Dr Ari Green on Promising Remyelination Therapies and Patient Outcomes in MS

Ari Green, MD, chief of the division of neuroimmunology and glial biology at the University of California, San Francisco, presented on remyelination, among other related topics, at this year’s Americas Committee for Treatment and Research in MS (ACTRIMS) Forum 2024 in his session titled, “Barriers in Neural Repair.”

Here, Green discusses the promising remyelination therapies that have emerged in clinical trials over the years, as well as explores the patient and disease factors that can have am impact on individual responses to treatment in multiple sclerosis (MS).

Transcript

In clinical trials, what remyelination therapies have shown positive results or potential efficacy in improving myelin repair in patients with MS?

So at this point, the one we've worked on that has shown the most capacity for validation and confirmation of the result, that's clemastine. That's a drug that, although it wasn't designed for this purpose, acts on a particular receptor known as the M1 receptor. Now, it's a little bit of a dirty drug in that it acts on multiple muscarinic receptors, as well as histamine receptors. It's not designed for this purpose, but it is the one that multiple laboratories have been able to confirm since we first identified it.

There are a few other drugs that have also shown effect. There are other drugs in that same pathway, the antimuscarinic pathway, that have shown some effect. In addition, drugs in the pathway known as selective estrogen receptor modulators have shown effect. The challenge is always making sure we have a therapy that works in combination with a tolerability profile that would make them useful for patient use.

So the ones that have been tested robustly in people are limited. So clemastine has been tested in 1 successful clinical trial; another drug known as bexarotene was tested by a group at Cambridge. That drug didn't meet its primary clinical end point, but actually on the same clinical end point that we used in our clemastine trials, did appear to show efficacy. That drug works on a completely different pathway known as RSR gamma.

But in terms of the drugs that have shown clinical effect, there's a number of other drugs that have been tested that weren't capable of showing a robust effect. But part of that is sometimes, it may not be the drug; it might be the means by which we assess whether or not the drug worked. So this always happens in concert where we work on the therapy and we work on the measurements at the same time in conjunction with one another.

What patient-specific factors, like disease subtype, MS duration, and individual responsiveness, influence the efficacy of remyelination treatments?

Definitely this issue of individual patient response is something that we need to spend time working on and identify individual factors, whether that even be related to genetics or it be related to other issues—diet or environment—that may influence people's responsiveness to therapeutics. But in addition to that, other things that might be predictive of people who are earlier in the course of disease and people who are younger are more likely to respond to therapy.

We also think that at the very least for chronic use of these drugs, we have to keep the inflammation at bay. So people should remain on their immunomodulatory disease modifying therapies, in conjunction with remyelinating therapies. That's kind of what I think, and I think most of the field thinks, is ultimately the most likely scenario for us in terms of treatment.

It goes without saying that the earlier you work at this, the more axons are available, the more likely remyelination is to be the most robust and potentially the most easy to detect.