Thursday, February 9, 2017

News From EASD (European Association to Study Diabetes)


Back in October 2016 was the European Association to Study Diabetes (EASD) conference, which is the largest scientific meeting on diabetes in Europe.  Much like ADA, it covers both type-1 and type-2 diabetes. The Europeans are way ahead of the American in terms of on-line access.  The EASD 2016 web site has recordings of many of the talks, and much more content than the ADA web site. You can see it here:
http://www.easdvirtualmeeting.org/

Clinical Trials Aimed at Curing Type-1 Diabetes
The only research which I saw which was directly aimed at curing type-1 diabetes was a talk and a poster given by Dr. Ali from the Cardiff Diabetes Vaccine Development Center (which is part of Cardiff University, Wales, UK).  This is part of the ongoing work by Dr. Peakman and others.

Results of the Monopept1de Phase-I Trial of An Insulin Peptide

This research has been on-going for at least 10 years.  Here is my previous blogging:
http://cureresearch4type1diabetes.blogspot.com/search/label/Proinsulin
The basic idea is to give people with type-1 diabetes an injection containing part of the insulin molecule, which will teach the body's immune system not to attack itself.  The idea is vaguely similar to giving people tiny amounts of peanut protein to desensitize them from peanut allergies.  It is important to remember that type-1 diabetes is NOT a classic allergy.  The analogy is not perfect, but that's the general idea.

The study showed that the treatment was safe and did not trigger any serious adverse effects, or unexpected adverse effects of any kind.  The success/outcome data was weaker.  C-peptide production did NOT increase, but insulin usage went down, and H1c numbers showed a downward trend in treated people.  None of this is strong data for effectiveness, but this trial was aimed at gathering safety data.  The researchers think the safety data is plenty strong enough to support a phase-II study.

Poster: http://www.easdvirtualmeeting.org/resources/proinsulin-peptide-immunotherapy-in-new-onset-type-1-diabetes-is-well-tolerated-and-associated-with-reduced-daily-insulin-usage
11 Minute Talk: http://www.easdvirtualmeeting.org/resources/proinsulin-peptide-immunotherapy-in-new-onset-type-1-diabetes-is-well-tolerated-and-associated-with-reduced-daily-insulin-usage-203021b2-7c50-4239-81b8-84fe0d8a0291
Older Poster On The Same Research: http://www.easdvirtualmeeting.org/resources/proinsulin-peptide-immunotherapy-in-type-1-diabetes-safety-data-of-a-first-in-new-onset-type-1-diabetes-phase-1b-trial--2

This same research group is working on another clinical trial called "MultiPepT1De", which is testing using several different proteins at once.  The trial reported on here only used one. The MultiPepT1De trial was scheduled to finish in Feb-2017, but is running late:
https://www.ukctg.nihr.ac.uk/trials/trial-details/trial-details?trialId=5462
https://clinicaltrials.gov/show/NCT02620332

Other Interesting Talks

Faustman
This was a 15 minute talk by Dr. Denise Faustman, where she discusses a particular chemical pathway (TNFR2):
http://www.easdvirtualmeeting.org/resources/in-vitro-tnfr2-agonism-for-correction-of-treg-activation-defect-in-type-1-diabetes-c96e016f-57c0-4432-9805-9918efcd364e

Viral Infections as Triggers
The talk in the next link discussed looking for viruses in the pancreases of 6 newly diagnosed adults. It is 30 minutes long and has 114 slides: 
http://www.easdvirtualmeeting.org/resources/the-pathogenesis-of-type-1-diabetes-virus-involved-lessons-from-the-divid-study
These researchers are trying to answer the question "does a viral infection trigger type-1 diabetes", by looking at pancreases close to the time of diagnosis.  They did find more viruses in people with type-1 diabetes, but it was low grade persistent infection, not an acute infection.  They were all enteroviruses, no two of the same strain, and the exact virus could not be identified (due to low levels).

Also, they found that 36% of the islets were still producing insulin approximately 5 weeks after diagnosis, which is higher than previous estimates that I'm familiar with.  This definitely comes down on the "viruses are involved in triggering type-1", but the study was a small pilot study, in need of follow up.

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.

Wednesday, January 25, 2017

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

Trial of Intranasal Insulin To Prevent Type 1 Diabetes (INITII) Is Fully Enrolled

The official title is "Trial of Intranasal Insulin in Children and Young Adults at Risk of Type 1 Diabetes (INITII)" and it is now fully enrolled.  Since people will be followed for a total of 10 years, results will be ready in 2026.  However, the primary end point is after 5 years, so it's possible that those results would be published sometime after 2021.

Previous blogging is here: http://cureresearch4type1diabetes.blogspot.com/2012/09/possible-cures-for-type-1-in-news-early.html (but it's not much).  The important information is this:

Several different groups are experimenting with using insulin to prevent or cure type-1 diabetes.  This is similar to giving people with food allergies the food they are allergic to in tiny doses, gradually building up the dose over years until they are no longer allergic.  (Although the truth is a little more complex than that: type-1 diabetes is not a simple allergy to insulin.)  Because insulin is basically a protein, it gets digested, so you can't take pills of insulin.  These researchers are experimenting with inhaled insulin, given to people who are at risk of developing type-1, but have not yet developed the disease.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT00336674

Results from IL-2 (the DLIT1D study)
Several groups of researchers are trying to cure type-1 diabetes by using IL-2 (Aldesleukin).  I've blogged on this before:
http://cureresearch4type1diabetes.blogspot.com/2016/05/general-update-on-il-2-research.html
The basic idea is that giving Aldesleukin raises the level of T-reg cells, and those cells kill off the bad T-killer cells, and that's good for people with type-1 diabetes.

This particular trial was aimed at finding the dose of Aldesleukin which would cause a 10%-20% increase in T-reg cells.  The technique was to give a dose of Aldesleukin to a small number of people, monitor them closely, and then based on those results, give a different dose to another small group, and so on.  After a couple of repetitions, they narrow in on the perfect dose.  This is not as easy as it sounds because Aldesleukin causes T-reg numbers to drop in the short term (which is bad), but go up in the longer term (which is good), so you need to evaluate these two effects by dose and frequency.

The researchers are happy with their results: they now know what Aldesleukin dose to use in future research, and they understand why some previous IL-2 research was unsuccessful.  Unfortunately, from my point of view, there was no improvement in C-peptide numbers or A1c numbers.  As an optimist, I'm hopeful that was because they were only testing a single dose in this trial, and improved numbers will be seen in studies with more doses over a longer period of time.

This research should lay the foundation for future clinical trials of Aldesleukin.

Abstract and Paper: http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002139
European Trial Registry: http://www.isrctn.com/ISRCTN27852285
American Trial Registry: https://clinicaltrials.gov/ct2/show/NCT01827735

Combining Diamyd Data
(My summary: "if you combine several smaller failures, you end up with one larger failure".)

This study is a testament to the optimism of researchers.  Diamyd ("GAD Vaccine") has been tested for over 10 years.  None of these trials has been particularly successful.  They culminated in an unsuccessful Phase-III trial years ago.  You can read my previous blogging on Diamyd here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Diamyd

However, researchers are natural optimists.  And it is important that they are.  Society needs optimistic researchers so that they will repeatedly attack problems, and not give up, even in the face of adversity.  In October, researchers published this paper, which basically pooled all the Diamyd data from several previous studies, and reported that it had a very small effect.  The researchers present this as a success, but the effect is so small that I consider it confirmation of failure.

People with type-1 diabetes are expected to lose insulin production during their honeymoon phase. This summary found that those given Diamyd lost 80% as much as those who were not treated.  In the last few years, several treatments have shown better results in clinical trials, and none of those have progressed to a cure, or even a treatment, so I'm not expecting this news to push Diamyd forward.  (By "better results" I mean that, when given during the honeymoon, they end up slowing beta cell destruction more than Diamyd slowed this destruction.)

Abstract: https://www.ncbi.nlm.nih.gov/pubmed/27704166


Polio Virus Trial Finished
The researchers finished gathering data in Nov-2016 so they should publish results in the next year (if successful) or two (if not).  This is an unusual trial.

The trial started in 1999, and was run by Dr. Hanna Viskari out of the University of Tampere in Finland.  These researchers believe that infection with an enterovirus would have an impact in later development of type-1 diabetes.  (It is unclear to me if they thought it would raise or lower the chance of getting type-1.)  To study this, they are following a group of 315 children who are at heightened risk of getting type-1 diabetes, because they are genetically predisposed to it.  Some of these children were given the OPV polio vaccine, which contained weakened, but still live, polio virus, while others got the IPV polio vaccine, which contains dead polio virus.  These children will be followed for 10 years to see if one group has a lower type-1 diabetes rate than the other group.

This trial is a "natural history" type trial, not an intervention trial.  Finland changed it's method of Polio vaccination, so these researchers followed children who got the "old" vaccination (OPV) to children who got the "new" vaccination (IPV).  The researchers did not randomize children to get one or the other vaccine, they merely tracked children who were already getting one or the other vaccine.

Polio is the most famous  (infamous?) enterovirus, but the family contains about 70 viruses including the Coxsackie viruses and the virus that causes Hand, Foot, and Mouth Disease.  More modern viruses in the family get numbers, rather than names, so viruses called EV-71 and EV-D68 are recently discovered enteroviruses.

Discussion
I think this study might provide general information on the relationship between enteroviruses and type-1 diabetes, but I don't think it will change people's behavior.   If the IPV polio vaccine group has a lower type-1 rate: that is already the polio vaccine that people in the US get normally.   On the other hand, if the OPV polio vaccine group has the lower type-1 rate, that vaccine has a tiny (but non-zero) chance of causing paralysis, so I don't see people switching to it in order to prevent type-1 diabetes.

Clinical trial record: https://clinicaltrials.gov/ct2/show/NCT02961595
Discussion of OPV vs. IPV: http://www.virology.ws/2015/09/10/why-do-we-still-use-sabin-poliovirus-vaccine/


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.

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
http://cureresearch4type1diabetes.blogspot.com/search/label/Zhao

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
http://cureresearch4type1diabetes.blogspot.com/search/label/Verapamil

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.

INSULETE
(no previous blogging: in animal testing)
http://www.wisbusiness.com/index.Iml?Article=383101

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
http://www.techtimes.com/articles/187635/20161203/malaria-drug-artemisinin-spurs-cells-to-produce-insulin-shows-promise-as-type-1-diabetes-treatment.htm

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.

Discussion

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
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.

Friday, December 16, 2016

The Impact of Advocacy

This blog is a little different from my usual subject matters.  Instead of reporting on the status of various clinical trials, I'm going to discuss a paper by Rachel Kahn Best entitled Disease Politics and Medical Research Funding: Three Ways Advocacy Shapes Policy.   This paper is about how the US government funds research into diseases.

Here is the paper: http://asr.sagepub.com/content/77/5/780.full.pdf+html
but it might require payment to see by the time I post this blog entry.  Here is some coverage of the paper:
http://scienceblog.com/56900/patient-led-advocacy-has-changed-how-us-government-funds-medical-research/#t3OR5WHhyOzpFFBc.99

My Summary of Best's Paper:
  • Prior to 1980s funding of medical research:
    • Was viewed as a benefit to the researchers being funded
    • Was allocated based on perceived quality of the proposed research
  • During the late 1970s to 1980s there were large social movements (largely focused on AIDS and breast cancer) which changed governmental thinking and policies
  • Starting in the 1990s funding of medical research:
    • Was viewed as a benefit to the people with the disease being researched
    • Was allocated based on impact of the disease being researched
  • Advocacy organizations can have a large impact in government funding of medical research. There is a strong link between advocacy and funding.
Some Details

Here is a key quote on funding:
Increases in the number of nonprofits and lobbying expenditures are both significantly associated with increases in research funding, with each $1,000 spent on lobbying associated with a $25,000 increase in research funds the following year.
Underfunding of Diseases Common to Women and African-Americans

Most of the news coverage of this paper has focused on the "underfunding" of women's and African-Americans' diseases.  This paper discusses the idea that research into diseases of women and African-Americans are underfunded in comparison to diseases of men and whites, including possible reasons for this.  Based on the available data, the paper suggests that the difference is caused by a lack of advocacy organizations.  That funding is based on advocacy organizations, and there are fewer advocacy organization for diseases of women and African-Americans as compared to men and whites.  (Put bluntly: the difference is more directly caused by economic discrimination rather than sexism or racism.)

However, rather than discuss this conclusion, I think it is more important to discuss the weaknesses of the basic idea that diseases of women and African-Americans are underfunded.  The paper lists these weaknesses very clearly:

First, women's diseases are NOT underfunded with respect to men's diseases.    A more accurate statement is that, for women's diseases, breast cancer is funded at a much higher level than men's diseases, and all other women's diseases are funded at a lower level, and everything averages out.  A serious argument can be made that funding should be allocated more evenly among women's diseases, but not that women's diseases as a whole are underfunded.  (Remember that breast cancer has several very strong advocacy organizations, which likely leads to it's "overfunding".)

Second, when the study talked about African-American's diseases being underfunded compared to others, it is very important to remember that only one disease uniquely common to African-Americans was included in the analysis: sickle cell anemia.  So when the study said African-Americans' diseases were underfunded, what it really meant was that sickle cell anemia was underfunded.  (That does sound racist, but it's a single data point, so I'm nervous about reading too much into it.)

Questions for you to Consider

You will notice I'm making no attempt to answer any of the questions below.  Each one of them is a separate "can of worms": worthy of an all night "bull session" in a college dorm room, with some good friends, over some beers.  They are the kind of questions where the discussion is more important than the answer (especially since most of them have no absolute answer).

1. Which model do you think should be the foundation of research funding?  Should research be funded as a benefit to the researchers or to the patients?

2. If you are a proponent of funding based on patient impact, then how do you deal with the problem of diseases which target people who are already discriminated against, being underfunded specifically due to that discrimination?   Early on many believed that AIDS was underfunded specifically because the administration (at the time) didn't care about gays.

3.  If you accept that medical research should be funded based on impact to patients, then how do you measure that impact?
  • Do you measure in terms of number of deaths?  If so, type-1 diabetes will have a relatively lower priority, since it is a less common direct cause of death.
  • Do you measure in terms of number of people with the disease?  If so, minor but common diseases (like the common cold) might get prioritized higher than major (but rare) killers like bone cancer. 
  • What impact should age have?  If two diseases kill the same number of people, but one kills 20 year olds, while the other kills 80 year olds, should they get equal funding?  (This is a classic AIDS vs. cancer argument.)
  • Although mortality and prevalence are common ways to measure impact, from society's point of view, lost productivity might be a better measure.  It does serve to merge depth and breadth of impact into one number.  But then are we going to fund "diseases of the rich" over "diseases of the poor"?  Because when we start measuring economic impact, that's often what it boils down to.
4.  If you accept that medical research should be funded based on impact to patients, then do you take into account other facts about your patients?
  • What impact should preventability have?  Consider three diseases: liver disease, syphilis, and type-1 diabetes:  Liver disease is often (but not always!) caused by alcoholism or drug addiction. Syphilis can be prevented via safe sex.  Type-1 diabetes can not be avoided in any way.  Should these facts impact the funding level for research into these diseases?
  • Many people are willing to underfund research into "diseases" like alcoholism and drug abuse (?are those diseases, or just bad habits?)  But what about lung cancer?  Are you going to fund research into curing the type that smokers get, or just the type that non-smokers get?  What about types that are more common in smokers but occasionally pop up in non-smokers?
Why did I write this blog?
Although we often don't think about it, the federal government is a huge funder of research aimed at curing type-1 diabetes (maybe the largest).  Even research they did not fund directly is often done by programs or sites they did fund.  Therefore, understanding what motivates federal spending is important to understanding research aimed at curing type-1 diabetes.  Even though this is not directly about a clinical trial, I still thought it was interesting and important to blog on.

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

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:
http://cureresearch4type1diabetes.blogspot.com/search/label/Ustekinumab

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: https://clinicaltrials.gov/ct2/show/NCT02117765

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:
https://cureresearch4type1diabetes.blogspot.com/search/label/Verapamil

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:
http://cureresearch4type1diabetes.blogspot.com/search/label/Leptin

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: https://clinicaltrials.gov/ct2/show/NCT01268644


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.

Wednesday, October 19, 2016

Golimumab / SIMPONI Starts a Phase-II? Trial (T1GER)

Golimumab (sold as Simponi) is an immune system modulator, which has been approved in the United States and many other countries for treatment of several autoimmune diseases, so testing it on type-1 diabetes makes a lot of sense.  It has already been approved to treat rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and ankylosing spondylitis.

The Study

This study will enroll 81 people.  Half will get the treatment, and half will get a placebo, as the study is double blind.  The treatment is a subcutaneous injection once a week.  This is the same kind of injection used for insulin itself.  Everyone will be followed for two years.  The primary data will be C-peptide generation (a marker for natural insulin production), and the secondary data includes A1c, insulin usage, side effects, more C-peptide data, etc.

They started in August 2016 and plan to run until October 2019.

The researchers are planning on recruiting at 30+ different locations throughout the United States. Their clinical trials page says that right now they are only active in Atlanta, Georgia and Lexington, Kentucky. However, I do think they are actively recruiting in Walnut Creek, California as well. (People often forget to update their clinical trial record as they add more sites.)   The contact point for enrollment is this email address: JNJ.CT@sylogent.com.

Discussion

Golimumab is a monoclonal antibody (meaning it very specifically targets one type of cell). In particular, Golimumab targets TNFα (Tumor Necrosis Factor alpha) an immune signalling protein, which triggers several immune responses, including inflammation.  This is slightly controversial because researchers such as Dr. Faustman are trying to cure type-1 diabetes by increasing the levels of TNFα, while these researchers are trying to cure type-1 diabetes by decreasing the levels of TNFα. This issue came up in 2009, when Embrel (which lowers TNFα) had a mildly successful Phase-I trial. I discussed the "TNFα: Friend or Foe" at that time:
http://cureresearch4type1diabetes.blogspot.com/search/label/ENBREL

This study is being done by Janssen Research and Development, which is a large pharmaceutical company.

Clinical Trials Registry: https://clinicaltrials.gov/ct2/show/study/NCT02846545
Drug Web Page: http://www.simponi.com/
Drug Wikipedia Page: https://en.wikipedia.org/wiki/Golimumab
TNF  Wikipedia Page: https://en.wikipedia.org/wiki/Tumor_necrosis_factor_alpha

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.

Wednesday, October 5, 2016

JDRF Funding for a Cure 2016

In the US, we are in the "Walking Season" when JDRF asks us to walk to raise money for a cure. So I'd like to do my part, by reminding you all of how important JDRF is to the human trials of potential cures for type-1 diabetes, which I track.

Let me give you the punch line up front: 71% of the treatments currently in human trials have been funded by JDRF. (And the number is 83% for the later phase trials) This is a strong impact; one that any non-profit should be proud of. This summary does not include Artificial Pancreas research or stem cell growth trials, because there are so many of those that it would be hard to include them all.

Below is a list of all the potential cures, grouped by phase of trial that they are currently in, and separated into potential cures that JDRF has funded, and those that JDRF has never funded.

This list is a list of treatments, and many of these are being tested in more than one clinical trial.  For example, the "ATG and autotransplant" treatment is actually running three trials, but since they are all testing the same treatment, it is only one item in the list. The list below uses the following marks to show the nature of the treatments:
    (Established) One or more trials are open to people who have had type-1 diabetes for over a year.
    (Prevention) This treatment is aimed at preventing type-1 diabetes, not curing it.

Also remember that I give an organization credit for funding a treatment if they funded it at any point in development; I don't limit it to the current trial. For example, JDRF is not funding the current trials for AAT, but they did fund earlier research into it, which helped it grow into human trials. I include indirect funding of various kinds. For example, the JDRF funds nPOD,  ITN, and several other organizations, so I include research done by these other groups as well as being indirectly JDRF funded.

New This Year: Phase-II? Trials
Starting this year, I'm dividing Phase-II trials into two groups.  Phase-II trials are "classic" phase-II trials; they are done after a successful Phase-I trial in type-1 diabetes.  What I call Phase-II? trials are done with treatments which are known safe, so they don't need Phase-I trials, but have never been tested on type-1 diabetes before.  These Phase-II? trials might be Phase-II from the point of view of safety, but they are Phase-I in terms of effectiveness, so I'm putting them in their own category.

Cures in Phase-III Human Trials
Summary: currently there are no treatments aimed at curing type-1 diabetes which are in phase-III trials (under the definition of cure that I use). This is the fourth year in a row there have been no phase-III trials underway, and it's not a good thing. Even worse, I don't see a phase-III study starting even next year.  Some people might be discouraged by that, but for me, it's a reason to donate.  Money is the thing that is going to move the Phase-II studies listed below into Phase-III studies, and the Phase-I studies to Phase-II, create more Phase-I studies, and so on.

Cures in Phase-II Human Trials
Summary: there are 24 trials in phase-II, and 20 of them have been funded by JDRF, while 4 have not. Here are the treatments that have been funded by JDRF:
  • AAT (Alpha-1 Antitrypsin) by Grifols Therapeutics and also Kamada 
  • ATG and GCSF by Haller at University of Florida (Established) 
  • Abatacept by Orban at Joslin Diabetes Center 
  • Abatacept by Skyler at University of Miami (Prevention) 
  • Aldesleukin (Proleukin) at Addenbrooke’s Hospital, Cambridge, UK 
  • Diabecell by Living Cell Technologies (Established) 
  • Diamyd, Ibuprofen ("Advil"), and Vitamin D by Ludvigsson at Linköping University
  • Diamyd, Etanercep, and Vitamin D  by Ludvigsson at Linköping University
  • Diamyd and Vitamin D by Larsson at Lund University (Prevention)
  • Gleevec by Gitelman at UCSF 
  • Gluten Free Diet: Three Studies  (Preventative)
  • Oral Insulin (Preventative) 
  • Polyclonal Tregs by both Trzonkowski and Gitelman  
  • Stem Cell Educator by Zhao (Established) 
  • Teplizumab (AbATE study team) 
  • Teplizumab by Herold/Skyler/Rafkin (Prevention)
  • Tocilizumab by Greenbaum/Buckner at Benaroya Research Institute 
  • Umbilical Cord Blood Infusion by Haller at University of Florida 
  • Ustekinumab by University of British Columbia
  • Verapamil by Shalev/Ovalle at University of Alabama at Birmingham
Not funded by JDRF:
  • ATG and autotransplant by Burt, and also Snarski, and also Li 
  • BCG by Faustman at MGH (Established) 
  • Dual Stem Cell by Tan at Fuzhou General Hospital 
  • Vitamin D by Stephens at Nationwide Children's Hospital (Prevention)
Cures in Phase-II? Human Trials
Summary: there are 4 trials in phase-II, and 1 of them has been funded by JDRF, while 3 have not. Here are the treatments that have been funded by JDRF:
  • Rituximab by Pescovitz at Indiana University
Not funded by JDRF:

  • Albiglutide by GlaxoSmithKline
  • Ladarixin by  Emanuele Bosi of Dompé Farmaceutici 
  • Rapamycin Vildagliptin Combo by IRCCS (Established)
Cures in Phase-I Human Trials
Summary: there are 24 trials in phase-I, and 16 of them are funded by JDRF, while 8 are not. Here is the list funded by JDRF:
  • Alefacept by TrialNet 
  • ßAir by Beta-O2's at Uppsala University Hospital in Sweden (Established) 
  • TOL-3021 by Bayhill Therapeutics (Established) 
  • CGSF by Haller at University of Florida 
  • Trucco at Children’s Hospital of Pitt / Dendritic Cells (DV-0100) by DiaVacs (Established) 
  • Exsulin and Ustekinumab by Rosenberg at Jewish General Hospital, Canada (Established) 
  • IBC-VS01 by Orban at Joslin Diabetes Center 
  • Leptin by Garg at University of Texas 
  • Metformin by Littleford at The University of Exeter (Prevention)
  • MultiPepT1De (Multi Peptide Vaccine) by Powrie at King’s College London
  • Nasal insulin by Harrison at Melbourne Health (Prevention)
  • Smart Insulin (MK-2640) by Merck (Established) 
  • Tauroursodeoxycholic Acid (TUDCA) by Goland at Columbia University
  • Polyclonal Tregs by both Trzonkowski and Gitelman 
  • Pro insulin peptide by Dayan at Cardiff University 
  • VC-01 by Viacyte (Established)
Not funded by JDRF:
  • CGSF and autotransplant by Esmatjes at Hospital Clinic of Barcelona (Established) 
  • Encapsulated Islets at University clinical Hospital Saint-Luc (Established) 
  • Mesenchymal Stromal Cell by Carlsson at Uppsala University
  • Microvesicles (MVs) and Exosomes by Nassar at Sahel Teaching Hospital 
  • Monolayer Cellular Device (Established) 
  • Rilonacept by White at University of Texas 
  • Substance P by Vanilloid Genetics at Hospital for Sick Children Toronto (Established)
  • The Sydney Project, Encapsulated Stem Cells (Established) 
    Summary of all Trials
    52 in total
    37 funded by JDRF
    So 71% of the human trials currently underway are funded (either directly or indirectly) by JDRF. Everyone who donates to JDRF should be proud of this huge impact; and everyone who works for JDRF or volunteers for it, should be doubly proud.

    Just Looking at Trials on Established Type-1 Diabetics
    15 of these treatments (29%) are being tested on established type-1 diabetics.
    Of these, 9 are funded by JDRF
    So 60% of the trials recruiting established type-1 diabetics are funded by JDRF.

    Compared to Last Year
    In 2015 there were 42 treatments in clinical trials, in 2016 there are 52 (growth of 24%)
    In 2015 there were no treatments in Phase-III trials, in 2016 there are none (no change).
    In 2015 there were 22 treatments in Phase-II and Phase-II? trials, in 2016 there are 28 (growth of 27%).
    In 2015 there were 20 treatments in Phase-I trials, in 2016 there are 24 (growth of 20%).

    How I Count Trials for This Comparison
    • I give an organization credit for funding a cure if it funded that cure at any point in it's development cycle. 
    • I mark the start of a research trial when the researchers start recruiting patients (and if there is any uncertainty, when the first patient is dosed). Some researchers talk about starting a trial when they submit the paper work, which is usually months earlier. 
    • If there are different clinical trials aimed at proving effectiveness as a cure and as a preventative, or effectiveness in honeymooners and established diabetics, then those are counted separately. 
    • For trials which use combinations of two or more different treatments, I give funding credit, if the organization in the past funded any component of a combination treatment, or if they are funding the current combined treatment. Also, I list experiments separately if they use at least one different drug. 
    • The ITN (Immune Tolerance Network) has JDRF as a major funder, so I count ITN as indirect JDRF funding. 
    • I have made no attempt to find out how much funding different organizations gave to different research. This would be next to impossible for long research programs, anyway. 
    • Funding of research is not my primary interest, so I don't spend a lot of time tracking down details in this area. I might be wrong on details. 
    • I use the term "US Gov" for all the different branches and organizations within the United States of America's federal government (so includes NIDDK, NIAID, NICHD, etc.) 
    • I don't work for the US Gov, JDRF, or any of the other organizations discussed here. I have a more complete non-conflict of interest statement on my web site. 
    Some Specific Notes:
    • Serova's Cell Pouch and DRI's BioHub: These two clinical trials are both testing one piece of infrastructure which might be used later in a cure. They are testing a part of a potential cure. However, in both cases, the clinical trials being run now require immunosuppression for the rest of the patient's life, so I'm not counting them as testing a cure.
    • Substance P at Hospital for Sick Children Toronto: This trial is avoiding the honeymoon period by tested for insulin production.  Patients must inject more than 1/2 unit/kg to be accepted, therefore they will accept recently diagnosed people, if they are injecting enough insulin to be passed the honeymoon.  I'm counting this as "Established".
    Treatments Removed This Year:
    • Etanercept (ENBREL) by Quattrin at University at Buffalo (no movement since 2008)
    • Brod at University of Texas-Health Science Center (no movement since 2009)

    This is an update and extension to blog postings that I've made for the previous seven years:
    Finally, please remember that my blog (and therefore this posting) covers research aimed at curing or preventing type-1 diabetes that is currently being tested in humans. There is a lot more research going on, not covered here.

    Special Note: The JDRF's Role in The First Artificial Pancreas Approval by The FDA
    Although not strictly a "cure" the artificial Pancreas is clearly a huge breakthrough in diabetes treatment which will vastly lower complications, hassle, and "dead in bed" situations.  The JDRF deserves a lot of credit for getting an AP to market now.   First, the JDRF funded a lot of the basic research (and some not-so-basic research as well).   But it also helped clear the regulatory hurdles.  Even five years ago, the FDA's policies and procedures made it very difficult to get an AP approved (even one that worked well).  Simpler medical devices were approved in the EU many months before they were approved in the US.  The JDRF was instrumental in changing that.  The JDRF organized and led an informal consortium of diabetes advocates which, on the one hand, assembled scientific evidence and, on the other hand, applied grassroots political pressure which together resulted in the FDA adopting reasonable policies, and (eventually) this AP approval.

    Please think of this posting as being my personal "thank you" note to all the JDRF staff, volunteers, and everyone who donates money to research a cure for type-1 diabetes:
    Thank You!
    Finally, if you see any mistakes or oversights in this posting, please tell me! There is a lot of information packed into this small posting, and I've made mistakes in the past.

    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.