Monday, March 3, 2014

Imatinib ("Gleevec" / "Glivec") Finally Starts a Phase-II Clinical Trial

A year ago, researchers (Drs. Gitelman and Bluestone) at UCSF filed the paperwork to start a clinical trial testing Gleevec on people.  Now, they can finally start enrolling people in the trial.  The generic name for this drug is Imatinib.  It is sold as Gleevec in the US and Glivec in most of the world.

Gleevec is a drug already approved for treating cancer.  Patients will take a daily pill, will visit the clinic at 2 weeks, then monthly for the first year, and after that twice per year.  The researchers will measure C-peptide (to see if patients are generating their own insulin) as well as how much injected insulin the person needs, and their A1c numbers.

I've previously blogged on this trial here:
http://cureresearch4type1diabetes.blogspot.com/2013/02/possible-cures-for-type-1-in-news-mid.html

I also created a "Timeline of Gleevec as a Potential Cure for Type-1 Diabetes" that you can look at.  This timeline is experimental, so if you have any suggestions on how to make ti better, please email them to me.

They are hoping to finish collecting data in 2016 and complete the trial by 2018. It is a 66 person trial (44 will get the treatment, 22 will be in the placebo group). But this is a honeymoon trial, only people within 100 days of diagnosis will be included. Imatinib is a relatively new cancer drug, which is popular because it targets an enzyme that only cancer cells have, so it is relatively non-toxic to non-cancer cells. (The buzzword is "targeted".) The obvious question is, why would it be expected to work on type-1 diabetes?  It's not clear (at least to me) exactly why Gleevec should stop type-1 diabetes.  It does target parts of the immune system and it does lower inflammation, so either one of those (or both) could be it's mechanism of operation.  Or, it could be something completely different.  The work done in mice suggests that it might be the last option: a completely different mechanism, but there is not enough data to be sure.

Unfortunately, right now, they are only recruiting patients 18 years and older (an FDA limitation). Since this is a honeymoon trial, that is a serious limitation, and will make it hard to find people to recruit. The hope is that after some adults are successfully included in the study (and no safety issues come up), they will be able to lower the recruitment age for future patients, and fill the rest of the trial more quickly.

They are recruiting at several locations:
San Francisco: Contact: Chrinstine Torok, RN 415-502-9089 torokc@peds.ucsf.edu
Denver Contact: Jennifer Smith 303-724-8272 jennifer.e.smith@ucdenver.edu
Indianapolis Contact: Jennifer K Terrell 317-944-2584 jkramey@iu.edu
Omaha Contact: Chris Smith 402-280-4319 christosmith@live.com
Philadelphia Contact: Charles Isaacs 215-590-7222 isaacsc@email.chop.edu

Wikipedia: http://en.wikipedia.org/wiki/Imatinib
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01781975
Orange Book Entry: http://www.accessdata.fda.gov/scripts/cder/ob/docs/temptn.cfm

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 Tidepool 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.

2 comments:

Jana Seibt said...

Why could Gleevec work?

Gleevec effects the production of cytokines. Cytokines are small proteins such as chemokines, interferon and TNF (see Dr Faustman). Cytokines are involved in immune response and fighting disease. If their expression (or production) becomes unregulated, they can cause cancer, autoimmune disease, sepsis and trauma.

One such illness that is caused by out-of-whack cytokines is pancreatitis, an inflammation of the pancreas that often leads to removal of the pancreas (and becoming T1 subsequently).

Gleevec effects a protein called NF-kB. NF-kB regulates DNA transcription, the first step of protein synthesis (and cell multiplication). The NF-kB in cancer cells is very active. Gleevec potentially shuts those NF-kBs down or alternatively activates cancer fighting B and T cells to increase in numbers (sorry, I haven't gone into the cancer studies, so I am not sure). In T1D, Gleevec works on the NF-kB of the beta cells and helps them to stand a chance against the autoantibodies.

It does that by making the beta cells less sensitive to cytokines. It usually means that the drug in question changes the antigen expression of the cell. In other words, the NF-kBs activated by Gleevec produce proteins that change one or more glycoproteins of the beta cells and now the cytokines can no longer attach to it, thus preventing cell death.

As an interesting site note: TNF is low in plasma in pre-dx'd T1. One assumption is that all the TNF are in the pancreas either trying to prevent or helping to kill the beta cells ... Later in developed T1, plasma TNF returns to normal.

Chris Wilson said...

Hi Josh,
I came across your interesting blog while I was just checking the interwebs to see if any updates have been posted about the Phase II imatinib clinical trials. I am a grad student at Vanderbilt University. My research is squarely focused on immune tolerance and reversal of Type 1 diabetes, and I have a keen interest in discovering molecular pathways important for driving immune tolerance. While the above post is very informative and points to a potential role for imatinib in T1D reversal (NFkB inhibition) I would like to point out NO mechanism has been defined for this reversal. The above poster also stated that imatinib may give the beta cells a "fighting chance" against autoantibodies...Not sure what that means. Autoantibodies, while being a robust biomarker for T1D risk, to date have no defined role in active destruction of the beta cells (T cells are the endstage destroyers or beta cells)

My research project focuses on the role c-Abl plays in B lymphocytes and how this pathway may drive tolerance. Interestingly, my research points to a role for imatinib in reprogramming the immune system through modulation of c-Abl.

Another point I would like to make is that imatinib reversal trials were carried out in the NOD mouse. This inbred mouse strain is the best model we have to date for T1D, but we must understand that this mouse may represent only one form of diabetes that humans have. Just as there are many roads home from work there are possibly many roads to beta cell destruction.

With no understanding of how it works we can not be sure if the clinical trials will be successful or not. T1D trials have suffered to a large degree because we poorly define mechanism of reversal in mice and then have no idea if we have reached the same therapeutic dose in humans or if this is even the appropriate therapy for this person.

In order to cure diabetes we must stop treating it like one disease and begin to understand that this is probably a myriad of diseases that has been lumped into one category. We must understand what immune pathways and cell types play a role in particular therapies in mice and see if those pathways and cells are being impacted and altered in humans in the same fashion as our preclinical mice models. We must embrace the age of truly "personalized medicine".