Possible Cures for Type-1 in the News (May)

Some smaller news items from May.

A Phase-I Trial of DFMO is Fully Enrolled 

Alpha Difluoromethylornithine (DFMO) is approved for two quite different issues.  The first is to remove/prevent facial hair in women, while the second is to treat sleeping sickness.  Neither of these are related to type-1 diabetes.   However, this drug was effective in preventing diabetes in NOD mice (which are predisposed to an autoimmune diabetes, similar to human type-1 diabetes), when given to these mice before they developed T1D.  That is what motivated this trial.

This trial finished enrolling new patients in Oct-2019.  Once a trial is fully enrolled, everyone knows when it will end, or at least when they will finish gathering the required data. So in a very real sense, we can see the end of the tunnel now. This trial will collect data for 6 months, so the data should be collected by April-2020, and (hopefully) will be published soon.  However, with COVID-19, nothing is certain.  My policy is to wait two years for a publication.  In fact, my experience is that successful studies are usually published in less than a year.  So from a practical point of view: if it is not out in a year, it is not likely to be successful.

Previous Blogging: https://cureresearch4type1diabetes.blogspot.com/2018/06/alpha-difluoromethylornithine-dfmo.html
Clinical Registration: https://clinicaltrials.gov/ct2/show/NCT02384889


Unsuccessful Results for a Phase-II? Trial of GNbAC1

While this trial was underway, the treatment got a new and improved name.  It is now called Temelimab.  Do not mix this drug up with Teplizumab or Tocilizumab.  All three of these drugs are different.

GNbAC1 is a monoclonal antibody which was developed by GeNeuro SA and has completed phase-II testing for treating Multiple Sclerosis, which (like type-1) is an autoimmune disease. This phase-II? trial finished in May-2019, but unfortunately was not successful.  The key sentence in the results section was this:

Concerning exploratory endpoints, there was no difference in the levels of C‐peptide, insulin use or HbA1c between treatment groups ...

Results: https://dom-pubs.onlinelibrary.wiley.com/doi/abs/10.1111/dom.14010
Previous Blogging: https://cureresearch4type1diabetes.blogspot.com/2018/06/gnbac1-starts-phase-ii-trial.html
Clinical Registration: https://clinicaltrials.gov/ct2/show/NCT03179423

Notes on Understanding Research Conclusions

Here is the entire Conclusions section for the results of the GNbAC1 study together with how I interpret them:

Temelimab appeared safe in patients with T1D. Pharmacodynamics signals (hypoglycaemia and anti‐insulin antibodies) under temelimab were observed. Markers of β‐cell functions were not modified by treatment. These results need to be further explored in younger patients with T1D with earlier disease onset.

Although if read quickly this sounds positive, it is (in fact) reporting on a failure.  So let me break it down into what each sentence actually means:

Temelimab appeared safe in patients with T1D.

Paradoxically, this is bad news when it is the first sentence in the conclusions.  Almost all T1D studies get information on both effectiveness and safety.  Because effectiveness is the more important information, if they lead with safety results, then that means the effectiveness results were not good.  For a successful study, one that gets us closer to a cure, a sentence about safety will be farther back in the conclusion section.

Pharmacodynamics signals (hypoglycaemia and anti‐insulin antibodies) under temelimab were observed. 

These results are not critical for curing T1D, especially when you remember the key result (no difference in C‐peptide, insulin use or HbA1c).  This is just reporting on what tiny crumbs of good news they could find at the bottom of their research data.   "Signals" usually means small (ie. not statistically significant) changes.  It sounds like the patients had slightly fewer low BG episodes and slightly fewer anti-insulin antibodies.

Markers of β‐cell functions were not modified by treatment. 

This is the most important result, because beta cell function means insulin production, but this did not change.  This is what matters in terms of a future cure.

These results need to be further explored in younger patients with T1D with earlier disease onset.

Normally, calls for more research should be ignored, because any research can be followed up with more research.  It is meaningless for a researcher to call for more research, because they always do this.  However, this sentence is more negative than most, because it says that the research should be done on different people than this study, which implies that more studies on these people would not be useful.  And, to make things worse, none of the conclusions suggest that this other group of people would have better results.

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.

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.