Tuesday, June 12, 2018
GNbAC1 Starts A Phase-II? Trial
GNbAC1 is a monoclonal antibody which has completed phase-II testing for treating Multiple Sclerosis, which (like type-1) is an autoimmune disease. GNbAC1 was developed by GeNeuro SA, a Swiss company, but is being tested in Australia. They have partnered with Servier, a large French pharma company to do the phase-III trials required to bring it to the Multiple Sclerosis market.
A monoclonal antibody is an artificially created antibody which targets one very specific type of cell in the body. Different monoclonal antibodies target different types of cells. So if a disease is caused by a problem in one type of cell, then using a monoclonal antibody to target that type of cell is a promising treatment. Because several monoclonal antibodies have been successful in treating other autoimmune diseases, they are an active area of research for curing type-1 diabetes.
Previously, GNbAC1 has been tested in four clinical trials as part of the Multiple Sclerosis development program, so its safety is well established (for an investigational drug). However, since this is the first trial aimed at type-1 diabetes, I'm calling it a "Phase-II?" trial. (The question mark meaning "no previous testing on people with type-1".)
This Study
This study has enrolled 60 people who were diagnosed with type-1 diabetes within the last 4 year. The first part will be double blind, with 2/3s getting the treatment and 1/3 not. After that will be a second, optional part which is not blinded (everyone will get the treatment). Unfortunately, the primary end point for this trial is safety related. But their press release does say that they will track various effectiveness outcomes as well (for example: C-peptide and insulin consumption). The drug will be given as an IV drip once a month (six doses in each part of the study). People in the study will be followed for about a year.
This study completed enrollment in January 2018, and GeNeuro plans to publish the results from the first part of the trial in September 2018, and the second part of the trial in the first half of 2019. That is pretty quick!
Press Release: http://www.geneuro.com/data/news/GeNeuro-TD1-Study-Enrollment-Complete.pdf
Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT03179423
Company: http://www.geneuro.com/
General Background News Article: http://www.biotuesdays.com/features/2017/11/16/geneuro-pioneering-hervs-against-neurodegenerative-and-autoimmune-diseasess
MS research:
● http://www.msdiscovery.org/research-resources/drug-pipeline/10103-gnbac1
● https://www.ncbi.nlm.nih.gov/pubmed/25392325
Background and Rational
This clinical trial has a very different rational, as compared to previous attempts to cure type-1 with monoclonal antibodies. In the past, these antibodies have been used to target one of the defective cell types within the immune system. The idea is to find an immune cell which is involved in the attack on the beta cells, and kill off those immune cells. That idea has led to some progress, some suggestive results, but nothing like a cure.
These researchers have a different idea. They note that part of the human genome contains HERVs, which are the remains of retroviral DNA which merged into our DNA millions of years ago. The researchers believe that while this DNA does nothing most of the time, infection can sometimes cause one of these HERVs (called "pHERV-W") to activate and generate a protein (called "pHERV-W env") used by the retrovirus the DNA came from originally. Even after the infection, the HERV DNA stays activated. The pHERV-W env, in turn, causes autoimmune diseases. If true, this would explain how viral infections can "trigger" type-1 diabetes.
These researchers believe that by using a monoclonal antibody to target pHERV-W, they can stop this process. So while previous attempts to use monoclonal antibodies targeted malfunctioning immune cells, this attempt is targeting HERV DNA which (according to this theory) is the root cause of the autoimmunity.
Background reading: https://en.wikipedia.org/wiki/Endogenous_retrovirus
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.
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6 comments:
Nice find! I appreciate your effort explaining these studies. This one sounds promising as a potential practical cure. I'll be following it closely. Thank you!
Since beta cells are like neurons, in that once damaged, they tend never to be able to recover, the real difficulty will not be in developing a method to halt the continuing autoimmune attack on them, but in finding a way to revive them once the attack is stopped. Since the decline in functionality of the pancreatic islets continues with the continuing autoimmune attack throughout the life of the patient, this study is deliberately skewed to yield a misleadingly positive result, since it is only testing patients who are less than four years out from diagnosis, when restoring the islets' function is a more promising prospect. Most likely the researchers presumed that no one past that point of disease duration would be able to profit from their intervention.
A. Davis, et al., "Prevalence of Detectable C-Peptide According to Age at Diagnosis and Duration of Type 1 Diabetes," Diabetes Care, 38 (3) 476-481 (2015), found that of those diagnosed before age 18, only 20% still had any detectable c-peptide six to nine years after diagnosis, showing that at least some islets were still functioning, while after ten to nineteen years, only 9% had detectable levels, falling to 7% after twenty-one to forty years, and 6% after forty years. Results were better for those diagnosed at or after age eighteen, with the detectable percentages being 78%, 60%, 35%, 7%, and 6% respectively. So this line of treatment, even if successful, would probably strand the vast majority of patients in the category of people who had suffered too much deterioration of islet function ever to experience clinically significant revival.
So this 'hope for a cure' is most likely a hope for a very partial one.
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I feel churlish for pointing it out given I appreciate what you're doing, but the noun referring to the reasons for something is 'rationale', not 'rational'. :)
Say Fred loses his temper and throws the television set through the window, and then wishes he had the tv back and in working order. We can never fix his tv by calming down his temper, even though his temper was the cause of the television being broken.
The same principle applies to type 1 diabetes: The old nostrum, that to fix something you need to know what causes it first, simply does not work with diabetes, where the initial problem damages the pancreatic beta cells permanently so that going back and correcting that cause makes no difference. With type 1 diabetes, you have a massive patient population who have well-established diabetes and too little residual beta cell function for sufficient recovery of beta cell function ever to be achieved so that the patient could avoid dependence on injected insulin. Granted, there is a miniscule patient population who are, at any time, new onset patients or who have still have sufficient residual c-peptide output to experience significant benefit from stopping the autoimmune attack, but they are exceptions, yet countless treatment efforts are directed at them, not at the bulk of patients who are left stranded.
@Oscar -- there is a growing body of evidence to support the idea that alpha cells regenerate and may also differentiate into beta cells. See https://asweetlife.org/of-mice-men-and-my-pancreas-a-closer-look-at-beta-cell-regeneration/
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