Objective: To present results from M-STAR, a phase 3, randomized controlled trial evaluating the disease modifying effect of verdiperstat in participants with MSA.

Background: MSA is a rare, adult-onset, rapidly progressive, and fatal neurodegenerative disease. Verdiperstat is a first-in-class, potent, selective, brain-permeable inhibitor of myeloperoxidase (MPO), an enzyme implicated in pathological oxidative stress and neuroinflammation underlying neurodegenerative diseases, such as MSA.

Method: M-STAR was a randomized, double-blind, placebo-controlled, parallel group study. Ambulatory participants, 40-80 years of age, with possible or probable MSA¹, including MSA-P or MSA-C, were randomized to 48 weeks of treatment with verdiperstat 600 mg twice daily or placebo. The primary efficacy endpoint was change from baseline to Week 48 on a score derived from the Unified MSA Rating Scale (modified UMSARS). Key secondary outcome measures were Clinical Global Impression of Improvement, motor/non-motor subscales of the MSA-Quality of Life and UMSARS Part I + II total score. Other relevant secondary/exploratory outcomes measures (eg, volumetric brain MRI) were also assessed.Trial registration: ClinicalTrials.gov: NCT03952806. EudraCT: 2019-001100-38.

Results: Between Sept 2019 and Sept 2020, 336 participants were randomized to verdiperstat or placebo (1:1) at 48 sites across 6 countries. Clinical efficacy was not demonstrated on mean change for the modified UMSARS at Week 48 (0.35; 95% CI -0.60, 1.30; p=0.47) or key secondary endpoints. Volumetric MRI analysis suggested less atrophy occurred in the verdiperstat group around the lateral ventricles (2.96%; 95% CI 1.31, 4.60; p=0.0005) and potentially in whole brain (-0.35%; 95% CI -0.72, 0.02; p=0.0664) and pons (-0.50%; 95% CI -1.07, 0.08; p=0.0908), but not in putamen or cerebellum. At least 1 TEAE was reported in 95.2% of verdiperstat treated participants vs. 92.9% for placebo, most mild or moderate in intensity and expected in MSA patients.

Conclusion: Verdiperstat was generally well tolerated but did not separate from placebo on primary and secondary endpoints. Trends toward reduced global and regional brain atrophy were observed. Ongoing analyses of subgroups and biomarkers may provide further insight into the effects of MPO inhibition with verdiperstat on neurodegeneration in MSA.

References: 1. Gilman, S, et al. Neurology. 2008;71(9):670-6.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/safety-and-efficacy-of-verdiperstat-a-novel-myeloperoxidase-inhibitor-in-msa/