Phase 2b Trial of the PDE10A Inhibitor MK-8189 in People With an Acute Episode of Schizophrenia

BACKGROUND: PDE10A inhibition represents a potential mechanism for treating schizophrenia. A 12-mg dose of the PDE10A inhibitor MK-8189 showed initial evidence of efficacy for improving schizophrenia symptoms after 4 weeks. We performed a follow-up study evaluating higher MK-8189 doses (16 mg and 24 mg, predicted to produce up to 80% sustained enzyme occupancy) over 6 weeks. METHODS: Randomized, double-blind, phase 2b study consisting of a 6-week acute treatment period and a 6-week extension (NCT04624243). Participants were diagnosed with schizophrenia and were experiencing active phase symptoms. For the acute treatment period, participants were randomized in a 2:2:2:1:2 ratio to 6 weeks of daily MK-8189 8 mg (dropped after a third of participants had been enrolled), 16 mg, 24 mg, risperidone 6 mg (for assay sensitivity), or placebo. The primary outcome was the change from baseline in Positive and Negative Syndrome Scale (PANSS) total score at 6 weeks. RESULTS: The number of treated participants in the acute period was: MK-8189 16 mg, N=132; MK-8189 24 mg, N=132; risperidone 6 mg, N=65; and placebo, N=129. MK-8189 16 mg and 24 mg did not show an improvement versus placebo for change-from-baseline in PANSS total score after 6 weeks [16 mg-placebo difference, -2.8 (95% CI: -8.3,2.6), P =0.241; 24 mg-placebo difference, -0.7 (95% CI: -6.3,4.9), P =0.784], whereas risperidone did [risperidone-placebo difference, -6.2 (95% CI: -12.9,0.6), P =0.040]. Over the 6-week acute period, more participants discontinued treatment due to an adverse event in the MK-8189 24 mg group (25.0%) than in the MK-8189 16 mg (12.9%), risperidone (12.3%) or placebo (12.4%) groups. CONCLUSIONS: These findings suggest that PDE10A inhibition does not have antipsychotic effects at the doses tested.