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.
Wednesday, January 25, 2017
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.
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.
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