Sunday, April 16, 2017

How Does JDRF Decide What Research To Fund?


I've always been interested in how JDRF decides what research to fund. So I was lucky that while attending the recent Bay Area Diabetes Summit  [d1] I attended a talk by Dr. Aaron Kowalski the Chief Mission Officer of JDRF [d2].  After the talk, I was able to ask him how JDRF made those decisions. He did his best, in the few minutes we had, to describe the process too me.  Later on, we followed up with a phone call, which allowed him to answer more detailed questions about the process. This blog is my summary of the process.  As always, any mistakes in this blog posting are mine alone.

Who Is Involved

There are three main groups of people involved in deciding who JDRF will fund:
  • The Research Staff:  This is a group of about 15-20 JDRF employees, most of whom are Ph.Ds, or have other degrees in medicine or science.
  • The Research Committee: More than half of this committee is made up of members of JDRF Board of Directors.  The remaining members bring specific skills and experiences to the table.   There are 13 people on this committee, and they all have close connections to the world of type-1 diabetes: 11 have one or more children with type-1 diabetes, 2 have type-1 themselves, and 2 have spouses with type-1 diabetes.  The total is more than 13 because 2 people fall into more than one category.  Full list is below [d3].  
  • The Board of Directors: More formally, the International Board of Directors.  This group is listed here: http://www.jdrf.org/about/leadership/#board-of-directors.  This is the governing board of JDRF, and is also overwhelming composed of people directly impacted by type-1 diabetes (people with the disease, parents of people with the disease, spouses, grandparents, etc.)
Allocation Funds: Priority, Strategy, Budget

JDRF's research staff makes proposals to the Board of Directors about how to allocate research money and if specific areas of research should be funded or not.  The Board of Directors makes the final decisions about what areas should be funded, and how money should be allocated between areas.  For the last few years, money has been allocated into six basic areas, and the division between these areas is done by the Board: Restoration, Beta Cell Replacement, Artificial Pancreas, Glucose Control, Prevention, and Complications [d4].

For each year, the Board of Directors makes decisions about JDRF's priorities, strategy, and overall budget.  These decisions help guide the Research Staff throughout the year.  Also, as described below, the Board is sometimes asked about specific research when it is significantly different from what JDRF has funded in the past.

You can read more about JDRF's 2017 research priorities here:
http://grantcenter.jdrf.org/information-for-applicants/research-priority-areas/
But the seven priorities are:
  • Beta Cell Replacement
  • Beta Cell Regeneration and Survival
  • Beta Cell Autoantigen-Specific Immune Therapies
  • Prevention of Type 1 Diabetes
  • Artificial Pancreas Device Systems
  • Glucose Modulating Agents
  • Diabetic Kidney and Eye Complications Therapies
But I encourage you to read the whole document, because it includes a high level vision statement, but also more specific goals in each area for 2017.

Specific Research

There are two "paths" that individual research proposals can follow in order to get approval, which I will call the "normal path" and the "unusual path".

The normal path goes as follows:
  1. The researcher submits a summary of the research they want to do.  This is not a detailed proposal, but an overview.
  2. JDRF's research staff reviews this summary focusing on if it fits in with JDRF's priorities, strategies, and budget.  If it does, they ask the researcher for a detailed proposal.
  3. The researcher then submits the detailed proposal.  This contains all the details of what will be done, where it will be done, who will do it, how long it will take, how much money is needed, why it is important, and how it can push forward the goals of JDRF.
  4. The detailed proposal is then reviewed both internally and externally.  The internal review is done by JDRF's research staff.  The external review is done by multiple researchers who work in the field, but are not involved in this specific research.  There are usually three such reviewers and they sign non-conflict of interest statements.
  5. Assuming the internal and external reviewers both like the proposal, it next goes to the Research Committee.  The Research Committee must approve all grants over $500,000.  These grants are each discussed separately, and the committee members can vote yes, no, or request more information for any grant.  They meet about once a month to do this work.  Grants under that amount are approved by staff, but presented to the Research Committee.  That committee can review all documentation of the staff decision (i.e. external reviews, etc.) and can question any grant.
  6. There is a separate group of people, referred to as "Operations Staff" who are responsible for the grant after it has been approved.  In general, this group is not involved in the funding decisions.
The unusual path covers research projects where the research staff is unsure if the project is even the kind of project that JDRF would fund.  These are usually new types of research, especially those requesting a large amount of money.  In these cases, the staff member will sometimes present the project to the Research Committee, prior to reviewing it.  The goal of this early discussion is to decide if the research proposal should even be considered; if it is the sort of project that JDRF would ever fund (regardless of the merits of this particular project).  If the Research Committee decides it is, then it goes through the normal path; if the Research Committee decides it's not, then it doesn't move forward.

Dr. Kowalski  pointed out several strengths of the system: First, nothing can be done based on one person's actions.  Every funding decision involved the Research Committee and multiple external and internal reviews.  Second, everyone on the Research Committee is directly impacted by type-1 diabetes.  Third, everyone on the Board of Directors is also similarly impacted by type-1 diabetes. Points two and three, taken together mean that both the overall policy decisions, and the specific research approvals are in the hands of people who have type-1 diabetes, or who have children, a spouse, grandchildren, etc. who have type-1 diabetes.

Discussion

I'm sure many people will want more details than I've provided here (or different details), and I hope that JDRF will publish a detailed description of the funding process.  This blog includes every scrap of information that I know on the subject.

Dr. Kowalski and I spent some time discussing how to make JDRF more transparent, which we both agreed is important moving forward.  It's a trade off however, because money spent developing web pages which describe how decisions are made takes money away from research.  We both bemoaned the lack of a "funding dashboard", a web site where you could see at a glance a high level overview of where money had been spent.  I'm hopeful that JDRF will get this information on-line soon.

If you want a searchable database of all the research projects which JDRF funds, that is available here:
https://jdrf.smartsimple.us/ex/ex_viewreport.jsp?key=&token=@GgoITRgTeFtYRhpcSRxRQ1BXZ1x8GHFg
(Or, from the main JDRF page, select "Our Work" and then "Search Research Abstracts".)
This is a good resource to find out if JDRF funded a particular researcher or university.  However, it uses a few terms that non-researchers will not be familiar with [d6] and you can search for words only in titles, but not in the body of abstracts or proposals themselves.  It contains information on individual projects only, there is no summary data of any kind.

This information comes directly out of the "SmartSimple" software that JDRF uses to track grant applications, grants, etc, and I do think that is the long term key to providing transparency without spending a lot of money on it.  Since JDRF is already using software to manage their grant process, if that software can be configured to provide summary data to the public, it would provide transparency without the constant work of updating the web pages.

Dr. Kowalski and I also discussed another topic called "funding mechanisms".  These are pools of money allocated for specific types of researchers or specific types of research.  For example, there is a funding mechanism for young researchers (to encourage people to enter the field of type-1 diabetes research).  There is a funding mechanism for early patient research (to help bridge the gap from animal to human trials), for specific projects which JDRF is encouraging [d6], etc.  All of these funding mechanisms go through the same process described above.  You can read more about them here:
http://grantcenter.jdrf.org/information-for-applicants/grant-mechanism-descriptions/

The process described in this blog post does not cover JDRF's recently announced "Venture Philanthropy" fund.  That fund has a similar process (also with a Board of Directors and an Investment Committee).  If there is interest, I'll try to make contact with the director over there, and see if I can write up a similar blog for them.

Finally: I want to say that if you have a question about how JDRF does something, or why JDRF does something, then I encourage you to look on the JDRF web site.  If you can't find what you are looking for, then try searching on google.com and adding "site:jdrf.org" to your search.  This tells google to only return hits on JDRF's site.  You can also add "filetype:pdf" which will only find PDF documents.

Extra Discussion

[d1] The Bay Area Diabetes Summit was a great event.  It was organized by CarbDM, DYF, with help from many other organizations, and everyone did a wonderful job. These Summits happen once a year, and if you are in the area, I strongly recommend attending.  There is lots to learn.   More info here:
https://carbdm.org/events/bay-area-diabetes-summit/

[d2] Dr. Aaron Kowalski is JDRF's Chief Mission Officer.  He's worked for JDRF for 13 years.  Prior to being CMO he was Vice President of Research.  Prior to working at JDRF he earned a Ph.D. in molecular genetics from Rutgers University and the University of Medicine and Dentistry of New Jersey.  He was diagnosed with type-1 diabetes when he was 13 years old in 1984, and so has lived with this disease for a long time.  His brother also has type-1 diabetes (diagnosed in 1977).
https://www.linkedin.com/in/aaron-kowalski-3221a35/

[d3] The current members are: Steve Newman, Randy Anderson, Tom Chapman, Tim Clark, Maarten de Groot, Karen Jordan, Doug Lowenstein, Preetish Nijhawan, Carol Oxenreiter, David Panzirer, Lorraine Stiehl, Jerry Wisler, and Michael White.

[d4] Of course, everyone wants to know how much is spent on each area.  The most recent data I could find myself (and it took me over an hour to find it, and I had to use my best google-fu) was updated in March 2015, but I think it covers the year of 2014:
  • Restoration ($31m)            [Restoration of insulin production in people with type-1 diabetes.]
  • Encapsulation ($13m)        [Recently replaced by the broader "Beta Cell Replacement".]
  • Artificial Pancreas ($16m)
  • Glucose Control ($5m)       [This includes smart insulin.]
  • Prevention ($14m)
  • Complications ($13m)
  • Multi-category Programs ($9m)
Source: https://www.hlc.org/app/uploads/2014/05/2015-JDRF-Fact-Sheet.pdf
which is the most recent fact sheet that has this level of detail.  Note that the total here ($101m) does not exactly match the data from fiscal year 2014 tax forms ($98m).  The fiscal year ends in June. That might be a summation/rounding difference, or this data might be for calendar year 2014, or for the 12 months preceding March 2015, or I might have messed up the numbers in some way.  I'm a software engineer, not an accountant.

[d5] Especially the term "funding mechanism", which I describe below.

[d6] JDRF refers to these as RFAs (Requests For Applications), but another common name is RFPs (Requests For Proposals).  Instead of just sitting back and seeing what proposals come in, the funding organization makes a public request for a specific type of proposal.  JDRF does this on occasion. These proposals go through the same approval process as others. You can see a few recent examples here:
http://www.jdrf.org/wp-content/uploads/2012/12/FY16-Beta-Cell-Replacement-Retrievable-RFA.pdf
http://grantcenter.jdrf.org/wp-content/uploads/2016/12/FY17-Microbiome-RFA-2016.12.21-2.pdf


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.

Tuesday, March 21, 2017

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

ViaCyte Starts A Three Year Follow-up Safety Study in Subjects Previously Implanted With VC-01™
This clinical trial is studying people who were part of ViaCyte's clinical trial of VC-01™, an encapsulated beta cell cure.  Once the device is removed at the end of the study, the patients can enroll in this follow on study which tracks them for three additional years, looking for adverse effects.

ViaCyte is a commercial company testing an encapsulated beta cell cure.  You can read my previous blogging about them here: http://cureresearch4type1diabetes.blogspot.com/search/label/ViaCyte
They are in the middle of a large Phase-I study, which could finish as early as 2020.

Clinical record: https://clinicaltrials.gov/ct2/show/NCT02939118

Discussion

I'm hopeful that this means that one person has finished the ViaCyte protocol, which is motivating them to start this follow on.  The other option is that they are just planning ahead.  Since there is no control group, the interim data could be published, if ViaCyte wanted.

Two Phase-I Studies Start with Umbilical Cord Treg Cells 
These two studies have a lot in common, so I'm going to discuss them together: first, their similarities, then their differences. Here are the similarities:
  • They are both run by the same researcher (Dr. Zhiguang Zhou) at the same hospital (Second Xiangya Hospital of Central South University).
  • They recruit at the same place: Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China, 410011
    Contact: Zhiguang Zhou, MD/PhD    86-731-85292154    zhouzg@hotmail.com
  • They have already started recruiting 40 people, and expect to finish in 2019.
  • These trials are open to people who have been diagnosed within 3 years and are between 6 and 60 years old.
  • Each has a primary end point which is safety related, and secondary endpoints which are effectiveness related and include C-peptide, A1c, insulin usage, etc.
  • Both studies will work with stem cells which have been harvested from umbilical blood, separated into components, and had the T-reg cells "grown out" for two weeks.  These enriched T-reg cells will be infused into patients.  T-reg cells are regulatory cells which are part of the immune system, and work by controlling other immune cells so that those other cells don't attack beta cells.

The first study is Safety Study and Therapeutic Effects of Umbilical Cord Blood Treg on Autoimmune Diabetes: This study will have two groups, one will get the treatment, and one will be a control group and will not get the treatment.

Clinical trial registry: https://clinicaltrials.gov/ct2/show/NCT02932826

The second study is Safety and Efficacy of Umbilical Cord Blood Regulatory T Cells Plus Liraglutide on Autoimmune Diabetes: This study has four groups.  One will get the treatment and also Liraglutide, another just the treatment, a third just Liraglutide, and a fourth will be a control group.  Liraglutide (sold as Victoza) is similar to exenatide (Byetta), which is a common type-2 medication, but is also sometimes used on type-1.  Victoza is a weekly injection. 

Clinical trial registry: https://clinicaltrials.gov/ct2/show/NCT03011021

Discussion

The researchers are not clear on why they are using Liraglutide, but site its "various benefits for beta cells". They expect it will increase the effectiveness of the new T-regs, possibly by encouraging beta cell growth.

JDCA's Update on Dr. Faustman's Research

An update on Dr. Faustman's BCG research by the JDCA (Juvenile Diabetes Cure Alliance) is here:
http://eepurl.com/cHrGqX

My key takeaway points are:
* The Phase-II trial should finish in 2023.
* They have enrolled 125 out of the 150 they need.
* An 8 year follow up from their Phase-I trial should be published by the end of 2017.

(Remember, I am a fellow of the JDCA and we regularly discuss various research programs, including this one.)
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, 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.