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Therapeutics for Progressive Multiple Sclerosis: Where to Go from Here?

Three criteria for finding an effective treatment for neurodegeneration


The phase 2b Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) was thought to be the next best hope for finding a drug therapy to slow neurodegeneration, but it has proved to be another dead end for people with progressive multiple sclerosis (MS). So report the study’s investigators in a new article published online by The Lancet Neurology.


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Amiloride, fluoxetine and riluzole — the three drugs chosen to be tested for neuroprotection — showed the best potential of more than 500 candidate test drugs screened in a systematic review. Nearly 450 patients were randomly assigned treatment with one of these three drugs or placebo over 96 weeks. An impressive 88% of patients completed the study. However, the well-designed, well-executed trial didn’t produce the much-anticipated result: reducing percentage brain volume change as detected by MRI. None of the test drugs performed better than placebo.

Robert Fox, MD, a neurologist with Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research, reflected on this outcome in an invited commentary that accompanies the MS-SMART report in The Lancet Neurology.

“These disappointing results raise an obvious question: Why was a promising treatment not identified to carry forward into phase 3 trials?” he writes.

Dr. Fox goes on to offer three possible explanations that correspond with possible modifications for future studies. To ultimately identify an effective therapeutic for progressive MS, he says, researchers first must:

  1. Better understand progressive MS pathophysiology. “The true pathophysiology of progressive multiple sclerosis remains unknown, and with this paucity of knowledge, accurate drug selection is compromised,” writes Dr. Fox. Leukocyte infiltration into the central nervous system, which is distinctive in relapsing MS, isn’t so in progressive MS. Rather, mitochondrial dysfunction, metabolic dysregulation and other mechanisms may be driving disease progression, he notes.
  2. Select a valid biological target. Ideally, uncovering the disease’s pathophysiology will reveal clear biological targets for clinical trials. This step isn’t as necessary when studying relapsing MS because MRI detection of brain lesions is sufficient to determine effectiveness of a study drug. Progressive MS doesn’t have a biomarker like that, at least none that is scientifically validated. For progressive MS, adequately evaluating a study drug requires identifying whether or how it engages with a biological target, such as a type of cell or molecule.
  3. Measure more specific treatment biomarkers. Whole-brain atrophy, the primary outcome measured in MS-SMART, was likely too broad to provide an accurate assessment of drug effectiveness, explains Dr. Fox. Its limitations include “day-to-day biological variability, slow dynamic change over time, limited scalar granularity as a full-brain metric, and technical challenges when MRI acquisition and equipment change over the course of a trial.” More specific study metrics might include magnetization transfer imaging, cortical atrophy and slowly growing lesions, he suggests.


“The negative outcome of MS-SMART, and many other trials in neurodegenerative diseases, points to an urgent need to rethink how we select and test experimental treatments for neurodegenerative conditions,” writes Dr. Fox.

Fortunately, MS-SMART also incidentally shows ways for neurology researchers to redirect their efforts. Hitting a dead end just signals another turn on our continuing journey toward an effective therapeutic for progressive MS.

Read Dr. Fox’s full commentary here. For more insights on this topic from Dr. Fox, check out the below episode of Cleveland Clinic’s Neuro Pathways podcast for healthcare professionals.

Image at top shows corticospinal tracts from a diffusion tensor imaging study from a patient with progressive MS.


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