Opicapone enhances the reversal of MPTP-induced Parkinson-like syndrome by levodopa in cynomolgus monkeys

Abstract

Opicapone is a third generation nitrocatechol catechol-O-methyltransferase inhibitor that has received regional market approval for use as adjunctive therapy to levodopa in Parkinson's disease patients with motor fluctuations. This study evaluated the effects of opicapone as adjunct to levodopa in reversing a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced Parkinson's-like syndrome in cynomolgus monkeys in during opicapone preclinical development program. A Parkinson's-like syndrome was induced in cynomolgus monkeys by daily administrations of MPTP. Evaluation of the animals included scoring with the Primate Parkinsonism Motor Rating Scale (PPMRS) and assessment of locomotor activity. MPTP produced a stable Parkinson's-like behavioural syndrome as evidenced by tremor, postural changes, rigidity, impaired movements and balance, (PPMRS scores of 10–15) and decreased locomotor activity (13% of pre-MPTP values). Opicapone treatment alone, for 14 days, did not change Parkinson's-like symptoms nor decreased subject's locomotor behaviour. Ascending combinations of levodopa/benserazide dose-dependently decreased PPMRS and improved locomotor behaviour reaching statistical significance for levodopa/benserazide doses of 18/4.5 mg/kg and those effects were enhanced in opicapone treated subjects. Opicapone treated subjects as compared vehicle-treated, had markedly reduced erythrocyte catechol-O-methyltransferase activity, significantly increased plasma levodopa levels (1.8-fold higher AUC) with no statistically significant changes in Cmax and significantly reduced 3-OMD AUC and Cmax values (7.8- and 6.8-fold respectively). Opicapone potentiated the improvements in Parkinson's-like symptoms produced by levodopa/benserazide combinations with concomitant increase in plasma levodopa exposure, reduction of plasma 3-O-methyldopa levels and erythrocyte catechol-O-methyltransferase activity, results that were later demonstrated in 2 large Phase 3 studies in Parkinson's disease patients.