Consistent Effects of Once-Daily Opicapone 50 mg on COMT Activity Across Participants: A Pooled Post Hoc Analysis of Two Phase 1 Studies (P14-11.014)

Abstract

<h3>Objective:</h3> To assess effects of adjunctive opicapone (OPC) 50 mg on catechol-O-methyltransferase (COMT) activity by participants’ baseline characteristics. <h3>Background:</h3> OPC is a once-daily COMT inhibitor approved as adjunctive treatment to carbidopa/levodopa (CD/LD) in patients with Parkinson’s disease (PD) experiencing “OFF”-episodes. In two Phase 3 trials, OPC reduced daily “OFF”-time in patients with PD and motor fluctuations. Phase 1 trials also showed that adding OPC 50 mg to CD/LD in healthy individuals and patients with PD decreased variability in plasma levodopa (LD) levels and COMT activity. However, the effects of participants’ baseline characteristics on COMT inhibition remain unknown. <h3>Design/Methods:</h3> This post hoc analysis included data from 2 open-label Phase 1 studies (Study 1: 16 patients with PD receiving immediate-release CD/LD; Study 2: 18 healthy participants receiving extended-release CD/LD) assessing the effect of OPC 50 mg on LD pharmacokinetics (PK). Blood samples to assess LD PK and soluble-COMT (S-COMT) activity were collected before and after 14–15 days of once-daily OPC 50 mg. Pooled data on S-COMT inhibition were analyzed by participants’ baseline characteristics: disease state (PD vs healthy), sex (male vs female), ethnicity (Hispanic/Latino vs non-Hispanic/Latino), body mass index (&lt;25 vs ≥25), and baseline S-COMT activity. <h3>Results:</h3> OPC added to CD/LD decreased mean (95% CI) S-COMT activity by ≥80% in patients with PD and healthy participants (Study 1: 83.0% [80.5–85.4%]; Study 2: 80.1% [78.5–81.8%]; Pooled: 81.4% [80.0–82.9%]). Mean percent reduction in S-COMT activity was 79–85% for all subgroups in individual and pooled studies, although some subgroups had small numbers of participants. Variability in S-COMT activity was lower in all participants after OPC compared to baseline. <h3>Conclusions:</h3> Adding once-daily OPC 50 mg to CD/LD resulted in substantial S-COMT inhibition with reduced variability regardless of baseline characteristics. In all participants, COMT inhibition shown by OPC with CD/LD leads to more consistent daily LD exposure. <b>Disclosure:</b> Gordon Loewen has received personal compensation for serving as an employee of Neurocrine. Gordon Loewen has received stock or an ownership interest from Neurocrine. Gordon Loewen has received intellectual property interests from a discovery or technology relating to health care. Kurt Olson has received personal compensation for serving as an employee of Neurocrine Biosciences Inc. Kurt Olson has stock in Neurocrine Biosciences Inc. Dr. Liang has received personal compensation for serving as an employee of Neurocrine Biosciences. Dr. Liang has stock in Neurocrine Biosciences. Dr. Klepitskaya has received personal compensation for serving as an employee of Neurocrine Biosciences, Inc.