Feast or famine in multiple sclerosis therapeutics
Authors: Robert J Fox
Journal: The Lancet Neurology (2020)

Over the past 30 years, the number of drugs approved for multiple sclerosis has gone from zero to more than 15, with several dosing variations and generic versions. Despite this great progress, current multiple sclerosis treatments seem to predominantly benefit the inflammatory lesion activity that underlies relapsing multiple sclerosis, leaving the progressive aspects (ie, gradual disability worsening without clinical relapses) mostly unabated. Siponimod and ocrelizumab are two agents with regulatory approval for progressive forms of multiple sclerosis (primary progressive and secondary progressive multiple sclerosis); these drugs provide the most benefit to patients with clinical relapses or disease activity on MRI.1Kappos L Bar-Or A Cree BAC et al.Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study.Lancet. 2018; 391: 1263-1273Summary Full Text Full Text PDF PubMed Scopus (498) Google Scholar, 2Montalban X Hauser SL Kappos L et al.Ocrelizumab versus placebo in primary progressive multiple sclerosis.N Engl J Med. 2017; 376: 208-219Crossref Scopus (981) Google Scholar As a result, when US and European regulators recommended approval of siponimod for secondary progressive multiple sclerosis, they restricted its use to patients with active disease. Treatments for patients with progressive multiple sclerosis who do not have active disease are scarce. In The Lancet Neurology, Jeremy Chataway and colleagues3Chataway J De Angelis F Connick P et al.Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trial.Lancet Neurol. 2020; (published online Jan 22.)http://dx.doi.org/10.1016/S1474-4422(19)30485-5Summary Full Text Full Text PDF PubMed Scopus (58) Google Scholar report their attempt to address this problem with a multiarm phase 2b trial in patients with secondary progressive multiple sclerosis, the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART). The authors selected three experimental drugs (amiloride, fluoxetine, and riluzole) for MS-SMART that were identified by extensive systematic review of 532 treatment candidates.4Vesterinen HM Connick P Irvine CM et al.Drug repurposing: a systematic approach to evaluate candidate oral neuroprotective interventions for secondary progressive multiple sclerosis.PLoS One. 2015; 10e0117705Crossref PubMed Scopus (41) Google Scholar These drugs target axonal pathobiology and neuroprotection, and have extensive evidence of use in humans with established safety profiles, so were ready for trial testing in progressive multiple sclerosis. The primary outcome was whole-brain atrophy and this endpoint is commonly used in progressive multiple sclerosis phase 2 trials. The study achieved target enrolment, and retention was excellent at 88% over 96 weeks. Despite rigorous theoretical grounding, sound experimental design, and admirable execution, MS-SMART did not achieve its primary outcome. None of the three tested drugs slowed progression of whole-brain atrophy compared with placebo. These disappointing results raise an obvious question: why was a promising treatment not identified to carry forward into phase 3 trials? The answer is unclear, but several possibilities merit consideration. The systematic review process of potential treatments seems inadequate. The true pathophysiology of progressive multiple sclerosis remains unknown, and with this paucity of knowledge, accurate drug selection is compromised. In progressive multiple sclerosis, leucocyte infiltration into the CNS is less prominent than in relapsing multiple sclerosis and is replaced by a shift to innate immune mechanisms sequestered behind the blood–brain barrier, mitochondrial dysfunction, metabolic dysregulation secondary to chronic demyelination, and possibly a magnified effect of normal aging and ongoing comorbid conditions. Researchers need to re-double their efforts to identify the true mechanisms driving multiple sclerosis progression, which then will enable effective drug selection.5Salvetti M Landsman D Schwarz-Lam P Comi G Thompson AJ Fox RJ Progressive MS: from pathophysiology to drug discovery.Mult Scler. 2015; 21: 1376-1384Crossref PubMed Scopus (34) Google Scholar This lesson probably applies across the spectrum of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. An increased mechanistic understanding of neurodegenerative disorders will enable validation of biological target engagement during trials. Without confirming that the investigative drug engaged with its molecular or cellular target, it is difficult to select the optimum drug dose. In relapsing multiple sclerosis, biological target engagement has been unnecessary because the presence of new lesions on MRI is a sensitive treatment response biomarker, regardless of the intended biological target. Biomarkers have a variety of uses in clinical medicine, including pharmacologic responses to therapeutic interventions.6Biomarkers Definitions Working GroupBiomarkers and surrogate endpoints: preferred definitions and conceptual framework.Clin Pharmacol Ther. 2001; 69: 89-95Crossref PubMed Scopus (4684) Google Scholar Target engagement becomes of greater importance in progressive multiple sclerosis because no biomarker outcomes have phase 3 trial validation. Whole-brain atrophy has inherent limitations, including 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. Better phase 2 trial metrics will improve trial efficiency, allowing fewer patients to be enrolled and shortening trial duration. Magnetisation transfer imaging, cortical atrophy, and slowly expanding lesions are example metrics that show promise to be more sensitive than whole-brain atrophy,7Fox RJ Coffey CS Conwit R et al.Phase 2 trial of ibudilast in progressive multiple sclerosis.N Engl J Med. 2018; 379: 846-855Crossref PubMed Scopus (149) Google Scholar, 8Elliott C Belachew S Wolinsky JS et al.Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis.Brain. 2019; 142: 2787-2799Crossref PubMed Scopus (80) Google Scholar although further validation studies are needed. Fluid-based treatment response biomarkers also are being sought, with neurofilament-light emerging as a leading candidate.9Khalil M Teunissen CE Otto M et al.Neurofilaments as biomarkers in neurological disorders.Nat Rev Neurol. 2018; 14: 577-589Crossref PubMed Scopus (806) Google Scholar MS-SMART models efficient trial design by comparing three active treatment arms with placebo. Industry is challenged to adopt similar multiarm designs, which could benefit from collaboration between companies and by possibly using independent trial networks such as NeuroNEXT or the Expert Consortium for Progression in Multiple Sclerosis Clinical Trials. 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. Informed selection of drugs requires an improved understanding of disease pathobiology, effective measurement of target engagement, and valid treatment-response biomarkers. Global collaborative efforts, such as that led by the Progressive Multiple Sclerosis Alliance, will further galvanise and align ongoing individual scientific efforts. These crucial enabling steps will help identify useful treatments more effectively and efficiently. Patients should not have to endure further frustrating delays and disappointing dead ends. I declare personal consulting fees from Actelion, Biogen, Celgene, EMD Serono, Genentech, Immunic, Novartis, Sanofi, Teva, and TG Therapeutics; have served on clinical trial advisory committees for Actelion, Biogen, Immunic, and Novartis; and have received clinical trial contract and research grant funding from Biogen and Novartis. I thank Jeffrey Cohen (Cleveland Clinic) for critical review of this Comment. Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trialThe absence of evidence for neuroprotection in this adequately powered trial indicates that exclusively targeting these aspects of axonal pathobiology in patients with secondary progressive multiple sclerosis is insufficient to mitigate neuroaxonal loss. These findings argue for investigation of different mechanistic targets and future consideration of combination treatment trials. This trial provides a template for future simultaneous testing of multiple disease-modifying medicines in neurological medicine. Full-Text PDF Open Access