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.

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

* http://www.ncbi.nlm.nih.gov/pubmed/22218624

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.

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.