How opicapone works to counteract 'wearing-off'
Opicapone, marketed under the brand name Ongentys, is a potent and selective inhibitor of the enzyme catechol-O-methyltransferase, or COMT. In Parkinson's disease, the standard treatment with levodopa and a DOPA decarboxylase (DDC) inhibitor is crucial for replenishing dopamine levels in the brain. However, the COMT enzyme in the body can break down levodopa peripherally, reducing the amount that reaches the brain.
By blocking the COMT enzyme, opicapone ensures that more levodopa is available in the bloodstream for a longer period. This leads to more stable plasma levodopa levels, which in turn results in a more continuous supply of dopamine to the brain. This sustained effect is key to combating the "wearing-off" phenomenon, where the benefits of a levodopa dose diminish before the next one is due. Unlike some other COMT inhibitors, opicapone is peripherally selective and does not cross the blood-brain barrier.
Key clinical benefits for patients
Clinical studies have demonstrated several significant benefits of adding opicapone to a levodopa regimen for Parkinson's patients experiencing motor fluctuations. These benefits are categorized into improvements in motor symptoms, non-motor symptoms, and overall convenience of treatment.
Improved motor fluctuations
- Reduced off-time: Landmark clinical trials, including the BIPARK I and BIPARK II studies, showed that a 50 mg once-daily dose of opicapone significantly reduces the amount of daily "off" time compared to a placebo. Patients experienced a reduction of nearly an hour per day, which translates to a substantial improvement in their daily functioning.
- Increased on-time without troublesome dyskinesia: The reduction in "off" time corresponds to an increase in "on" time, meaning the patient's medication is working effectively for a longer duration. Crucially, this increase in "on" time did not lead to a significant increase in troublesome dyskinesia, or involuntary movements, a common concern with some dopaminergic therapies. In some cases, there was even a shift from "on" time with dyskinesia to "on" time without it, allowing for a better quality of motor control.
Improvement in non-motor symptoms
Beyond motor symptoms, opicapone has shown a positive impact on non-motor fluctuations, which are often debilitating for PD patients.
- Better mood and cognition: Studies have documented significant improvements in anxiety, depression, executive functions, and attention in patients treated with opicapone. Non-motor symptoms are a major contributor to a reduced quality of life, so addressing them can be very impactful for patients.
- Enhanced quality of life: Improvements in both motor and non-motor symptoms have led to a better overall quality of life, as measured by patient-reported questionnaires.
Convenient once-daily dosing
One of the most notable advantages of opicapone over other COMT inhibitors is its once-daily dosing schedule. Entacapone, for example, must be taken with every dose of levodopa, which can be burdensome for patients who take levodopa multiple times a day. Opicapone's long-lasting inhibitory effect on the COMT enzyme, which lasts for over 24 hours, allows for a single nightly dose, simplifying the medication regimen and improving adherence.
Comparison of COMT inhibitors
| Feature | Opicapone (Ongentys) | Entacapone (Comtan) | Tolcapone (Tasmar) |
|---|---|---|---|
| Dosing frequency | Once-daily at bedtime | With every levodopa dose (multiple times daily) | Multiple times daily |
| Effect duration | Long-acting (>24 hours) | Short-acting (~2 hours) | Long-acting |
| Hepatotoxicity risk | Low; not associated with severe hepatic impairment | Not associated with liver toxicity | High; associated with severe hepatic failure (black box warning) |
| Gastrointestinal side effects | Low incidence of diarrhea | Common; may cause diarrhea and urine discoloration | Frequent, including diarrhea |
| Dosing simplicity | High; single daily dose | Low; tied to levodopa dosing frequency | Medium; multiple daily doses |
Sustained long-term efficacy
Open-label extension studies, following the initial double-blind trials, have shown that the benefits of opicapone are maintained over at least one year of continuous use. Patients who continued on opicapone 50 mg sustained their reductions in "off" time, while those who switched from placebo or entacapone to opicapone saw further improvements. This suggests a durable, long-term effect for patients needing continuous management of motor fluctuations.
Conclusion
For patients with Parkinson's disease experiencing motor fluctuations and "off" episodes, opicapone offers a compelling and effective adjunctive treatment option. Its powerful, long-lasting peripheral COMT inhibition leads to more stable levodopa levels, resulting in significant reductions in "off" time and increases in functional "on" time. By requiring only a once-daily dose, opicapone substantially simplifies the treatment regimen compared to older COMT inhibitors like entacapone. Furthermore, its favorable safety profile and positive impact on non-motor symptoms like anxiety and cognition contribute to a notable improvement in overall quality of life for many patients. With its potent efficacy, convenient dosing, and good tolerability, opicapone is a valuable addition to the therapeutic strategies available for managing advanced Parkinson's disease.
