PROOF-HD Trial Results Show Benefits of Pridopidine as Huntington Disease Treatment in Those Not Taking ADMs

New data presented at the American Academy of Neurology (AAN) 2025 Annual Meeting suggest that treatment with pridopidine (Prilenia Therapeutics; Waltham, MA) may improve function, cognition, and motor performance in individuals with Huntington disease (HD) not taking antidopaminergic medications (ADMs). Pridopidone, an investigational sigma-1 receptor (S1R) agonist, may be used to treat motor and behavioral symptoms in HD and is also being evaluated as a potential treatment for amyotrophic lateral sclerosis (ALS).

PROOF-HD (NCT04556656), a phase 3 randomized, double-blind, placebo-controlled trial with an open-label extension, evaluated the efficacy and safety of pridopidine in patients diagnosed with HD. The study enrolled individuals with total functional capacity (TFC) scores >7 and randomized them to receive either pridopidine 45 mg twice daily or placebo for 104 weeks. The end point was changes in TFC with a secondary end point of changes in the composite Unified Huntington's Disease Rating Scale (cUHDRS) score and additional end points of changes in Q-Motor finger-tapping (FT) inter-onset interval (IOI), cognition (SWR), and quality of life (QOL). Participants taking ADMs were excluded from prespecified subgroup analyses.

Although the primary end point was not met, in participants who were not taking ADMs, pridopidine showed significant improvements from baseline compared with placebo for at least 1 year in:

• cUHDRS scores (wk52 Δ0.43, P=.04), suggestive of slowing disease progression
• SWR scores increased (wk52 Δ4.22, P=.02), indicating better cognition
• Q-Motor FT IOI improved (wk52 Δ-22.84, P=.04)

QOL was also preserved through week 78. Benefits were maintained through the open-label extension to week 104 when compared with a propensity score weighted control from the TRACK-HD observational study.