Pridopidine treatment in ALS: subgroup analyses from the HEALEY ALS Platform trial

<i>Objectives</i>: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options. Pridopidine, a selective sigma-1 receptor agonist, was evaluated in Regimen D of the HEALEY ALS Platform Trial. Although the primary endpoint (ALS Functional Rating Scale-Revised (ALSFRS-R) total score accounting for survival at 24 weeks) was not met, a predefined subgroup analysis suggested slowed disease progression in ALS patients with definite and early disease (&lt;18 months from onset). This report presents an exploratory analysis that further investigates pridopidine in rapidly progressing participants with definite/probable ALS and early-disease, where treatment effects may be more pronounced. <i>Methods</i>: The randomized, double-blind, placebo-controlled phase 2 trial assigned participants to pridopidine 45 mg bid or placebo, and placebo patients were shared across four trial regimens. The primary outcome was ALSFRS-R total score, with secondary outcomes assessing respiratory, bulbar, and speech functions. <i>Results</i>: Of 163 participants randomized to Regimen D, 72 met subgroup criteria (pridopidine: <i>n</i> = 37; shared placebo: <i>n</i> = 35). At week 24, pridopidine slowed ALSFRS-R total score decline (32%; Δ2.90, <i>p</i> = 0.03) and slowed decline of ALSFRS-R respiratory function (62%; Δ1.20, <i>p</i> = 0.03) and dyspnea (88%; Δ0.85, <i>p</i> = 0.005). ALSFRS-R-Bulbar function stabilized, with articulation and speaking rate declines reduced by 93% (Δ0.43, <i>p</i> = 0.0007) and 70% (Δ0.43, <i>p</i> = 0.002), respectively. Pridopidine was well-tolerated, with a safety profile comparable to placebo. All <i>p</i> values are nominal. <i>Conclusion: Post hoc</i> subgroup analysis suggests therapeutic benefits of pridopidine in patients that had definite/probable ALS and with early-disease progression, supporting further evaluation in a Phase 3 trial.