Verdiperstat Fails to Improve ALS Disease Progression, HEALEY-ALS Results Show

Merit E. Cudkowicz, MD, MSc

Official results from the verdiperstat (Biohaven) arm of the HEALEY-ALS Platform trial (NCT04297683), a double-blind, perpetual platform design study, were recently published in JAMA Network. Overall, treatment with the investigational agent at 600 mg twice daily doses failed to meet its prespecified end point and was found to be unlikely to alter disease progression in patients with amyotrophic lateral sclerosis (ALS).¹

In this randomized controlled trial, the primary analysis comprised 167 patients with ALS who were randomly assigned 3:1 to either oral verdiperstat, 600 mg, twice daily or matching placebo for a duration of 24 weeks. At the conclusion of the trial, the estimated disease rate ratio (DRR) was 0.98 (95% CI, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression), which corresponded to a 2% slowing in the rate of ALS progression, measured through ALS Functional Rating Scale (ALSFRS-R) and survival, relative to placebo.

At week 24, the change from baseline in mean slopes of ALSFRS-R total score in the FAS dataset among survivors was –1.02 (SD, 0.09) vs –1.05 (SD, 0.09) points per month for verdiperstat vs shared placebo, respectively. In addition, there was no difference in survival as well, as the estimated rate of deaths or death equivalent events per month was 0.01 (posterior SD, 0) for verdiperstat vs 0.01 (posterior SD, 0) for shared placebo, respectively.

"Despite the negative results of this particular regimen, it is worth mentioning that the adaptive platform trial design efficiently answered the important question about clinical efficacy of verdiperstat in ALS," study authors, including senior investigator Merit E. Cudkowicz, MD, MSc, wrote.¹ "In this respect, the overall platform trial achieved its main objective of rapidly screening experimental drugs for clinical efficacy signal in an adequately powered phase 2 randomized clinical trial and excluding drugs and/or targets if not relevant in ALS."

Coming into the study, a total of 219 participants (76%) were receiving riluzole, 70 (24%) were receiving edaravone, and 63 (21%) were receiving both riluzole and edaravone. While the study was not powered for secondary outcomes, investigators still observed no between-group differences for the rate of survival among those on verdiperstat vs placebo. Furthermore, these two cohorts failed to differentiate on other secondary outcomes of hand-held dynamometry (HHD) upper limb, slow vital capacity, HHD lower limb, and ALSFRS-R total score. In addition, mortality outcomes did not differ based on the treatment assigned.

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Verdiperstat, a myeloperoxidase inhibitor (MPO), was considered safe and well tolerated. Treatment-emergent adverse events (TEAEs) like nausea, insomnia, and elevated thyrotropin level were more common in the verdiperstat arm. In addition, there were 4 TEAEs that resulted in death during the double-blind portion of the trial in the group treated with verdiperstat, although none were attributed to the investigational agent.

Nausea was considered the most common TEAE related to study drug that led to early drug discontinuation, occurring in 5 patients (4.0%) on verdiperstat and 1 patient (0.8%) on placebo. Following that, fatigue and dizziness were the next most common TEAE that led to early discontinuation. Notably, the 3 most common TEAEs that were related to study drug and led to permanent dose reduction were urticaria (verdiperstat: 0.8%; placebo: 0%), tonsilitis (verdiperstat: 0.8%; placebo: 0%), and tinnitus (verdiperstat: 0.8%; placebo: 0%).

"The pathological role and cellular origin of MPO in the central nervous system of human ALS remains unclear,” the study authors wrote. “Our expectation of benefit from verdiperstat in ALS is derived from other neurodegenerative disorders with overlapping biological pathways such as neuroinflammation, oxidative stress, and autophagy, as well as preclinical data in ALS models. Although verdiperstat and a few other experimental drugs targeting the neuroinflammation pathway or targets have not demonstrated efficacy in single-agent trials in ALS, there may still be value in pursuing additional experimental therapies modulating the neuroinflammation pathway in this disease."

REFERENCE
1. Babu S, et al. Verdiperstat in Amyotrophic Lateral Sclerosis: Results From the Randomized HEALEY ALS Platform Trial. JAMA Network. Published online February 17, 2025. doi:10.1001/jamaneurol.2024.5249