MILAN — While multiple sclerosis (MS) is “one of two or three great success stories of modern molecular medicine,” we’re still only “halfway home,” University of California, San Francisco, neurology professor Stephen Hauser, MD, told colleagues in a highlighted lecture at the 9th Joint ECTRIMS-ACTRIMS meeting.
Going forward, the MS field should emphasize identifying early biomarkers of MS, Dr. Hauser said.
He noted that many experts had anticipated “that, if we could intervene early in the relapsing phase of the disease, we would stabilize neurodegeneration and patient disability. But one of the big surprises was that that was not the case. Instead, the observed course was that by silencing relapses and focal inflammation, a clinically silent, slow, insidious progression continues during the relapsing phase of disease in patients who are not having ongoing relapses.”
Even as focal activity detected via MRI is silenced, “progression continues” he said. “This remains the great unsolved challenge.”
Dr. Hauser asked colleagues to consider a three-stage model of MS that begins with benign autoimmunity followed by pathogenic autoimmunity with subclinical tissue damage. The third stage is clinical autoimmunity.
How can you determine who’s at risk? Genetics can only fill in part of the picture because they can’t pinpoint exactly who’s likely to develop the disease. “In other autoimmune diseases, serologic autoantibodies have been by far the most effective biomarkers,” he said. “There is real-world support – not only in mice – for the concept that autoimmunity begins as a highly focused immune response that then spreads over time.”
In systemic lupus erythematosus, the cascade toward disease begins about 9 years before clinical presentation, he said. It’s 7 months in type 1 diabetes, and 20 years in rheumatoid arthritis. “These have been enormously powerful in designing both observational and therapeutic studies to try to interrupt autoimmunity at the earliest possible stage.”
What can be done if a MS biomarker is developed and shows that a person is at risk? Dr. Hauser highlighted how the anti-CD3 antibody teplizumab has been developed – and Food and Drug Administration approved – to greatly reduce the risk of type 1 diabetes in high-risk patients. Per a 2021 study, a single-14-day course of the drug was linked to lowering the risk of disease over a median 923 days by more than 50% (hazard ratio, 0.457; P
“We’ve not yet had those serologic biomarkers in MS. But I’d like to show you that maybe we are getting close to having them,” Dr. Hauser said. He pointed to new research into a U.S. Department of Defense serum repository that’s turned up “a pretty rock-solid prediagnostic biomarker specific to MS.”
Moving on to therapy, Dr. Hauser said it’s clear that “the earlier that we treat, the more likely we are to have a large response. Highly effective therapies delivered as first-line therapies have better long-term outcomes for disability then does a graded approach that doesn’t begin with high-efficacy therapy.”
What constitutes a cure?
What else needs to be done going forward? Dr. Hauser called for the MS field to develop a definition of cure. “We should take the lead from cancer therapeutics, where they define what a cure means.” In B-cell leukemia, for example, patients are considered cured “if they remain completely disease-free in terms of clinical symptoms and biomarkers of clonal proliferation for 4 years. They have less than a 1% lifetime risk of relapse. They’re essentially cured. Our equivalent could also be developed for MS.”
He highlighted the IMPACT MS phase 4 trial, a small single-center study of ocrelizumab, which just finished enrollment and will examine the effect of the drug on treatment-naive patients at the moment of their first-ever attack. The primary endpoint is oligoclonal bands in 3 years. “I think more of these studies will probably follow,” Dr. Hauser said.
Is intervention possible at the presymptomatic stage? Targets could be members of families with multiple affected relatives who test positive for the predictive antibody signature and who have a high genetic score, he said. “We could do perhaps an Epstein-Barr virus intervention trial in this population. Then, if we have the courage and are more confident in our biomarkers, perhaps even a therapeutic trial, as has been done in these other diseases.”
As for next-generation therapies, “we’ll need to neutralize multiple cell types, especially in later disease,” he said. Bruton tyrosine kinase inhibitors “seem to be a class of drugs that was designed for the MS patient because they not only hit B cells, but also the plasmablasts that CD20s don’t hit and are the main component of the humoral pathology in chronic MS lesions.”
Dr. Hauser discloses scientific board (Accure, Alector, Annexon), board of directors (Neurona), consulting (BD, Moderna, NGM Bio), and travel reimbursement/writing support (Roche and Novartis).
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
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Publish date : 2023-10-26 13:50:48
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