Dropping Four Research Programs

Every year in September or October I write a blog posting which summarizes all research being done in humans, aimed at curing type-1 diabetes.  That blog is going to be published in 2-4 weeks.   While putting that blog together I have found several research projects which I should not cover any more, and I'm listed those here, with a brief note on why they are no longer of interest.

I understand that this posting is a downer, and I'm sorry for that, but it is important to know what studies are no longer looking promising, and why.  Research naturally gets a lot of press when there is good news, but it's important to keep track of the bad news, and the "no news is bad news" situations as well.

Dendritic Cell Therapy  (DV-100) by DiaVacs
This trial was supposed to start in 2013, but never did.  The company is working on a follow on product, DV-200, and when that starts clinical trials I will follow it.  But since there has been a five year break between DV-100 and DV-200, I'm going to wait until a trial actually starts before restarting coverage.

BCG by Faustman at Harvard
This research is being removed for two reasons:

• Her phase-II trial is not using C-peptide data as either a primary or secondary outcome.  C-peptide is the standard measure for progress to a cure, so not having it as a primary or even secondary outcome means this research is no longer "aimed a curing type-1 diabetes".  (I will continue to follow it, and especially any C-peptide data that comes out, but unless C-peptides are a primary or secondary outcome, it is not cure focused for me.)
• The phase-I trial extended results show that Dr. Faustman's original theory (the TNF theory) of how BCG might cure type-1 diabetes is wrong.  The paper said specifically that the theory did not explain the results seen, and presented a new theory.  However the new theory is based on how the body digests carbs (not regenerating beta cells), and therefore is not a cure focused theory.  (Indeed, several type-2 diabetes treatments are based on similar theories).  So even if this theory is correct, the result would be treatment, not cure.

Obviously, this research group is continuing to talk about curing type-1 diabetes, but one the rules of my blog is "Actions speak louder than words" and if the clinical trial is not focused on C-peptide data, I don't think they are focused on a cure, no matter what is said.

Rilonacept by White at University of Texas

This group published their phase-I results in June 2018, but they were unsuccessful: "Rilonacept treatment for 6 months is well-tolerated in individuals with T1D of recent onset, but is unlikely to be efficacious as a single agent in preserving beta cell function."  So I don't expect any follow up work.

The Sydney Project (Encapsulated Stem Cells)
I can not find any recent references to this project.  The closest I can find is an encapsulated stem cell project being funded by the Australian Foundation for Diabetes Research.  It is doing animal research right now, so not clinical trials.


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.

NextCell Starts a Phase-I Study of Mesenchymal Stromal Cell Treatment

NextCell pharma is running a clinical trial of their ProTrans product.  This is a stem cell product derived from "Wharton´s Jelly", which is a specific part of the umbilical cord.  ProTrans is made from umbilical cords from third parties, not the person receiving the transplant.  (So this is not self transplants, where the person gets stem cells which were originally harvested from themselves.)

The difference between ProTrans (the product being tested), and generic stem cells from Wharton's Jelly in the umbilical cord, is some proprietary testing.  NextCells thinks they have a way of identifying which batches of stem cells will be more effective, so they test each batch of stem cells, and the ones that pass are used to make ProTrans.

The Clinical Trial

The clinical trial being run right now, can be thought of as two mini-trials, being run one after the other.  They were both approved at the same time, which is why there is only one clinical trial registry.  However, when you read it, it is very clear that there is a 9 person trial, followed by a 15 person trial.  The first part is focused on finding the best dose, and the second part is focused on finding how effective that dose is.  The researchers have published their entire study protocol, which you can read here:
http://www.clinicaltdd.com/article.asp?issn=2542-3975;year=2018;volume=3;issue=2;spage=32;epage=37;aulast=Carlsson
Note that this published protocol description is not the same as the FDA clinical trial registry description.  I'm assuming that the published protocol is correct, as it was published months after the FDA registry was last updated.

Both parts of this study are limited to adults (18-40 years old) who are within 2 years of diagnosis.
The first part will be men only, the second part will be men and women.  The treatment is one intravenous infusion.  No immune supressives will be given.  The primary end points are safety and C-peptide generation (this measures the body's ability to generate insulin) after a year.  Secondary end points include insulin independence, insulin use, A1c numbers, and more C-peptide results.

Part 1

This part of the study is not blinded, and will include three groups of three people each, all of whom will get the treatment (no control group).  Each group will get a different dose of stem cells.  The first group will get 25 million cells, the next 100 million cells, and the third will get 200 million.

Results: No serious adverse effects as of June-2018.  Initial (one-month) results expected Oct-2018.

Part 2

This part of the study is double blind.  Ten people will get the treatment and five will get a placebo as a control group.  Everyone in this group will get the same dose, and that dose will depend on which one gives the best results in the first part of the trial.

Results:  Full results expected 2020.

NextCell's web site: http://www.nextcellpharma.com/
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT03406585
Paper on Wharton's Jelly in general:
https://stemcellsjournals.onlinelibrary.wiley.com/doi/full/10.1002/sctm.16-0492


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.

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.