Thursday, January 12, 2017

What To Fund in 2017?

Several weeks ago, I was having lunch with someone heavily involved in JDRF, and he asked me for my opinion about what research they should fund.   I'm embarrassed to say that I was surprised by the question, and I did not have a good answer for it.  However, I've now had some weeks to think about it, and it is a question that has come up before, so here are my "top five" answers:

The Cell Educator

The stem cell educator is a machine which takes the immune cells from a person's blood, exposes them to various organic molecules which are designed to change their behavior so they learn not to attack beta cells.  The cells are then returned to the body.  This device has already gone through a phase-I trial in China, and the results were the best I've ever seen in terms of people generating more of their own insulin after treatment.  The effect lasted for months and in some cases years.  It was very positive.

So my simple minded attitude is, if this is the best phase-I results I've ever seen, it makes sense to fund a push into phase-II (or at least a second phase-I trial done in the US).  Now this is not as obvious as it might sound.  JDRF did fund some animal work at the University of Florida, but the results were never published.  (Not a good sign.)   Similarly, there was some work in Spain, in people, and it was discussed in conferences, but never published, at least not that I've seen.  (Not a good sign, either.)   And that Spanish data did not sound as positive as the original Chinese work.  But at the end of the day, I'm willing to put some money into seeing what happens when a clinical trial is run in the US, even it if is a small one.


Verapamil is a high blood pressure medicine which the researchers hope could cure type-1 diabetes if given during the honeymoon phase.  As far as I know, it's method of operation is unique.  Plus, it has the advantage of already being approved, so it could quickly be used off label, and eventual approval would be quicker than other drugs.  But it is honeymoon only.

The reason they are on the list is because it is clear to me that they are having trouble recruiting enough people to complete their study.   I hate that.  They are running the entire study from one site, and that limits the area from which they can recruit.   I'm hoping some JDRF money would let them start up another site or two, so they could get the people they need.

(no previous blogging: in animal testing)

Because this research is still in animal testing, I've never blogged on it, so why do I like it?  For several reasons: First, it uses gene therapy to reprogram a person's cells to generate insulin in response to sugar, and that is novel, at least as far as I know.  Second, the targeted cells are not pancreatic cells, they are liver cells.  This is important, because I think there is a reasonable chance that these new cells will not be targeted by the body's autoimmune attack.

It's not a sure thing; we don't know exactly why beta cells are targeted.  If it has something to do with their pancreatic location or their beta cell nature, then these "hotwired" liver cells will not be targeted.  (Unfortunately, if beta cells are targeted because they generate insulin, then these new cells will be targeted as well, and this research will not lead to a cure.)

Finally, gene therapy involves risk; it is still in it's infancy.  I think that risk is scaring away pharma money, and for me, that is a good reason for JDRF to put some money in. This company is hoping to go into clinical trials in 2018.  I'm hoping some JDRF money could get them there faster.

If more than one research group is working on turning liver cells into functional beta cells, then I'd organize a "cage fight," as described below, between the data from the different groups.

Artemisinin-Class Cage Fight

Artemisinin is an antimalarial drug, which (in animals) encourages pancreatic alpha cells to naturally morph into beta cells.  Since beta cells are what are being killed off in type-1 diabetes, this is important.  However, I've never thought that a drug like this could cure type-1 by itself, because the body's autoimmune attack would kill off the new beta cells same as it killed off the old ones. However, a drug like this might end up being half of a cure; the other half would be something to stop the autoimmune attack.  It also may extend the honeymoon period, or maybe make the honeymoon permanent.  And getting the body to generate it's own beta cells might be a lot easier than producing them from stem cells, growing them in test tubes, or whatever.

Now I don't want to just say "fund Artemisinin", partly because it's only half a cure, and partly because I think there are several drugs with effects potentially similar to this one.  That is where the "cage fight" comes in.  I want JDRF to lock some of their research staff in a room with all the animal data for all the drugs which are supposed to help convert alpha cells into beta cells, and then reach consensus among themselves as to which of the drugs is most promising in animals (especially NOD mice), and fund that one.  This form of research "cage fight" involves comparing the existing data on specific results in a head-to-head way, and funding only the best.  (If you read the book Moneyball you will see some similarities.)  If JDRF is feeling flush, maybe they can fund the top two.  Of course, maybe they already do this, and I just don't know about it.

Quarterback Option (on Phase-I)

For those of you who do not follow American football: a quarterback option is when one player takes the ball and starts a play, and then, based on what the  other team does during the play, changes the play to try to take advantage of what is seen, as it happens.  In this context, what I mean is that JDRF should pay particular attention to several interesting, ongoing phase-I trials, and if any of them are clearly successful, rush some funding in there quickly.

By "clearly successful" I don't mean that the researchers themselves say it is a success (they almost always do).  Rather, before the study is published, I think JDRF's team should look at the data being gathered, and decide internally what level of result would cause JDRF to call up the researchers the week after publication and say "We've got a half million dollars (or whatever) and we want to push your research ahead, quickly.  What can we do together, now."

For example, there is a 5 person, 6 month, phase-I combination trial of Exsulin and Ustekinumab. Now Exsulin (previously known as INGAP) has been tested twice before, in much larger trials, and did not have good results either time, so I'm not "holding my breath".  But combining it with Ustekinumab is unique, and could be the missing link needed for success.   This trial is so small that even success might not be successful enough to get pharma interested.  But if JDRF had a preloaded internal decision, something like if two or more patients do not need to inject insulin for 4 or more months then they should release 1/2 million or a million for quick-starting phase-I trial to get some more data (maybe lasting longer, or enrolling children, or testing different doses, or something that builds on the previous trial).

I think JDRF should have these sort of preloaded funding triggers ready for many of the small phase-I trials that are ongoing.  Of course, maybe they do, and I just don't know about it.


Choosing these particular research areas was hard for several reasons:

The hardest to explain is the success/support trade off.  To put it bluntly, if research is really successful already, there is little need for JDRF to fund it, because companies will already be interested in it, and will fund it themselves without non-profit help.  So there is no need for JDRF to fund research which has already been successful enough to attract corporate support.

On the other hand, I don't want to suggest that JDRF fund a bunch of research which is failing, either! So I'm looking for research which is in a "sweet-spot".  It shows promise and deserves some extra funding, but is not so obviously successful that commercial companies already have enough information to fund it.

This "sweet-spot" exists mostly as phase-I clinical trials and research which is almost ready to start phase-I trials.  If research has started phase-II trials, then pharma is likely already interested in it, and even if not, by the end of phase-II there will certainly been enough news to attract pharma, if the news is good.  On the other hand, any earlier in animal tests, means the chance of failure is high enough, that I'd prefer to put money into something a little more promising.  So all of the research I suggested above is either in phase-I trials, or near to starting them.

One of the reasons I've never made a blog posting like this one, is that I know I'm going to piss off every researcher not on the list above (which is most of them!)   And I'm sorry for that.  If it's any consolation, many of the already running clinical trials are not here either because pharma is already supporting them (example: T-Rex, artificial pancreases, Viacyte, etc) or because the existing trials are large enough so that they will answer the important questions without more funding (examples: BCG, Gleevec, etc.)

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.


Rick said...

Josh, As a person who uses and has used immunosuppressants I just do not hold out much hope. The find that our body has a knack for overcoming most immunosuppressants I have used, usually in short order. Even if they work well at first it seems that over time the immune system just works.

I hope it works out, I just can't fathom a day it might happen reliably or inexpensively enough.

celsus said...

Since there are already 1.25 million type 1 diabetics in the United States alone, I am not enthusiastic about 'cures' for the disease which only address those who are just becoming victims of it while leaving the veterans stranded. Both the Cell Educator and Verapamil suffer from this limit. A cure only for newly-diagnosed patients might discourage efforts to cure those already afflicted, and to that extent it would be counter-productive.

Insulette has some promise, especially since the liver is an immunologically privileged site, and is relatively protected from the autoimmune processes that destroy beta cells in the first place. But I share your concerns about the riskiness of gene therapy, which has already killed some patients on whom experimental therapies were tried.

Artesmisinin class drugs that would turn pancreatic alpha cells into beta cells are a nice idea, but having to use immunosuppression to stop the autoimmune attack on them would effectively ruin the benefit, since the toxicity of immunosuppressive drugs is worse than the toxicity of uncontrolled diabetes.

Generally, since it takes about 16 years to go from a new drug idea to its final approval for clinical application, it is best to focus on simple methods that can be brought into clinical use quickly. For this reason, I have less confidence in elaborate manipulations of the patient's genetic profile or transforming various cells into beta cells, and more interest in using more straightforward mechanical solutions. There has been a lot of progress in islet cell encapsulation, which doesn't involve poisoning the immune system or turning the patient's cells from one type to another, but just inserts a plastic package containing insulin producing cells under the skin. These capsules have already been proven to prevent the autoimmune and immune response to the implanted cells, and now we only need to improve the oxygenation of the cells to complete the cure. The immunological barrier is good enough to permit porcine cells to be used, so the supply of cells is not limited, as is the case with islet or whole pancreas transplants, both of which work very poorly in any case. So why not just concentrate all efforts on encapsulation, which has only a small, mechanical problem to overcome?

Joshua Levy said...

A couple of quick points:

The cell educator is not limited to honeymoon diabetics. They are testing it on people who have had type-1 for years. (Verapamil, on the other hand, is honeymoon only.)

As far as "why not just concentrate all efforts on encapsulation" question, I think there are at least two issues: First, there is the general issue of "putting all your eggs in one basket". Sure if you guess right, you will speed things up, but if you guess wrong, you will delay everything. It's a big gamble. It is based on knowing now what will cure type-1 in the future. I'm not so confidant in my answer, that I'm prepared to put all my focus on one cure, because I'm so sure it will work. Second, about encapsulation specifically: sure it sounds good, but it's been tried before, and has not worked yet. Previous encapsulation companies have failed in human trials, several went out of business in the early 2000s. LCT has many years head start developing encapsulation technology (compared to ViaCyte) and yet does not have a cure.

Joshua Levy

celinhogomes1 said...

Mutatis mutandis, man took centuries to reach a cure for leprosy. No one had any idea how to stop the destruction that the bacillus did. I see the T1D on the same path. One day (tomorrow or 2350) will happen.

celsus said...

The reason for concentrating on the small, technical improvements still required to make islet implantation an effective treatment is that the problem is purely a matter of mechanical tinkering -- getting a steady supply of oxygen into capsules -- and does not involve elaborate, speculative efforts to manipulate complex physiological processes like the immune system, which are likely to have many unwanted side-effects and take decades to perfect, provided they are even the correct approaches.

The situation in type 1 diabetes research now is analogous to efforts to develop an atomic bomb in the late 1930s. There were many differing approaches, a lot of wild speculation, and very little cooperation, so the diffusion of effort had stalled progress. Only when General Grove was put in charge of organizing and focusing efforts to develop the bomb did the goal become achievable in a reasonable time. We need something like a General Grove approach to diabetes research, so that for the three to five years it will take to solve the oxygenation problem for islet capsules we can concentrate on solving the simplest and smallest difficulty en route to the goal. If that small amount of time and resources is wasted, that is something we can afford, and then we can return to the unfocused, broad-ranging, speculative approaches now being pursued.

A more difficult issue that lurks over the horizon is the fact that hyperglycemia may not be the source of all the problems in diabetes. The initial disease process, which persists throughout the patient's lifetime, has nothing to do with high blood sugar, and involves only autoimmunity. There is some evidence that autoimmune processes are in fact involved in at least some of the complications of diabetes. Also interesting is the evidence that the timing and character of some diabetic complications runs in families, suggesting a genetic component to the characteristic sequelae of the disease. The Joslin Clinic's 50-year survival study has shown that many long survivors with the disease have extremely high A1c values but very few complications, and this dissonance between complications and blood sugar has been noted in other investigations as well, such as the Accord study. What all of this could mean is that treatments for type 1 diabetes which focus only on restoring physiological levels of blood sugar may miss at least part of the cause of the complications.

Christopher Meek said...

Josh, Great work you are doing with this blog, I've been regularly reading your posts since my daughter was diagnosed at three years old a few years ago. It is a great resource to those of us who want to understand the T1D cure research landscape, but do not have a background in health sciences.

I'm curious about your take on the retraction of the HSCI Melton Lab paper on betatrophin. I'm glad to see that science "worked", despite the disappointing results. However it is not entirely clear in the popular press the implications of this on the other work that Melton's lab is doing. Does this affect or cast doubt on the results claimed regarding the large quantity of stem-cell derived beta cells or is this a completely separate project? Are there other implications of this retraction on the ecosystem of T1D cure research?

Joshua Levy said...

I commented extensively on Betatrophin saga in this blog entry:

I just reread that post. Obviously, now the paper has been formally retracted, however I think my blog posting is still very on target. Retracting the paper doesn't really change the issues you asked about (and I discussed). But my quick summary is this:
1. I don't think it directly casts doubt on non-betatrophin research.
2. But does it indirectly cast doubt on Dr. Melton's other research? Maybe. It's a serious question, certainly. I don't think people outside his lab can know. The solution to this is time. If his work in beta cell growth continues to move forward over time, then it is good. If it doesn't, then it is bad. It is that simple. Some people hate waiting; they want an answer now. But I'm content to get the right answer, even if it takes years. (Which it often does.)
3. Are there questions for the "ecosystem of T1D cure research"? I don't think so; not any worse than any other medical research. Medical research has well known weaknesses. I discuss some of these in my blog. However, I don't think type-1 diabetes cure research is worse than any other medical research.