Early Opicapone Initiation in Parkinson Leads to Continued Long-Term Therapeutic Benefits

A recently published post-hoc analysis of two phase 3 studies (BIPARK-I; BIPARK-II) showed that earlier initiation of opicapone (Ongentys), a COMT inhibitor, led to significant reductions in OFF time and improvements in ON time among patients with recently diagnosed Parkinson disease (PD).¹

The pooled analysis featured 227 patients with PD who completed one of the BIPARK, double-blind, placebo-controlled trials of opicapone and their 1-year open-label extensions (OLEs). Coming into these trials, which had double-blind periods lasting 14-15 weeks, most participants were being treated with 3 to 5 levodopa doses at baseline, and most were treated with at least 1 concomitant PD medication.

Overall, results revealed that treatment with opicapone at 50 mg doses significantly reduced absolute daily OFF time, with least square (LS) placebo-adjusted treatment effects of –65.5 (95% CI, –105.5 to –25.6) minutes (P = .0014) favoring the therapy. Encouragingly, reductions in OFF time were also mirrored by significant increases in good ON time, with placebo-adjusted treatment effects of 88.3 (95% CI, 47.0-129.6) minutes, and ON time in general (placebo-adjusted treatment effect, 84.8; 95% CI, 45.3-124.2).

“These findings broaden the evidence base for COMT inhibition across all stages of fluctuating PD, suggesting a potential benefit for adding opicapone earlier (within 2 years of motor fluctuations onset),” lead author Joaquim Ferreira, MD, PhD, director of the Labortory of Clinical Pharmacology and Therapeutics at the University of Lisbon, and colleagues, wrote.

In the double-blind portions of the studies, significant differences favoring opicapone were observed on Unified Parkinson Disease Rating Scale (UPDRS)-Activities of Daily Living (ADL) scores (LS mean placebo-adjusted differences, –1.4; 95% CI, –2.6 to –0.2; P =.002). Additionally, while not significant, opicapone-treated participants demonstrated more favorable outcomes on UDPRS motor scores (–1.3; 95% CI, –3.1 to 0.5; P = 0.2). Notably, a greater number of patients on opicapone reported improvement across Patient Global Impression-Change (67.5% vs 55.0%) and Clinician Global Impression-Change (70.1% vs 51.8%) scales.

“Prospective, long-term studies in PwP with early fluctuations are warranted,” the study authors added. “Our observations support the importance of recognizing wearing-off symptoms early and optimizing treatment promptly to maximize long-term benefits.”

Opicapone, an adjunctive therapy to levodopa/carbidopa in patients with PD, was first introduced in the EU in 2016 and in the United States a few years later (2020). The drug acts by inhibiting peripheral COMT, one of the key enzymes that metabolizes levodopa in the periphery into 3-0-methyldopa. By blocking COMT, opicapone reduces levodopa breakdown, increases circulating levodopa exposure, and prolongs levodopa’s clinical effect, which can translate into reduced OFF time and more stable ON time.

Among the original cohort from BIPARK I and II (n = 535), 228 patients entered the OLE, where additional data was collected. Here, investigators observed that those who switched from placebo in the double-blind phase to opicapone had reductions in mean OFF time (–58.8; 95% CI, –98.1 to –19.4 minutes) and increases in ON time (67.7; 95% CI, 28.3-107.0 minutes) after around 4 weeks of open-label opicapone treatment.

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Additional data from the OLE phase showed that after 1 year of opicapone treatment, those who transitioned to the therapy had an adjusted mean SE reduction of –45.6 (±15.8) min of OFF time (–120.5 [±16.3] vs double-blind baseline) and a mean increase of 54.5 (±15.3) min of ON-time (116.2 [±16.1] min vs. double-blind baseline). Among those who continued on with opicapone from the double-blind phase, these patients maintained symptomatic effect, based on diary results.

Despite clinically meaningful improvements after participants in the placebo-opicapone (PBO-OPC) arm switched to active treatment, their outcomes did not fully converge with those who received OPC throughout. By the end of the open-label follow-up, the OPC-OPC group continued to trend toward less OFF time compared with the PBO-OPC group, with a mean treatment difference of −30.0 minutes (95% CI, −74.8 to 14.8) versus double-blind baseline (P = 0.2). Similarly, participants randomized to OPC-OPC spent more time in the ON state than those in the PBO-OPC group, with a mean treatment difference of 43.8 minutes (95% CI, −0.7 to 88.2) versus double-blind baseline (P = 0.05).

Changes in Good ON time closely mirrored those seen in total ON-time, suggesting that most of the ON-time gain reflected better-quality motor time rather than problematic fluctuations (Table 2). Overall, mean ON-time with troublesome dyskinesia (bad ON-time) remained largely unchanged across the open-label phase. That said, among participants who already had dyskinesia at double-blind baseline, responses appeared more variable over time, reflected by larger standard errors, compared with those without baseline dyskinesia.

REFERENCE
1. Ferreira JJ, Stocchi F, Antonini A, et al. Early start of opicapone in Parkinson’s disease: evidence from a pooled analysis of phase 3 trials for sustained benefit in patients with recent onset of motor fluctuations. Front Neurol. 2025;16. doi:10.3389/fneur.2025.1715748