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.

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

These two news updates are both interesting, and each probably deserves it's own blog entry.  However, since I'm backlogged, I'm putting them together in one posting (together with a Zhao update).  Even after this posting, I'm still a month or more behind.

Results from a Polish Trial of Polyclonal Tregs

What is being tested?  I call this technique "Polyclonal Tregs", but I'm not sure if it has a more official name.  Basically, the researchers remove one specific type of T regulator cell (called a "CD3(+)CD4(+)CD25(high)CD127(-)" T regulator) from a person with type-1 diabetes.  They use these cells to grow a lot more of these cells outside of the body, and then put them back in the body.  Since regulatory T cells naturally regulate the body's immune system, the hope is that they will prevent the autoimmune attack which causes type-1 diabetes.  Previous research in both animals and people has supported the idea that increasing regulator T cells may be a path to a cure.  

The Polish group tested this technique on 10 recently diagnosed (within 2 months) type-1 patients and compared them to 10 patients who did not get the treatment.  4 people got a lower dose (10 × 10^6 Tregs/kg) and 6 people got a high dose (twice as much).  In my opinion, they packed a lot of research into a small trial.  However there were no differences between the lower dose group and the higher dose group.  

Because it was an early trial, safety was an important consideration, and there were no safety related issues.  So that was good.  The publication had effectiveness data from a short (four month) follow up.  Basically:

• The treated patients generated about 50% more C-peptide than untreated.
• The treated patients used about half the injected insulin as untreated.
• A1c levels were about the same.

You can see that here:
http://care.diabetesjournals.org/content/35/9/1817/F1.large.jpg
Remember: grey bars are untreated and white bars are treated.

But remember, these people were within 2 months of diagnosis, and even at the end of the data presented here, were within 7 months of diagnosis, so well within the common honeymoon timeframe.  So I think longer follow on is critical to understanding how important these results are.  If these patients are still using half the insulin that untreated patients are using after 2 years, that would be wonderful.

The good news right now is that they already have one year follow up data, and expect to get it published later in 2013.  Beyond that, they have some improvements to the protocol, and hope to start a follow on trial with an updated protocol soon.  

The Other Polyclonal Treg Study ...

This is not the only study using this "Polyclonal Treg" method.  About two years ago a very similar study started in San Francisco.  Dr. Gitelman is running it, and results are expected in 2016.   I've blogged in the past about this trial here:
http://cureresearch4type1diabetes.blogspot.com/2011/01/possible-cures-for-type-1-in-news-jan.html

This trial has now enrolled its first two groups (out of four total).  I'm told all subjects are doing well with stable pancreas function. The researchers are currently in the middle of the 3rd group, and they anticipate completing the full study enrollment this year.  Each group gets 8 times as large a dose as the previous group so the last group will get about 500 times as much as the first.

... and the Ethics of Experimenting on Children

There is an obvious question here: If both studies started at about the same time, why does one have results 4 years sooner than the other?  I think there are two answers to this question.  The first is pretty simple: the Polish researchers published data covering 4 months after treatment.  The American researchers are gathering data for years.  But that only explains about 20 months of difference.

The second reason might be more important: The American researchers are only enrolling adults, people over 18 years old.  The Polish researchers enrolled children, 5-18 years old.  Obviously, when you are looking for recently diagnosed type-1 diabetics, there are a lot more to be found in the 5-18 year range than the 18+ year range.  By limiting recruitment to adults, the Americans have a much smaller pool of people, and it will therefore take them much longer to fully populate their trial.

But why are the American researchers only enrolling adults?  That answer is a combination of ethics and previous experience.  There is a general ethical principal (enshrined in various FDA rules, and international guidelines) that research should be done on adults first, before it is done on children, if that is feasible.  That makes a lot of sense, of course, but here we see the impact.  For a disease like type-1 diabetes, it is possible to recruit recently diagnosed adults, but it is far harder and slower.  So if we insist that the first bunch of patients are adults, it serves to slow down research disproportionately.

The Polish group had previously run a similar clinical trial in adults with a different disease (graft vs. host disease).  Now measuring safety in adults with one disease is not exactly the same as measuring safety in adults with a different disease, but it is similar.  Therefore, they could recruit children based on the safety profile with adults in the previous study.  Also, they could test different doses more quickly, again based on the previous experience.

Abstract: http://www.ncbi.nlm.nih.gov/pubmed/22723342
Full paper: http://care.diabetesjournals.org/content/35/9/1817.long (Thanks to ADA's DiabetesCare.)

Clinical trial record for the American study: http://clinicaltrials.gov/show/nct01210664

More Details on This Treatment

One way to view the immune system is a balancing act.  We want aggressive immune cells to attack foreign cells, but overly aggressive cells might attack our own beta cells and cause type-1 diabetes.  So we also want regulatory immune cells to keep the aggressive cells in line.  But we don't want those cells too strong, because then they would prevent an attack on the foreign cells.  In this view, type-1 diabetes can be seen as a too aggressive immune system, and therefor boosting the regulatory side might be a cure.

The regulatory cells which are been grown out (or "amplified" might be a better word) are general purpose regulatory cells.  That's a good place to start, but it would be even better if the researchers could multiply a regulatory cell that specifically targeted autoimmune cells (the "bad" cells that are attacking the wrong target).  Unfortunately, the technology is not there yet, although people are working on it.  But in any case, we need to start somewhere.

Below is a link to a study that suggests that newly diagnosed type-1 diabetic children have lower levels of these T regulator cells, than children who do not have type-1 diabetes.  (Although it was a small group.)  http://www.ncbi.nlm.nih.gov/pubmed/19454187

A Note About "Remission"

Some type-1 researchers use the term "remission".  Specifically, they use it to mean "Uses less than 1/2 a unit of insulin per kg of body weight per day".   Don't be confused.  Non-researchers think of "remission" as meaning "doesn't use insulin", but that is NOT how researchers use the term.   If your child weighs 40 kg (about 88 pounds), and uses 20 units of insulin, or less, then they are "in remission", and this does happen to some people during the honeymoon.


Perle Bioscience Starts two Phase-III Clinical Trials of Cyclosporine and Lansoprazole ("Prevacid")

Dr. Claresa Levetan at Perl Bioscience has filed the paperwork to start two very interesting studies.   Both studies are looking at a combination of Cyclosporine and Lansoprazole (commonly known as "Prevacid") as a cure for type-1 diabetes.  The two studies are identical, but one recruits honeymooners and the other established type-1 diabetics.  These are combo clinical trials exactly like many people have been hoping for, for years:  Cyclosporine is known to stop the autoimmune attack and Lansoprazole is known to encourage the natural regrowth of pancreatic beta cells.  Both are approved drugs (for other diseases).  Lansoprazole (as "Prevacid") is over the counter, so has a very good safety profile.  Cyclosporine has a more complex safety profile.  I'm sure if this study pans out, the relative safety of Cyclosporine is going to be an important topic of discussion.

Both studies are expected to enroll 200 people (half getting the treatment and half getting placebo).  They plan to start in September 2013 and end by March 2014 (so very quick).   There will be four groups: one group getting both drugs, one just getting Cyclosporine, one just getting Lansoprazole, and one getting neither.  This is good experimental design for a two drug combination. They will measure C-peptide in response to eating, A1c, and insulin usage.

Note on phases: The researchers running this trial have described it as a "phase-III trial", however I consider it a phase-II trial.  Why the difference?  For me, size is the most important issue.  At 200 people, it is right on the border between what I consider phase-II and phase-III for clinical trials aimed at curing type-1 diabetes.  (For comparison, all eight recent phase-III trials have involved 300 people.  That seems to be the magic number for FDA approval as a pivotal trial in type-1 diabetes.)  Also, this combination of drugs has never (to my knowledge) been tested on type-1 diabetics before.  Since both drugs are approved for other things, I'm willing to call it phase-II (rather than phase-I), but with zero experience with the combination, I'm not willing to call it a phase-III.

Of course, the important question is not what I consider the trial, or even what the researchers consider the trial, the real question is how will the FDA consider the trial?  That remains to be seen, but remember: since both drugs are already approved for other uses, your doctor can prescribe this combination right now.  It would be an off label use.

The researcher working on this, Dr. Claresa Levetan, previously worked on CureDM, and sold that to Sanofi-Aventis two years ago.  My understanding is that they are developing the CureDM technology (a peptide which stimulates beta cell development) for the type-2 market.

Wikipedia on Lansoprazole: http://en.wikipedia.org/wiki/Lansoprazole
Wikipedia on Cyclosporine: http://en.wikipedia.org/wiki/Cyclosporine
Clinical Trial Record (Honeymoon): http://www.clinicaltrials.gov/ct2/show/NCT01762644
Clinical Trial Record (Established): http://www.clinicaltrials.gov/ct2/show/NCT01762657

More Background on
http://www.ncbi.nlm.nih.gov/pubmed?term=3125434

Zhao Updates from Spain 

Previous blogging on Zhao's "Stem Educator" is here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Zhao

These two links go to Spanish language news reports on people getting treated with the Stem Educator in Spain.  I found that using Chrome to translate them into English worked pretty well for me:
http://www.rtpa.es/ciencia:El-HUCA-busca-financiacion-para-un-proyecto-pionero-en-el-tratamiento-de-la-diabetes_111357993752.html
http://diabetesmadrid.org/2012/12/05/el-huca-lidera-la-lucha-contra-la-diabetes/

The basic summary is that the clinical trial in Spain has started.  Two patients had their first session of stem cell educator therapy in December 2012.  The plan is to treat a total of 30 people.  (Not sure how many are placebo and how many will get the real treatment.)  The two treated so far have had type-1 for over 10 years.  This trial is expected to end in September 2014, but we will not know with certainty until it is fully enrolled.

JDCA State of the Cure 2012


The JDCA (Juvenile Diabetes Cure Alliance) is trying to focus more research dollars into cure research (as opposed to treatment research, cause research, etc.)  They publish research papers, which are often quite interesting.  They use my blog as a source, and we sometimes discuss various research issues.

The article below is their year end summary, and well worth a read.  Although I certainly don't agree with everything in it, it is a rich source of information.  (I especially object to their not including Dr. Zhao's research as a possible cure, and JDCA did cover Zhao in a report after this one.)

http://www.thejdca.org/wp-content/uploads/2012/11/State-of-the-Cure-report.pdf

A Final Note

In the past, I have included a specific "thank you" when people reviewed a blog posting, provided information for it, or pointed out the news to me (when only one person did so).  Unfortunately, keeping track of who helped with what, and also making sure it was OK to thank them by name, has become too much of a burden.
So I'm going to stop doing that.

I'm very sorry I will not be able to thank people individually for their help in writing this blog.  But I do want to thank:

• My wife, who improves my English, and puts up with the hours I spend yelling at the computer when I should be talking with her.
• All the researchers who have answered my questions and provided extra information.
• Everyone who emails me when they see news that I should cover.

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