Sunday, January 31, 2016

Research In The News (January)

These are a couple of old news items that I'm catching up with.

Kamada Changes Phase-II Alpha-1 Antitrypsin (AAT) Study
Kamada has announced a major change to their Phase-II trial of AAT.  Although there are several AAT trials underway, this is the farthest along, and the largest.  You can read my previous blogging here:
http://cureresearch4type1diabetes.blogspot.com/search/label/AAT

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.

Prior to the change: The trial would collect data on 180+ people for two years.  The first half would be double blind, but at the half way point (90 people and 1 year) the data would be analysed unblinded, to check for safety and do futility analysis.  Results from the completed trial probably would not be published until 2019, maybe longer, depending on how long recruiting took.

After the change: The 60 patients enrolled by the end of 2015 will be followed for one year, and then results will be published, probably in 2017.

What does this mean?  It means we will see results from this trial quicker than originally planned, but it also means there will be less data.  Is this good or bad?  I thought about this question quite a bit, and there are two ways to answer that question.  From my point of view, this is good, because it will mean that we have results faster.  It is true they will not be as definitive, but my gut reaction is that if there is clear good news, then it will show up even in a 60 person study.  The only danger is that with 60 people, the results will not be clear.  But my belief is that if they are not clear with 60 people, then the answer is "no".  I think it's unlikely that a drug which is so-so with 60 people is going to show as a cure with 120 or 180 people.

Of course, another question is, do these changes mean that Kamada thinks the drug is working, or do they mean Kamada thinks the drug is failing?  My answer to that is "I don't know".  The trial is double blind, so officially Kamada should not know anything about the outcome.  Even if they did, good results could motivate them to speed things up, but so could bad results (to lower expenses). I don't see a good way to "read meaning" into a shorter trial.

In the non-scientific world, it could mean that the company is running low on money, or that it is harder than expected to recruit people for the study.  As originally designed, this study would require 180+ honeymooners to enroll in one country: Israel.  That's a lot of fish to pull out of a small fishing hole.  (My very "back of the envelope" calculations suggest that about 350 people are diagnosed with type-1 in Israel per year, so you'd need to get about half of them to enroll.  If you recruited for two years then "only" 1/4 of everyone diagnosed in the entire country would need to sign up. That is hard.)

Press release: http://www.businesswire.com/news/home/20151202005422/en/Kamada-Update-Alpha-1-Antitrypsin-Development-Newly-Diagnosed

About the inhaled version (being tested for a different disease):
AAT is already approved as an intravenous injection for treating AAT deficiency.  This is not the same type of injection as insulin; it generally requires a trip to a clinic for treatment.  However, Kamada is also testing an inhaled form to treat AAT deficiency.  If this is approved, and if AAT is found to work for type-1 diabetes, then having different forms will be convenient.  They have finished enrolling their inhaled AAT study, which is a good milestone:
http://www.businesswire.com/news/home/20151208005129/en/Kamada-Completes-Enrollment-U.S.-Phase-2-Study



Albiglutide Starts a Phase-II Trial

Albiglutide (tradenames Eperzan and Tanzeum) was approved in both the USA and the EU in 2014. It is a Byetta-like drug, designed to be used once per week, so the dosing is more like Victoza.  Like both of those drugs, Albiglutide is part of a large class of drugs called GLP-1 inhibitors.  All of these drugs are commonly used by people with type-2 diabetes.  It is not clear to me why it would cure type-1, but GlaxoSmithKline is testing it in type-1 diabetics, and it might improve A1c numbers.

This trial involves about 68 people, of whom 51 will get the drug and 17 will be in the placebo group.

The trial will take about 17 months per person.  Two months of pre-treatment screening, 12 months of treatment, and three months of post treatment monitoring.  They started in November 2014 and hope to finish by December 2016.

They will be recruiting people at about 29 different sites, in five different countries (France, UK, Germany, Italy, and Spain).  See the complete list in the clinical trial record below.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02284009
Wikipedia: http://en.wikipedia.org/wiki/Albiglutide

My plan is to follow this study, and see if this drug turns out to be a promising treatment, a promising cure, or neither.  If it doesn't show cure potential, I will stop covering it.

If this drug does prove useful in curing (or even treating) type-1 diabetes, there are several other widely available drugs in the same category which could be tested (some are available for off label use immediately). In addition to Victoza and Byetta there are: Bydureon, Dulaglutide, and Lixisenatide.

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.

Friday, January 22, 2016

Exsulin / Ustekinumab Combo Starts Phase-I Clinical Trial


Exsulin is a drug designed to trigger beta cell growth and Ustekinumab is designed to modulate the immune system.  These researchers are testing them together as a combination cure for type-1 diabetes.

My previous blogging on Exsulin (previously called INGAP) is here:
    http://cureresearch4type1diabetes.blogspot.com/search/label/INGAP
    http://cureresearch4type1diabetes.blogspot.com/search/label/Exsulin
My previous blogging on Ustekinumab is here:
    http://cureresearch4type1diabetes.blogspot.com/search/label/Ustekinumab

The Trial

The trial is on 5 people with no control group.  It started in Nov-2015 and will finish in June-2017.  It is open to adults who have had type-1 diabetes between 2 and 10 years, so this is for established type-1 diabetes, not honeymooners.  The people in the trial will get two injections of  Ustekinumab (one month apart) and twelve weeks of daily Exulin injections.

Results will be measured after six months.  The primary outcomes are "safety and tolerability" while the secondary outcomes are various C-peptide measures and one A1c measure.

This trial is recruiting at the Montreal General Hospital (Montreal, Quebec, Canada):
Contact: George M. Tsoukas, MD    514 934-8017    g.tsoukas@gmail.com
Contact: Louise Ullyatt, RN    514-934-1934 ext 42115    lullyatt@gmail.com
 

Discussion

Exsulin (INGAP) is a treatment with a history.  It's gone through two major cycles of clinical trials, and neither one panned out.  The researchers think that this was because Exsulin was stimulating beta cell growth, but these new beta cells were destroyed by the autoimmune attack, so even though the Exsulin was working, it was not benefiting the patients.  They are optimistic that by pairing it with an immune modulator (Ustekinumab), patients will see the benefit.

Obviously, five people is a very small trial.  However, since these are established, adult type-1 diabetics, they should have consistently very low C-peptide numbers.  Any increase should be noticeable and would be important.

It will be interesting  to compare these results to the Ustekinumab honeymoon results.  Honeymoon is a time when the body is still naturally producing enough insulin to make a difference, so comparing Ustekinumab+honeymoon to Ustekinumab+Exsulin will tell us something about Exsulin  (or maybe effective Ustekinumab doses).  The Ustekinumab trial is scheduled to finish in March.  However, that study is still listed as recruiting and needs 20 adult honeymooners (which is a tough recruitment goal). So it might take longer than expected.

News Article: http://medicalxpress.com/news/2015-11-clinical-trial-diabetes-jgh-muhc.html
Press Release: http://www.eurekalert.org/pub_releases/2015-11/mu-lct112515.php
Clinical Trials: https://www.clinicaltrials.gov/ct2/show/NCT02204397

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.

Sunday, November 29, 2015

Tauroursodeoxycholic Acid (TUDCA) Starts a Phase-I Trial

Tauroursodeoxycholic Acid (also known as TUDCA or Taurolite) is a chemical found in bile (especially bear bile).  Mouse and rat studies have found that can preserve beta cells, and it is already approved for us in Europe for relatively rare liver diseases.  It is also widely available as a "dietary supplement" in the US.

This study will enroll 20 adult, honeymooning type-1 diabetics.  Half will get the drug, half a placebo.  Treatment will be TUDCA pills each day for a year.  C-peptide levels after a meal are the primary outcome, and will be measured for 18 months.  They will also check liver function, as a safety issue.  They hope to complete the study by December 2018.  This clinical trial is funded by JDRF. (Note that the study is officially phase-II, but I consider it phase-I because of it's size and first-in-type-1 nature.)

This study is recruiting at one site:
    Naomi Berrie Diabetes Center, Columbia University, 1150 St. Nicholas Ave.
    New York, New York, United States, 10032
    Contact: Ellen Greenberg, MA    212-851-5425    emg25@columbia.edu
    Contact: Robin Goland, MD    212-851-5492    rsg2@columbia.edu

Why Test TUDCA? TUDCA has been found to relieve stress in a particular part of the beta cell (called the ER).  The hope is, by lowering this stress, beta cells will not be killed, and either type-1 will not occur, or it will be less severe, or be delayed.  This is based on type-1 diabetes being caused by the following chain of events:
Autoimmune attack  –causes→ ER stress –causes→ Type-1 Diabetes
so if you can stop/lessen/delay the ER stress you can stop/lessen/delay type-1 diabetes.

3 Minute Video: https://vimeo.com/118597801
Information For Patients: http://www.nbdiabetes.org/news/unique-jdrf-funded-clinical-trial-tudca
Press Release and Video: http://jdrf.org/blog/2015/02/09/t1d-trial-looks-to-teach-an-old-drug-new-tricks/
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02218619
Wikipedia entry: https://en.wikipedia.org/wiki/Tauroursodeoxycholic_acid
Earlier News Article: http://www.hsph.harvard.edu/news/press-releases/newly-discovered-mechanism-suggests-novel-approach-to-prevent-type-1-diabetes/


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.

Saturday, November 21, 2015

Perle Biosciences Starts a Phase-II Trial Of A Combo Cure

This turned out to be a much longer blog posting than I expected.  Lots of interesting digressions and complexities.

Perle Biosciences is a startup aimed at curing type-1 diabetes.  This is their first trial of a combination therapy: one drug to stop the bad autoimmune attack (Cyclosporine) and another drug to regrow beta cells (Omeprazole).  Both are taken as pills and both are already FDA approved for other uses.  Omeprazole is an antacid more commonly known by the brand name "Prilosec" and is available "over the counter" in the US.  Cyclosporine is an immunosuppressive drug, available by prescription only, and has earned a "black box" warning.

Note: This is the first study that I have blogged on which is registered in the European trial registry, but not the US one.  In the past, even the European trials were registered in the US.  Initially, it looks like the EU registry has at least as much useful information as the American one, I'm happy about that.

A summary of the trial:
  • The trial will recruit in Europe.  (Exact locations are still shifting: contact the company to find a site near you.)
  • 81 patients between 10-20 years old will be enrolled.  All will be newly diagnosed.
  • No control group, but 2/3s of the patients will get both drugs, and 1/3 will only get Omeprazole.
  • Dosing for Omeprazole will be 30mg twice daily for children and double that for adults.
  • Dosing for Cyclosporine will be 2.5mg/kg twice daily and then later adjusted. 
  • Patients will be followed for six months.
  • Primary end point will be insulin independence.
  • Secondary end points will include A1c, BG highs and lows (via CGM), insulin usage, autoantibodies, and a collection of safety measures.

News: http://www.medscape.com/viewarticle/847379
http://www.news-medical.net/news/20150624/Perle-Bioscience-announces-enrollment-for-Phase-3-trial-of-combination-therapy-in-type-1-diabetics.aspx
Press Release: http://perlebioscience.com/wp-content/uploads/2014/09/Perle_IIT_Release_6.23.15.pdf
Trial Registry: https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-000105-39/ES
EudraCT Number: 2015-000105-39

The Cyclosporine Safety Issue

Cyclosporine's safety profile is a subject complex enough, and important enough, so that I will probably spend some time researching it specifically, and writing a blog focused solely on safety.  I hope to do that before this study reports results (which I would not expect for at least 18 months).

Cyclosporine has two "black box" warnings, which are the strongest warning the FDA puts on drugs.
This drug is approved to prevent organ rejection after transplantation and also to treat two autoimmune diseases: rheumatoid arthritis and psoriasis.  The dose being given in this trial is similar to the dose given for transplantation, which is about twice the dose given for the autoimmune diseases.  (Although doctors are free to change dosing in any case, based on their professional judgement.)  The big difference is that for transplantation, the drug is often given permanently, while in this trial, it will only be given for six months.

I did a very quick look at Cyclosporine long term safety studies.  Using Cyclosporine for two or more years does appear to be associated with increases in certain kinds of cancer, in some studies.  It's hard to make a clear determination for several reasons: there are not many long term studies on Cyclosporine safety, different diseases are treated with different doses, and many (all?) of the diseases that Cyclosporine is used for, also have bad health effects of their own, so separating out the bad effects of long term treatment and bad effects of the disease is hard to do.

This was the only study I found that looked at Cyclosporine in type-1 diabetics.  It found that using Cyclosporine for a year (on average) during the honeymoon was associated with worse kidney function years later.  This was a 40 person study, and I'm not sure how much worse the kidney function was, but it's definitely something to look into:
http://www.researchgate.net/publication/13193142_Cyclosporine_nephrotoxicity_in_type_1_diabetic_patients._A_7-year_follow-up_study._Diabetes_Care_22_478-483

Cyclosporine has several common names, in different countries. It is sold under several brand names, which have different formulations and are NOT interchangeable.  To add to the confusion, there are several drugs with similar names, some of which are quite toxic.  So if you want to do your own research, use Wikipedia to include synonyms and exclude similarly named drugs.  (I'm sure the PhDs will be horrified, but I've never had a problem getting basic drug facts from Wikipedia.) And tell me what you find!  Also remember that "high dose" (which I think generally refers to doses 7.5mg/kg/day and higher) shows more side effects than "low dose" (generally 5mg/kg/day or less).  This trial starts out at the "low dose" of exactly 5mg/kg/day.

Previous Research With These Drugs

Cyclosporine
This drug was tested as a honeymoon cure for type-1 diabetes in the 1980s and early 1990s.  I would summarize the results as this: Cyclosporine caused many patients to go into remission while it was given, but when stopped, type-1 diabetes returned.  Especially in the high dose trials, people did drop out specifically because of the side effects.

Here are abstracts for some of those studies:
http://www.sciencemag.org/content/223/4643/1362
http://link.springer.com/article/10.1007%2FBF00403182
http://www.ncbi.nlm.nih.gov/pubmed/1611143
* http://www.ncbi.nlm.nih.gov/pubmed/9115576
http://www.ncbi.nlm.nih.gov/pubmed/2210078
* http://www.ncbi.nlm.nih.gov/pubmed/1397785
http://www.ncbi.nlm.nih.gov/pubmed/20440520 (for trial https://clinicaltrials.gov/ct2/show/NCT00905073).

Proton Pump Inhibitors
Omeprazole is a Proton Pump Inhibitor (which is a specific type of antacid), and this type of drug is known to improve A1c numbers in type-2 diabetics, but only slightly (for example 0.6, so from 7.7 to 7.1).  This might be because these drugs encourage the growth new Beta cells (which would be part of a cure for type-1 diabetes) or it might be because these drugs increase the production of existing Beta cells (which would not help, because type-1 diabetics have too few Beta cells to effect).

Type-2 research (there is a lot more):
http://www.ncbi.nlm.nih.gov/pubmed/22886351

Points of Discussion

Phase-II vs. Phase-III
Perle Bioscience's press release refers to this trial as a phase-III trial, but I make my own determination of phase.  In this case I'm treating it as a phase-II for these reasons:
  1. 81 people is solidly in the phase-II size (around 100 people), and far short of the common phase-III size (around 300 people).
  2. There is no control group, most phase-II and all phase-III trials that I'm familiar with, have a control group.   Only phase-I trials commonly don't have control groups.
  3. This is the first trial anywhere by anyone on this combination of drugs.
  4. The clinical trials registry for this trial lists it as a "Phase-IIb/III" trial, and I generally use the lower number phase, when two are given, because that is where they are starting.
I consider phase-III trials to be the pivotal trials that give the FDA enough information for approval, and I don't see that happening for this trial.  (Of course, since both of these drugs are already available for other uses, they could be used "off label" without any formal FDA approval.)

Primary End Point
The primary end point for this trial is "insulin independence, defined as use of exogenous insulin of [less than] 0.2 units/kg body weight/day and hemoglobin A1c [less than] 6.5%".  For comparison common doses for type-1 diabetics are between 0.5 and 1.0 units/kg/day.

Since I've been following type-1 diabetes research, I've never seen a trial which used insulin usage coupled with A1c numbers as a primary outcome; they usually use C-peptide.  I think insulin plus A1c is a harder to reach milestone, and makes it harder to see incremental progress.  C-peptide is particularly good at seeing a tiny step forward.  But I'm not sure that's been a good thing.  Several recent studies have shown a tiny step forward, but have not been extended to something a person would care about.  Obviously, not needing insulin is something every patient would care about, but is changing from 0.7 per day to 0.2 per day a successful outcome?  For an initial trial, a drop down to 1/3 or 1/4 the insulin you used to use would be a great result.

Taken together, I'm a little mystified by this choice of primary outcomes.  In some ways, I think they have selected a higher bar than other studies, and certainly a non-standard one.  But if they are successful against this higher bar, so much the better.

History
Perle Biosciences first filed paperwork related to a combination clinical trial in January 2013.  At that time they envisioned two large (200 person) trials, one for honeymooners and one for people with established type-1.  Each trial would include four treatment groups (both drugs, both placebos, one drug and placebo, and the other drug and placebo).  Also they were going to use Lansoprazole rather than Omeprazole.  They are similar drugs: both PPIs (proton pump inhibitors), and I don't know why they switched.

Finally, I started researching this blog before the European trial registry was completed.  Therefore I started out getting my information from emails with Perle Biosciences, their facebook page, and a press release.  I'd like to thank them for replying quickly to my emails.  The information here comes from all of these sources (trial registry, email, facebook, and press release).

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.

Saturday, November 14, 2015

Research In The News (November)


MK-2640 ("Smart Insulin") Completes Enrollment Collection of a Phase-I Clinical Trial And Then Adds a New Part

MK-2640 is the Merck identifier for what we all know as Smart Insulin.  It is the only "self dosing" insulin currently in human trials.  The idea behind this drug is that you could inject it (maybe twice a day, maybe once a day, maybe once a week), and then it would release insulin if your BG numbers were high, and not if they were low.  It is sort of a chemical artificial pancreas.

Because there is no data from human testing (nor have I seen any animal data), there is no way for me to know if MK-2640 is going to turn into a "lantus killer" (i.e. a great basal insulin), or if it is going to turn into something much closer to an artificial pancreas.   For example, something you take once a week and not count carbs or otherwise worry about type-1 diabetes.

The First News 

On 29-June-2015 Merck updated the clinical trial record to show that they were no longer recruiting people for this trial.   Since this trial collects data for 37 days, that tells me that they finished in August. However, a different part of the record suggests they might have finished collecting data even earlier.  Yet another part of the record was updated to show an "Estimated Study Completion Date" of October 2015.  So that was all good news, and I was looking forward to them publishing results.

The Second News

Then (in September) they added a third part to what had previously been a two part clinical trial. Part three seems to be a continuation of part two (meaning they are testing in type-1 diabetics and are comparing MK-2640 to regular insulin.  They are now recruiting again (presumably for part three), and have pushed out the completion date to early 2016.  Part three will add 16 people to the test (from 58 to 74), but the testing looks pretty similar to part two.

A (Very Little) Discussion

Most of this clinical trial involves giving people MK-2640 (different groups of people getting three different doses), and then dripping sugar into them for 9 hours (7 hours in part three) and seeing what happens.  The sugar is an IV drip ("intravenous infusion"), not eaten in a meal.  In this case "what happens" means things like: side effects, BG levels, how quickly the body "clears" the drug out of the system, etc.

For me, the most important data will be how quickly MK-2640 lowers BG levels when sugar first starts hitting the bloodstream. If it lowers BG levels quickly, that means that it will work for meals (and is more of an AP replacement). However if it is slow to lower BG levels, that implies that it is more of a Basal insulin, and might replace Lantus/Levemir in the market, but not replace pumps/APs.

However, as I am an optimist, I will not forget that IV sugar is much faster acting than carbs eaten in a meal, so even if the results are so-so for IV sugar, I would expect better results from a real meal.  Of course, it could turn out exactly the opposite: the slower sugar absorption might result in slower MK-2640 reaction times.  I guess we'll have to wait for the first "real world food" tests.  I only hope it gets that far.

I interpret adding the new part three section to be all good news.  They added that after they had run the first two parts, and I don't think they would do more testing if the first parts did not look good.  (A pessimist might say that if part two was not good, they were hoping to save the trial with data from the new part.  However, I am an optimist so I think if part two was not good they would have just stopped, and since they pushed ahead, that is good news.)

Similarly, part two followed people for 9 hours, but part three only followed them for 7 hours.  Is that good news, because it means that Smart Insulin reacted quickly?  Or is it bad news because, Smart Insulin lost effectiveness after that?  There is no way to tell, until they publish.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02269735

MultiPepT1De (Multi Peptide Vaccine) Starts A Phase I Study

This is a follow on study to one of the very first clinical trials I ever followed:
http://cureresearch4type1diabetes.blogspot.com/search/label/Peakman
That older trial injected a peptide (part of an insulin molecule) in the hopes that the immune system would learn not to auto-attack.  This new study injects a mix of peptides to provide a broader education to the immune system.  The basic idea is like injecting peanut proteins to teach the immune system not to be allergic to peanuts.

The study will enroll 24 adults, within four years of diagnosis.  There is no information available on number of injections, duration of the study, primary or secondary end points.  They are recruiting in London, England.  Contact information is:  Ms Rhanya Chaabane, Tel: 02071888472 Ext: 81932,
rhanya.chaabane@gstt.nhs.uk.

Note: This trial is registered with the United Kingdom's clinical trial registry which contains a lot less information than the United States clinical trial registry.  It is also registered with the European Union clinical trial registry, but they don't publish records for phase-I trials at all.  Therefore, I have a lot less information about this trial than other trials, which is why they are not getting a blog posting of their own.

Trial web site: http://www.multipeptide.co.uk/
Magazine article: http://www.multipeptide.co.uk/pdf/jdrf_article_on_multipeptide.pdf
Clinicial Trial Record: http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=19114


Stop Following Gevokizumab (Xoma 052)

I've decided to stop following the drug Gevokizumab (which started it's research life as Xoma 052). You can see my previous coverage here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Xoma%20052

The last news I had related to this drug in type-1 diabetes was that it started a Phase-II clinical trial in 2009.  The clinical trial record was updated to "Completed" in 2014, but there is no listing for published results.  I have searched for any results, but can find none, so I'm going to assume that the phase-II trial was a failure.  (It was run by a commercial company, so there is no reason for them to publish the results, if the trial failed.)

Since that time, Xoma, the company developing Gevokizumab, has published clinical trial results for both type-2 diabetes and Behçet's disease uveitis (both failed their primary end point).

Based on all this, I'm going to remove Gevokizumab (Xoma 052) from the list of possible cures of type-1 diabetes that I follow.

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.

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
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.

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.

http://www.ncbi.nlm.nih.gov/pubmed/21916971
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.
http://www.ncbi.nlm.nih.gov/pubmed/19607951
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.
http://www.ncbi.nlm.nih.gov/pubmed/2074915
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.
http://www.ncbi.nlm.nih.gov/pubmed/19459478
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.
http://www.ncbi.nlm.nih.gov/pubmed/2789342
No significant difference was found between diabetic patients and control subjects with respect to antibody response after vaccination. 
http://www.ncbi.nlm.nih.gov/pubmed/9607024
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.
http://www.ncbi.nlm.nih.gov/pubmed/21994316
Risks for Guillain-Barré syndrome, multiple sclerosis, type 1 diabetes, and rheumatoid arthritis remained unchanged.

http://www.ncbi.nlm.nih.gov/pubmed/3678660
In Type 1 (insulin-dependent) diabetic patients the incidence of non-responders to two vaccine components was significantly increased
Summary
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
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.