A phase 3 trial examined the safety and effectiveness of adjunctive opicapone in patients with Parkinson disease treated with levopoda.
Adjunctive opicapone is effective and safe in levodopa-treated patients with Parkinson disease (PD) who are experiencing end-of-dose motor fluctuations, according to a phase 3 trial published online in JAMANeurology.
“Treatment with opicapone effectively reduced off-time and increased on-time without increasing the frequency of troublesome dyskinesia, and this benefit was maintained for at least 1 year of therapy without increasing the levodopa dose,” wrote corresponding author Patricio Soares-da-Silva, MD, of BIAL–Portela & Ca SA, and colleagues with the BIPARK-2 Study.
The study further found that 50 mg/day but not 25 mg/day of opicapone significantly decreased off-time compared to placebo.
“The magnitude of treatment effect with the 50-mg/d dosage of opicapone is considered clinically relevant, with approximately 1 hour of reduction in off-time,” the authors added.
While catechol-O-methyltransferase (COMT) inhibitors are standard therapy for treating end-of-dose motor fluctuations related to levodopa therapy, available drugs in this class result in only moderate improvement, or increase the risk for liver toxicity. Opicapone is a new COMT inhibitor with once daily dosing, and was designed to strongly inhibit COMT and decrease toxicity.
The double-blind, placebo-controlled trial included 427 patients with PD (60.4% men, 39.6% women). Participants had end-of-dose deterioration and a mean total awake off-time of at least 1.5 hours (excluding morning akinesia).
Researchers randomized 129 participants to adjunctive therapy with 25 mg/day opicapone, 154 participants to 50 mg/day opicapone, and 144 participants to placebo for 14 to 15 weeks. Of 376 participants who finished the double-blind phase (88.1% of randomized participants), 286 (77.9%) completed a one-year open-label phase in which all patients received active opicapone. Patients started at opicapone 25 mg/day and were titrated up to 50 mg/day as necessary.
Patients self-reported symptoms in 24-hour diaries. The double-blind phase took place from March 2011 to June 2013 at 71 centers in 12 countries. The open label phase took place at 64 sites.
Double-blind phase results:
• Change in off-time: Reduced with opicapone
♦ Placebo: −64.5 minutes
♦ 25 mg/day opicapone: −101.7 minutes
♦ 50 mg/day opicapone: −118.8 minutes
• Adjusted treatment difference vs placebo:
♦ 25-mg/d opicapone treatment effect: −37.2 minutes; (P=0.11)
♦ 50 mg/day opicapone treatment effect: −54.3 minutes (P=0.008)
• Change in on-time: Increased with opicapone
♦ Placebo: 58.7 minutes
♦ 25 mg/day opicapone: 104.1 minutes
♦ 50 mg/day opicapone: 111.3 minutes
♦ Improvement in on-time was mostly without troublesome dyskinesias
• Common adverse events for opicapone vs placebo: dyskinesia, constipation, dry mouth
Open-label phase results:
• Mean total off-time decreased by 18.31 minutes
• Mean total on-time increased by 24.9 minutes
The authors noted that the placebo response (64.5 minutes) was much higher than expected (30 minutes). That may suggest that the study was not large enough to detect significant differences between 25 mg/day opicapone and placebo.
They also highlighted the lack of liver toxicity with opicapone and emphasized that treatment was not associated with diarrhea, which is considered a class effect of COMT inhibitors.
“The simplicity afforded by the once-daily administration means that addition of this drug will not further complicate the patients’ current drug regimen, while allowing more sophisticated adjustments to the levodopa regimen that are harder to achieve, in practice, when giving levodopa in a combined pill with a COMT inhibitor,” they concluded.
• A double-blind, randomized, placebo-controlled, multinational study found that opicapone decreased off-time and increased on-time in levodopa-treated patients with Parkinson disease who are experiencing end-of-dose motor fluctuations.
• The treatment effect was significant only for opicapone 50 mg/day but not for opicapone 25 mg/day.
• Opicapone was well tolerated without liver toxicity or diarrhea.
• Advantages of opicapone include once daily dosing and a favorable safety profile.
The study was supported by BIAL-Portela & Ca SA
One or more authors reports personal fees, other funding, consulting, honoraria, lecture fees, and/or grants from one or more of the following: BIAL–Portela & Ca SA, Reta Lila Weston Institute of Neurological Studies, University College London, and Institute of Neurology, Britannia Pharmaceuticals, PSP Association, Weston Trust, The Reta Lila Howard Foundation, UCB, Roche, Novartis, Boehringer Ingelheim, Lundbeck, GE Healthcare, Teva, GSK, Ipsen, Allergan, Orion, Bial, AbbVie Lucid, Nordiclnfu Care, GlaxoSmithKline, Novartis, Lundbeck, Solvay, Abbott, BIAL, Merck-Serono, Merz, Ipsen, and Biogen, Biogen, Grunenthal, MSD, Allergan, FundaÃ§Ã£o MSD (Portugal), AbbVie, BIA, Boston Scientific, Ipsen, Medtronic, MSD, Merck-Serono, Merz Pharmaceuticals, Orion Pharma, Zambon, Abbvie, Mundipharma, Sanofi, Servier, XÃ©noPort, GSK, Institut National de la SantÃ© et de la Recherche Medicale–DHOS, Michael J Fox Foundation, Programme Hospitalier de Recherche Clinique, and/or Recherche Clinique Translationnelle.
Ms McCrory reports being employed by Quintiles. Mr Rocha and Dr Soares-da- Silva are employees of BIAL–Portela & Ca SA.
Reference: Lees AJ, et al. for the BIPARK-2 Study Investigators. Opicapone as adjunct to levodopa therapy in patients with Parkinson disease and motor fluctuations: a randomized clinical trial. JAMA Neurol. 2016 Dec 27.