applies pretty much the same to all three. They all failed in about the same way and at almost the same point in their development cycle.  They were all in phase-III clinical trials.)

This is a vaccine like treatment designed to teach the body's own immune system to stop attacking it's own beta cells. You can think of it like the anti-alergy injections that people sometimes get. They give a little of the allergen so that the body slowly becomes used to it. The company's description is this: "with Diamyd® is thought to induce tolerance to GAD, thereby intervening in the autoimmune attack and preserving the capacity to produce insulin in patients with autoimmune diabetes".

Where is Diamyd Now?

The situation for Diamyd is a little more complex than for ToleRx or MacroGenics, because there are more different studies being done with Diamyd's drug than for ToleRx's or MacroGenics's drugs, and those studies are being done by more different people.  Diamyd is planning to continue their large phase-III trial in the US, which is basically a twin of this trial that failed.  And they are also going to continue following the patients in this trial, just in case there are good results after a longer period of time.  I don't hold out much hope for either of those studies being successful.

Additionally, there is at least one study which is using Diamyd to try to prevent type-1 diabetes by giving it to people who have not yet been diagnosed.  There is at least one phase-II study being done by academics in the US (so not run by Diamyd).  Finally, there is a very small "combo" study being done at the NIH where Diamyd is being combined with two other drugs to try to either regrow beta cells, or get more insulin out of the existing beta cells.  The hope is the combination of all three drugs might impact type-1 diabetes.  I expect all three of these trials to continue, and they are all a little different from the one that failed, so there still is some hope.

So Where are We Now?

I think everyone needs to understand that these last six months have been disastrous in for human trials designed to lead to a cure for type-1 diabetes.   We've gone from having 4 drugs in phase-III trials -- the last phase before market approval -- to having just 1.  The remaining one is DiaPep277.  On average, a drug which enters phase-III trials should successfully move to the next stage (market approval) about 55% of the time.  In fact, for type-1 diabetes we are currently somewhere between 0% and 25% (the higher number only if DiaPep277 eventually gets approved).

Also, it is disturbing to note that no new drugs have started phase-III trials in the last two years.  We have gotten new phase-I and phase-II drugs, but nothing has entered phase-III trials to take the place of the three that have dropped out.  That's a bad sign as well.

I'm not sure the proper musical background for this blog entry, but definitely something by Nine Inch Nails,  maybe "Something I Can Never Have".

You Won't Hear It Here, First
I was talking on the phone to a research analyst months ago, and he as me "how do you know all this research news before anyone else".  I was so shocked, I almost dropped the phone.  Because it's not true.  Almost never am I the first person to publish something in my blog.  Why not?  First, because I'm in California.   That means if something happens in Europe or the East Coast, local bloggers will be posting about it hours before me.  But the big reason is that I'm not trying to to be quick; I'm trying to provide context and thoughtful reflection on the news.  I'm not trying to be news clipping service.  My own goal, is to blog on important events within a week of when they occur, and more minor events within a month.  But I don't always succeed even at that.


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

Orban's Phase-I Results

I'm a little embarrassed that it has taken me so long to blog about Dr. Orban's results.  They were announced almost a year ago.


Data from Orban's Phase-I Trial

This research is a vaccine-like attempt to teach the body's immune system to stop attacking it's own beta cells.  A molecule (insulin B chain) similar to insulin was given along with IFA (an adjuvant, a chemical that makes the immune system react more strongly to a vaccine) to try to train the immune system not to attack beta cells.  This was a single injection during the honeymoon phase and patients were then followed for two years.

In terms of safety, the results were fine: nothing bad happened, and this is a new treatment, so safety was an important question.  But in terms of effectiveness, the results are mixed.  The vaccine did result in a specific immune system change that looks promising.  The exact quote was:

The induction of a lasting, robust immune response generating autoantigen-specific regulatory T cells provides strong justification for further testing of this therapy in type 1 diabetes.

But no effectiveness was seen during the trial.  Their was no improvement in C-peptide generation of the treated group compared to the non-treated group.  They were checked every six months.  Dr. Orban works at the Joslin center.

Opinions

In my mind how you view these results says a lot more about your personality, than the results themselves.  If you are an optimist, then you say "they proved safety, and they proved the treatment induced the change in the immune system the researchers were looking for so this is a success, and they should move on to phase-II testing to find a dose that will have a good effect on the person".  If you are a pessimist, then you say "it did not effect the patient's C-peptide numbers, so there is no reason to think it will end up curing (or even improving) type-1 diabetes".  The American phrase for this dichotomy  is "Is the glass half empty or half full?"

But the truth is, that my opinion doesn't matter, and neither does your's.  (Unless you happen to be funding Dr. Orban, of course!)  If Dr. Orban gets funded for the next phase, then this study is a success on a path that might lead to a cure.  If not, then it is a failure.  That's not a very scientific view of success, but it is very pragmatic.

In the past, I know that ITN has discussed the possibility of doing a phase-II trial, but nothing ever came of it.  I don't know why.  Also, Dr. Orban has started his own company, specifically to bring this cure to market.  Their web page is here: http://www.orbanbiotech.com/

The most recent news I have have from them is that in Nov 2010 they got a grant from the US Government: http://www.marketwire.com/press-release/orban-biotech-awarded-244000-qualifying-therapeutic-discovery-grant-from-us-government-1354039.htm
"Orban Biotech Awarded $244,000 Qualifying Therapeutic Discovery Grant From U.S. Government"
Abstract: http://www.ncbi.nlm.nih.gov/pubmed/19931408
Summary: http://www.immunetolerance.org/studies/autoantigen-vaccination-newly-diagnosed-type-1-diabetes-mellitus
Full Paper: http://www.immunetolerance.org/sites/files/2010.04_Orban_JAutoimmunity.pdf
(Thank you Immune Tolerance Network!  For making this available on your web site.)
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT00057499

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

Possible Cures for Type-1 in the News (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