Rapamycin Vildagliptin Combo Start a Phase-II? Clinical Trial

These researchers are running a three-armed clinical trial.  One group will get two drugs: Vildagliptin and Rapamycin.  Another group will get Rapamycin and a placebo, while a third group will get two placebos.

Rapamycin is an immune modulator, so (I assume) it is being used to shut down the autoimmune attack. Vildagliptin is given to type-2 diabetics because it increases their insulin output.  Recent research suggests that it does this both by encouraging beta cell replication and by reducing natural beta cell death (see more discussion below).  Both of these would be valuable if Rapamycin is successful in lowering the autoimmune attack on beta cells.

There will be 20 people in each group.  All patients will be adults (over 18 years old), who have had type-1 diabetes for five years or longer.  This is NOT a honeymoon trial.  Data will be collected over a 12 week period.  The trial started in May of 2016 and they hope to finish by December 2018.

The primary outcome is C-peptide response (a marker for natural insulin production), and secondary outcomes include insulin use, A1c numbers, more C-peptide data, and adverse reactions.

This trial is recruiting in Milan, Italy:
    IRCCS San Raffaele Scientific Institute
    Contact: Lorenzo Piemonti, MD       piemonti.lorenzo@hsr.it    phone: 0226432706 ext +39
    Contact: Andrea Bolla, MD       andrea.bolla@hsr.it    phone: 0226432822 ext +39

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02803892
Wikipedia entries:
    https://en.wikipedia.org/wiki/Sirolimus
    https://en.wikipedia.org/wiki/Vildagliptin

Discussion

There is a lot to like about this study.  First, the people being treated have had type-1 for a long time. Second, it's the kind of combination therapy (one drug to lower the immune attack, another to spur beta cell regrowth) that a lot of researchers have been talking about for years.  Finally, it's quick.  They will follow people for about 3 months, which means results will be available soon.  Also, the drugs are already approved for use (one in the US the other in Europe) which should make them easier to get.

The official title for this study is "Monotherapy With Rapamycin in Long-standing Type 1 Diabetes (MONORAPA)", but I have no idea why, as it's clearly testing a combination therapy, not a monotherapy.

I'm considering this trial to be a Phase-II? ("Phase-II previously untested") trial, because these two drugs have never been tested together for type-1 diabetes, but Rapamycin/Sirolimus alone is being actively tested in several different clinical trials, which I've blogged about before:
http://cureresearch4type1diabetes.blogspot.com/search/label/IL-2

Vildagliptin (sold as Galvus) is approved in Europe as a treatment for type-2 diabetes.  It is a member of a class of drugs called DPP-4 inhibitors.  More famous members of this class include Januvia and Tradjenta.  Another name for DPP-4 is CD26.

Sirolimus (also known as Rapamycin) is an IL-2 inhibitor and immunosuppressant.  It was approved in the US in 1999 for organ rejection and cancer.

About "Natural Cell Death"

It's important to remember that individual cells do not last as long as people live.  Cells naturally die and new cells grow within your body all the time.  Research (mostly in animals) has suggested that Vildagliptin might have two separate effects on beta cells.  On the one hand, it seems to cause beta cells to naturally divide and grow, and on the other hand, it seems to delay beta cell's "natural death", so they live longer.    Both of these effects may be important to curing type-1 diabetes, but it is not clear.  This is why research is important.  For example, even if Vildagliptin triggers a divide-and-grow reaction, it will only be effective if there are some beta cells to start with, and we just don't know if there are enough to get things started.  On the cell death side, if the autoimmune attack directly kills beta cells, then stopping natural cell death may have little impact.  Those cells will be killed by autoimmunity before they can die of "old age".  However, if the autoimmune attack works by triggering natural cell death (which some researchers believe) then slowing natural cell death could have a large impact.

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.