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J06 A randomized, double-blind, placebo-controlled phase ii efficacy and safety study of the PDE10A inhibitor PF-02545920 in huntington disease (amaryllis)
  1. Marielle Delnomdedieu1,
  2. Ye Tan1,
  3. Adam Ogden2,
  4. Zdenek Berger1,
  5. Ralf Reilmann3,4,5
  1. 1Pfizer Inc., Cambridge, MA, USA
  2. 2Pfizer Early Clinical Research, Groton, CT, USA
  3. 3George Huntington Institute and QuantiMedis GmbH, Muenster, Germany
  4. 4Dept. of Clinical Radiology, University of Muenster, Muenster, Germany
  5. 5Dept. of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany


Background 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.

Aims To assess efficacy on motor function, safety and tolerability of the phosphodiesterase-10A inhibitor PF-02545920 in HD.

Methods AMARYLLIS was a double-blind, placebo-controlled, randomized trial (, 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.

Results 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.

Conclusions 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.

  • Amaryllis
  • PDE10
  • clinical trial

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