Ongentys (Opicapone): A New COMT Inhibitor for the Treatment of Parkinson’s Disease

Objective To describe the safety and efficacy of opicapone, a newly Food and Drug Administration–approved catechol- O-methyltransferase (COMT) inhibitor, as an adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease (PD) experiencing off episodes. Data Sources A literature search through PubMed and International Pharmaceutical Abstracts (January 2000 to October 2020) was conducted using the following search terms: Ongentys, opicapone, COMT inhibitor, Parkinson’s disease, and Parkinson’s. Study Selection and Data Extraction Articles selected included those describing preclinical and clinical studies examining the pharmacokinetics, efficacy, and/or safety of opicapone. Data Synthesis In preclinical trials, opicapone demonstrated marked S-COMT inhibition, despite its short half-life, while maintaining an acceptable safety and efficacy profile. Results from phase 3 clinical trials further supported the safety and efficacy of opicapone as an adjunct to levodopa. In addition, opicapone, at a dose of 50 mg once daily, was shown to be superior to placebo and noninferior to entacapone in reducing time spent in the off state. Adverse effects commonly reported with opicapone include dyskinesias, constipation, hypotension/syncope, increased blood creatine kinase, and decreased weight. Relevance to Patient Care and Clinical Practice Additional medications, such as COMT inhibitors, become necessary adjunctive treatments as the disease progresses. Compared to other COMT inhibitors currently on the US market, opicapone offers the advantage of once-daily dosing. Conclusion Opicapone is a safe and effective COMT inhibitor shown to reduce off episodes in patients with PD.

3 The dopaminergic balancing act: a literature review of a novel COMT inhibitor opicapone with a focus on the risk of visual hallucinations

AimsParkinson’s Disease (PD) medications are well-evidenced for improving motor symptoms. However, often a balancing act is required to ameliorate positive neuropsychiatric symptoms, such as visual hallucinations (VH). Opicapone, a novel COMT inhibitor, has been shown by BIPARK-1 and BIPARK-2 studies to improve wearing-off phenomena but little is known about associated neuropsychiatric symptoms. The aim of this literature review was to investigate any association between opicapone and VH.MethodsA literature review was undertaken on the 18th July 2019 using PubMed, Ovid (using key resources of Embase, Ovid MEDLINE, Global Health and PsycINFO), Web of Science and Scopus. The search terms used were ‘Parkinson’s Disease’ and ‘Opicapone’. The search included full-texts, abstracts, conference abstracts and posters.ResultsThe initial search produced 398 articles; 391 were excluded. Of the 7 articles reviewed there were two randomised controlled trials (RCTs) (BIPARK-1 and -2), two observational studies, two post-hoc analyses of BIPARK-1 and -2, and one retrospective analysis. BIPARK-1 reported VH in 1% of the entacapone group, 8% opicapone 25 mg group and 4% of the opicapone 50 mg group. BIPARK-2 did not report on VH in their randomised phased and reported VH in 0.8% of opicapone patients in their open-label phase but without specifying the associated dose.Chaudhuri et al.’s (2018) post-hoc analysis of BIPARK-1 reported VH in 8% of COMT- naive patients given opicapone, vs. 1% of those given entacapone. Lees et al.’s (2019) post-hoc analysis of BIPARK-1 & -2 reported VH in 4.6% of patients receiving opicapone who were ≥70 years old, vs 0.6% in those younger. Gandor et al.’s (2018) prospective observational study reported VH in 14.8% of patients given opicapone.ConclusionsSeveral factors limit the conclusions drawn about the risk of VH in patients taking opicapone. The RCTs were designed and powered to assess ‘on-off’ phenomena and didn’t include patients >65 or with a psychiatric history. This also limits their post-hoc analyses’ generalisability. The more ‘real-world’ observational studies were small and only available in abstract form with limited details. Lees et al.’s (2019) post-hoc analysis nevertheless reported a higher incidence of VH in the older age group, which is concordant with known risk factors for neuropsychiatric adverse events. Further investigation is required, focusing on older patients and those with a psychiatric history or cognitive impairment.

Development of a PC12 cell-based assay forin vitroscreening of catechol-O-methyltransferase inhibitors

ABSTRACTThe male rat adrenal pheochromocytoma cell-originated PC12 cell line can synthesize and release catecholamine neurotransmitters, and it has been widely used as a model system in cell biology and toxicology research. Catechol-O-methyltransferase (COMT) is involved in the inactivation of the catecholamine neurotransmitters, and it is particularly important for theregulation of dopamine. In this study, we explored the feasibility of using PC12 cells as anin vitrodrug screening platform to compare the activity of multiple COMT inhibitors. Incubation of PC12 cells with tolcapone, a highly potent and selective COMT inhibitor, increased the concentrations of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) while reducing the metabolites 3-methoxytyramine (3-MT) and homovanillic acid (HVA) in the cell culture medium. LIBD-3, a novel, non-nitrocatechol COMT inhibitor produced similar effects compared to tolcapone. LIBD-4, a less potent inhibitor, exhibited the expected right-shift in functional inhibition in the assay. These results match the knownin vivoeffects of COMT inhibition in rodents. Together, these data support the continued use of PC12 cells as anin vitroscreen that bridges cell-free enzyme assays and more costlyin vivoassays.

Novel, non-nitrocatechol COMT inhibitors modulate dopamine neurotransmission in the frontal cortex and improve cognitive flexibility

Cognitive impairment is a primary feature of many neuropsychiatric disorders and there is a need for new therapeutic options. Catechol-O-methyltransferase (COMT) inhibitors modulate cortical dopaminergic function and have been proposed as potential cognitive enhancers. Unfortunately, currently available COMT inhibitors are not good candidates due to either poor blood-brain barrier penetration or severe toxicity. To address the need for safe, brain-penetrant COMT inhibitors, we tested multiple novel COMT inhibitors in a set of preclinical in vivo efficacy assays to determine their viability as potential clinical candidates. We found that multiple COMT inhibitors, exemplified by LIBD-1 and LIBD-3, significantly modulated dopaminergic function measured as decreases in homovanillic acid (HVA) and increases in 3,4-Dihydroxyphenylacetic acid (DOPAC), two dopamine metabolites, in cerebrospinal fluid (CSF) and the frontal cortex. Additionally, we found the LIBD-1 significantly improved cognitive flexibility in a rat attentional set-shifting assay (ASST), an effect previously seen with the COMT inhibitor tolcapone. These results demonstrate that LIBD-1 is a novel COMT inhibitor with promising in vivo activity and the potential to serve as a new therapy for cognitive impairment.