Adding opicapone to levodopa therapy in patients with Parkinson's disease (PD) experiencing motor fluctuations reduces "off" time by almost an hour and increases "on" time, without affecting the rate of troublesome dyskinesia, according to a new phase 3 study with an open-label extension.
Opicapone (Ongentys, BIAL) is "an efficacious compound" that is relatively safe and easy to take because it needs only once-a-day dosing as a result of its long duration of action, said study author Patricio Soares-da-Silva, MD, PhD, Department of Research and Development, BIAL, Porto, Portugal.
Motor fluctuations are a key factor limiting the effectiveness of dopamine medication. Patients fluctuate between "on" times, or periods when the medication is working and symptoms are controlled, and "off" times, when the medication isn't working, leading to decreased mobility.
Results with the drug were published online December 27 in JAMA Neurology.
Opicapone is a high-potency inhibitor of catechol O-methyltransferase (COMT). These inhibitors are involved in the metabolism of levodopa and dopamine; they increase levodopa's half-life in plasma, helping to boost and prolong the dopaminergic effects.
The new two-part multicenter study included 427 patients with PD (mean age, 63.1 years) who had been improving for at least a year on levodopa (and/or a dopa decarboxylase inhibitor) but had experienced signs of end-of-dose deterioration for at least 4 weeks. They had a mean total awake off-time (state of akinesia or decreased mobility) of at least 1.5 hours, excluding morning akinesia.
These patients were randomly assigned to receive oral opicapone at 25 mg/day or 50 mg/day, or matching placebo, for 14 to 15 weeks.
Depending on the group, the mean time since diagnosis for study participants ranged from 7.7 to 8.5 years. They had been receiving levodopa for a mean of 6.8 to 7.2 years. The mean daily levodopa dose was 700 to 806 mg, and the mean duration of wearing off was 3.0 to 3.2 years.
Patients used 24-hour diaries to record their status as off, on with troublesome dyskinesia, on with nontroublesome dyskinesia, on without dyskinesia, or asleep, for every 30-minute interval during the day for 3 consecutive days before each clinic visit.
Of those randomly assigned, 88.1% completed the double-blind phase of the study.
During this phase, the mean change in off-time was –64.5 minutes for the placebo group, –101.7 minutes for the 25-mg group, and –118.8 minutes for the 50-mg group. The adjusted mean change in absolute off-time was largest in the 50-mg group.
The adjusted treatment difference compared with the placebo group was significant for the 50-mg group (treatment effect, –54.3 minutes [95% confidence interval (CI), –96.2 to –12.4 minutes]; P = .008) but not for the 25-mg group.
That the lower dose reduced off-time but the difference with placebo wasn't significant might be due to the higher than expected placebo effects, according Dr Soares-da-Silva.
He also pointed out that there's usually a relationship between the amount of a drug taken and the benefit or effect it provides, "and this was the case with opicapone."
The Unified Parkinson Disease Rating Scale motor function and other scale-based measures, including nonmotor symptoms and quality of life, also improved during the double-blind phase, but there were no significant differences between the groups.
"This result may be because the patients were already receiving levodopa treatment for symptomatic control and the study was not designed and powered to address a potential differentiation in motor fluctuations," the authors write.
Another possibility, Dr Soares-da-Silva said, is that the effect of improved motor activity on quality of life may take time. "Usually, improvements in quality of life are not perceived by patients after a short time of treatment," he told Medscape Medical News.
Of those entering the open-label phase, 77.9% completed follow-up. The analysis here found that the off-time reduction was sustained during this year-long phase.
That most patients maintained the levodopa dose and dosing frequency from the end of the titration phase to the end of the study "can be considered an additional indicator of sustained control of motor fluctuations during the long term," note the authors.
Adverse Events Common
About two thirds of patients (68.6%) experienced at least one adverse event, usually mild or moderate in intensity. During the double-blind phase, the most common adverse events in the opicapone groups compared with the placebo group were dyskinesia, constipation, and dry mouth. Discontinuations due to adverse events were most frequent for the higher-dose opicapone group.
There were no relevant liver function findings in either phase.
Opicapone is approved for patients with PD in Europe but not in the United States. Only two COMT inhibitors — tolcapone and entacapone — are available in the United States.
Each of these latter COMT inhibitors has drawbacks. For tolcapone, it's possible liver toxicity, so although this drug reduces off-time by about as much as opicapone, it requires frequent laboratory checks, Dr Soares-da-Silva said.
As for entacapone, it requires frequent dosing. "Every time you take levodopa, you have to have entacapone," said Dr Soares-da-Silva. This drug also discolors urine, which may be a deterring factor for patients, he said.
A recent randomized, double-blind, controlled trial published online December 22 in Lancet Neurology, that compared opicapone, entacapone, and placebo in patients with PD taking levodopa showed that opicapone 50 mg was superior to placebo (mean difference in change in time in the off state from baseline, –60.8 minutes [95% CI, –97.2 to –24.4 minutes]; P = .0015) and noninferior to entacapone.
The current study was "well designed" and recruited patients "from a diverse population of patients representing 71 centers across 12 countries," Allison Boyle, MD, University of Texas Medical School, Houston, and colleagues, pointed out in an accompanying editorial.
However, they also noted that the study was restricted to patients with moderate PD. This, they said, raises the question of "how effective once-a-day opicapone dosage would be in late-stage PD with unpredictable off episodes and morning akinesia."
Once-daily dosing may increase patient adherence, allow "more sophisticated" levodopa adjustments requiring less frequent dosing, and could result in an "easier and practical treatment approach" for patients and clinicians, according to the editorial writers.
"The simplicity afforded by the once-daily administration means that addition of this drug will not further complicate the patients' current drug regimen," which helps position the drug "as a strong candidate for the adjunct treatment of motor fluctuations in PD," the study authors conclude.
Commenting on the study for Medscape Medical News, Michael S. Okun, MD, chairman, Department of Neurology, University of Florida, Gainesville, and medical director, Parkinson's Foundation, said the results suggest that opicapone likely will provide a beneficial alternative to other COMT drugs "in a select group" of patients with PD.
Patients with PD, said Dr Okun, "continue to yearn" for drugs that facilitate less frequent dopaminergic dosing but have the same "or even added" symptomatic improvement compared with currently available medicines.
Doctors have used COMT inhibitors for many years to try to "fill this gap," but this use has been limited by the need for frequent dosing, diarrhea, and dyskinesia, said Dr Okun.
"Opicapone has the advantage of once-daily dosing and it provides slightly more Parkinson 'on' time than entacapone," he said. "Not unexpectedly, dyskinesia emerged as the most worrisome side effect of this drug."
The study was supported by BIAL-Portela & Ca SA. Dr Soares-da-Silva reports being employed by BIAL-Portela & Ca SA. The editorial writers and Dr Okun have disclosed no relevant financial relationships.
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Cite this: Opicapone Helps Control Motor Fluctuations in Parkinson's - Medscape - Jan 06, 2017.