Once-Daily Opicapone Adds 'On Time' in PD Phase 3 Studies

Damian McNamara

May 06, 2019

PHILADELPHIA — The peripheral catechol-O-methyltransferase (COMT) inhibitor opicapone in development increased "on time" in people with Parkinson's disease (PD) without causing troublesome dyskinesia in new research.

Investigators compared once-daily opicapone (BIA9-1067) to placebo in two phase 3 studies. One of the studies also included entacapone (Comtan, Novartis, plus generics). At the end of the 14-to-15 week study, patients receiving a target dose of opicapone experienced a mean additional 2 hours of on time compared with baseline.

Combined findings from the BIA9-1067 in Idiopathic Parkinson's Disease Patients (BIPARK) -1 and -2 studies were presented here at the American Academy of Neurology (AAN) 2019 Annual Meeting.

"Total improvement of responders was 65% versus placebo, so more than two thirds had improved on-time response" in the double-blind phase of the study, lead author Peter A. LeWitt, MD, professor of neurology at Wayne State University School of Medicine and director of the Parkinson's Disease and Movement Program at Henry Ford Hospital in West Bloomfield, Michigan, said at the meeting.

Opicapone and other COMT inhibitors block an enzyme that breaks down levodopa, helping to increase and extend levodopa's dopaminergic effects. "None of the clinically available COMT inhibitors achieves 100% inhibition of the enzyme," LeWitt said, suggesting there remains a need for additional agents in the class.

Double-Blind Studies

In the double-blind phase of the BIPARK-1 study, 119 people were assigned to 5 mg opicapone, 116 to the 25-mg dose, 115 to the 50-mg dose, and 120 to placebo.

LeWitt presented the 50-mg dose findings here at the AAN meeting. This dose group experienced an increase from baseline to week 14 or 15 in absolute on time without dyskinesia versus placebo. The least-squares mean change was 1.9 ± 0.2 hours in this treatment group versus 0.9 ± 0.2 hours with placebo, and the difference was significant (P = .002).

In BIPARK-2, researchers assigned 125 participants to 25 mg opicapone, 147 to 50 mg, and 135 to placebo. Investigators observed an increase of 1.7 ± 0.3 hours of absolute on time with opicapone 50 mg versus 0.9 ± 0.3 hours in the placebo group (P = .025).

"As your patients will tell you, any improvement in on time is important. And the increased on time was not at the price of troublesome dyskinesias," LeWitt told meeting attendees.

Once-daily dosing of opicapone distinguishes it from the other COMT inhibitors in the class, such as entacapone or tolcapone (Tasmar, Bausch Health, plus generics), each of which require multiple doses per day.

The 50-mg dose of opicapone emerged as the most effective. The BIPARK studies "had results showing consistently improved on time on home PD diary data, with the 50-mg once-daily opicapone dose compared with lower doses and compared with the entacapone regimen," LeWitt told Medscape Medical News.  

People who completed the 14- to 15-week double-blind treatment were eligible for the 1-year open-label phase. Mean changes from the double-blind phase baseline to the endpoint of the open-label study in 494 participants treated with any dose of opicapone was 2.0 ± 2.6 hours in BIPARK-1. Among the 339 participants in BIPARK-2, this increase was 1.8 ± 3.2 hours.

Dyskinesia as a treatment-emergent adverse event (TEAE) was reported in 17.4% of all opicapone-treated participants compared with 6.2% of the placebo cohort in a pooled, double-blind safety population of 631 participants. "In the study you can report this as a side effect, but more than half of patients came with dyskinesias [at baseline]," LeWitt said.

Discontinuations because of dyskinesia as a TEAE occurred in 1.9% of the opicapone group and 0.4% of the placebo group. Discontinuations because of serious dyskinesia occurred in 0.3% of the opicapone group and 0% of the placebo group.

Mechanism of Action Questioned

A meeting attendee asked about the mechanism of action — specifically, how opicapone increases on time without causing dyskinesias.

"There is probably a window or therapeutic range for improvement of levodopa without meeting the threshold in every patient for dyskinesia," LeWitt responded. "Obviously, if you went too high in this patient population, dyskinesias would have occurred," he added. "It shows you the tailoring of the pharmacokinetics seems to have been successful for keeping patients away from troublesome dyskinesias."

"You almost seem to have identical peaks and troughs of the levodopa levels if I understood that correctly," another meeting attendee commented. He asked why opicapone as a once-daily, long-acting agent did not produce "more of a plateau effect."

"Good question," LeWitt responded. "Levodopa is a unique drug in that it has a threshold effect — nothing really happens below the 1000 ng/mL concentration — and a full effect is achieved whether you get to 1000 ng/mL, 1500 ng/mL, or 2000 ng/mL."

The metabolism and clearance of levodopa occur through multiple mechanisms, he added. Therefore, COMT inhibitors only address "one of the metabolic factors that govern the pharmacokinetics."

"So what you're seeing is...levodopa modulated to some extent in its clearance phase," he said. "It's an improvement over non-COMT inhibition, but it's not the same as a continuous infusion. You're absolutely right about that."

"Both studies are well designed, well conducted, and had positive results," session moderator Tanya Simuni, MD, chief of movement disorders, department of neurology, and professor of neurology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois, told Medscape Medical News when asked to comment on the research.

"I don't have any relationship with the company, but I anticipate the drug will get approved," she said.

The once-daily dosing is an advantage, Simuni said. Entacapone, by contrast, is administered up to five times per day, generally in conjunction with carbidopa-levodopa, she added.

"My question stands: How meaningful are the data? Because 1 hour of additional on time is considered to be meaningful. However, unfortunately, it does not differentiate it from a number of other adjunctive therapies," she added. "That is strictly my opinion."

The study was sponsored by Neurocrine Biosciences. LeWitt and Simuni have reported no relevant financial relationships.

American Academy of Neurology (AAN) 2019 Annual Meeting. Abstract #S4.003. Presented May 5, 2019.

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