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Degeneration of striatal medium-spiny neurons underlies corticostriatal dysfunction in Huntington disease (HD). Inhibition of Phosphodiesterase-10A, an intracellular signaling regulator preferentially expressed in medium-spiny neurons, increases corticostriatal function in preclinical models providing a promising therapeutic target for HD.To assess efficacy on motor function, safety and tolerability of the phosphodiesterase-10A inhibitor PF-02545920 in HD.AMARYLLIS was a double-blind, placebo-controlled, randomized trial (ClinicalTrials.gov, NCT02197130). The primary outcome was the Unified-Huntington’s-Disease-Rating-Scale Total-Motor-Score (UHDRS-TMS). Patients with genetically confirmed symptomatic HD in stages I-II, UHDRS-TMS≥10 and no neuroleptic treatment, were randomized to 5 mg, 20 mg PF-02545920 or placebo twice daily for 26 weeks.216 (79%) of 272 randomized subjects completed AMARYLLIS (5 mg=79, 20 mg=56, placebo=81). UHDRS-TMS and the secondary efficacy assessments UHDRS-Total-Maximum-Chorea score and Clinical-Global-Impression of Improvement showed no benefits compared to placebo. Pre-specified exploratory quantitative motor (Q-Motor) measures showed consistent and dose-dependent improvements. Adverse events were mild or moderate and occurred more frequently at the 20 mg (90%) compared to 5 mg (86%) dose and placebo (72%), most common were somnolence, fatigue, and weight-decrease. Adverse-event-related discontinuations were higher at 20 mg (26%) compared to 5 mg (14%) and placebo (6%). Serious adverse event were not dose-related and <10% across groups.PF-02545920 was generally safe and sufficiently tolerated. This study did not provide evidence of efficacy in primary or secondary clinical endpoints. But rater-independent improvements in pre-specified Q-Motor measures suggested proof-of-concept for a dose-dependent central effect on motor coordination of unknown clinical significance. Exploration of higher doses possibly in earlier stages of HD may be considered.