Diamyd Update Part 2: JDRF Flexibilty In Funding and Diamyd In More People

My previous blog posting:
https://cureresearch4type1diabetes.blogspot.com/2023/12/diamyd-update.html
described the main line of DIAGNODE clinical trials designed to get Diamyd FDA approval for people in their honeymoon phase.  You should read that posting for a lot of background material.  In this blog, I'm going to cover two additional clinical trials aimed at expanding the people who can use this treatment and some interesting details about how JDRF is funding this research.

DIAGNODE Expansion Trials

These two trials are using the same DIAGNODE technique (injecting Diamyd into the lymph nodes of people with the HLA DR3-DQ2 gene).  The first is aimed at people who are at-risk of T1D, rather than the honeymooners, which is what previous trials focused on.  The second is aimed at people with LADA, rather than people with the more classic T1D onset, which is (again) what previous trials focused on.

DiaPrecise (Diamyd For At-Risk)

 

This is a small (16 people), trial where half the people get 2 Diamyd injections and the other half get 3, so there is no control group.  Everyone in the study has two autoantibodies, but has not yet been diagnosed with T1D.  Using Trialnet terminology they are in stage 1.

This study is ongoing now and is expected to finish in 2025.

Clinical Trial Registry: https://clinicaltrials.gov/study/NCT05683990

 

GADinLADA (Diamyd For LADA)

This is another small (14 person), phase-II trial done on people with LADA (an autoimmune form of diabetes diagnosed in older people).  People got three injections of Diamyd, one month apart, into lymph nodes.

 

It was successful in the sense that there were no serious side effects, and it is clear that they can do a larger, randomized, blinded study in the future if they wish.  However, I can't evaluate if Diamyd actually helped these people.  They have published C-peptide numbers, which show that the people who got the treatment lost some of their ability to generate C-peptide.  This is not good, but I don't know what happens to people who are not treated, so I cannot tell if the Diamyd helped them or not. 

Journal Article: https://dom-pubs.onlinelibrary.wiley.com/doi/pdf/10.1111/dom.15239

Clinical Trial Registry: https://clinicaltrials.gov/study/NCT04262479 

Money: JDRF, but not T1D Fund

Diamyd (the company) has gotten some money from JDRF through their Industry Partnership Program, and that money is contingent on Diamyd (the treatment) meeting certain successful results.  For me, this is a very interesting development and warrants some discussion.

In the past JDRF operated like most other medical research charities (and the US government) and gave grants to researchers.  The researchers would propose research and if JDRF liked it, they would give the researchers the money to do it.  This is the way most non-profits fund most of their research even to this day.  

However, in 2016 some people active in JDRF became frustrated by the gap between academic research (funded by grants) and commercial research which, for small companies, was funded by venture capital and for large companies, by corporate capital.  So they created The T1D Fund: https://t1dfund.org (especially read the "about" tab).

This fund uses money seeded into it by JDRF and from other sources (mostly wealth investors) to fund commercial medical development work aimed at T1D.  It operates as a venture capital firm.  It makes investments in companies doing work in the T1D space.  As investors they are (generally) part owners of the companies they invest in, and if those companies are successful, they will profit from the success.  Those profits will then be rolled into new investments.

A complete description of how venture capital works (and therefore how the T1D Fund works) is well beyond what I can do in a blog post.  I can't even (quickly) find a good on-line summary that someone else has written!

So as of 2016, there were two separate funding methods for getting T1D products to market: 

• JDRF, traditional grant-based early research focused.
• The T1DFund, venture capital-based and early product development focused.

But now (finally) to the Diamyd point: the funding that Diamyd received is not exactly either of these two funding methods.  It is in between.  The money is coming from JDRF but has some very business like conditions, as described in the bullet point items below.  (These items are taken from a Diamyd press release.)

• Payments from JDRF are earned when Diamyd Medical completes various milestones in the DIAGNODE-3 study, with these milestones spanning the years 2023 - 2027. 
• JDRF can also use its global type 1 diabetes network to raise awareness of the study, which may contribute to patient recruitment, and also provide advisement as Diamyd Medical prepares for a potential commercial approval. 
• If Diamyd Medical in the future gets Diamyd® commercially approved and the sale of the drug becomes a commercial success, JDRF will receive a limited royalty on the revenue, if within the framework of the partnership agreement. 

These are all very business like terms; similar to how one company funds another.  I discuss the details more below, but the summary point is that JDRF is expanding the kinds of funding it can give which adds flexibility to all future investments.  For me, this is a good thing because you never know which kind of investment will benefit a new line of research the most.

Why is all this important?

Most importantly, it means that JDRF will share in the monetary success of Diamyd, if there is any.  This is very different than traditional research grant work, and it addresses a recent frustration.  I know some people were frustrated because JDRF has put money into the academic research with led to the development of Teplizumab, but had not gotten any money out when Teplizumab became a commercial product or even when the company was bought out (for $3 billion US dollars!)  This is perfectly normal in academic grant making, which is traditionally what medical research non-profits have done, but it can leave a bad taste in a donor's mouth.  The Diamyd funding model avoids this.

Also important: Diamyd only gets money when they meet certain milestones.  This is not speculative research grant money;  this is payment on success, motivational money.  It is very common in the world of corporate financing, but I've never before seen it in the world of research grant making.

In another way, I view this as JDRF having more flexibility in funding cures than academic research projects, but not yet self-funding commercial projects. 

Press release: https://www.diamyd.com/docs/pressClips.aspx?ClipID=4676370

Joshua Levy

http://cureresearch4type1diabetes.blogspot.com

publicjoshualevy at gmail dot com

All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My kid has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

 

Diamyd Update

This is my first update on the Diamyd company in many, many years.  It is focused on their DIAGNODE-3 clinical trial, but before I discuss that one study, I cover Diamyd's history, and after I discuss the study, I've included a list of all the studies the company has done (which is a lot: about 19 studies in about 20 years).

But that is not all that Diamyd is active with.  In a future blog, probably in February, I'm going to discuss two more clinical trials which are important to applying Diamyd to at-risk people and people with LADA.  DIAGNODE-3 is focused on honeymooners.  That future blog will also include some interesting discussion of JDRF's funding of Diamyd.

The drug Diamyd is a form of GAD65.  GAD65 is an enzyme, which is common in the pancreas and is used to make GABA and it is also a target of the immune system which can cause type 1 diabetes.  The company Diamyd believes that the drug Diamyd works by teaching immune cells not to attack beta cells and therefore beta cells will not be destroyed at the onset of T1D.  The technical phrase for this is "antigen-specific tolerizing beta-cell preserving therapeutic".  It is also sometimes called a reverse vaccine, because it teaches your immune system not to attack a specific kind of cell (your beta cells), while a standard vaccine teaches your immune system to attack a cell (the attacking virus).

History

When I first started this blog, in 2006, Diamyd was already one of the potential cures most advanced in the research pipeline.  In 2008 they started two phase-III clinical trials in people in the honeymoon phase of T1D.  If successful, these could have led to government approval.  In January 2009, I considered the start of these clinical trials to be one of the "big-5" best news of the year.  At that time they were also running several phase-II trials to test out Diamyd in other situations.

However, in 2011 one of the phase-III trials ended  unsuccessfully ("did not meet the primary efficacy endpoint"), and in the next year, the other phase-III study was terminated.  In the years after that, several of the previously started phase-II were unsuccessful, and the company started a few more studies, but again none of these were particularly successful.

Later, in 2015 the company started the DIAGNODE clinical trial which involved injecting the Diamyd treatment directly into a person's lymph nodes.  Previous studies injected Diamyd right under the skin, much like insulin.  Results from that study were available in 2020 and the follow on DIAGNODE-2 had results in 2021.  I took a quick look at them, and they did not look successful to me.  (See the details below, the trial was unsuccessful, but also included some results that gave hope.)  So I never blogged on them.

Meantime, the company ran some meta analysis which pooled data from more than one of their studies.  They included some genetic subtyping and the results were successful and statistically significant for some genetic types.  I go into the details below.  This led Diamyd to a much more optimistic view of the results, and so they started the DIAGNODE-3 clinical trial.

The DIAGNODE-3 Trial

This phase-III trial will recruit 330 people in the honeymoon phase of T1D, within 6 months of diagnosis.  They will be between 12 and 29 years old and will have a specific gene called HLA DR3-DQ2.

Each patient will get three injections of Diamyd, one month apart, and also take vitamin-D for 2 months, and will be followed for 2 years.  The primary end points are C-peptides and A1c.  Secondary end points include time-in-range, insulin dose, and unexpected lows.

This study started recruiting in Europe in 2022, but the recent news is that in September 2023 it started recruiting in the United States.  This is a big study, with 60 recruiting locations all over Europe and the United States.  The trial has it's own web page here:
https://www.diagnode-3.com/
which includes a cool interactive map to find a clinic near you:
https://www.diagnode-3.com/Clinics.aspx
(Remember to select your country, if it starts off displaying a different country.)

Diatribe has a good article on this clinical trial as well:
https://diatribe.org/trial-investigates-promising-new-beta-cell-treatment

News Coverage: https://www.precisionmedicineonline.com/business-news/diamyd-medical-expand-phase-iii-diabetes-drug-trial-us
Clinical Trial Registry: https://clinicaltrials.gov/study/NCT05018585
Corporate Web Site: https://www.diamyd.com/

Discussion

For me, there are two areas of discussion for this clinical trial: (a) will it work, when previous research didn't, and (b) will the FDA approve it, based on successful results from this one study, or will more research be needed?

The big question is: will the current clinical trials be successful when the previous ones were unsuccessful?  As far as I can see, there are two differences.  The first is that for the recent studies, Diamyd is injected into a lymph node, while in the older studies it was injected under the skin, far from lymph nodes.  Because the lymph nodes are part of the system that educates immune cells to attack the foreign cells, getting more Diamyd closer to them could make it more effective.

The second difference is that they are only accepting people who have the HLA DR3-DQ2 gene (technically they must "carry the HLA DR3-DQ2 haplotype").  The gene is associated with autoimmune diseases, especially T1D, and it is involved in synthesizing GABA, so again, it makes sense that people with this gene would be more sensitive to the Diamyd treatment. About half the people with T1D have this gene.

Are these differences enough to create success?  The obvious way to measure this is to look at the phase-II DIAGNODE-2 study, which was published here:
https://diabetesjournals.org/care/article/44/7/1604/138800/Intralymphatic-Glutamic-Acid-Decarboxylase-With
https://academic.oup.com/jcem/article/107/9/2644/6602344

Unfortunately, the data is not clear.  This study recruited enough people to run the analysis in a statistically significant way looking at the whole population, but when it was designed the impact of the HLA DR3-DQ2 gene was not known.   After the study started a meta-analysis combining past studies suggested that people with the HLA DR3-DQ2 were much more likely to be helped by the treatment.  So the researchers added a HLA DR3-DQ2 analysis to the study while it was underway and still blinded, but they did not enlarge the study.  Once the study finished, they did their analysis separately: once for everyone and again for people with the HLA DR3-DQ2 gene.  Sure enough, the study was unsuccessful when everyone was analyzed together.  But when just the HLA DR3-DQ2 people were analyzed, the treated group did better than the untreated group.  However, it was not statistically significant.  There were not enough people with that gene in the study to get a statistically significant result.  

In summary, we have three pieces of data:

1. The phase-II study as a whole was unsuccessful.
2. The phase-II study looking just at the one genetype suggests success, but is not big enough to be sure.
3. A meta analysis combining previous studies was successful for the genetype.
   

The phase-III trial is only enrolling people with the HLA DR3-DQ2 gene, and is enrolling more people.  So I do expect a clear yes or no answer from this trial.

As for the question of FDA approval, that is much simpler to answer: no one knows, but the company is optimistic and plans to submit for FDA approval if the clinical trial is successful.  On paper, the FDA requires two phase-III clinical trials, and for T1D these trials involve about 300 people each.  So normally, I would say they need to run another study before getting approval.  

However, "in real life" (as opposed to the "on paper" requirements) the FDA did approve Teplizumab, which did not have two phase-III studies.  Instead, it had one phase-III and several older studies.   And Diamyd has a phase-III study and even more older studies than Teplizumab had.   Diamyd has a long history of safety in previous clinical trials, something like 15 trials covering over 1000 people.   Finally, Diamyd already has an orphan drug designation from the US FDA, and the company believes that will help get approval.

But no one except the FDA knows for sure what will happen if it were submitted for approval based on the phase-III trial currently underway.  The path to approval is clear: Complete the clinical trial, get a successful result, submit for approval, and then it is in the hands of the US FDA.

Diamyd More Generally

Diamyd has run 18 different clinical trials, which you can see here:

https://clinicaltrials.gov/search?term=diamyd

Below, I've organized them into five groups:

 

The DIAGNODE trials which enroll people with the HLA DR3-DQ2 gene and Diamyd is injected into the Lymph node.  These are aimed at getting government approval and turning Diamyd into a product for honeymooners.

More info:

https://clinicaltrials.gov/study/NCT05018585 "DIAGNODE-3" Recruiting honeymooners

https://clinicaltrials.gov/study/NCT05351879 "DIAGNODE-B" Extension to DIAGNODE-2

https://clinicaltrials.gov/study/NCT03345004 "DIAGNODE-2"

https://clinicaltrials.gov/study/NCT02352974 "DIAGNODE-1" 

DIAGNODE expansion trials.  These are using the same DIAGNODE technique, but the first is aimed at people who are at-risk of T1D, not honeymooners, and the second is aimed at people with LADA.  These are the studies I will discuss in a future blog posting.

More info:

https://clinicaltrials.gov/study/NCT05683990 "Diaprecise" Recruiting at-risk 

https://clinicaltrials.gov/study/NCT04262479 GADinLADA" Testing on LADA patients

The DIAPREVENT trials were supposed to get the data required for governmental approval, for what I would call "classic Diamyd", which is injected under the skin (not into the Lymph node), and given to any honeymooner (not just those with HLA DR3-DQ2).

More info:

https://clinicaltrials.gov/study/NCT00723411 Phase-III "DIAPREVENT-2" Unsuccessful 

ended in 2011

https://clinicaltrials.gov/study/NCT00751842 Phase-III "DIAPREVENT" Terminated in 2012

https://clinicaltrials.gov/study/NCT01129232 Phase-II 

https://clinicaltrials.gov/study/NCT00435981 Phase-II

These studies were "Diamyd And" studies, where the company Diamyd tested the Drug Diamyd and one or two other medicines, hoping for better results.  these are all "classic Diamyd" style clinical trails:

https://clinicaltrials.gov/study/NCT02002130 Diamyd and GABA

https://clinicaltrials.gov/study/NCT02387164 Diamyd and Vitamin D

https://clinicaltrials.gov/study/NCT01785108 Diamyd, Vitamin D, and Ibuprofen
https://clinicaltrials.gov/study/NCT02464033 Diamyd, Vitamin D, Vitamin D, and Etanercept 

Other Old Studies:

https://clinicaltrials.gov/study/NCT00837759 NIDDK

https://clinicaltrials.gov/study/NCT00529399 NIDDK (Trialnet?)

https://clinicaltrials.gov/study/NCT00456027 Diamyd on LADA
https://clinicaltrials.gov/study/NCT01122446 For at-risk people, not honeymooners.

https://www.diamyd.com/docs/pressClips.aspx?ClipID=4665003 Reanalysis of two previous studies.

Joshua Levy

http://cureresearch4type1diabetes.blogspot.com

publicjoshualevy at gmail dot com

All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My kid has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

T1D Research News (Quick Bits for July)

This blog is a collection of smaller news items about T1D.

COVID Not Likely to Increase T1D in Children

From the beginning of COVID there has been an expectation that T1D rates would go up because COVID would either "cause" or "trigger" T1D.  

(I might be splitting hairs by separating "causing" and "triggering",  but in my mind, these are two different things.  If X causes Y, that means that if the person avoids X they will never get Y.  That X takes a healthy person and they get Y.  On the other hand, X triggers Y, means that the person was always likely to get Y, and X changed the timing so that the person got Y right then, but they still would have gotten Y eventually, even if X had not happened.  I think there is widespread agreement that many illnesses "trigger" a diagnosis of T1D, but the question of weather they "cause" T1D is very much open.)

In any case, this research suggests that T1D diagnosis rates did go up, but not because of COVID, but rather because of changes in behavior due to the lock down.

Source: https://www.news-medical.net/news/20230322/SARS-CoV-2-not-likely-to-increase-the-incidence-of-type-1-diabetes-in-children.aspx

From the article:

More children and adolescents than usual developed type 1 diabetes in Finland in the first 18 months of the coronavirus pandemic. According to a recently completed study, the cause was not the novel coronavirus, but altered environmental factors.

According to the study, the incidence of type 1 diabetes increased in children in Finland by 16% in the first 18 months of the pandemic. However, very few children or adolescents who developed type 1 diabetes had SARS-CoV-2 antibodies indicating a past infection.

According to the researchers, the increase in the incidence of type 1 diabetes in the early stages of the pandemic is not likely to have been caused directly by coronavirus. Instead, it may be related to the society-wide lockdown in the pandemic period and the resulting social isolation.

"According to what is known as the biodiversity hypothesis, microbial exposure and infections in early childhood can boost the protection against autoimmune diseases. The reduction in contacts in connection with the societal lockdown significantly reduced acute infections in children, which may have increased the risk of developing diabetes," Knip [one of the paper's author's] explains.

Combination of GABA and GAD Unsuccessful in Phase-II Trial

I previously blogged on this study here: https://cureresearch4type1diabetes.blogspot.com/2018/08/gaba-starts-phase-ii-clinical-trial-in.html

Summary of results from the abstract:

The primary outcome, preservation of fasting/meal-stimulated c-peptide, was not attained. Of the secondary outcomes, the combination GABA/GAD reduced fasting and meal-stimulated serum glucagon, while the safety/tolerability of GABA was confirmed. There were no clinically significant differences in glycemic control or diabetes antibody titers. ... although GABA alone or in combination with GAD-alum did nor preserve beta-cell function in this trial.

The paper: https://www.nature.com/articles/s41467-022-35544-3
The Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02002130

Discussion

This is a classic example of "slow publishing means bad results".  The study finished in 2019, but the results were not published until 2022.

Also, this is not good news for GAD, which Diamyd has been testing for many years.  One group of this study got GABA and GAD, but did no better than the control group.  If GAD were effective, you would expect to see some good effect in this group.

Abatacept Unsuccessful at Preventing the Onset of T1D

I previously blogged on this study here: https://cureresearch4type1diabetes.blogspot.com/2020/04/possible-cures-for-type-1-in-news-april.html

Summary of results:

This trial of 1-year treatment with abatacept in participants with stage 1 type 1 diabetes did not show a statistically significant effect on progression to stage 2 or stage 3 type 1 diabetes.

This was a 200 person study (half got Abatacept, half got a placebo), for people at-risk of T1D (called "stage 1").  These are people with two or more autoantibodies, so the assumption is that they will move to abnormal blood glucose tests ("stage 2") and then diagnosis of T1D ("stage 3"), as the disease progresses.   The goal was to delay this progression. 

News Article: https://www.hcplive.com/view/abatacept-misses-mark-for-preventing-type-1-diabetes-in-phase-2-trial
Journal Article: https://diabetesjournals.org/care/article/doi/10.2337/dc22-2200/148547/Abatacept-for-Delay-of-Type-1-Diabetes-Progression
Note to the T1D Community: https://www.trialnet.org/our-research/completed-studies/abatacept
Trial Registry: https://clinicaltrials.gov/ct2/show/NCT01773707

Discussion

Abatacept has been tested in several different clinical trials going back at least 15 years.  In a case of unfortunate timing, researchers in Australia started a new Abatacept study about 3 weeks before the unsuccessful results of this study were announced:
https://www.clinicaltrials.gov/ct2/show/NCT05742243
The Australian study is enrolling people who have been diagnosed with T1D, while the earlier study was enrolling people who had 2 autoantibodies, but no abnormal blood sugar tests, and no other symptoms.  So it is possible that one would be successful even though the other has failed, but I think it is a "long shot". 

Joshua Levy

http://cureresearch4type1diabetes.blogspot.com

publicjoshualevy at gmail dot com

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

GABA Starts A Phase-II? Clinical Trial in Honeymooners

This blog has two parts.  The first part describes a phase-I clinical trial in honeymooners which started recently.  The second part summarizes the rest of the GABA (Gamma-Aminobutyric Acid) research done so far in people.  GABA is well known as a neurotransmitter, but it also is generated by pancreatic beta cells and also the immune system, both of which are heavily involved in type-1 diabetes.

GABA is widely available as a "dietary supplement", and you can read a lot more about it here:
https://en.wikipedia.org/wiki/Gamma-Aminobutyric_acid
There are several mouse studies that show effectiveness against type-1 diabetes.

The Current Clinical Trial

This trial will enroll 95 people with honeymoon type-1 diabetes into three groups as described below.  It is recruiting children aged 4 to 18.  They plan to finish in June 2019.  Primary outcomes are insulin usage and C-peptide generation, while secondary outcomes are levels of diabetes autoantibodies.  All of these will be measured one year after dosing.  People will get two injections of GAD, one month apart.  They will take GABA pills twice a day.  I think the pills will be for a year, but I might be wrong about that.

The three patient groups are:
    Some people will get two different placebos, and be a control group.
    Some will get GABA and a placebo for GAD.
    Others will get both GABA and GAD.

GAD is developed by Diamyd corporation, and has been tested for at least 10 years.  I've blogged on it in the post many times:
https://cureresearch4type1diabetes.blogspot.com/search/label/Diamyd
It has a long history of safety, but also of not being effective.  So I don't hold out much hope for the GAD alone being effective.  But that doesn't really matter, because GAD alone is not being tested.  Since two different arms will get GABA, if that is effective, it will be obvious.  If the GAD + GABA arm is more successful than the GABA only arm, that would breathe new life into GAD research.  In animals, GAD is part of the biochemical mechanism which creates GABA, so the two are related.

This trial is marked in the FDA registry as still recruiting at one site, however the press release from Diamyd says it is already fully enrolled:
    Children's [Hospital] of Alabama, Birmingham, Alabama, United States, 35233
    Contact: Sharon D. May, BSN    205-638-5031    smay@peds.uab.edu 
    Contact: Heather Choat, MD    205-638-9107    hchoat@uab.edu 
    Web page: https://www.childrensal.org/endocrinology-research

The researchers considered this a phase-I trial, but because of the size and the previous GABA clinical trials, I'm treating it as a phase-II? trial, meaning a trial big enough to be phase-II, but without results from a previous phase-I trial done on people with type-1 diabetes.

Press Release: https://www.diamyd.com/docs/pressClips.aspx?ClipID=2827171
USA Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT02002130
WHO Clincal Trial Registry: http://apps.who.int/trialsearch/Trial3.aspx?trialid=NCT02002130

This research is funded by JDRF and the companies that manufacture GAD (Diamyd / Johnson and Johnson) and GABA (NOW foods).

Preview of Coming Attractions: Diamyd, the company that researched GAD is now also working on a GABA based drug called Remygen.  A research group in Sweden is planning to start a trial of this drug in people with established type-1 diabetes in Sept 2018. I'll blog on these trials when it starts.  Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT03635437

A Little History

Back in 2012 Penny Jester, a researcher at the University of Alabama at Birmingham, tried to start a clinical trial in GABA.  However, the FDA did not approve her IND (Investigational New Drug) application, and so the trial was never started.  You can see the registration here:
https://www.clinicaltrials.gov/ct2/show/NCT01561508

In 2013 Zhaoyun Zhang and fellow researchers at Huashan hospital in Shanghai, China ran a small study (confirming safety) on GABA in healthy people, reported here:
https://www.ncbi.nlm.nih.gov/pubmed/26617516

and  registered here:

https://clinicaltrials.gov/ct2/show/NCT01917760

Then in 2013 the same group started a 60 person phase-II? study of GABA on people with honeymoon type-1 diabetes, but I have not been able to find published results.

You can read Dr. Zhang's rational for testing GABA in this paper:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4322886/

More Reading

Because both GABA and GAD have long histories as potential cures for type-1 diabetes, there is lots of previous research to read, if you want:

    https://www.the-scientist.com/news-opinion/studies-unable-to-reproduce-results-of-two-diabetes-papers-64630

    http://diabetes.diabetesjournals.org/content/62/11/3674.full

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136292/ (mice)
    https://www.uu.se/en/news-media/news/article/?id=10440


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

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

This posting is a collection of small updates.

Verapamil's Phase-II? Trial Completes Enrollment

Verapamil is a drug which has been used in the US since 1982 for high blood pressure, migraines, and heart problems.  It also lowers levels of a protein called TXNIP.  The researchers running this trial believe this is important because they believe TXNIP kills beta cells as part of the onset of type-1 diabetes.  So giving Verapamil should lower TXNIP which should improve beta cell survival, and stop type-1 diabetes.  In addition TXNIP is known to lower inflammation, and that might have an effect on type-1 diabetes as well. TXNIP worked in mice trials.

The news here is that they have completed enrollment.  There is good and bad news in that.  The good news is we now know that the trial will finish in 2019, since they completed enrollment in Jan 2018 and need to gather data for a year.  The bad news is that they only recruited 32 people; they were hoping for 52.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02372253

Vitamin D Didn't Impact The Honeymoon In A Phase-I Trial

Vitamin D has been a hot topic for the last few years, and there are several different clinical trials looking at it in three different contexts: Does low Vitamin D help trigger type-1?  Does increasing Vitamin D help prevent type-1?  And, does increasing Vitamin D to people who have type-1, help treat or cure it?   All together, there are 15 completed trials, 6 recruiting, and 2 underway but not recruiting, and one not yet started.  That is strong interest.

This trial was a phase-I, honeymoon trial of 36 people.  Half got Vitamin D, and half got a placebo.  The patients who got Vitamin D did do a little better (used less insulin during their honeymoon), but the effect was not statistically significant.

Press Release: http://www.nationwidechildrens.org/medical-professional-publications/vitamin-d-and-the-honeymoon-period-of-type-1-diabetes?contentid=146302
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT01724190

Diamyd and Vitamin D start a phase-II Trial (DIAGNODE-2)

This clinical trial will test a Diamyd injection and oral Vitamin D in honeymoon type-1 diabetes.

It is recruiting in several European countries: Czechia, Spain, and Sweden.  See the clinical trial record for a list of exact sites, there are many in each country.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT03345004

Discussion

You can read my previous blogging on Diamyd here:
https://cureresearch4type1diabetes.blogspot.com/search/label/Diamyd

Diamyd has been tested for over 10 years.  All previous trials (which have completed) have been unsuccessful.  There are currently two other Diamyd and Vitamin D trials underway.  While I'm always hopeful that these tests will be successful, Diamyd's long history without success does not give me much to hope for with this trial.


How well can you predict the outcome of clinical trials? Not as well as you may think.

One of the guiding quotes of this blog is "Opinions are not important; but what is important is the reasoning behind them, the data and information they are built on, etc. In short: why a person has opinions is more important than the opinions themselves. And that includes my opinions. Especially "my opinions."  This is a news article on researcher's ability to predict the outcome of studies in their field.  I thought it was interesting reading:
https://www.statnews.com/2018/01/22/clinical-trials-forecasting-outcomes/

A Stock Market Opinion: Diabetes Clinical Trials to Watch

This is a finance/stock analysis of what's important in 2018:
https://www.gurufocus.com/news/622818/three-diabetes-clinical-trials-to-watch-in-2018
From my point of view, they are all type-2 focused (which makes sense from a market share point of view: type-2 is 90% of the market).

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

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

Trial of Intranasal Insulin To Prevent Type 1 Diabetes (INITII) Is Fully Enrolled

The official title is "Trial of Intranasal Insulin in Children and Young Adults at Risk of Type 1 Diabetes (INITII)" and it is now fully enrolled.  Since people will be followed for a total of 10 years, results will be ready in 2026.  However, the primary end point is after 5 years, so it's possible that those results would be published sometime after 2021.

Previous blogging is here: http://cureresearch4type1diabetes.blogspot.com/2012/09/possible-cures-for-type-1-in-news-early.html (but it's not much).  The important information is this:

Several different groups are experimenting with using insulin to prevent or cure type-1 diabetes.  This is similar to giving people with food allergies the food they are allergic to in tiny doses, gradually building up the dose over years until they are no longer allergic.  (Although the truth is a little more complex than that: type-1 diabetes is not a simple allergy to insulin.)  Because insulin is basically a protein, it gets digested, so you can't take pills of insulin.  These researchers are experimenting with inhaled insulin, given to people who are at risk of developing type-1, but have not yet developed the disease.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT00336674

Results from IL-2 (the DLIT1D study)
Several groups of researchers are trying to cure type-1 diabetes by using IL-2 (Aldesleukin).  I've blogged on this before:
http://cureresearch4type1diabetes.blogspot.com/2016/05/general-update-on-il-2-research.html
The basic idea is that giving Aldesleukin raises the level of T-reg cells, and those cells kill off the bad T-killer cells, and that's good for people with type-1 diabetes.

This particular trial was aimed at finding the dose of Aldesleukin which would cause a 10%-20% increase in T-reg cells.  The technique was to give a dose of Aldesleukin to a small number of people, monitor them closely, and then based on those results, give a different dose to another small group, and so on.  After a couple of repetitions, they narrow in on the perfect dose.  This is not as easy as it sounds because Aldesleukin causes T-reg numbers to drop in the short term (which is bad), but go up in the longer term (which is good), so you need to evaluate these two effects by dose and frequency.

The researchers are happy with their results: they now know what Aldesleukin dose to use in future research, and they understand why some previous IL-2 research was unsuccessful.  Unfortunately, from my point of view, there was no improvement in C-peptide numbers or A1c numbers.  As an optimist, I'm hopeful that was because they were only testing a single dose in this trial, and improved numbers will be seen in studies with more doses over a longer period of time.

This research should lay the foundation for future clinical trials of Aldesleukin.

Abstract and Paper: http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002139
European Trial Registry: http://www.isrctn.com/ISRCTN27852285
American Trial Registry: https://clinicaltrials.gov/ct2/show/NCT01827735

Combining Diamyd Data
(My summary: "if you combine several smaller failures, you end up with one larger failure".)

This study is a testament to the optimism of researchers.  Diamyd ("GAD Vaccine") has been tested for over 10 years.  None of these trials has been particularly successful.  They culminated in an unsuccessful Phase-III trial years ago.  You can read my previous blogging on Diamyd here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Diamyd

However, researchers are natural optimists.  And it is important that they are.  Society needs optimistic researchers so that they will repeatedly attack problems, and not give up, even in the face of adversity.  In October, researchers published this paper, which basically pooled all the Diamyd data from several previous studies, and reported that it had a very small effect.  The researchers present this as a success, but the effect is so small that I consider it confirmation of failure.

People with type-1 diabetes are expected to lose insulin production during their honeymoon phase. This summary found that those given Diamyd lost 80% as much as those who were not treated.  In the last few years, several treatments have shown better results in clinical trials, and none of those have progressed to a cure, or even a treatment, so I'm not expecting this news to push Diamyd forward.  (By "better results" I mean that, when given during the honeymoon, they end up slowing beta cell destruction more than Diamyd slowed this destruction.)

Abstract: https://www.ncbi.nlm.nih.gov/pubmed/27704166


Polio Virus Trial Finished
The researchers finished gathering data in Nov-2016 so they should publish results in the next year (if successful) or two (if not).  This is an unusual trial.

The trial started in 1999, and was run by Dr. Hanna Viskari out of the University of Tampere in Finland.  These researchers believe that infection with an enterovirus would have an impact in later development of type-1 diabetes.  (It is unclear to me if they thought it would raise or lower the chance of getting type-1.)  To study this, they are following a group of 315 children who are at heightened risk of getting type-1 diabetes, because they are genetically predisposed to it.  Some of these children were given the OPV polio vaccine, which contained weakened, but still live, polio virus, while others got the IPV polio vaccine, which contains dead polio virus.  These children will be followed for 10 years to see if one group has a lower type-1 diabetes rate than the other group.

This trial is a "natural history" type trial, not an intervention trial.  Finland changed it's method of Polio vaccination, so these researchers followed children who got the "old" vaccination (OPV) to children who got the "new" vaccination (IPV).  The researchers did not randomize children to get one or the other vaccine, they merely tracked children who were already getting one or the other vaccine.

Polio is the most famous  (infamous?) enterovirus, but the family contains about 70 viruses including the Coxsackie viruses and the virus that causes Hand, Foot, and Mouth Disease.  More modern viruses in the family get numbers, rather than names, so viruses called EV-71 and EV-D68 are recently discovered enteroviruses.

Discussion
I think this study might provide general information on the relationship between enteroviruses and type-1 diabetes, but I don't think it will change people's behavior.   If the IPV polio vaccine group has a lower type-1 rate: that is already the polio vaccine that people in the US get normally.   On the other hand, if the OPV polio vaccine group has the lower type-1 rate, that vaccine has a tiny (but non-zero) chance of causing paralysis, so I don't see people switching to it in order to prevent type-1 diabetes.

Clinical trial record: https://clinicaltrials.gov/ct2/show/NCT02961595
Discussion of OPV vs. IPV: http://www.virology.ws/2015/09/10/why-do-we-still-use-sabin-poliovirus-vaccine/


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

Research In The News (March)

Here are a few updates related to possible cures for type-1 diabetes being tested in people:

Grifols Therapeutics Completes Recruiting on a Phase-II Trial of AAT

In February 2016, Grifols completed recruiting people for their phase-II trial of AAT (Alpha-1 Antitrypsin).  This is a 76 person study with two different dose treatment groups and a placebo group. Assuming the study progresses normally, they will finish collecting data in February of 2018 and publish the year after that.

AAT is an anti-inflammatory / immunomodulatory drug, which the body makes naturally, and which is already FDA approved for people who have a rare condition where they don't make enough of it on their own. Using AAT to treat type-1 diabetes is based on the idea that one of AAT's effects (lowering inflammation, immune modulation, or wound healing) can cure/prevent/treat the disease.  My previous blogging on AAT is here:
http://cureresearch4type1diabetes.blogspot.com/search/label/AAT

Discussion: My summary of AAT's status is this: after several phase-I studies which did not give a strong signal of success, we now have two phase-II studies (the other is Kamada's involving about 60 people) and these will finish collecting data in 2016 and 2018, respectively.   When those two trials are published, we should have a clear success/failure signal.

Previous blogging on AAT: http://cureresearch4type1diabetes.blogspot.com/search/label/AAT
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02093221

Combo of Diamyd and Vitamin D Starts a Phase-II Prevention Trial

This is a classic prevention trial.  The researchers will enroll 80 children (between 4 and 18) who are positive for two autoantibodies (GAD and any one other), but not yet showing any symptoms of type-1 diabetes.  These people will be followed for 5 years to see how many are diagnosed in that time. This study started in March 2015 and is expected to finish in March 2022.  Half the children will be given Diamyd and Vitamin D, the other half, just Vitamin D.

Diamyd is similar to GAD, which is the target of the most common autoantibody seen in type-1 diabetes.  The hope is that Diamyd will train the immune system not to autoattack.

This study is enrolling "by invitation only", so if you are interested in enrolling, you can contact Dr. Helena Elding Larsson at Lund University, Clinical Research Center, Pediatric Endocrinology, Jan Waldenströms gata 35, 60:11 Malmö, Sweden, 20502

Discussion: Diamyd was unsuccessful at curing honeymoon type-1 diabetes in a large phase-III clinical trial and also unsuccessful in curing adult onset type-1 diabetes, but their earlier, smaller phase-II trial showed better results, so this study is testing it as a preventative. According to TrialNet research, essentially all of the people in this trial will eventually be diagnosed with type-1, but not within 5 years.  It will be interesting to try to match up the numbers from this study and TrialNet.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02387164

Combo of Diamyd, Vitamin D, and Etanercept Starts a Phase-II Trial

This trial will test a combination of Diamyd, Vitamin D, and Etanercept as a cure for type-1 diabetes.
The trial will enroll 20 honeymooning children (ages 8 to 18), all of whom will get the treatment. There will be no control group.  People will be followed for 2 1/2 years, checking for C-peptide (natural insulin generation), A1c, and insulin, plus a bunch of safety measures and immunological measures.  This trial is expected to finish in November-2018, but that will only happen if they are fully enrolled by May-2016, which is coming up quickly!

The hope for this trial is that Diamyd will stop or lower the autoimmune attack, Etanercept will lower inflammation and stop the immediate loss of beta cells, and Vitamin D will do some unspecified good (based on the fact that countries closer to the equator have more sunlight so more Vitamin D and less type-1 diabetes).

They are recruiting people all over Sweden:
Eskilstuna Hospital -- Eskilstuna, Sweden -- Contact: Ulf Söderström, MD      
Helsingborg Hospital -- Helsingborg, Sweden -- Contact: Anna-Karin Albin, MD      
Linköping University Hospital -- Linköping, Sweden -- Contact: Johnny Ludvigsson, MD      
Lund University Hospital -- Lund, Sweden -- Contact: Annelie Carlsson, MD      
Skåne University Hospital, UMAS -- Malmö, Sweden -- Contact: Tore Vigård, MD      
Sachsska, Södersjukhuset -- Stockholm, Sweden -- Contact: Björn Rathsman, MD      
Uddevalla Hospital -- Uddevalla, Sweden -- Contact: Ragnar Hanås, MD      
Västerås Hospital -- Västerås, Sweden -- Contact: Carl-Göran Arvidsson, MD      
Örebro University Hospital -- Örebro, Sweden -- Contact: Stefan Särblad, MD

Discussion: Diamyd has been tested in much larger trials, and has not been found effective.  Vitamin D has not yet been tested in an intervention trial (and the news is mixed from population studies), but Etanercept did have one successful phase-I trial, but it did not (by itself) rise to the level of a cure. I've blogged about all these separate treatments, but this is the first study I know of which combines them:
http://cureresearch4type1diabetes.blogspot.com/search/label/Diamyd
http://cureresearch4type1diabetes.blogspot.com/search/label/Vitamin%20D
http://cureresearch4type1diabetes.blogspot.com/search/label/Etanercept

Don't mix this research up with the DIABGAD trial (also done by Dr. Johnny Ludvigsson), which combined Diamyd, Vitamin D, and Ibuprofen.  Although the two projects are similar in that they are both Diamyd plus Vitamin D and an anti-inflammatory.  Ibuprofen and Etanercept are both anti-inflammatories, although they use different mechanisms: Ibuprofen is a COX inhibitor, while Etanercept is an TNF inhibitor.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02464033

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

Possible Cures In The News (March)

Here are some bits and pieces of research, that I found interesting:

GAD65 Not Effective for LADA

GAD65 is one of the molecules targeted in the autoimmune attack which leads to type-1 diabetes.  A company called Diamyd, developed it as a honeymoon cure for type-1 diabetes.  The hope was it would train the immune system not to attack pancreas cells, and that would stop type-1 diabetes. It looked OK in phase-II trials, but failed phase-III trials a few years ago.

However, there were a few other studies underway when the phase-III data came in, and this is one of those studies.  The researchers were giving GAD65 to people who had LADA (Latent Autoimmune Diabetes of Adults).  LADA is a not separate form of diabetes, but a name given to people who have type-1 diabetes, but are diagnosed in adulthood (usually over 25).

In this trial, GAD65 treatment had no effect.

Abstract: http://care.diabetesjournals.org/content/early/2014/03/04/dc13-1719.abstract?papetoc


Non-Cure Research

When Does Type-1 Diabetes Start?

Currently, type-1 diabetes is diagnosed when symptoms are seen.  Usually, those symptoms are signs of high blood sugar: excessive urination and thirst, unexplained weight loss, lack of energy, etc.  More recently, some people have been diagnosed because their after meal blood sugar spikes above 200, even before the other symptoms are seen.

But now, there is some discussion that maybe we should change the definition of type-1 diabetes even earlier.    You can read about that in the link below:

JDRF News: http://bayarea.jdrf.org/blog/redefining-diagnosis/

Another Veo Safety Study

The Medtronic Veo is the first (very small) step to an artificial pancreas.  It shuts off for a few hours if blood sugar levels go low for too long.  This could be a huge step forward in preventing "dead in bed" fatalities, which are a significant cause of death for people with type-1 diabetes.

Anyway, there was a clinical trial to find out what would happen if the Veo cut off insulin incorrectly, when the BG levels were high (instead of low).  This is the exact opposite of what the Veo is supposed to do, and it has not been seen to happen in actual use.  However, the idea was to test to see what would happen, if the pump failed in this way.

The researchers found that even if this failure occurred, nothing bad happened to the person using it.  So that gives an added level of safety for this product (and presumably similar products, when they come to market in the future).

Abstract: http://care.diabetesjournals.org/content/37/3/773.abstract?etoc

Future Postings

I'm currently working on three blog postings, which I hope to get out in the next month, but obviously, I'm way behind, so no promises.  And I don't know what order they will come out in:

• Dr. Damiano's Bihormonal Artificial Pancreas
• Dr. Faustman's Phase-II study of BCG
• General Update on AAT 

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

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

Clinical Trial of Diamyd, Ibuprofen ("Advil") and Vitamin D

Diamyd (GAD65) is a protein which is one of the targets of the autoimmune attack that starts off type-1 diabetes. It was developed with the idea that giving it to people with type-1 diabetes would teach their immune systems to not attack their own beta cells. It would be like giving someone who is allergic to peanuts, just a tiny amount of the peanut protein that triggered their allergy, in the hopes that they would build up tolerance.

Unfortunately, although it worked in mice and (to some degree) in phase-II studies in people, it failed in phase-III studies in newly diagnosed type-1 diabetics.   There are still a couple of smaller on going studies.  For example, to see if Diamyd will help prevent type-1 in high risk people who have not yet been diagnosed with the disease.

So that brings us to this study. The idea behind it is:

1. Give more Diamyd vaccine than was given in the past. About twice as much.
2. The Vitamin D is supposed to stimulate the part of the immune system that reacts to the Diamyd vaccine, so it makes for a more powerful vaccination effect.
3. The Ibuprofen ("Advil") lowers the inflammation in the pancreas, which may help save beta cells, and may help the vaccine work better, and may do both.

The study will include 60 children (aged 10 to 18) in the honeymoon phase. They will be followed for 30 months, but expect some results after only 6 months. The participants will be divided into 4 groups of 15. One will be a placebo group, and the other three will each get different combinations of the three treatments.  Since they hope to start in February 2013, I think it is reasonable to expect the 6 month results in the second half of 2015 and the 30 month results by the end of 2017.  That's assuming it takes them 2 years to recruit 60 people.  I have not yet seen a clinical trials record for this, yet.

Press release: http://www.diamyd.com/docs/pressClip.aspx?section=investor&ClipID=738266

More About Diamyd

This is a full PhD thesis that was written based on data from Diamyd's phase-II clinical trial.
http://liu.diva-portal.org/smash/record.jsf?pid=diva2:562438
http://liu.diva-portal.org/smash/get/diva2:562438/FULLTEXT01

Imatinib ("Gleevec" / "Glivec") Starts a Phase-II Clinical Trial

This study has not yet started recruiting, but when it does, it will be a 66 person trial.  It is double blind and placebo controlled.   It is open to honeymooners (first 100 days), including children.  They hope to start in April 2013 and end by April 2017.  I"m not sure of the details, but I think patients will take a pill daily for the first year.  They will have clinic visits monthly for the first year, and twice a year thereafter.

Imatinib is a relatively new cancer drug, which is popular because it targets an enzyme that only cancer cells have, so it is relatively non-toxic to non-cancer cells.  (The buzzword is "targeted".)  The obvious question is why would it be expected to work on type-1 diabetes.   The work done so far in mice suggests that it is a different pathway entirely, which leads to it's effect against type-1.

Some background on why this might work (in order, earliest to most recent):
   Animal models 2007: http://www.fasebj.org/content/21/2/618.abstract
   More mice 2008: http://www.ncbi.nlm.nih.gov/pubmed?term=19015530
   Press release: http://www.ucsf.edu/news/2008/11/4166/cancer-drugs-type-1-diabetes
   Human tissue 2011: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0024831

Notice the progression, and the speed:  First tested in animals in 2007.  First tested in people in 2013.  And remember: this is for a drug that is already approved, for another disease!

Wikipedia: http://en.wikipedia.org/wiki/Imatinib
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01781975

Vitamin D Starts a Phase-II Clinical Trial

So far, there is no evidence that Vitamin D can cure or treat type-1 diabetes, and only a little evidence that it can prevent the disease.  This trial is trying to cure or treat type-1 diabetes by giving Vitamin D during the honeymoon phase.

The trial is being done in Nationwide Children's Hospital (Columbus, Ohio, USA) by Dr.Kathryn J Stephens and Dr. Robert P Hoffman.  It has not started enrollment, but they plan to enroll 54 people.  Half will get vitamin D for 9 months, half will get a placebo.  They hope to have results in March 2014.

I had previously reported on a vitamin D trial, but that was a population based trial, not an intervention trial.  This is an intervention trial, which are typically much higher quality. 

Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01724190

A Note About Terminology

I know that some people are very emotional about saying "a person who has type-1 diabetes" vs. saying "a type-1 diabetic", as in "they gave the drug to five people with type-1 diabetes" vs. "they gave the drug to five type-1 diabetics".  Some people object strongly to the second form, because they think that it defines the person by the disease; that it signals in some way that the disease is the person or the person is the disease.

Personally, I usually use the first form, because I prefer it and because I know that some people really object to the second form.  But I'm not fanatical about it, and you will occasionally see me refer to "type-1 diabetics".  I'm not trying to insult anyone when I use the second form.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.   Thanks to everyone who helps with the blog.
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

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

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

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

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

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

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

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

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

GCSF/Neulasta phase-II Study Completes Enrollment

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

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

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

Thymoglobulin (ATG) Phase-II Study Completes Enrollment

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

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

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

Combo (Diamyd, Lansoprazole and Sitagliptin) Trial Fails

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

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

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

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

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

More Stable Glucagon

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

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

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

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

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

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

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

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

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

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

Diamyd Publishes Their GAD Failure in Phase-III

Diamyd published a full, peer reviewed article on their phase-III clinical trial.  I don't think there is any new information there, but there are a lot of details to read.  However, I do think there are two lessons to be learned here.  One relates to spin.  Take a look at these headlines:

No Improvement in C-Peptide Levels With GAD-Alum‎
Autoantigen Tx Benefits Some Type 1 Diabetics
Type 1 Diabetes Treatment Disappoints in Trial‎
GAD-alum Antigen Therapy Fails to Halt Progression of Type 1 Diabetes‎ 

They are all actual headlines on different web sites for this same news.  That second one gives the news a different spin, than the rest. In this case, most of the headlines are accurate, but if you happen to see that one "outlier" headline, you will get a very different view of the results.

The second relates to timing.  The timeline for these results are as follows:

May 2011: Diamyd announces that the phase-III trial had failed it's primary end point (press release)
June 2011: Data on this failure presented at ADA 71 (non-peer reviewed scientific presentation)
Feb 2012: Publication in the New England Journal of Medicine (top-flight, peer reviewed publication)

The take home point for me, is that this study went from completion to publication in about 10 months.  Furthermore, this study was (a) very large, (b) negative, and (c) published in one of the most important peer viewed medical publications in North America.  All of these factors would usually make the publication slower.  So I think it is a particularly bad sign when trials are completed but have not published in a year or two or more!

Press Release: http://www.marketwatch.com/story/diamyd-medicals-phase-iii-study-published-in-the-new-england-journal-of-medicine-2012-02-02

Gardasil Vaccine does not Trigger Type-1 Diabetes

Obviously, this is not cure research, but I know some people continue to be nervous about vaccinations, and the Gardasil vaccine is given during the time when type-1 diabetes is often diagnosed, so this study should provide a lot of confidence that the two are not related.

Basically, a large health maintenance company (which runs both insurance and hospitals) compared their records for people who got Gardasil and people who were diagnosed with type-1 diabetes within 6 months. These records were then double checked "by hand" and compared to similar people who did not get the vaccine.  They looked for many different autoimmune diseases, including type-1 diabetes, and were able to cover a huge number of patient records (about 190,000).  This was a huge study, so it could generate good data even for relatively rare diseases like type-1.

I don't believe that any one study can prove something with absolute certainty, but I do think that this is very well done study, and should carry a lot of weight.

News Coverage: http://medicalxpress.com/news/2012-01-gardasil-trigger-autoimmune-conditions-vaccination.html

Personal note: I was reading something about Gardasil, and found a great quote by a cancer researcher.  I didn't save it, so this is a paraphrase from memory:  "For decades, people have been clamoring for a vaccine to prevent cancer.  We finally developed one, but some people don't like it, because it has something to do with sex!"

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

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

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

Polyclonal Tregs Starts a Phase-I Clinical Trail

This one is a little complex.  The body's immune system includes T-regulatory cells, which help control the "killer" T-cells which (in type-1 diabetes) mistakenly attack the beta cells.  Some researchers have attempted to reduce the number of "killer" T-cells, while other researchers are trying to raise the number of T-regulatory cells.  This research is trying to raise the number of T-regulatory cells.  The basic technique is as follows: remove some of a patient's own T-regulatory cells, which is the same processes as giving blood.  Then separate and purify those T-reg cells, and grow them for about 2 weeks.  You can end up with 1000 times as many as you started with. Finally, put them back into the patient.  Since these cells naturally regulate (or control) the body's immune system, having more of them may result in the body stopping it's own autoimmune attack.   They've had good results in NOD mice.  Finally, some researchers believe that the previously seen good results in some other treatments (such as anti-CD3 and ATG) might be caused by these treatments stimulating T-reg production, rather than, or in addition to, lowering "killer" T-cell production.

This study involves 14 people, who have had type-1 diabetes for more than 3 months, but less than 2 years.  It is primarily a safety trial (to make sure the procedure is safe), but has secondary measures to also see if the treatment improves type-1 diabetes (for example: higher C-peptides, lower A1Cs, etc.).  It is a single site study, being done at UCSF (San Francisco, California, USA).  Dr. Gitelman  ("Dr. Steve", if you attend Bearskin Meadows camp) is running it.

Unfortunately, this study will not be quick.  It is expected to last until 2016.

Clinical trial record: http://www.clinicaltrials.gov/ct2/show/NCT01210664
UCSF's web page: http://www.diabetes.ucsf.edu/clinical-care-education/clinical-trials/type-1-diabetes/new-onset-type-1-diabetes-age-6-45-years-wit

Canakinumab Starts a Phase-II Clinical Trial

Canakinumab is a monoclonal antibody, which is designed to lower inflammation.  It was approved in 2009 (both US FDA and EU EMEA) for a collection of rare autoimmune based inflammatory diseases.  Good results have been seen in people with type-2 diabetes, and it has been used in children as young as 3. Therefore, it is known safe, and can start a phase-II trial for type-1 diabetes.  The trial is for 66 people who will be followed for 4 years.  It is honeymoon only (100 days from diagnosis).  The treatment is monthly injections for a year: 2/3 get treatment, 1/3 get placebo.  My general comments on inflammation based cures apply here: http://joshualevy.pbworks.com/w/page/24444346/ConceptsAndBackground#Inflammation

This is a large trial, recruiting in many locations in the US, which are listed in the clinical trial record below.  For locals: both UCSF and Stanford are participating.

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

Data Published from extended follow up to Diamyd Phase-II Trial

Diamyd as published some extended follow up up data from their phase-II trials, which I have not had time to review, but you can see it here:

Full Paper: http://www.springerlink.com/content/k7051252031r1671/fulltext.html
Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT00435981

Not Yet In Human Trials

There were several new types of artificial pancreas which I heard about in 2010, and this is the latest.  It is called a "Bionic Pancreas" and is basically a dual-hormone (insulin and glucagon) AP, but designed as a single, custom computer chip.  They hope to start human trials "this year [2011]".  These guys know about the dual-hormone work being done at Harvard, and the two groups are using some of the same ideas, but pushing different parts of the technology.  The Harvard guys are focused more on exact algorithms, and these guys (at Imperial Collage, in the UK) are focused more on a single chip package.

News report: http://spectrum.ieee.org/biomedical/devices/bionic-pancreas

Not Type-1 Diabetes Related

The following article describes the ethical issues of a chemist who works with brain chemicals in rats, and who's work is often used by black marketeers to create street drugs, which sometimes kill people.  It is an interesting read and an interesting moral dilemma.

http://news.yahoo.com/s/ap/20110105/ap_on_sc/us_sci_haunted_scientist;_ylt=Apj8w6un3xq9J8J_t4MMSEAPLBIF;_ylu=X3oDMTJwM2I5NnNlBGFzc2V0A2FwLzIwMTEwMTA1L3VzX3NjaV9oYXVudGVkX3NjaWVudGlzdARjcG9zAzEEcG9zAzIEc2VjA3luX3RvcF9zdG9yeQRzbGsDc2NpZW50aXN0aGF1

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