Friday, February 2, 2018

University of Alberta Starts the Mozobil Phase-I Clinical Trial


Note: I'm calling this the Mozobil study, because that is the trade name of one key drug being used, and I don't have a better name for the study.  However, as described below, this study is using five different drugs.  The official title of this study is: Autologous Hematopoietic Stem Cell Mobilization (Plerixafor) and Immunologic Reset in New Onset Type 1 Diabetes Mellitus.  See why I"m going to call it the Mozobil study? :-)

This study is an attempt at "immunological reset" to cure type-1 diabetes.  The basic idea is you give one or more drugs designed to knock down the existing immune system and then one or more drugs designed to build it back up.  Since the existing immune system has the autoimmunity flaw (it attacks beta cells), the hope is the rebuilt immune system will not.

The study will start out by giving people alemtuzumab and the trio of anakinra, etanercept, and liraglutide.  The next day they will get plerixafor, and the trio, and then they will continue to get the trio of drugs for a year.
  • The alemtuzumab (sold as Campath/Lemtrada) targets one type of immune cell for destruction (CD52 cells).
  • The anakinra (sold as Kineret) and etanercept (sold as Enbrel) modulate the immune system and may lower the autoimmune attack.
  • The liraglutide (sold as Victoza) may help the body grow new beta cells.
  • The plerixafor (sold as Mozobil) encourages the body to generate new immune cells of the CD34 type.
All of these drugs are already approved in the USA and the EU for treating other diseases.

People with long memories may think this sounds familiar, and it does.  It is similar to the "Burt Brazilian Research" from 10+ years ago.   You can read my blog about it here:
https://cureresearch4type1diabetes.blogspot.com/2008/12/burts-brazilian-research.html
and to read all my blogs about it, use this link:
https://cureresearch4type1diabetes.blogspot.com/search/label/Burt
You can think of this research as being a "kinder, gentler" immune system reset.   Etanercept (used in this study) has a black box warning, but nothing like the safety issues associated with cyclophosphamide (used in the earlier research).

A "black box warning" is a serious warning placed inside a black box in the FDA-mandated drug labeling.  The text will be printed on the drugs "package insert", on the FDA's web pages and on many other web pages and reference books that doctors commonly use to get information on he drugs.  (They are not printed on the label of the pill bottle, however.)  About 9% of prescription drugs have "black box warnings", and the etanercept used in this trial is one of those that has this warning.  More details are here: https://en.wikipedia.org/wiki/Boxed_warning

The Mozobil Study

This study will enroll 60 people, and is not blinded.  Half the patients will be treated immediately, while the other half will not (thus forming a control group for the first year).  After a year, the second group of patients will be treated.  Patients must be over 18 years old, and within 6 months of diagnosis.  They hope to finish the study by Dec 2022.

They are recruiting at the University of Alberta, Edmonton, Alberta, Canada
Web site contact: May 780-407-8755 qcai3@ualberta.ca
Web site contact: Cecilia 780-407-1480 chamming@ualberta.ca
Clinicaltrial.gov contact: Andrew Malcolm, PhD    (780) 407-6952    andrew.malcolm@ualberta.ca 
Clinicaltrial.gov contact: Parastoo Dinyari, BSc    (780) 407-3904    parastoo@islet.ca 

More information: http://www.islet.ca/research/mozobil
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT03182426
Alternate: https://www.1trial.com/clinicaltrials/nct03182426/stem-cell-mobilization-plerixafor-and-immunologic-reset-in-type-1-diabetes-t1dm#full_text_view

The web page has a short video.  From about the 1/2 way point to the 3/4 way point the video discusses this research: http://drifcan.com/drifcan-research/

Wikipedia entries for the drugs involved:
https://en.wikipedia.org/wiki/Anakinra
https://en.wikipedia.org/wiki/Alemtuzumab
https://en.wikipedia.org/wiki/Etanercept
https://en.wikipedia.org/wiki/Liraglutide
https://en.wikipedia.org/wiki/Plerixafor
https://en.wikipedia.org/wiki/CD52
https://en.wikipedia.org/wiki/CD34

The primary investigator for this trial is James Shapiro, of Edmonton Protocol fame, who is also working with ViaCyte.

Discussion

Comparisons To Burt
There is no question that the earlier "Burt" research has been the most successful in terms of curing type-1 diabetes.  More than half the people treated in the Burt study did not need to inject insulin for 3 or more years after treatment.  That's big.  Unfortunately, the safety issues in the Burt study were big as well.  One doctor I emailed (doing related research) felt there was an approximately 1% chance of fatality in Burt-like trials, and the treatment required a hospital isolation ward for a period of time, since the patient's immune system was so compromised.

However, this Mozobil trial does not use the highly toxic drugs used by the early Burt research.  Indeed, since all of the drugs used here are already approved for use for other diseases, we know a lot about how safe they are.  Based on the Burt research, we know that an "immune reset" can cure type-1 for a period of years.  Therefore, I can hope that we have the right combination of safety and effectiveness.

Experimental Design
The "treat half immediately and then treat the other half after a year" is a interesting experimental design that I have not seen before.  It has a couple of advantages.  First, everyone who participates will get treated.  (I know that some people don't like going through all the work of a trial, and then being in the control group and not getting the treatment.  That will not happen in this trial.)  But even though everyone will be treated, there will still be a control group for the first year, which will make it easier to see if the treatment is working or not.  Finally, the second group will be treated, but after their honeymoon phase is over.  Even though this second group will not have a control group, we will see how well this treatment works past their honeymoon phase.  Non-honeymoon diabetes is a disease that does not show spontaneous improvement over time, so it should be pretty obvious if the treatment is working, even without a placebo group.

What is a CD number (such as CD34 or CD52?)
CD stands for "cluster of differentiation", which is a unique chemical (often a protein or peptide) on the surface of a cell which is part of the immune system.  Different types of cells can have different CDs on them, and one cell can have more than one.  These CDs control how the cell interacts with other cells and are also markers which identify the cell.  For example, the CD34 marker is found only on stem cells, while the CD52 marker is found only on mature cells, and CD4 marker is found only on a specific immune cell called a "helper T-cell".

Wikipedia has more details:
https://en.wikipedia.org/wiki/Cluster_of_differentiation

Note: the researchers describe this study as a Phase-1 / Phase-2 study, and it is bigger than most Phase-I studies.  However, since I've never seen anything like it before, I'm treating it as a Phase-I study.

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.

3 comments:

Rick said...

I am doubtful of the outcome, but applaud the effort.

Oscar said...

Were the treated patients you mentioned who required no insulin for a while after the treatment still in the Honeymoon phase of the disease? I ask because in type 1 diabetics whose immune systems are powerfully suppressed to allow acceptance of transplanted organs, there is no spontaneous recovery of the body's ability to make insulin, and thus no reduction in the required insulin dose. At the very beginning of the transplant period, or when cases of hyperacute rejection are being treated, the immunosuppression is massive, and yet still, the insulin requirements not only do not go down, but they are considerably inflated by the prednisone required.

Joshua Levy said...

To Oscar: they were honeymoon diabetics, and if you look at the Chinese confirmation trial, the treatment worked for people within 3 months of diagnosis, but failed when used after that...