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.

6 comments:

celsus said...

Any interventions which either prevent or stop type 1 diabetes in its initial development will leave the millions of people who already have an established case of the disease stranded, since the motivation of governments, the general public, charities, large donors, researchers, and financially motivated pharmaceutical companies to find a genuine cure will be greatly diminished. This is why I am less than enthusiastic about intranasal insulin, Diamyd, or a novel polio vaccine, which only aspire to prevent or just stop type 1 diabetes in its early phase.

I am also cautious about any lines of treatment which involve manipulations of the immune system, as Il-2 and Diamyd do, since immunity is one of the most complicated and poorly understood aspects of human physiology. This means that the possibility of dangerous side-effects, which may well only become evident over decades, makes these approaches very risky.

Simply stopping the autoimmune attack on beta cells, such as IL-2 and Diamyd attempt to do, seems unlikely to achieve very much, since all the evidence so far shows that damaged beta cells are difficult to coax back into operation even if the autoimmune assault is suspended. This is why Dr. Faustman, for example, has been trying to find some additional element to induce beta cells to recover function after the immunological attack has been blocked. It is interesting to note in this context that of all the countless type 1 diabetics who have endured sizeable and persisting immunosuppression, often for many decades, to tolerate a transplanted organ, not a single one has ever had any restoration of beta cell function.

The tolerogenic approach attempted with intranasal insulin would be faced with the experimental difficulty that it is difficult to know what population is really at risk for type 1 diabetes, since while the disease is in part genetically conditioned, other factors are also involved, such that occasionally identical twins are seen in which one is a type 1 diabetic and the other is not. By the time immunological alterations are measurable, it may well be too late to achieve anything much. Also, there is considerable evidence that what induces the immunological attack on beta cells is not any problem with the immune system itself, but instead the deformed development of the beta cells, which causes the body to identify them as foreign tissue and attack them, even with a perfectly normal immunity.

In short, the physiologically sophisticated approaches to curing type 1 diabetes all suffer either from having a great danger of side-effects, not being able to revive the beta cells even if the autoimmune attack is stopped, or taking many, many decades to be refined into a clinically applicable treatment. That is why I prefer a concerted effort to perfect a simple, mechanical solution like ensuring a sufficient oxygen supply for encapsulated islet cells.

Rick said...

I personally will be excited if a preventative intervention is found. For me, I would much rather a prevention be found than a cure is found for my diabetes. After 42 years. It is all about the grandchildren and their children.

Bruno said...
This comment has been removed by a blog administrator.
Joshua Levy said...

The comment just above this (by Bruno) contained a personal story about someone who got a vaccination, and then later came down with type-1 diabetes (with no history of type-1 in the family). I deleted it.

Please remember: almost everyone gets vaccines. Therefore almost everyone who is diagnosed with type-1 diabetes has been vaccinated. And since almost everyone who is diagnosed with type-1 has been vaccinated, some of them will be recently vaccinated, just by chance. Also, remember that most people diagnosed with type-1 diabetes do not have a known history of type-1 in their families. But these same families often do have a history of other autoimmune diseases (with related genetics). Also, unless you know exactly how all your grandparent's (and great-grandparent's) siblings died, then you don't really know about type-1 in your family.

The important thing is that many studies have been done on vaccines and type-1 specifically, and they have never found that people who are vaccinated are at higher risk overall. I've blogged about this before:
http://cureresearch4type1diabetes.blogspot.com/2015/02/hpv-vaccination-and-type-1-diabetes.html (for HPV vaccines specfically)
http://cureresearch4type1diabetes.blogspot.com/2015/10/seasonal-flu-vaccine-and-type-1-diabetes.html (flu vaccines specifically)

I have a draft for childhood vaccines, but it's not finished. I guess I should put some work into finishing it.

Joshua

Bruno said...
This comment has been removed by a blog administrator.
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