TIXIMED Starts a Phase 1 Study of TIX100

TIX100 is a protein which inhibits the action of TIXNP (thioredoxin-interacting protein).  It is being developed by the TIXIMED company.  TXNIP is elevated in pancreatic islets of people with type-1 diabetes and causes beta cell death and dysfunction.  The hope is that inhibiting that protein will protect beta cells and therefore delay or prevent T1D.

Anath Shalev, a researcher at the University of Alabama, Birmingham is leading this research effort, first at UAB and now also at TIXIMED.  She first identified TXNIP in 2002 in human islets exposed to high glucose and then later showed that it played a role in glucose toxicity and diabetic beta cell loss.  Research has shown that inhibiting TXNIP protects beta cells and promotes beta cell health and function.

Recently she has run clinical trials for Verapamil, which lowers TXNIP and is already approved in the USA for the treatment of high blood pressure, migraines, and heart problems.  I have blogged several times on those studies, but especially the results from a phase-II trial here:

https://cureresearch4type1diabetes.blogspot.com/2023/03/results-from-phase-ii-verapamil-study.html

I also listed it as a drug to watch in 2024:

https://cureresearch4type1diabetes.blogspot.com/2024/01/what-to-watch-in-2024.html

because there is another phase-II study ongoing in Europe, but it is now scheduled to finish in 2025 or 2026.

TIX100 is an oral medicine, and a "small molecule", but I have not found any other public information on what it actually is.  It has been tested in animals for T1D, T2D, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).  For example: 
https://diabetesjournals.org/diabetes/article/72/Supplement_1/97-OR/150782/97-OR-Antidiabetic-TIX100-Improves-NAFLD-NASH-in

This Study

This is a blinded dosing study done in healthy people.  They are recruiting 35 people, none of whom have T1D, and giving them 6 different doses ranging from none to 200 mg of TIX100.   The goal is to make sure all potential doses are safe.  

This is a single dose study, follow up is after one week, and they expect to be done by May.  Because the end points are all safety and side effect related, we will not know anything about efficiency (if it actually works against T1D), but "the trip of 1000 miles starts with a single step".  Good results here will presumably enable an efficiency focused phase-II study.

The good things about this study are that it is quick and easy to participate in.  They are recruiting in one location:

Chula Vista, California, United States, 91911

ProSciento, Inc.  619-427-1300   hello@myproscientostudy.com

Corporate Web Page: https://tiximed.com/

Corporate Interview: https://www.youtube.com/watch?v=sezKoZi7lJU

To see a longer history of research into curing type-1 diabetes by targeting TIXNP, you can read this article: https://www.news-medical.net/news/20240731/FDA-clears-UAB-startups-TIX100-for-clinical-trials.aspx

Clinical Trial Registry: https://www.clinicaltrials.gov/study/NCT06800729

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 kid has type-1 diabetes and has participated 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!

Results from a Phase-II Verapamil Study

Verapamil is a drug which has been used in the US since 1982 for high blood pressure, migraines, and heart problems.  It also lowers levels of a protein called TXNIP.  Some researchers believe this is important because they believe TXNIP kills beta cells as part of the onset of type-1 diabetes.  So giving Verapamil should lower TXNIP which should improve beta cell survival, and stop type-1 diabetes.  In addition TXNIP is pro-inflammatory, so lowering it should lower inflammation, which could also have a good effect on type-1 diabetes. Verapamil has already undergone phase-II trials for T1D in the United States, which I discuss below.

You can read my previous blogging on Verapamil here:
https://cureresearch4type1diabetes.blogspot.com/search/label/Verapamil

What Were The Results?

The summary is that, after one year, people who got Verapamil generated 30% more insulin, than people who did not.  However, it is important to remember, that one year after diagnoses, most people with T1D are generating almost no insulin at all.   So 30% of almost nothing is a pretty small difference between the Verapamil and non-Verapamil groups.

Over the years that I have been following honeymoon clinical trials, there have been a couple of treatments which, when measured after a year, the treated people were generating twice as much insulin as the untreated people.  So a bigger difference than seen here.  However, twice a very small amount is still a very small amount, and none of these treatments have become successful from such a small starting point.

JDRF's report: https://www.jdrf.ca/exciting-news-new-drug-in-clinical-trials-shows-slowed-type-1-diabetes-progression-in-newly-diagnosed-children-and-teens/?utm_source=ENTwitterVerapamil

News Coverage:
https://www.medscape.com/viewarticle/988806?src=soc_tw_230228_mscpedt_news_endo_diabetes&faf=1
https://jamanetwork.com/journals/jama/fullarticle/2801974

This Study: https://www.clinicaltrials.gov/ct2/show/NCT04233034

Other Verapamil Studies

A previous, smaller study found that Verapamil treated people generated 40% more insulin after a year.  So pretty similar to these findings.

Previous Verapamil Study: https://www.clinicaltrials.gov/ct2/show/results/NCT02372253

There is a third study underway, covering 138 people and expected to finish in February 2024.  I blogged about that one last year:
https://cureresearch4type1diabetes.blogspot.com/2022/02/verapamil-sr-starts-phase-ii-trial-ver.html

Another Verapamil Study: https://www.clinicaltrials.gov/ct2/show/study/NCT04545151

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.

Verapamil Starts A Phase-II Trial (Ver-A-T1D)

Verapamil is a drug which has been used in the US since 1982 for high blood pressure, migraines, and heart problems.  It also lowers levels of a protein called TXNIP.  Some researchers believe this is important because they believe TXNIP kills beta cells as part of the onset of type-1 diabetes.  So giving Verapamil should lower TXNIP which should improve beta cell survival, and stop type-1 diabetes.  In addition TXNIP is known to lower inflammation, and that might have an effect on type-1 diabetes as well. Verapamil has already undergone phase-II trials for T1D in the United States, which I discuss below.

The Ver-A-T1D Study

This is a 138 person study, randomized, controlled, and double blind.  It is for adults in the honeymoon phase (within 6 weeks of diagnosis).  Half the participants will get Verapamil for a year, the control group will get a placebo.  All will be followed for a total of 2 years, so one year while they get the drug, and then one additional year.  The study started in Feb-2021 and is expected to end in May-2023.

The primary outcome is a measure of C-peptide generation, which measures how much insulin a person is naturally generating.  There are 10 secondary outcomes, mostly measurements of C-peptides, but also insulin use, proinsulin generation, BG in range, and A1c.  There are a few tertiary (or "other") outcomes, which are quality of life questionnaires. 

This trial will recruit in 22 different locations, at least.  These sites are all over Europe and the United Kingdom.  There is a list in the clinical trial registry below, but the exact status of each site might be out of date.  If you are unsure if one of the listed sites is actually recruiting, you can contact the study organizers here:

Martina Brunner  +43 316 385 ext 72841 martina.brunner@medunigraz.at
Karin Brandner  +43 316 385 ext 72800 karin.brandner@medunigraz.at

Clinical Trial Registry:
https://www.clinicaltrials.gov/ct2/show/study/NCT04545151
The European Clinical Registry number is 2020-000435-45.

This study is being funded by the JDRF, among others.

Discussion

There are a couple of interesting discussion points here.

What happened last time?

This is the second phase-II trial for Verapamil.  I blogged on the previous phase-II trial here:
https://cureresearch4type1diabetes.blogspot.com/2018/09/results-from-phase-ii-verapamil-trial.html

So, for me, the most important question for any T1D cure that has been tested previously is, how did it work before, and why do we think it will be better this time? This is especially true for a trial like Ver-A-T1D, where the dose and duration of the study is the same as the previous study.

The results from that trial were definitely interesting.  The visual summary of that study is here.  Remember that people in the study were given the drug for 12 months:

My summary:

• For three months after treatment, C-peptide number went up, and this is great news.  That is on the path to a cure.  However, after three months, C-peptide numbers went down and did so at basically the same rate as the untreated (placebo) group.
• The treated group started out at a noticeably higher C-peptide level than the untreated group.  That is not a good thing.  The two groups should start out the same.

Clinical Trial registry for the earlier study:
https://clinicaltrials.gov/ct2/show/NCT02372253

INNODIA and T1DUK

This study is part of the INNODIA and T1DUK networks.  INNODIA is a European collection of research universities, commercial companies, and patient organizations aimed at fighting T1D.  Their research goal is "to advance in a decisive way how to predict, stage, evaluate and prevent the onset and progression of type 1 diabetes (T1D)."  T1DUK is a UK collection of research universities focused on Immunotherapy research.  Its principal aim is "To help get immune therapy into the market as part of the management for type 1 diabetes".  Both networks are funded by JDRF.  T1DUK is also funded by Diabetes UK (and others) while INNODIA is funded also funded by the Helmsley Trust (and others).

I plan to blog on both of these research networks in the future, but in the meantime, I view them as similar to TrialNet in the US.

Recruiting Issues
(Children vs Adults. Honeymoon vs Established. Money and More Money)

This study is using 22 different sites to recruit 138 people.  Think about how expensive that is.  Each site must be staffed, trained, and supported.  They are expecting to be able to recruit about 6 people per site (on average).  Why so few people?  Well, they are recruiting adults because of safety concerns and a general regulatory assumption that clinical trials should be run on adults when possible.

But these assumptions create problems for T1D research.  Most people with T1D go through their honeymoon phase as children, so if recruiting for a honeymoon treatment is limited to adults, most people are excluded.  And if most people are excluded, then you need to cast a very wide net to get the people you need, and that adds to the expense. 

For this trial, there is the question of, why limit it to adults?  The drug they are testing is already approved.  Although the disease it is approved for affects adults, there are no age restrictions on the approval.  It can be prescribed to children.  More specifically, it has already been tested in people with T1D, so it would be quite reasonable to test it on children in this, the second, T1D study done.  But they chose not to do this.  That decision is going to result in a more expensive and slower clinical trial, which is too bad. 

The study will not finish in May-2023.

Although the plan is for the study to finish in May-2023 (as listed in the clinical trial registration), we already know that it will not.  How?   Because the study is still recruiting people now, and once those people are recruited, it takes 2 years to gather the data.  Therefore, the study can't possibly finish before Feb-2024. (Unless they have finish recruiting and just forgot to update the clinical trial registration.  That is possible, but unlikely.)

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.

Results from a Phase-II Verapamil Trial

Verapamil is a drug which has been used in the US since 1982 for high blood pressure, migraines, and heart problems.  It also lowers levels of a protein called TXNIP.  The researchers running this trial believe this is important because they believe TXNIP kills beta cells as part of the onset of type-1 diabetes.  So giving Verapamil should lower TXNIP which should improve beta cell survival, and stop type-1 diabetes.

I previously blogged about this trial when it started:
https://cureresearch4type1diabetes.blogspot.com/2015/03/verapamil-starts-phase-ii-trial.html

This included 32 people.  The treatment was a Verapamil pill once a day.  The study was done on honeymooners and was double blind.  The primary end point was C-peptides, which are key for a cure, as they measure the body's ability to create insulin.  You can see the results below:

Graph is from the published paper, and is presented
 for educational purposes only.

Remember these are honeymooners, and they were given Verapamil for the entire time.   Normally, people continue to loose C-peptide during the year after diagnosis, and you can see that in the placebo (untreated) group in black above.  But the treated people (in red above) improved their C-peptide production for the first three months, and still produced more C-peptide than untreated people after 12 months.

Discussion

Having the C-peptide numbers go up noticeably in the first three months is a good outcome, but it is not -- by itself -- a cure or a prevention.  The treated people were still doing much better than the untreated group after a year, but again, that's not a cure by itself.  So the real question is how to move these good results forward to a cure, and I think there are four ways to think about that question:

One big question is, why did C-peptide production (and thus insulin production) improve so much for the first three months, but then stop improving?  Remember, that the drug was given for 12 months, but the improvement was seen only in the first 3 months.  Obviously, if we could make the Verapamil continue to help insulin production for longer, it would be much closer to a cure.

Another question is, what would happen if Verapamil was given to people who had two autoantibodies, but were not showing any symptoms of type-1 diabetes?  Would Verapamil result in a delay of onset, or could it prevent type-1 completely?  Current research shows that essentially everyone who has two autoantibodies will eventually show symptoms of type-1 diabetes, but this study shows that for the length of time of the study, C-peptide generation was basically the same at the end of the trial as at the beginning.  If people without symptoms were treated, would they continue to be symptom free as long as they were treated?  That would be a preventative (and possibly the first step to a cure).

A third option would be to try to improve the treatment, either by combining Verapamil with another drug which helps preserve beta cell function, or by finding a better dosing regimen, with results in a better outcome.

Finally, this study was done on recently diagnosed adults, and the researchers mention that running a similar study on recently diagnosed children in the honeymoon phase be worthwhile.
Paper: https://www.nature.com/articles/s41591-018-0089-4 (behind a paywall)
Trial Registry: https://clinicaltrials.gov/ct2/show/NCT02372253

I'd like to thank the authors for sending me a copy of the paper, which is otherwise behind a pay wall.



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, JDCA, or Bigfoot Biomedical news, views, policies or opinions. In my day job, I work in software for Bigfoot Biomedical. 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.

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

This posting is a collection of small updates.

Verapamil's Phase-II? Trial Completes Enrollment

Verapamil is a drug which has been used in the US since 1982 for high blood pressure, migraines, and heart problems.  It also lowers levels of a protein called TXNIP.  The researchers running this trial believe this is important because they believe TXNIP kills beta cells as part of the onset of type-1 diabetes.  So giving Verapamil should lower TXNIP which should improve beta cell survival, and stop type-1 diabetes.  In addition TXNIP is known to lower inflammation, and that might have an effect on type-1 diabetes as well. TXNIP worked in mice trials.

The news here is that they have completed enrollment.  There is good and bad news in that.  The good news is we now know that the trial will finish in 2019, since they completed enrollment in Jan 2018 and need to gather data for a year.  The bad news is that they only recruited 32 people; they were hoping for 52.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02372253

Vitamin D Didn't Impact The Honeymoon In A Phase-I Trial

Vitamin D has been a hot topic for the last few years, and there are several different clinical trials looking at it in three different contexts: Does low Vitamin D help trigger type-1?  Does increasing Vitamin D help prevent type-1?  And, does increasing Vitamin D to people who have type-1, help treat or cure it?   All together, there are 15 completed trials, 6 recruiting, and 2 underway but not recruiting, and one not yet started.  That is strong interest.

This trial was a phase-I, honeymoon trial of 36 people.  Half got Vitamin D, and half got a placebo.  The patients who got Vitamin D did do a little better (used less insulin during their honeymoon), but the effect was not statistically significant.

Press Release: http://www.nationwidechildrens.org/medical-professional-publications/vitamin-d-and-the-honeymoon-period-of-type-1-diabetes?contentid=146302
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT01724190

Diamyd and Vitamin D start a phase-II Trial (DIAGNODE-2)

This clinical trial will test a Diamyd injection and oral Vitamin D in honeymoon type-1 diabetes.

It is recruiting in several European countries: Czechia, Spain, and Sweden.  See the clinical trial record for a list of exact sites, there are many in each country.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT03345004

Discussion

You can read my previous blogging on Diamyd here:
https://cureresearch4type1diabetes.blogspot.com/search/label/Diamyd

Diamyd has been tested for over 10 years.  All previous trials (which have completed) have been unsuccessful.  There are currently two other Diamyd and Vitamin D trials underway.  While I'm always hopeful that these tests will be successful, Diamyd's long history without success does not give me much to hope for with this trial.


How well can you predict the outcome of clinical trials? Not as well as you may think.

One of the guiding quotes of this blog is "Opinions are not important; but what is important is the reasoning behind them, the data and information they are built on, etc. In short: why a person has opinions is more important than the opinions themselves. And that includes my opinions. Especially "my opinions."  This is a news article on researcher's ability to predict the outcome of studies in their field.  I thought it was interesting reading:
https://www.statnews.com/2018/01/22/clinical-trials-forecasting-outcomes/

A Stock Market Opinion: Diabetes Clinical Trials to Watch

This is a finance/stock analysis of what's important in 2018:
https://www.gurufocus.com/news/622818/three-diabetes-clinical-trials-to-watch-in-2018
From my point of view, they are all type-2 focused (which makes sense from a market share point of view: type-2 is 90% of the market).

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.

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.

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.

Verapamil Starts a Phase-II Trial

Soundtrack is "I'm Bad, I'm Nationwide" by ZZ Top:
http://grooveshark.com/#!/s/I+m+Bad+I+m+Nationwide/3OTEOT

Verapamil Starts a Phase-II Trial

Verapamil is a drug which has been used in the US since 1982 for high blood pressure, migraines, and heart problems.  It also lowers levels of a protein called TXNIP.  The researchers running this trial believe this is important because they believe TXNIP kills beta cells as part of the onset of type-1 diabetes.  So giving Verapamil should lower TXNIP which should improve beta cell survival, and stop type-1 diabetes.  In addition TXNIP is known to lower inflammation, and that might have an effect on type-1 diabetes as well. TXNIP worked in mice trials (but see discussion below).

Drs. Anath Shalev and Fernando Ovalle at the University of Alabama at Birmingham have started a clinical trial. They are enrolling 52 adult, honeymoon type-1 diabetics; half will be treated, half are a (double blind) placebo control group. Patients will get Verapamil for a year, at the same doses that it is commonly prescribed.  The primary end point is C-peptide levels after a meal. The researchers will also track several other outcomes: insulin usage, A1Cs, TXNIP, beta cell markers, glucose generation, and two measures of BG stability.  They expect to finish in July 2017, which breaks down to about 1 1/2 years to recruit all the patients, and 1 year to run the trial.

This study is funded by JDRF, and is being conducted at The University of Alabama at Birmingham. Contact information is:
Tiffany H Grimes, RN    205-934-4112    tdgrimes@uab.edu
Kentress Davison    205-934-4112    kdavison@uab.edu  

News: http://www.medpagetoday.com/Blogs/DiabetesDiscovery/49622
News: http://www.uab.edu/medicine/diabetes/new-clinical-trial
News: http://www.uab.edu/news/innovation/item/5508
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02372253
Mouse study: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314354/
Wikipedia: http://en.wikipedia.org/wiki/Verapamil

Discussion and Opinions

There is a lot to like about this trial.  Using an already approved drug means they don't need to do a phase-I trial; they can start out with a larger group.  It also means if they report good results, off label use becomes a possibility, and could result in much faster availability.

I particularly like the list of outcomes these researchers will measure.  C-peptide (their primary outcome) is the surrogate end point recommended by the FDA for type-1 cures.  But they are also watching insulin usage, A1C numbers, and BG stability, which are of practical importance to people with type-1.  Finally, they are tracking several biochemical changes which should help them understand what is happening "on the inside".

On the downside, they are only recruiting adults.  That's unfortunate, because it will take them much longer to find 52 honeymooning adults, than 52 honeymooning children.  (I know that sentence only makes sense in the world of type-1 diabetes.)  Since the drug is already approved, it's too bad they could not include the people who are most likely to be in the honeymoon phase.  But Verapamil is typically prescribed for high blood pressure or angina, so I suspect there is not much experience giving it to children.

My Opinions About Those Mice....

These researchers have succeeded in preventing type-1 diabetes in mice, by treating during the mouse honeymoon.  But I don't put much stock in mice tests, because there have been so many treatments that have led nowhere in people.  Hundreds of cures in mice and (so far) no cures in people. However, the mice used in these tests were STZ mice, which I'm particularly nervous about. Basically, the researchers took healthy mice and injected them with a toxin (streptozotocin) which killed their beta cells.  These are are referred to as STZ-mice.  They are commonly used as an animal model of type-1 diabetes, however they do not have autoimmune diabetes.  In comparison NOD-mice, also used as an animal model of type-1 diabetes, do have autoimmune diabetes.

In my opinion, STZ-mice are fine for testing new insulins and pumps, and also for doing tests related to long term complications.  However, I don't think they are good models for testing cures, because they lack the ongoing autoimmune beta cell destruction which is the hallmark of real type-1 diabetes.

The danger is that even if Verapamil does cause the body to grow more beta cells, they will be destroyed by the autoimmune attack, and patients will not see any improvement.  This treatment could be combined with something that stops the autoimmune attack, and the combination might be a cure, but testing Verapamil alone is unlikely to give good results.  The researchers understand this; the interview with Dr. Anath Shalev makes that clear.  Her hope is that by carefully measuring BGs (using a CGM) and C-peptides, she will see a small improvement, which will have good health effects (even if it is not a cure).   My blog posting "The Value of a Few Beta Cells" discusses this point:
http://cureresearch4type1diabetes.blogspot.com/2013/10/the-value-of-few-beta-cells.html
Also, a small improvement could provide the justification for a combination trial (Verapamil and an immune modulator/suppressor), and such a combination could be a cure in the future.

But in a certain sense, even discussing the mouse research is a waste of time, once the human trials have started.  Only the human trial results will matter moving forward.

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.