Neurology
Multiple Sclerosis
The Need for Effective Therapies for Relapsing-Remitting Multiple Sclerosis and Primary Progressive Multiple Sclerosis
Overview
Highly effective anti-inflammatory therapies are available for treating patients with relapsing-remitting multiple sclerosis (MS), and these therapies have also shown some benefits to patients who are in the earlier progressive stage of the disease. However, treatment options are still limited for patients who have entered the late progressive phase of MS and are experiencing progressive neurodegeneration. Anti-inflammatory therapies may not be as effective for the late stages of progressive MS because, at that point in the patient’s disease course, inflammation has declined and neurodegeneration is progressing. Patients with progressive MS may benefit from neuroprotective/repair therapies. Therapies that stimulate remyelination may only be effective in combination with anti-inflammatory drugs and in lesions with sufficient axons to be remyelinated. Biomarkers to determine the extent of spontaneous and treatment-induced remyelination and to define the associated mechanisms are needed for use in clinical trials. Challenges to clinical trial design may be met through the establishment of new industry-academic initiatives, including independent consortia under the umbrella of the Progressive MS Alliance with the endorsement of MS organizations and scientific societies such as the European Committee for Treatment and Research in Multiple Sclerosis. In addition, it may be necessary to change the approach for phase 2 studies with the goal of improving the success rate of phase 3 studies for patients with late-stage progressive MS. One possibility is to design “proof of concept” trials that would confirm the mechanism of action proposed for the study drug in the appropriate MS phenotype patient before moving to a definitive phase 3 trial. Our featured experts in the field discuss ways to address the need for effective therapies for relapsing MS and primary progressive MS.
Q: How should the need for effective therapies for relapsing MS and primary progressive MS be addressed?
Staley Brod, MD
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“It would be advantageous to look for changes in biomarkers, either in the blood or the cerebrospinal fluid, with the therapies that potentially provide neuroprotection or repair.”
We need to go beyond the inflammatory issues and try to look at therapies that provide neuroprotection or repair, and, in this line of drugs, the fingolimod molecule is very interesting. It is a small molecule, it will get into the central nervous system, it can access those follicles on the meninges, and it may be able to stimulate remyelination. Nevertheless, we have to deal with the issues associated with the drug, such as progressive multifocal leukoencephalopathy (PML) at a low level, and cryptococcal meningitis. We have biomarkers, classic biomarkers for remyelination, such as brain-derived neurotrophic factor (BDNF), neural cell adhesion molecule (NCAM), ciliary neurotrophic factor, and platelet-derived growth factor—particularly, NCAM (that has been associated with central nervous system repair) and BDNF. We could even monitor such molecules in the peripheral blood. So, it would be advantageous to look for changes in biomarkers, either in the blood or the cerebrospinal fluid, with the therapies that potentially provide neuroprotection or repair.
David A. Hafler, MD
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“We do not understand the biology of progressive disease, and right now we just have to keep trying different things to see what really works.”
I think that the real question is, how long do we need to use these drugs? We do not want to keep someone on lifelong therapy with an anti-CD20 compound or any of these drugs. There are issues with white counts dropping with fingolimod and dimethyl fumarate. We have to carefully monitor the white count drop and potential complications such as PML. We need to know if there is a way of resetting the immune thermostat, so to speak, and reducing the amount of time that the patient has to be on the drug. I think that that is a really big issue. As I said earlier, we do not understand the biology of progressive disease, and right now we just have to keep trying different things to see what really works.
“We need to understand the mechanisms of neurodegeneration better. We need biomarkers, whether those are imaging biomarkers or biomarkers that we can test in blood or spinal fluid, or other measures to help us understand in a valid way how to measure true neurodegeneration.”
Well, I think that, even though there is still room for improvement in our ability to treat relapsing MS, the challenge for both relapsing and primary progressive MS is to better understand the mechanisms that ultimately lead to transition to progressive disease or drive progressive disease in the first place. We need to understand the mechanisms of neurodegeneration better. We need biomarkers, whether those are imaging biomarkers or biomarkers that we can test in blood or spinal fluid, or other measures to help us understand in a valid way how to measure true neurodegeneration. Then, once we have biomarkers that seem to be valid prognostic indicators of neurodegeneration, we can start to target medications more precisely toward those biomarkers and the mechanisms associated with them. And that should ultimately improve our ability to design targeted clinical trials and efficient trials that will get us the right answer.
References
Lassmann H. Targets of therapy in progressive MS. Mult Scler. 2017;23(12):1593-1599.
Wolinsky JS. Patient selection for trials. Mult Scler. 2017;23(12):1636-1641.
Zaratin P, Comi G, Leppert D. ‘Progressive MS – macro views’: the need for novel clinical trial paradigms to enable drug development for progressive MS. Mult Scler. 2017;23(12):1649-1655.
