Opicapone May Reduce Off Time for Patients With Parkinson’s Disease

Administering 50 mg of opicapone as an adjunct to levodopa treatment decreases the amount of off time by approximately 61 minutes, compared with placebo, for patients with Parkinson’s disease and end-of-dose motor fluctuations, according to research published in the February issue of Lancet Neurology. Data indicate that the drug is safe, well tolerated, and noninferior to entacapone for this indication.

Opicapone is “the only once-daily catechol-O-methyltransferase (COMT) inhibitor to provide a mean reduction in time in the off state that is clinically relevant,” said Joaquim J. Ferreira, MD, Professor of Neurology and Clinical Pharmacology at the University of Lisbon, and colleagues. Administering the drug once daily could simplify a patient’s drug regimen by permitting the physician to decrease the total daily levodopa dose, increase the dosing interval, and reduce the number of intakes, thereby maximizing the benefit of therapy, he added.

Comparing Opicapone, Entacapone, and Placebo

The half-life of oral levodopa is between 60 and 90 minutes and is linked with end-of-dose motor fluctuations. COMT inhibitors increase the plasma elimination half-life of levodopa and decrease peak–trough variations. Entacapone, a COMT inhibitor, provides moderate reductions in daily off time, but needs to be administered with each dose of levodopa. Neurologists thus have sought a more effective COMT inhibitor that can be used easily in clinical practice.

Dr. Ferreira and colleagues assessed the safety and efficacy of opicapone as an adjunct to levodopa, compared with placebo and entacapone, in patients with Parkinson’s disease and motor fluctuations. Eligible participants had had a clinical diagnosis of Parkinson’s disease for at least three years, a Hoehn and Yahr stage of 1 to 3 during the on state, and at least one year of clinical improvement with levodopa treatment. People who had used entacapone previously, had significant dyskinesia disability, or had severe or unpredictable off periods were excluded from the study.

Equal groups of patients were computer randomized to once-daily opicapone (5 mg, 25 mg, or 50 mg), placebo, or 200 mg of entacapone with every levodopa intake. The participants and investigators were blinded to treatment allocation throughout the study. Opicapone capsules and entacapone tablets were overencapsulated to maintain blinding.

Doses of study drugs were given concomitantly with each levodopa intake. Patients in the opicapone groups received placebo for the daytime doses and active treatment for the bedtime dose. Patients in the entacapone group took the active treatment during the day and placebo as the bedtime dose. Investigators assessed participants at screening, baseline, and at five subsequent time points.

The study’s primary end point was the change from baseline to the end of study treatment in absolute off time, as assessed by daily patient diaries. Secondary end points included the change from baseline to the end of study treatment in the proportion of patients who had at least a one-hour reduction in absolute off time and the change from baseline to the end of study treatment in the proportion of patients who had at least a one-hour increase in absolute total on time.

For statistical analysis, population sets were defined as the full analysis set, which included all randomly assigned patients who took at least one dose of study drug and had at least one assessment of time in the off state after baseline; the per-protocol set, which included all patients in the full analysis set who did not have any major protocol deviations; and the safety set, which included all patients who received at least one dose of study drug.

Opicapone Was Noninferior to Entacapone

The researchers enrolled 600 patients, of whom 121 received placebo, 122 received 200 mg of entacapone, 122 received 5 mg of opicapone, 119 received 25 mg of opicapone, and 116 received 50 mg of opicapone. The full analysis included 590 patients, and the per-protocol analysis included 537 patients. In all, 542 patients completed the study. Patient demographics, baseline Parkinson’s disease characteristics, and treatment history did not differ between the treatment groups in the safety analysis.

In the full analysis, the adjusted mean change from baseline in absolute off time was –116.8 minutes in the opicapone 50 mg group, compared with –96.3 minutes in the entacapone group, –91.3 minutes in the opicapone 5 mg group, –85.9 minutes in the opicapone 25 mg group, and –56.0 minutes in the placebo group. The per-protocol analysis yielded similar results.

The investigators only tested the 50-mg dose of opicapone for noninferiority of absolute off time. This treatment was superior to placebo and noninferior to entacapone. The researchers found no significant differences between placebo and opicapone 5 mg or opicapone 25 mg. Entacapone was superior to placebo.

Compared with placebo, the proportion of patients with a reduction in off time of at least one hour was significantly higher in patient who received 25 mg or 50 mg of opicapone, and the proportion of patients with an increase in on time of at least one hour was significantly higher in patients who received 50 mg of opicapone. No significant differences were noted in off and on state rates for entacapone versus placebo. Results for the other secondary end points supported those of the primary analysis.

Adverse Events Were Uncommon

The percentage of patients who discontinued because of treatment-emergent adverse events was low and similar across the treatment groups. The most common treatment-emergent adverse events leading to discontinuation were diarrhea, visual hallucinations, and dyskinesia. Dyskinesia was the most frequently reported treatment-emergent adverse event possibly related to the study drug, and the highest incidence occurred in the opicapone groups. Approximately 80% of treatment-emergent dyskinesias occurred in patients in all groups who already had dyskinesia at baseline. The incidence of serious treatment-emergent adverse events was low (ie, 7% or less) in all groups, and 35% of these events were judged to be unrelated to the study drug.

“The beneficial effects of opicapone 50 mg at reducing the time in the off state were accompanied by a corresponding increase in time in the on state without troublesome dyskinesia, whereas the duration of time in the on state with troublesome dyskinesia did not change,” said Dr. Ferreira. The study results “suggest an overall positive risk-to-benefit ratio for the use of opicapone in patients with Parkinson’s disease with end-of-dose motor fluctuations,” he added. Results of the authors’ open-label extension study will be published in the future.

—Erik Greb

Administering 50 mg of opicapone as an adjunct to levodopa treatment decreases the amount of off time by approximately 61 minutes, compared with placebo, for patients with Parkinson’s disease and end-of-dose motor fluctuations, according to research published in the February issue of Lancet Neurology. Data indicate that the drug is safe, well tolerated, and noninferior to entacapone for this indication.

Opicapone is “the only once-daily catechol-O-methyltransferase (COMT) inhibitor to provide a mean reduction in time in the off state that is clinically relevant,” said Joaquim J. Ferreira, MD, Professor of Neurology and Clinical Pharmacology at the University of Lisbon, and colleagues. Administering the drug once daily could simplify a patient’s drug regimen by permitting the physician to decrease the total daily levodopa dose, increase the dosing interval, and reduce the number of intakes, thereby maximizing the benefit of therapy, he added.

Comparing Opicapone, Entacapone, and Placebo

The half-life of oral levodopa is between 60 and 90 minutes and is linked with end-of-dose motor fluctuations. COMT inhibitors increase the plasma elimination half-life of levodopa and decrease peak–trough variations. Entacapone, a COMT inhibitor, provides moderate reductions in daily off time, but needs to be administered with each dose of levodopa. Neurologists thus have sought a more effective COMT inhibitor that can be used easily in clinical practice.

Dr. Ferreira and colleagues assessed the safety and efficacy of opicapone as an adjunct to levodopa, compared with placebo and entacapone, in patients with Parkinson’s disease and motor fluctuations. Eligible participants had had a clinical diagnosis of Parkinson’s disease for at least three years, a Hoehn and Yahr stage of 1 to 3 during the on state, and at least one year of clinical improvement with levodopa treatment. People who had used entacapone previously, had significant dyskinesia disability, or had severe or unpredictable off periods were excluded from the study.

Equal groups of patients were computer randomized to once-daily opicapone (5 mg, 25 mg, or 50 mg), placebo, or 200 mg of entacapone with every levodopa intake. The participants and investigators were blinded to treatment allocation throughout the study. Opicapone capsules and entacapone tablets were overencapsulated to maintain blinding.

Doses of study drugs were given concomitantly with each levodopa intake. Patients in the opicapone groups received placebo for the daytime doses and active treatment for the bedtime dose. Patients in the entacapone group took the active treatment during the day and placebo as the bedtime dose. Investigators assessed participants at screening, baseline, and at five subsequent time points.

The study’s primary end point was the change from baseline to the end of study treatment in absolute off time, as assessed by daily patient diaries. Secondary end points included the change from baseline to the end of study treatment in the proportion of patients who had at least a one-hour reduction in absolute off time and the change from baseline to the end of study treatment in the proportion of patients who had at least a one-hour increase in absolute total on time.

For statistical analysis, population sets were defined as the full analysis set, which included all randomly assigned patients who took at least one dose of study drug and had at least one assessment of time in the off state after baseline; the per-protocol set, which included all patients in the full analysis set who did not have any major protocol deviations; and the safety set, which included all patients who received at least one dose of study drug.

Opicapone Was Noninferior to Entacapone

The researchers enrolled 600 patients, of whom 121 received placebo, 122 received 200 mg of entacapone, 122 received 5 mg of opicapone, 119 received 25 mg of opicapone, and 116 received 50 mg of opicapone. The full analysis included 590 patients, and the per-protocol analysis included 537 patients. In all, 542 patients completed the study. Patient demographics, baseline Parkinson’s disease characteristics, and treatment history did not differ between the treatment groups in the safety analysis.

In the full analysis, the adjusted mean change from baseline in absolute off time was –116.8 minutes in the opicapone 50 mg group, compared with –96.3 minutes in the entacapone group, –91.3 minutes in the opicapone 5 mg group, –85.9 minutes in the opicapone 25 mg group, and –56.0 minutes in the placebo group. The per-protocol analysis yielded similar results.

The investigators only tested the 50-mg dose of opicapone for noninferiority of absolute off time. This treatment was superior to placebo and noninferior to entacapone. The researchers found no significant differences between placebo and opicapone 5 mg or opicapone 25 mg. Entacapone was superior to placebo.

Compared with placebo, the proportion of patients with a reduction in off time of at least one hour was significantly higher in patient who received 25 mg or 50 mg of opicapone, and the proportion of patients with an increase in on time of at least one hour was significantly higher in patients who received 50 mg of opicapone. No significant differences were noted in off and on state rates for entacapone versus placebo. Results for the other secondary end points supported those of the primary analysis.

Adverse Events Were Uncommon

The percentage of patients who discontinued because of treatment-emergent adverse events was low and similar across the treatment groups. The most common treatment-emergent adverse events leading to discontinuation were diarrhea, visual hallucinations, and dyskinesia. Dyskinesia was the most frequently reported treatment-emergent adverse event possibly related to the study drug, and the highest incidence occurred in the opicapone groups. Approximately 80% of treatment-emergent dyskinesias occurred in patients in all groups who already had dyskinesia at baseline. The incidence of serious treatment-emergent adverse events was low (ie, 7% or less) in all groups, and 35% of these events were judged to be unrelated to the study drug.

“The beneficial effects of opicapone 50 mg at reducing the time in the off state were accompanied by a corresponding increase in time in the on state without troublesome dyskinesia, whereas the duration of time in the on state with troublesome dyskinesia did not change,” said Dr. Ferreira. The study results “suggest an overall positive risk-to-benefit ratio for the use of opicapone in patients with Parkinson’s disease with end-of-dose motor fluctuations,” he added. Results of the authors’ open-label extension study will be published in the future.

—Erik Greb

Administering 50 mg of opicapone as an adjunct to levodopa treatment decreases the amount of off time by approximately 61 minutes, compared with placebo, for patients with Parkinson’s disease and end-of-dose motor fluctuations, according to research published in the February issue of Lancet Neurology. Data indicate that the drug is safe, well tolerated, and noninferior to entacapone for this indication.

Opicapone is “the only once-daily catechol-O-methyltransferase (COMT) inhibitor to provide a mean reduction in time in the off state that is clinically relevant,” said Joaquim J. Ferreira, MD, Professor of Neurology and Clinical Pharmacology at the University of Lisbon, and colleagues. Administering the drug once daily could simplify a patient’s drug regimen by permitting the physician to decrease the total daily levodopa dose, increase the dosing interval, and reduce the number of intakes, thereby maximizing the benefit of therapy, he added.

Comparing Opicapone, Entacapone, and Placebo

The half-life of oral levodopa is between 60 and 90 minutes and is linked with end-of-dose motor fluctuations. COMT inhibitors increase the plasma elimination half-life of levodopa and decrease peak–trough variations. Entacapone, a COMT inhibitor, provides moderate reductions in daily off time, but needs to be administered with each dose of levodopa. Neurologists thus have sought a more effective COMT inhibitor that can be used easily in clinical practice.

Dr. Ferreira and colleagues assessed the safety and efficacy of opicapone as an adjunct to levodopa, compared with placebo and entacapone, in patients with Parkinson’s disease and motor fluctuations. Eligible participants had had a clinical diagnosis of Parkinson’s disease for at least three years, a Hoehn and Yahr stage of 1 to 3 during the on state, and at least one year of clinical improvement with levodopa treatment. People who had used entacapone previously, had significant dyskinesia disability, or had severe or unpredictable off periods were excluded from the study.

Equal groups of patients were computer randomized to once-daily opicapone (5 mg, 25 mg, or 50 mg), placebo, or 200 mg of entacapone with every levodopa intake. The participants and investigators were blinded to treatment allocation throughout the study. Opicapone capsules and entacapone tablets were overencapsulated to maintain blinding.

Doses of study drugs were given concomitantly with each levodopa intake. Patients in the opicapone groups received placebo for the daytime doses and active treatment for the bedtime dose. Patients in the entacapone group took the active treatment during the day and placebo as the bedtime dose. Investigators assessed participants at screening, baseline, and at five subsequent time points.

The study’s primary end point was the change from baseline to the end of study treatment in absolute off time, as assessed by daily patient diaries. Secondary end points included the change from baseline to the end of study treatment in the proportion of patients who had at least a one-hour reduction in absolute off time and the change from baseline to the end of study treatment in the proportion of patients who had at least a one-hour increase in absolute total on time.

For statistical analysis, population sets were defined as the full analysis set, which included all randomly assigned patients who took at least one dose of study drug and had at least one assessment of time in the off state after baseline; the per-protocol set, which included all patients in the full analysis set who did not have any major protocol deviations; and the safety set, which included all patients who received at least one dose of study drug.

Opicapone Was Noninferior to Entacapone

The researchers enrolled 600 patients, of whom 121 received placebo, 122 received 200 mg of entacapone, 122 received 5 mg of opicapone, 119 received 25 mg of opicapone, and 116 received 50 mg of opicapone. The full analysis included 590 patients, and the per-protocol analysis included 537 patients. In all, 542 patients completed the study. Patient demographics, baseline Parkinson’s disease characteristics, and treatment history did not differ between the treatment groups in the safety analysis.

In the full analysis, the adjusted mean change from baseline in absolute off time was –116.8 minutes in the opicapone 50 mg group, compared with –96.3 minutes in the entacapone group, –91.3 minutes in the opicapone 5 mg group, –85.9 minutes in the opicapone 25 mg group, and –56.0 minutes in the placebo group. The per-protocol analysis yielded similar results.

The investigators only tested the 50-mg dose of opicapone for noninferiority of absolute off time. This treatment was superior to placebo and noninferior to entacapone. The researchers found no significant differences between placebo and opicapone 5 mg or opicapone 25 mg. Entacapone was superior to placebo.

Compared with placebo, the proportion of patients with a reduction in off time of at least one hour was significantly higher in patient who received 25 mg or 50 mg of opicapone, and the proportion of patients with an increase in on time of at least one hour was significantly higher in patients who received 50 mg of opicapone. No significant differences were noted in off and on state rates for entacapone versus placebo. Results for the other secondary end points supported those of the primary analysis.

Adverse Events Were Uncommon

The percentage of patients who discontinued because of treatment-emergent adverse events was low and similar across the treatment groups. The most common treatment-emergent adverse events leading to discontinuation were diarrhea, visual hallucinations, and dyskinesia. Dyskinesia was the most frequently reported treatment-emergent adverse event possibly related to the study drug, and the highest incidence occurred in the opicapone groups. Approximately 80% of treatment-emergent dyskinesias occurred in patients in all groups who already had dyskinesia at baseline. The incidence of serious treatment-emergent adverse events was low (ie, 7% or less) in all groups, and 35% of these events were judged to be unrelated to the study drug.

“The beneficial effects of opicapone 50 mg at reducing the time in the off state were accompanied by a corresponding increase in time in the on state without troublesome dyskinesia, whereas the duration of time in the on state with troublesome dyskinesia did not change,” said Dr. Ferreira. The study results “suggest an overall positive risk-to-benefit ratio for the use of opicapone in patients with Parkinson’s disease with end-of-dose motor fluctuations,” he added. Results of the authors’ open-label extension study will be published in the future.

—Erik Greb