Saturday, November 5, 2016

Possible Cures for Type-1 in the News (November)

Ustekinumab Is Fully Enrolled

Ustekinumab, an immune modulating drug, started a Phase-II? trial in July 2014.  I previously blogged about it here:

They completed enrollment on May 24, 2016, which means they should finish gathering data by May 24, 2017, because they need to gather data for a year.  Successful results are usually published in less than a year after completion.

This drug was approved in the US in 2009 for treating psoriasis, which is an autoimmune disease (where the immune system self attacks skin cells rather than pancreas cells, as with type-1).  It has also been tested on multiple sclerosis, Crohn's disease, and sarcoidosis (also all autoimmune diseases).  Ustekinumab is thought to work by blocking inflammation, and specifically blocking two immune molecules called IL-12 and IL-23.

Clinical Trial Record:

In July, A Phase-II? Verapamil Trial Was 20% Enrolled
A research group at the University of Birmingham (Alabama) is testing Verapamil on people in the honeymoon period.  The hope is that Verapamil will cause beta cells to naturally regrow.  I've previously blogged on this research here:

They have been recruiting for over a year, but have only enrolled 12 people, out of the 52 they need. At this rate, they will not be fully enrolled within 2 years as they had hoped, and that's a problem.

The drug they are testing is already approved (and pretty widely used) for high blood pressure, so it should not be that hard to recruit for this study.  However, only adults can be recruited (per FDA rules).  Obviously, limiting recruitment to adults still in their honeymoon phase makes this process much more difficult, since most honeymooners are youth, not adults.

Terminated: Leptin by Garg at University of Texas

On June 23, 2015 a Phase-I trial of Leptin being run by Dr. Garg at the University of Texas, was cancelled.  The clinical trial record says terminated at the request of the sponsor.  Since it was being sponsored by JDRF and by Amylin (which makes Leptin), I assume that Amylin shut down the research. You can read my previous blogging here:

At one time they were going to dose 15 people, but they ended up only dosing 7.   It was a Phase-I, pilot study, so there was no control group.  The researchers do hope to publish results, and I'll blog on them when they come out.

Clinical Trial Record:

Joshua Levy 
publicjoshualevy at gmail dot com 
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.


celsus said...

Which would you rather have, type 1 diabetes or a 30% risk of having solid organ cancer within 10 years? To me it seems a fairly even choice, so knowing that immunosuppressive drugs like Ustekinumab carry that cancer risk, in addition to having a number of other toxic effects, I have to ask why bother listing that as a possible 'cure' for diabetes, since it doesn't have any net advantage over just leaving the diabetes alone and treating it only with insulin?

Rick said...

Immunosuppressants are used these days for many different types of diseases. I use them for RA and yes they are scary medications. They are also wonderfully effective. The main issue is that when they stop working they really stop. I fear that these might be only a temporary holding action at best. In the world of RA we cannot predict which medications will work for who and how long they will hold RA at bay. It is interesting research but it may be a tough road to get to the best results.

This item has been referred to the TUDiabetes Blog page for the week of October 31, 2016

Joshua Levy said...

Celsus: I prefer real data to made up bullshit. If you really think that Ustekinumab increases cancer, post the data. In the meantime, here is some real Ustekinumab data, which shows no increase in cancer rates. It's from the paper "Long-term Safety of Ustekinumab in Patients With Moderate-to-Severe Psoriasis: Final Results From 5 Years of Follow-Up", and this is the entire conclusions section of the abstract:

No dose-related or cumulative toxicity was observed with increasing duration of ustekinumab exposure for up to 5 years. Rates of AEs [Adverse Effects] reported in ustekinumab psoriasis trials are generally comparable with those reported for other biologics approved for the treatment of moderate-to-severe psoriasis.

This study pooled data from 4 different Ustekinumab studies.

Here is the reference:

Celsus: if you have any scientific basis for your comment about solid organ cancers, please post it now. If you say something like that, I expect you to back it up with references.

celsus said...

Professor Gabriel Danovitch, 'Handbook of Kidney Transplantation,' Philadelphia: Lippincott, 2001, p. 189, says that, as a result of the immunosuppressive drugs necessary for renal transplantation, the "cumulative incidence of non-skin malignancies is about 33% by 30 years after transplantation." The elevated cancer risk from the use of immunosuppressive drugs, of which Ustekinumab is an example, is non-controversial, though it varies with the dose of immunosuppression applied as well as with the duration of treatment. Five years is too short a time to determine the full risk of toxicity from an immunosuppressive. Since Ustekinumab would have to be used indefinitely to suppress the immune response which destroys pancreatic beta cells in type 1 diabetics, and since type 1 diabetes usually begins early in life, patients would have a very long dose duration with all the attendant risks.

Scott S said...

celsus, the "evidence" you provide is not peer-reviewed, its the equivalent of "Professor so-and-so said its bad", hence your comments are not really relevant in this discussion. If you're going to posit that there is real harm, YOU have an obligation to provide the scientific evidence of that harm. Right now, you have provided no such evidence.

Joshua Levy said...

Celsus: I think that Scott makes a good point: basically books are not peer reviewed.

But I'd also like to make another point:
Compare your safety data with mine, and with the study I was blogging about:
(a) Your book was written before Ustekinumab was used, my two studies were on Ustekinumab, specifically.
(b) Your book was about people who started out so sick, they lost a kidney. My safety data was on basically healthy people with Psoriasis, and the study is on basically healthy people with T1D.
(c) Your book was on people who took multiple drugs for 30 years, my study was on people who took one drug for five years, and this study would give the drug 5 times over 9 months.
(d) Your book is 15 years old, my studies are 3-5 years old.

In short, you are taking data far different from the study, and claiming it shows danger, when there is ample data, much closer to the study, that shows it is safe. I think my point (a) above is particularly important. You are grouping all immunosuppressive drugs together as though they were the same. That is unfair, and made worse by the timing. People who had renal transplants are often given a "cocktail" of several drugs, so comparing them to people given one drug is a mistake. Furthermore, post-transplant drugs given 30-15 years ago (the experiences described in a 15 year old book) were much more toxic than those given now. Ustekinumab is a monoclonal antibody, which is a relatively modern type of drug which is specifically targeted at one part of the immune system. As a class of drugs it is quite different than the older broad spectrum immunosuppressive drugs the book refers to.

In short, you are using old, and different data when there is much more recent and on-point data available. I am at a lost to understand why you would use 15 year old data not from Ustekinumab in order to argue that Ustekinumab is unsafe, when there are several more recent studies that were done specifically on Ustekinumab available! The good, recent data shows safety, so you quote the older, less applicable data to show danger.

celsus said...

Just think in terms of first principles. One of the main functions of the body that keeps the cancer risk in check is the immune system. Type 1 diabetes is caused by the immune system going out of control and attacking the beta cells of the pancreas and destroying them, causing an insulin lack which results in hyperglycemia. Thus, if you try to 'cure' type 1 diabetes by suppressing the action of the immune system to alleviate the destruction of beta cells and hope they regrow (they don't, but that's another story), you greatly increase the cancer risk, since you disarm the body's main weapon against cancer. Anything that interferes with the action of T-cells simply has to have this unfortunate side-effect. As for the authority I cited being 15 years old, I hardly have to say that nothing about suppressing the immune system and increasing the cancer risk has changed in that time period, nor is it likely ever to change, which is why encapsulation of pancreatic beta cells makes more sense.

As for books not being peer-reviewed, I can tell that no one commenting here has ever published an academic monograph, since the first thing that happens when you submit a manuscript to an academic publisher is that it is referred to leading experts in the field for feedback and an assessment. Professor Danovitch is the type of person to whom scientific journal articles are referred for peer review, so when he publishes a monograph, it is taken as authoritative. His text, which you should look at, is also filled with academic references supporting everything he says.

Reverse Developer said...

Celsius, first do no harm, precaustionary principles have their place. And I can tell that you have never written a monograph about your life as a Diabetic. But if you are ready to write that monograph about the risk/benefits of conditions with high potential for fatality/morbidity or about therapies for such conditions, ethical analysis MUST include patient expectations. And I can tell you from personal experience that the main ravage of Type 1 diabetes is burnout and other psychological complications. Despite all the cheerful encouragement that they can do anything normal people do, Diabetics know the real score. If they twist an ankle in the woods and cannot get help for 72 hours, even a sackful of food and water won't help them if they don't have insulin. A diabetic either accepts lowered expectations through their behavior and unrelenting preparation or they crash and burn in denial of that enormous 24/7 burden. The prospect of even odds on a cure vs cancer by age 60 may look pretty good to the diabetic that has already had one kidney transplant at age 40; or even to one struglling with control that can read the cards at 20 years of age. NOT YOUR CALL!!

celsus said...

The risks associated with immunosuppressive therapy are worth it in cases requiring a heart or liver transplant, since such patients will die without a functioning graft. In patients requiring a kidney transplant, the immunosuppressive risk is also worthwhile, since patients on dialysis have a quality of life which is about 10% of a normal person's life, in part because dialysis compensates for only 10 to 14% of normal renal function, and in part because of the life-destroying burden of the dialysis treatment itself. If patients withdrawing from dialysis are counted among the suicide total for dialysis patients, then 25% of people on dialysis eventually commit suicide. The life expectancy of younger dialysis patients is only about 10 years, while that of older patients is around 5 years.

But contrast these disease burdens with those of type 1 diabetes, which diminishes quality of life by only about 50%, and which now costs patients only around 7 or 8 years of their normal life expectancy. The disease burden of type 1 diabetes is simply not comparable to that of patients requiring a cardiac, liver, or kidney transplant, so while the risks of immunosuppressive therapy are cost-effective in those cases, they are too great in the case of type 1 diabetes.

Reverse Developer said...

More can be read into what you don't say than from what you do.

Contrast your quality of life with the 50% loss you have somehow quantified for Diabetics. Maybe you are sturdier than most and do not flinch at the prospect of a 50% loss. The psychological burden is higher than you imply. 10% of teens meet their glucose control targets. 35% of Adults. The statistic I heard is that avg Diabetic LE is 12 years less than non-D - a stat that has not changed since GMO insulins appeared.

All other "data" aside, still not your call. I was up all night administering carbs to my son who is "overdosed on his basal insulin". He was late to school. This all because we had to raise his basal dose the week before when hormones (we presume) interfered with his insulin such that he was in the 300's for long periods. My blood pressure has risen to 150 since he was diagnosed two years ago and I don't even have diabetes! If I stroke out and die and my son has no father to help him adjust, tell me what is the disease burden?

You do great damage by attempting to diminish the impact of this disease on patients and the health care system. The numbers you trot out do not shed even the faintest light on what it is like to live with this "burden". I hope you are more responsible when given a podium and consider what Rick, Scott and Josh above point out above with respect to the potential of immunosuppressives in various procedures and drug combination therapies, experimental and otherwise.

celsus said...

With respect to the view that my negative cost effectiveness judgment regarding immunosuppressives for the treatment of type 1 diabetes is "not my call," the proof of my position is in the pudding, since the usual clinical practice is not to perform pancreas or beta cell transplants in diabetics unless they also require immunosuppressives for another reason which the medical profession does consider serious enough to require such dangerous drugs, such as the need for a kidney transplant. The general clinical consensus is that type 1 diabetes alone does not justify the risks of seriously weakening the immune system, except for a very few centers which will perform pancreas transplants on type 1 diabetics in the case of uncontrollable blood glucose or severe problems with hypoglycemia. In practice, if you seek a pancreas transplant for a type 1 diabetic you will find that the decision is indeed not your call, either, since the common practice among transplant surgeons is not to proceed unless immunosuppressives are already necessary for another reason. Like it or not, the medical profession is not a 'common carrier' ready to provide all services requested of them, but rather, it will only cooperate with interventions that are safe and effective according to its own call, not yours.