Introduction
The success of levodopa used together with other antiparkinsonian drug classes means that most patients living with Parkinson’s disease (PD) enjoy a good quality of life for many years [
1,
2]. Nevertheless, the long term therapeutic response is marred in many by the emergence of disabling fluctuations and dyskinesias [
3,
4] that lead to a reduced quality of life and motor handicap [
2,
5]. Wearing-off results from levodopa’s short duration response which reflects the amino acid’s short half-life (~ 60–90 min) [
6]. Over time, patients will experience more and more hours per day in a disabling OFF-state and some will develop intrusive and adventitious involuntary movements [
7].
Current treatment guidelines consider adjunctive treatment with catechol-
O-methyltransferase (COMT) inhibitors, dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors, as efficacious to reduce OFF time in patients treated with levodopa/dopa decarboxylase inhibitor (DDCI) therapy [
8‐
10]. In routine practice, many physicians will also consider various formulations of levodopa (e.g. controlled-release and extended-release preparations) as well as dosing manipulations to increase the dose and/or dosing frequency of levodopa. COMT inhibitors have been an established first-line strategy to manage motor fluctuations for over 25 years [
11‐
14], and are the only adjunct class to directly address the peak-trough variations in plasma levodopa levels that clinically manifest as wearing-off fluctuations [
15]. The third generation COMT inhibitor – opicapone (Ongentys®, BIAL-Portela & Cª, S.A. Portugal) – has been approved in Europe since 2016 as adjunct therapy to preparations of levodopa/DDCI for end-of-dose motor fluctuations. Based on rational drug design, opicapone was specifically developed to reduce the risk of toxicity and improve peripheral tissue selectivity [
16]. In one pharmacokinetic study, opicapone (50 mg once daily) significantly increased levodopa bioavailability compared with both placebo and entacapone (200 mg TID) by increasing substantially the trough plasma levels and each dose systemic exposure time (half-life) by at least 1 h [
17]. Phase III studies have established that treatment with opicapone 50 mg once daily reduces daily OFF-time, without significantly increasing ON-time with troublesome dyskinesia versus placebo, and most patients show an improvement in the Clinician’s Global Impression of Change (CGI-C) [
18,
19].
While placebo-controlled trials remain the gold standard in assessing response to a therapeutic intervention, alone they do not provide sufficient information of clinical effectiveness and safety. Many regulators and payers now encourage the supplementation of randomized controlled trials with other forms of evidence, such as ‘real-world’ studies [
20,
21]. The aim of this study was to evaluate the change in the patient’s perception about his/her global PD condition (as assessed by CGI-C) after 3 months of routine treatment in clinical practice with once-daily opicapone 50 mg.
Discussion
Taken overall, the results of this large open-label study in PD patients with motor fluctuations are the first to confirm the effectiveness, safety and tolerability of once daily opicapone 50 mg as used in routine clinical practice. The majority of patients showed improvements in their perception about global PD condition (≥70% as judged by clinicians and the patients themselves) 3 months after they started treatment with opicapone 50 mg. Treatment was generally well-tolerated and adverse events were as expected for a dopaminergic therapy in patients with PD.
While randomized controlled studies are often criticized as recruiting patients who might best meet study endpoints [
27], this large study mirrored a clinical setting population by allowing the inclusion of a broader population of fluctuating PD patients, including patients with Hoehn and Yahr Stage IV. It is of interest to note that more patients were judged to have shown clinical improvement in this real life study than had been reported in the pivotal trials (71.3% in this study vs. 59.6% in the combined pivotal studies [
28]). Even more notable was the proportion of patients who were judged as much/very much improved (43.0% in this study vs 25.2% in the combined pivotal studies [
28]). These judgements made by the investigators were corroborated by the patients themselves with 40.5% patients reporting they were much or very much improved after 3 months treatment with opicapone 50 mg. Treatment with opicapone was also associated with a small but significant improvement in overall quality of life, as assessed using the PDQ-8. As also observed from the pivotal studies [
18,
19], there was a proportion of patients who did not respond well to adjunct therapy with opicapone. Studies with entacapone have shown that the response to COMT inhibition is modulated by the COMT Val158Met polymorphism, with significantly enhanced efficacy in patients with the COMT (HH) genotype [
29]. The impact of the COMT genotype on the opicapone response is unknown and merits further study.
Despite optimized anti-PD therapy (according to clinician’s judgement) and the fact that most (78.8%) patients were receiving levodopa plus another PD medication, UPDRS motor and ADL scores significantly improved (by 4.6 and 3.0 points, respectively) with opicapone as adjunct therapy. These magnitudes of effects have been reported to be clinically significant [
30‐
32] and may therefore indicate that treatment with opicapone, not only increases ON time, but also improve the quality of ON time. Non-motor symptoms are now acknowledged as an important source of disability and contributor to worse quality of life for people living with PD [
33,
34]. In line with prior pivotal studies with opicapone, this study also hinted towards an overall improvement in non-motor symptoms [
18,
19]. Some non-motor domains are known to correlate with the motor OFF-state and be dopa-responsive [
35,
36] – with the implication that optimization of the pharmacokinetic and pharmacodynamic profile of levodopa with opicapone may be beneficial in their management. As recently suggested by Fabbri et al. [
37], the effect of opicapone on various non-motor symptoms merits further investigation.
Patients in this study maintained their levodopa dose for up to 6 months with sustained benefits in symptomatic control. Similar observations have also been seen in the 1-year-long extensions of the pivotal studies [
28,
37,
38]. This hints at a possible long-term delay of need for levodopa increase.
Opicapone 50 mg was generally well-tolerated, with the majority of events reported as mild or moderate in severity. While the most common reason for withdrawal from the study was adverse events (17.0%), the causes were diverse, with the most frequent (nausea) affecting only 2% of patients (
n = 10). While differences in study duration and settings make comparisons difficult, similar discontinuation rates due to AEs were reported in open-label studies with entacapone [
39,
40]. Although dyskinesia was reported as a TEAE in 11.5% of patients, only five patients (1%) discontinued from the study due to dyskinesia. The rate of serious TEAEs considered at least possibly related to treatment was low (1.4%). One death was reported; the 69 year old male patient died due to severe endocarditis which was considered by the investigator not to be related to the study medication.
Strengths of this study lie in its size, broad inclusion criteria and routine practice setting. Although this study permitted inclusion of a broad range of disease severities (Hoehn and Yahr I-IV), we did not capture sufficient data in this pragmatic study to analyze by subgroups. Other weaknesses include those inherent to open-label studies without placebo control, where both the clinician and patient have expectations from treatment. Also, the study was only conducted in two countries (UK and Germany) and all patients were white Caucasian. We did not study OFF and ON time since patient diaries carry significant patient burden [
41], which we wanted to minimize in this routine practice study.
Acknowledgements
We thank the study staff and patients involved in the trial. Medical writing support (literature searching, preparation of tables, styling of the manuscript) was provided by Dr. Anita Chadha-Patel (ACP Clinical Communications) funded by BIAL.
OPTIPARK Study Investigators group: Germany: Csaba Antal Zolnai, Claudius Bartels, Andreas Barth, Kriemhild Barth, Stephan Behrens, Arnfin Bergmann, Ralf Bodenschatz, Rommy Born,Moriz Brandt, Sebastian Brock, Bernd Brockmeier, Christof Brücke, Norbert Brüggemann, Bernhard Bühler, Uwe Bungard, Lukas Cepek, Ilona Csoti, Max Deist, Carl Detlev Reimers, Ulrich Dölle, Sylke Domke, Imanuel Dzialowski, Georg Ebersbach, Heike Eggert, Karla Eggert, Reinhard Ehret, Jana Engel, Urban Fietzek, Anke Friedrich, Michael Fritzinger, Florin Gandor, Klaus Gehring, Stephan Gierer, Stephanie Gierer, Vasil Gjaurov, Doreen Gruber, Özkan Günes, Thomas Haas, Kirsten Hahn, Anna Eszter Haraszti, Rolf Hartmann, Bernhard Haslinger, Eva Heiss, Heinz P. Herbst, Frank Hoffmann, Werner E. Hofmann, Günter Höglinger, Wolfgang Jost, Anna-Maria Kavcic, Christoph Kellinghaus, Bertold Klemperer, Fabian Klostermann, Thomas Knoll, Natalia Koleva-Alazeh, Jiri Koschel, Diana Waltraud Kraft-Safavi, Almut Kronenberger, Andrea Kühn, Andreas Kupsch, Thomas Lehnhoff, Peter Laumen, Paul Lingor, Karla Lippmann, Michael Lorrain, Fabian Maass, Siegfried Muhlack, Thomas Müller, Michael Nagel, Stephan Neudecker, Katja Odin, Christian Oehlwein, Hakan Orbasli, Wolfram von Pannwitz, Heidi Pape, Robert Pfister, Tino Prell, Reinhard Puzich, Daniela Rau, Rene Reese, Gerd Reifschneider, Gernot Reimann, Stefani Ries, Christoph Rieth, Charlotte Rewitzer, Ali Safavi, Alexander B. Schmied, Johannes Schwarz, Wolfgang Schwarz, Joachim Springub, Inga Suttrup Claus, Vera Tadic, Klaus Tiel-Wilck, Lars Tönges, Jens Tröger, Christoph Schrey, Alexander Schulze, Sven Thonke, Tobias Wächter, Achim S. Wannenmacher, Tobias Warnecke, Bettina Wieder, Martin Wimmer, Christian Winkler, Otto Witte, Dirk Woitalla, Samis Zella, Uwe Ziebold. UK: Jane Alty, Reem Amin, Michaela Boca, Stephen Butterworth, Camille Carroll, Gavin Charlesworth, K. Ray Chaudhuri, Rajkumar Chinnadurai, Jemima Collins, Jeremy Stephen Cosgrove, Samantha Cravey, Dinesh Damodaran, Nikolay Dimitrov, Rory Durcan, Simon Ellis, Adbdul Elmarimi, Jonathan Evans, James Fisher, Donald Grosset, Stuart Jamieson, Christopher Kobylecki, Sze Hway Lim, Veronica Lyell, Biju Mohamed, Sophie Molloy, Nicola Pavese, Dominic Paviour, Madeleine Purchas, Khalid Rashed, Christopher Rickards, Tabish Saifee, Gillian Sare, Christine Schofield, Naveen Setty, Jagdish Sharma, Ray Sheridan, Siew Lee Shu, Monty Silverdale, Rani Sophia, Sarah Statton, Malcolm Steiger, Christopher Thomas, Richard Walker, Tai Yen Foung.