Redefining the strategy for the use of COMT inhibitors in Parkinson’s disease: the role of opicapone

ABSTRACT

Introduction

Levodopa remains the gold-standard Parkinson’s disease (PD) treatment, but the inevitable development of motor complications has led to intense activity in pursuit of its optimal delivery.

Areas covered

Peripheral inhibition of dopa-decarboxylase has long been considered an essential component of levodopa treatment at every stage of illness. In contrast, only relatively recently have catechol-O-methyltransferase (COMT) inhibitors been utilized to block the other major pathway of degradation and optimize levodopa delivery to the brain. First and second-generation COMT inhibitors were deficient because of toxicity, sub-optimal pharmacokinetics or a short duration of effect. As such, they have only been employed once ‘wearing-off’ has developed. However, the third-generation COMT inhibitor, opicapone has overcome these difficulties and exhibits long-lasting enzyme inhibition without the toxicity observed with previous generations of COMT inhibitors. In clinical trials and real-world PD studies opicapone improves the levodopa plasma profile and results in a significant improvement in ON time in ‘fluctuating’ disease, but it has not yet been included in the algorithm for early treatment.

Expert opinion

This review argues for a shift in the positioning of COMT inhibition with opicapone in the PD algorithm and lays out a pathway for proving its effectiveness in early disease.

KEYWORDS:

• COMT
• enzyme inhibition
• levodopa
• motor fluctuations
• non-motor fluctuations
• opicapone
• Parkinson’s disease
• wearing-off

Article highlights

• When levodopa is administered with a dopa decarboxylase inhibitor (DDCI), peripheral levodopa metabolism is shunted to the catechol O-methyl transferase (COMT) pathway, and <10% of levodopa crosses into the brain.

• Opicapone is a third generation COMT inhibitor rationally designed to reduce the risk of toxicity and improve COMT inhibitory potency and peripheral tissue selectivity compared with other COMT inhibitors.

• Opicapone has sub-picomolar binding affinity to S-COMT in peripheral tissues where its tight binding and slow complex dissociation characteristics mean that its COMT inhibitory activity is prolonged and outlasts the clearance of the drug from the systemic circulation.

• Administration of opicapone as an adjunct to levodopa/DDCI increases levodopa plasma bioavailability (AUC) and trough levels (C_min) with lesser effect on peak levels (C_max).

• The efficacy and safety of opicapone in reducing OFF time in patients with Parkinson’s disease and established motor fluctuations is well established in randomized clinical trials and observational studies.

• This article sets out the clinical trial pathway for proving effectiveness in earlier ‘stable’ disease.

Acknowledgments

The authors thank Anita Chadha-Patel and Elizabeth Hocking of ACP Clinical Communications Ltd (funded by BIAL) for medical writing support (literature searching, referencing and editing) in the development of this report.

Reviewer disclosures

A reviewer on this paper is a scientific advisor and has received shares/financial compensation from and KeiferX (co-founder), Sun Pharmaceuaticals Research Industry, Neumentum and Jupiter Orphan Therapeutics. They are also an inventor on a number of Georgetown University Patents to use tyrosine kinase inhibitors and USP13 inhibitors to treat neurodegenerative diseases. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Declaration of interest

P Jenner has received honoraria for consultancy and advisory boards from AbbVie, Adamas, Bial, Britannia Pharmaceuticals, FP Pharmaceuticals, Kyowa Kirin, Roche, UCB, Worldwide Clinical Trials, Zambon, Chiesi Pharmaceuticals and Profile Pharma. J Ferreira and O Rascol have participated in clinical trials sponsored by Bial and have received honoraria for consultancy and advisory boards from Bial. In addition, J Ferreira has received grants from GlaxoSmithKline, Grunenthal, Fundação MSD (Portugal), TEVA, Allergan, Novartis, Medtronic and consultancy fees from GlaxoSmithKline, Novartis, TEVA, Lundbeck, Solvay, BIAL, Merck-Serono, Merz, Ipsen, Biogen, Acadia, Allergan, Abbvie, Sunovion Pharmaceuticals, Zambon, Neuroderm and Affiris. O Rascol has acted as a scientific advisor for drug companies developing antiparkinsonian medications (Abbott, Abbvie, Acorda, Adamas, Affiris, Biogen, Britannia, Cynapsus, Denali Pharmaceuticals, Impax, Lundbeck, Merck, Neuroderm, Novartis, Orian Pharma, Osmotica, Oxford-Biomedica, Prexton, Servier, Sunovion, TEVA, UCB, Zambon) and has received unrestricted scientific grants from academic non-profit entities (Toulouse University Hospital, French Health Ministry, MJFox Foundation, France-Parkinson, European Commission EU FP7 and Horizon 2020). JF Rocha and P Soares-da-Silva are employed by Bial. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Additional information

Funding

This paper was supported by BIAL, who employs two of the authors and procured medical writing support. No author received any remuneration for the preparation of this article.