Time to Revisit Off-Label COMT Use?

PHILADELPHIA — Early adjuvant use of opicapone (Ongentys) may reduce the risk for complications in patients with early Parkinson’s disease (PD) and no motor complications.

The US Food and Drug Administration approved opicapone, a once-daily peripheral catechol-O-methyltransferase (COMT) inhibitor, in 2020 as add-on therapy to reduce “off” periods in patients with PD on a stable levodopa/carbidopa regimen.

For the EPSILON study, however, investigators compared off-label opicapone with placebo for 24 weeks in patients with PD and no motor complications, followed by a 1-year extension phase during which all patients received the drug. Participants had PD for 5 years or less and were on a stable regimen of levodopa and a dopa decarboxylase inhibitor.

Patients were randomly assigned to receive either once-daily opicapone 50 mg (n = 177) or placebo (n = 178). Of these participants, 163 (92%) and 159 (89%), respectively, completed the 24-week, double-blind phase.

Topline results released in 2023 showed only that opicapone was superior to placebo for the primary endpoint of Movement Disorders Society–Unified PD Rating Scale (MDS-UPDRS) Part III (motor score) and did not increase motor complications, as measured by the MDS-UPDRS Part IV.

EPSILON international principal investigator Joaquim Ferreira, MD, PhD, director, Laboratory of Clinical Pharmacology and Therapeutics, University of Lisbon, Lisbon, Portugal, fleshed out details and provided longer-term results in a clinical breakthrough session at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2024.

Sustained Effect

Specifically, the least-squares mean change from baseline in the MDS-UPDRS Part III after 24 weeks was −6.5 in the opicapone group vs −4.3 in the placebo group.

The 2.2-point difference was statistically significant (P = .010) and falls within the minimal clinically important difference range of 1.5-2.4 points, based on data in the literature, he said. “So it’s in the range of what we may consider clinically relevant.”

The open-label extension phase included 120 patients who were started on opicapone first and 126 patients who switched from placebo to opicapone at the end of the double-blind phase. The primary efficacy endpoint was change in MDS-UPDRS Part IV (motor complications) from open-label baseline to week 52.

The least-squares mean change from baseline in the MDS-UPDRS Part III (motor score) at 1 year was −0.6 in opicapone-first group and −2.1 in the placebo-opicapone group (difference, 1.3 points; P = .196).

Although not statistically significant, “numerically, patients that started first on opicapone seemed to do better,” Ferreira said, adding that there was a sustained effect over 1 year.

Further, and to the researchers’ surprise, patients in the placebo-opicapone group had a higher risk for motor complications than those in the opicapone-first group during both the double-blind phase (9.7% vs 5.5%) and open-label phase (15.6% vs 11.6%), he said.

The change from open-label baseline in MDS-UPDRS Part IV total score was not significantly different between groups at either 6 months (difference, −0.1 point; P = .220) or 1.5 years (difference, −0.1 point; P = .721).

“Earlier and longer opicapone exposure clearly did not increase the risk of motor complications in this clinical trial scenario,” Ferreira said.

The most common treatment-emergent adverse events (TEAEs) in the opicapone-first group at the end of the open-label period were “on” and “off” phenomenon, dyskinesia, dizziness, and falls. Overall, the incidence of these TEAEs was 2%.

There were five serious TEAEs leading to death in the opicapone-first group vs none in the placebo-opicapone group, and six vs four TEAEs, respectively, leading to withdrawal. No further details were provided.

Ferreira said the results reopen the discussion about whether there is a benefit of adding opicapone or another COMT inhibitor in patients without motor fluctuations and “also reopens the discussion about treating patients at an early stage.”

Clinically Meaningful?

Following the presentation, discussant Tanya Simuni, MD, director, Parkinson’s Disease and Movement Disorders Center, Northwestern Feinberg School of Medicine, Chicago, said the biggest question is whether the two-point difference in motor scores favoring opicapone at 6 months is clinically meaningful.

She also pointed to the placebo effect in the study, resulting in a four-point gain in motor scores at 6 months. “Placebo is a great drug in Parkinson’s disease.”

Finally, Simuni asked whether 18 months is sufficient to really comment on the impact of adjunctive therapy on time to onset of motor complications. “Again, these are not critical comments of the study, it’s for discussion of the group,” she said.

Another discussant said the motor effect of opicapone is very clear but one might get that same effect with just more levodopa and suggested that an additional study with a longer observation period may be necessary to determine whether opicapone truly delays motor complications.

Ferreira replied that adding 50 mg of opicapone is not the same as adding 50 mg of levodopa to a patient’s regimen. “We are playing with the total levodopa dose, and we are playing with the levodopa pharmacokinetics in the blood that then converts to the brain,” he said.

“Is 16 months enough? Probably not, but are we able to conduct many more trials for more than 2 years, 3 years? Probably not. So we need to make decisions based on the data we have,” said Ferriera.

Worth Considering

Commenting for Medscape Medical News, Matthew B. Stern, MD, session co-chair and emeritus professor of neurology, University of Pennsylvania, Philadelphia, said “it’s debatable whether a 2.2-point difference [in motor scores] is a clinically meaningful difference but I think what’s interesting is that we don’t have a standard of care for treating patients with early disease.”

“There’s still some debate about how to treat with the long-term outcome in mind,” he added. “This study suggests that patients may do better and may actually have a lower risk of motor fluctuations, which is what we’ve been looking for in an early therapy for years. If that turns out to be true, then it would make sense to start patients earlier on levodopa with a COMT inhibitor.”

Stern also questioned the idea of simply increasing levodopa doses. “The pharmacodynamics are different,” he said. “If you up the levodopa, you get more intermittent plasma peaks, but if you add a COMT inhibitor, you get a smoother pharmacokinetic profile.”

He pointed out that a lot of new subcutaneous therapies, for example, are aimed at giving the body a continuous level of levodopa in patients with PD, which can actually treat motor fluctuations and complications.

“The whole idea is continuous dopaminergic stimulation, and if we can do that with an oral drug, even imperfectly, it might translate into a better long-term response,” Stern said. “I think what this study showed is that you’re certainly doing no harm, you might be doing some improvement, so certainly worth considering.”

The study was funded by Neurocrine Biosciences. Ferreira was a steering committee member for the clinical development of opicapone and received payments for consultancy, advisory boards, and grants from Neurocrine, Abbott, AbbVie, AFFiRiS, Allergan, Angelini, BIAL, Biogen, Fundação MSD (Portugal), GlaxoSmithKline, Grünenthal, Ipsen, Lundbeck, Medtronic, Merck Serono, Merz, MSD, and Nordic Infucare. Simuni and Stern reported having no relevant conflicts of interest.