Sunday, October 25, 2015

JDRF Funding for a Cure 2015

In the US, we are in the "Walking Season" when JDRF asks us to walk to raise money for a cure. So I'd like to do my part, by reminding you all of how important JDRF is to the human trials of potential cures for type-1 diabetes, which I track.

Let me give you the punch line up front: 69% of the treatments currently in human trials have been funded by JDRF. (And the number is 77% for the later phase trials) This is a strong impact; one that any non-profit should be proud of. This summary does not include Artificial Pancreas research or stem cell growth trials, because there are so many of those that it would be hard to include them all.

Below is a list of all the potential cures, grouped by phase of trial that they are currently in, and separated into potential cures that JDRF has funded, and those that JDRF has never funded.

This list is a list of treatments, and many of these are being tested in more than one clinical trial. For example, the "ATG and autotransplant" treatment is actually running three trials, but since they are all testing the same treatment, it is only one item in the list. The list below uses the following marks to show the nature of the treatments:
    (Established) One or more trials are open to people who have had type-1 diabetes for over a year.
    (Prevention) This treatment is aimed at preventing type-1 diabetes, not curing it.

Also remember that I give an organization credit for funding a treatment if they funded it at any point in development; I don't limit it to the current trial. For example, JDRF is not funding the current trials for AAT, but they did fund earlier research into it, which helped it grow into human trials. I include indirect funding of various kinds. For example, the JDRF funds nPOD and helps to fund ITN and several other organizations, so I include research done by these other groups as well, as being indirectly JDRF funded.

Cures in Phase-III Human Trials
Summary: currently there are no treatments aimed at curing type-1 diabetes which are in phase-III trials (under the definition of cure that I use). This is the third year in a row there have been no phase-III trials underway, and it's not a good thing. Even worse, I don't see a phase-III study starting even next year.  Some people might be discouraged by that, but for me, it's a reason to donate.  Money is the thing that is going to move the Phase-II studies below into Phase-III studies, and the Phase-I studies to Phase-II, create more phase-I studies, and so on.

Cures in Phase-II Human Trials
Summary: there are 22 trials in phase-II, and 17 of them have been funded by JDRF, while 5 have not. Here are the treatments that have been funded by JDRF:
  • AAT (Alpha-1 Antitrypsin) by Grifols Therapeutics and also Kamada 
  • ATG and GCSF by Haller at University of Florida (Established) 
  • Abatacept by Orban at Joslin Diabetes Center 
  • Abatacept by Skyler at University of Miami (Prevention) 
  • Aldesleukin (Proleukin) at Addenbrooke’s Hospital, Cambridge, UK 
  • Diabecell by Living Cell Technologies (Established) 
  • Diamyd, Ibuprofen ("Advil") and Vitamin D by Ludvigsson at Linköping University 
  • Gleevec by Gitelman at UCSF 
  • Oral Insulin (Preventative) 
  • Rituximab by Pescovitz at Indiana University 
  • Stem Cell Educator by Zhao (Established) 
  • Teplizumab (AbATE study team) 
  • Teplizumab by Herold/Skyler/Rafkin (Preventative)
  • Tocilizumab by Greenbaum/Buckner at Benaroya Research Institute 
  • Umbilical Cord Blood Infusion by Haller at University of Florida 
  • Ustekinumab by University of British Columbia
  • Verapamil by Shalev/Ovalle at University of Alabama at Birmingham
Not funded by JDRF:
  • ATG and autotransplant by Burt, and also Snarski, and also Li 
  • Atorvastatin (Lipitor) by Willi at Children's Hospital of Philadelphia 
  • BCG by Faustman at MGH (Established) 
  • Brod at University of Texas-Health Science Center 
  • Vitamin D by Stephens at Nationwide Children's Hospital (Prevention)
Cures in Phase-I Human Trials
Summary: there are 20 trials in phase-I, and 12 of them are funded by JDRF, while 8 are not. Here is the list funded by JDRF:
  • Alefacept by TrialNet 
  • ßAir by Beta-O2's at Uppsala University Hospital in Sweden (Established) 
  • TOL-3021 by Bayhill Therapeutics (Established) 
  • CGSF by Haller at University of Florida 
  • Trucco at Children’s Hospital of Pitt / Dendritic Cells (DV-0100) by DiaVacs (Established) 
  • IBC-VS01 by Orban at Joslin Diabetes Center 
  • Leptin by Garg at University of Texas 
  • Nasal insulin by Harrison at Melbourne Health (Prevention)
  • Smart Insulin (MK-2640) by Merck (Established) 
  • Polyclonal Tregs by both Trzonkowski and Gitelman 
  • Pro insulin peptide by Dayan at Cardiff University 
  • VC-01 by Viacyte (Established)
Not funded by JDRF:
  • CGSF and autotransplant by Esmatjes at Hospital Clinic of Barcelona (Established) 
  • Encapsulated Islets at University clinical Hospital Saint-Luc (Established) 
  • Etanercept (ENBREL) by Quattrin at University at Buffalo School of Medicine
  • Mesenchymal Stromal Cell by Carlsson at Uppsala University
  • Microvesicles (MVs) and Exosomes by Nassar at Sahel Teaching Hospital 
  • Monolayer Cellular Device (Established) 
  • Rilonacept by White at University of Texas 
  • The Sydney Project, Encapsulated Stem Cells (Established) 
Summary of all Trials
42 in total
29 funded by JDRF
So 69% of the human trials currently underway are funded (either directly or indirectly) by JDRF. Everyone who donates to JDRF should be proud of this huge impact; and everyone who works for JDRF or volunteers for it, should be doubly proud.

Just Looking at Trials on Established Type-1 Diabetics
13 of these treatments (31%) are being tested on established type-1 diabetics.
Of these, 8 are funded by JDRF
So 62% of the trials recruiting established type-1 diabetics are funded by JDRF.

Compared to Last Year
In 2014 there were 40 treatments in clinical trials, in 2015 there are 42 (growth of 5%)
In 2014 there were no treatments in Phase-III trials, in 2015 there are none (no change).
In 2014 there were 21 treatments in Phase-II trials, in 2015 there are 22 (growth of 5%).
In 2014 there were 19 treatments in Phase-I trials, in 2015 there are 20 (growth of 5%).

How I Count Trials for This Comparison
  • I give an organization credit for funding a cure if it funded that cure at any point in it's development cycle. 
  • I mark the start of a research trial when the researchers start recruiting patients (and if there is any uncertainty, when the first patient is dosed). Some researchers talk about starting a trial when they submit the paper work, which is usually months earlier. 
  • If there are different clinical trials aimed at proving effectiveness as a cure and as a preventative, or effectiveness in honeymooners and established diabetics, then those are counted separately. 
  • For trials which use combinations of two or more different treatments, I give funding credit, if the organization in the past funded any component of a combination treatment, or if they are funding the current combined treatment. Also, I list experiments separately if they use at least one different drug. 
  • The ITN (Immune Tolerance Network) has JDRF as a major funder, so I count ITN as indirect JDRF funding. 
  • I have made no attempt to find out how much funding different organizations gave to different research. This would be next to impossible for long research programs, anyway. 
  • Funding of research is not my primary interest, so I don't spend a lot of time tracking down details in this area. I might be wrong on details. 
  • I use the term "US Gov" for all the different branches and organizations within the United States of America's federal government (so includes NIDDK, NIAID, NICHD, etc.) 
  • I don't work for the US Gov, JDRF, or any of the other organizations discussed here. I have a more complete non-conflict of interest statement on my web site. 
Some Specific Notes:
  • Serova's Cell Pouch and DRI's BioHub: These two clinical trials are both testing one piece of infrastructure which might be used later in a cure. They are testing a part of a potential cure. However, in both cases, the clinical trials being run now require immunosuppression for the rest of the patient's life, so I'm not counting them as testing a cure.
This is an update and extension to blog postings that I've made for the previous seven years:
Finally, please remember that my blog (and therefore this posting) covers research aimed at curing or preventing type-1 diabetes that is currently being tested in humans. There is a lot more research going on, not covered here.

Please think of this posting as being my personal "thank you" note to all the JDRF staff, volunteers, and everyone who donates money to research a cure for type-1 diabetes:
Thank You!
Finally, if you see any mistakes or oversights in this posting, please tell me! There is a lot of information packed into this small posting, and I've made mistakes in the past.

Joshua Levy
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.

Thursday, October 22, 2015

Seasonal Flu Vaccine and Type-1 Diabetes

Every now and then I get asked about any safety issues for a flu vaccination for someone who has type-1 diabetes.  So I researched that question, and below is my summary of research to date.  Note that this summary focuses on flu vaccines only;  I have separate summaries for childhood vaccinations and also for HPV vaccinations.

I looked for all clinical trials where they gave flu vaccine to type-1 diabetics, specifically.  I did not think there would be any such studies, because recruiting from such a limited population would be tough.  But I was wrong.  There were several, but I only had time to look at the first 8 (listed below); some studies covered more than one area:
  • Two studies focused on safety, and these found no added risk to type-1 diabetics.
  • Four studies focused on effectiveness, and three of these found no differences in effectiveness between type-1 diabetics and the general population.  One study found that flu vaccines were less effective for type-1 diabetics as compared to the general population.
  • Three studies focus on flu vaccines affecting the immune system in a way which would contribute to type-1 diabetes, and these found that it did not.
Rather than summarize each study, I'm letting each study "speak for itself" by quoting the abstract from each one.  You can click on the abstract to see the exact study design: most were intervention studies with control groups; one was a population registry study.
One injection of 2009 pandemic influenza A(H1N1) MF59-adjuvanted vaccine is immunogenic and safe in young patients with Type 1 diabetes who are at increased risk of influenza morbidities. Pandemic vaccine can be safely co-administered with seasonal influenza vaccine.
The results indicate that in older children and young adults with type I diabetes influenza vaccination with a virosomal or a standard subunit vaccine is safe and adequately immunogenic against the three influenza vaccine strains. In addition, the virosomal vaccine may show better long-lasting immune response than the standard subunit vaccine, especially in subjects without pre-existing antibodies to influenza strains.
From these results it is concluded that IAA [an autoantibody linked to type-1 diabetes] formation is not a direct sequela of viral infection or vaccination.
Use of Pneumo 23 vaccine or its combination with Grippol vaccine in patients with DM1 did not result in increase of levels of autoantibodies to n-DNA, d-DNA and pancreatic tissue, was not able to initiate or lead to disease progression as well as positively influenced on the immune response with tendency to normalization of the several arms of the immune system and, at the same time, did not result in activation of autoimmune process.
No significant difference was found between diabetic patients and control subjects with respect to antibody response after vaccination.
The influenza-specific antibody response in both serum and oral fluid were similar for both groups, and also showing a kinetic profile in accordance with our earlier data for healthy adults. Our study did not detect a difference in the humoral immune response between juvenile diabetics and healthy controls.
Risks for Guillain-Barré syndrome, multiple sclerosis, type 1 diabetes, and rheumatoid arthritis remained unchanged.
In Type 1 (insulin-dependent) diabetic patients the incidence of non-responders to two vaccine components was significantly increased
Taken together, these studies show that flu vaccines are safe for type-1 diabetics, do not worsen the immunology behind type-1 diabetes, and are effective for type-1 diabetics. One one study found that flu vaccines were less effective for type-1 diabetics than for the general population, but less effective does not mean "not effective"!

Joshua Levy 
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.

Friday, October 2, 2015

Summary of EASD 2015

EASD is the European Association for the Study of Diabetes.  Their conference is the largest diabetes research gathering in Europe.  I did not attend, but reviewed all the abstracts, posters, and 100s of tweets sent with the EASD2015 hashtag.  This posting is my summary.

Unfortunately, as with ADA 2015 earlier this year, there was not much research aimed at a cure which had reached human trials.  I've divided this posting into four areas: news on human trials aimed at a cure, artificial pancreas research, high buzz research, and other research I found interesting.  But there was only one abstract dealing with a cure in human trials.  Disappointing.

Research In Human Trials Aimed At A Cure

Proinsulin peptide immunotherapy in type 1 diabetes: safety data of a first in new-onset type 1 diabetes phase 1b trial || Abstract #503
These researchers are testing a type-1 diabetes vaccine made from part of an insulin molecule.  They are testing it for safety in newly diagnosed type-1 diabetics.
The poster is not on line, but you can see the abstract.  It appears that the study was strictly safety-only, and there were no safety issues, but no data on effectiveness, either.

Artificial Pancreas Research

There was a lot of AP research.

This was a presentation by the Cambridge group:
33 adults used an AP for 12 weeks "free range".  Trial was open label, cross-over design.  (Meaning that all patients were both treatment group and control group at different times.)  AP did not handle meals.  AP did better than non-AP in terms of average BG, and no worse for lows.  AP also did better on A1c.  This research was published in the New England Journal of Medicine:
and is also discussed here:
and here:

This was a presentation by groups in France and Italy using the University of Virgina AP:
35 adults used an AP overnight for two months. Trial was cross-over design.  AP did better than non-AP in terms of time in target, with less time in both high and low BG.
One patient dropped out of this study because he was not able to trust the device enough to participate in the study.  This patient was a professor of mathematics.  (This got a laugh during the presentation.)
These researchers are now testing 24 hour use of the device.

This presentation was by Steven Russell on the Bionic AP (same project as Dr. Damiano works on):
This presentation included previous data from adults and camp kids, but also new (to me) data from younger children (6-11 years old).  This was also at camp, and was 5 days on, 5 days off (cross-over design).  The BG improvements seen in these younger kids was better than seen in adults or in camp kids.  In my opinion, the improvements seen in these kids were striking.

He then presented data from a "free range" trial of 40 adults for 11 days on, and 11 days off (cross-over) study.  This data was also very good.  The whole presentation was well done, and well worth viewing, but if you just want some quick data: fast forward to slide 25 (usual care) and then compare it to 26 (AP); this is for one selected patient, but you can see the huge improvement.

He then presented data from a comparison of glucagon vs. no glucagon study.

Finally he presented their target (hoped for) timeline:

  • Transitional Studies: 2013 - 2016
  • Production of a fully integrated device (prototype already made via private donations).
  • Bridging Studies: starting in 2016
  • Pivotal Studies: 2017 - 2018
  • Review by FDA: 2018
  • Commercial availability: late 2018 or early 2019

Dr. Russell said that the FDA had indicated that this device and long term glucagon use, could be approved based on a single pivotal trial of 450 patients for 6 months, with a 6 month extension for 100 of the patients.  (And this length and size is due to the needs of the glucagon approval.)

Also, Tidepool is collaborating with this research team in creating the user interface for their AP.

High Buzz Research

The research which generated the most buzz, by far, was the results of the EMPA-REG study.
However, this was a huge study of a SGLT2 drug in type-2 diabetes, so I won't comment.

There were also a lot of "Insulin vs. Insulin" and "New Insulin" papers and posters.  These are studies which show that one type of insulin is better than another, or that a new type of insulin is safe and effective.  I didn't count, but suspect there were over 20 of them, but this kind of research does not excite me.  There was some early work on a weekly shot basal insulin, and that is interesting to me. The research was on people, too.  But it is still years off, I think.

Glucagon nasal powder: an effective alternative to intramuscular glucagon in youth with type 1 diabetes (Abstract #42) generated some buzz:
You can watch the 15 minute presentation or read the abstract, at this web page.
Slide #5 shows clearly that glucagon nasal powder is similar to glucagon injection.
This tweet contains a one chart summary:
Patients in this study were between 4 and 17 years old; a previous study had focused on adults.
The nasal formulation was much easier to use, and (of course) no needle was needed.  Also the same nasal dose can be used for youth of all ages, so no more "half shots" for younger/smaller kids.
One patient sneezed immediately after getting the nasal glucagon, and this patient's BG levels did not rise, but the researcher wasn't worried because glucagon is usually given to unconscious people, who don't sneeze.  The company involved (Locemia Solutions) is "in discussions with regulatory agencies".

There was a phone app (I think called "gocarb") where you took a picture of a plate of food, and it estimated carbs.  Here are some of the tweets for that:
I'm a little dubious about this whole idea, but it did generate a lot of positive tweets.

Dexcom's G5 will soon be available in Europe:

The Google/Dexcom tiny BG sensor also generated some buzz:

Other Research I Found Interesting

The talk by Andrew Hattersly:
This is a one hour talk given by Dr. Hattersly, who basically discovered monogenic diabetes (often called MODY).  I really enjoyed it, even if I did not understand all of the science.  The talk is good because it shows how different scientific work comes together to make important discoveries, and how science is a team effort, and patients are involved.  Monogenic diabetes  is caused by a single genetic mutation.  There are several different types of monogenic diabetes , each involves the mutation of a different single gene.  This is quite different than classic type-1 diabetes, where there are many genetic features, some of which make type-1 more likely, some less likely, plus environment triggers, all of which come together to cause type-1 diabetes.  Monogenetic is binary: you have the gene, you get the disease.

The key points from this talk are two fold:

  1. Anyone diagnosed with type-1 diabetes when they are under six months of age, actually has neonatal diabetes (one form of monogenic diabetes ).  Neonatal diabetes can be treated with insulin, but can also be treated with a much cheaper pill (no shots!)  If you, or someone  you know, was diagnosed when less than six months old, and uses insulin, you (or they) may want to talk to your doctor about trying to switch to the pill.  More information:
  2. Dr. Hattersly estimates that between 1% and 3% of the people diagnosed with type-1 diabetes actually have some form of monogenitic diabetes. Except for neonatals, these people generally must be treated with insulin, just like type-1s, but it's still valuable knowledge.  He has an experimental web page to calculate a person's chance of having monogenic type-1 diabetes:

Autoimmune diseases in children and adults with type 1 diabetes from the type 1 diabetes exchange clinic registry || Abstract #499
This link has an abstract, the poster, and a 5 minute discussion by the author.
The Type 1 Diabetes Exchange is a huge project, funded by the Helmsly trust, to gather all kinds of data on over 25k people who have type-1 diabetes.    Some findings:
The #1 additional autoimmune disease found in type-1s is thyroid disease at 19%.
Celiac's is #2 at 6%.

Sustained glycemic control and less nocturnal hypoglycemia with new insulin glargine 300 U/ml versus glargine 100 U/ml over 1 year in Japanese people with type 1 diabetes mellitus (EDITION JP 1) || Abstract #4
ADA 2015 had at least one paper (which I found interesting) suggesting that higher density insulins were better for type-2 diabetics.  Some extremely obese type-1 diabetics need to refill their pump every day with standard u100 insulin, but only every other day with u300 insulin.  This is a money and convenience issue.  But additionally, there was evidence that higher density insulins were more effective; that fewer units were needed for the same carb or basal situations.  This study found that type-1s used more insulin, but had lower nocturnal numbers and at the same time, fewer lows.  That's still a good outcome.

I found the comparison to u100 to higher density insulins interesting, especially if we get sets that can last longer than 3 days, the pressure for high density will become stronger.

Joshua Levy public
joshualevy 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.