J008 The phase 3 proof-hd trial demonstrates benefits of pridopidine on progression in Huntington Disease

<h3>Introduction</h3> Pridopidine is a potent S1R agonist in clinical development for Huntington disease (HD). <h3>Aims</h3> To evaluate the safety and efficacy of pridopidine (45mg bid) in participants with early HD (TFC≥7). <h3>Methods</h3> Primary and key secondary endpoints were change to week 65 in total functional capacity (TFC) and cUHDRS, respectively. Additional endpoints included cognition (SWR), motor (Q-Motor) and Quality-of-Life (HD-QoL). Prespecified subgroup analyses excluded participants on antidopaminergic medications (ADMs) as ADMs are associated with faster functional and cognitive decline in HD. <h3>Results</h3> Pridopidine was well tolerated with a safety profile comparable to placebo. The primary and key secondary endpoints were not met in the full analysis set. In participants off ADMs, pridopidine shows improvement from baseline in cUHDRS up to week 52, with benefits at all timepoints through week 78. Pridopidine demonstrates maintenance or improvement from baseline in SWR and Q-Motor through week 78. Early improvements in Q-Motor are highly predictive of later benefits in function and cUHDRS. Pridopidine preserves quality-of-life through week 78. Subjects on lower doses of ADMs maintain the positive effects of pridopidine. Subjects on higher doses of ADMs show blunting of pridopidine’s benefit for numerous endpoints, and plasma levels of VMAT2 inhibitors are elevated in the presence of pridopidine (CYP2D6 inhibitor). <h3>Conclusions</h3> Pridopidine shows consistent, sustained, and clinically meaningful benefits across multiple endpoints including function, disease progression, cognition, motor and QoL in subjects off and on low doses of ADMs. Remarkably, pridopidine demonstrated unprecedented improvements from baseline in cUHDRS, SWR, Q-Motor and HD-QoL, for at least 1 year.