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.