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Safety Profile of Opicapone in the Management of Parkinson's Disease

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Safety Profile of Opicapone in the Management of Parkinson's Disease 733 Safety Profile of Opicapone in the Management of Parkinson’s Disease Andrew Leesa, Joaquim J. Ferreirab,c, Jose´-Francisco Rochad, Olivier Rascole, Werner Poewef , d d,g,h,∗ Helena Gama and Patr´ıcio Soares-da-Silva a University College London, Reta Lila Weston Institute, London, UK bInstituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Portugal cCNS – Campus Neurolo´gico Se´nior, Torres Vedras, Portugal d Department of Research and Development, BIAL – Portela & Ca SA, S. Mamede do Coronado, Portugal eDepartment of Clinical Pharmacology and Neurosciences, INSERM and University Hospital of Toulouse, Toulouse, France f Department of Neurology, Innsbruck Medical University, Innsbruck, Austria gDepartment of Pharmacology and Therapeutics, Faculty of Medicine, University Porto, Porto, Portugal hMedInUP, Center for Drug Discovery and Innovative Medicines, University Porto, Porto, Portugal Abstract. Background: Opicapone is a catechol O-methyltransferase (COMT) inhibitor indicated for use as adjunct to levodopa therapy in patients with Parkinson’s disease (PD) and motor fluctuations. Objective: To characterize the safety and tolerability of adjunct opicapone (25 and 50 mg) in a pooled population of levodopa- treated PD patients who participated in the opicapone Phase-3 clinical program. Methods: Patient-level data (placebo, opicapone 25 mg and 50 mg) from the BIPARK-1 and BIPARK-2 double-blind and open-label studies were combined. Results: Pooled analyses included 766 patients from the double-blind studies and 848 patients from the open-label studies. In the double-blind studies, 63.3% of opicapone-treated patients reported treatment-emergent adverse events (TEAEs) versus 57.2% in the placebo group. The most common TEAEs reported in the opicapone group compared to placebo were dyskinesia, constipation and insomnia. The incidence of serious TEAEs was similar across opicapone and placebo groups (3.5% versus 4.3%, respectively). Overall, 71.3% patients treated with open-label opicapone reported at least one TEAE; most occurred within the first 2 months of the open-label studies, and then decreased thereafter. Throughout the Phase-3 clinical program, there were no serious AEs suggestive of hepatic toxicity, and the incidence of gastrointestinal disorders such as nausea and diarrhea remained low (<2%). There were no relevant changes in laboratory parameters including liver enzymes, vital signs, physical or neurological examinations, or ECG readings. Conclusions: Long-term use of opicapone once-daily over 1-year at doses of 25 mg or 50 mg was generally safe and well tolerated, supporting its clinical usefulness in the management of PD motor fluctuations. Keywords: Clinical trials, motor fluctuations, opicapone, Parkinson’s disease, safety INTRODUCTION Opicapone is a third generation, catechol O- ∗Correspondence to: Professor P. Soares-da-Silva, Department methyltransferase (COMT) inhibitor that was of Research and Development, BIAL, A Av. da Siderurgia approved in 2016 by the European Union for use as Nacional, 4745-457S. Mamede do Coronado, Portugal. Tel.: adjunctive therapy to preparations of L-DOPA/DOPA +351 229866100; Fax: +351 229866192; E-mail: psoares.silva@ bial.com. decarboxylase inhibitors (DDCIs) in adult patients 734 with Parkinson’s disease (PD) and end-of-dose day, excluding pre-dose morning akinesia. Patients motor fluctuations who cannot be stabilized on those with clinically significant and unstable cardiovascu- combinations [1]. The preclinical development of lar disease or psychiatric illnesses (including major opicapone was based on a rational, analogue-based depression, dementia, impulse control disorders, and research approach and was specifically designed to suicide ideation) or with relevant liver disease or reduce the risk of toxicity and improve peripheral transaminase levels greater than 2x the upper nor- tissue selectivity compared with other COMT mal limit (ULN) were excluded. Concomitant stable inhibitors [2]. treatment for PD was allowed, with the exception The efficacy, safety and tolerability of opicapone of tolcapone, apomorphine (withdrawn≥ 1 month given once daily as adjunct to levodopa has been before screening), and entacapone (other than that established in two large randomized clinical trials supplied for BIPARK-1). (BIPARK-1 [3] and BIPARK-2 [4]) and their Both double-blind studies assessed the safety and associated open-label extension studies [4, 5]. Taken tolerability of opicapone 25 mg and 50 mg versus together, they provide safety data for up to 1 year placebo [3, 4]. However, BIPARK-1 was an active for 848 patients. Similarities in the design of the controlled study and included an additional enta- two double-blind, randomized, placebo-controlled capone arm, and a low dose (5 mg) opicapone arm studies and their extensions permit a pooled analysis (not relevant in the present analyses) [3]. The open- to provide further information on the safety and label studies began the day after completing the tolerability of opicapone and were an important double-blind phase, and continued until the patient component of the approval process in Europe [6]. had completed 52 weeks of open-label treatment. Moreover, Olanow et al recently proposed that Patients started open-label treatment with the 25 mg adverse event (AE) safety reporting in PD trials dose, and could be up-titrated to 50 mg if greater should also include information regarding the symptomatic control was required. In cases dopamin- temporal profile of the AE’s reported, particularly ergic adverse events (AEs), the levodopa dose was dyskinesia [7]. The aim of this pooled analysis was to be adjusted first, followed by opicapone down- to provide a comprehensive overview of the safety titration in those with persisting AEs [4, 5]. Adverse of opicapone, including more information on the event reporting was collected at every visit through- temporal profile of potentially treatment-related out the studies. Laboratory and vital sign tests were AEs, in a pooled population of levodopa-treated performed at screening, baseline, day 14 or 21 and patients experiencing motor fluctuations. monthly thereafter up to end-of-study/early discon- tinuation visit. METHODS Analysis BIPARK-1 [3] and BIPARK-2 [4] were random- ized, double-blind placebo-controlled studies, full Patient-level data from matching treatment arms details of which have been published. Both were in the double-blind studies (placebo, opicapone followed by open-label extension studies which fol- 25 mg and opicapone 50 mg) and all treatments from lowed patients for up to a year of treatment [4, 5]. their open-label extensions was combined and ana- All four studies were conducted in accordance with lyzed using descriptive data. Safety was assessed Good Clinical Practice and the provisions of the by incidence of treatment-emergent adverse events International Conference on Harmonization and were (TEAEs), laboratory parameters, ECGs and vital sponsored by BIAL - Portela & Ca, S.A. signs. In accordance with European Medical Agency Study designs guidelines [8], we predefined the following TEAEs as being of special interest to COMT inhibitors or In brief, both studies recruited adult (aged 30–83 Parkinson’s disease: psychosis, depressive events, years) patients with a 3-year diagnosis of idiopathic sleep disorders, orthostatic hypotension, serious hep- PD and a Hoehn and Yahr stage between 1–3 during atic events, severe diarrhea, myocardial infarction, ON. For the double-blind studies, eligible patients increased creatine phosphokinase (CPK), impulse had to be receiving 3–8 daily doses of levodopa control disorders and/or melanoma. For the double- for at least 1 year and experiencing end-of-dose blind studies, we also performed an analysis of motor fluctuations with ≥1.5 hours of OFF-time per changes in hepatic laboratory parameters, including 735 aspartate and alanine transaminases (AST and ALT), their parkinsonian symptoms. Most patients (>88%) alkaline phosphatase (ALP), total bilirubin (TBL) had a co-morbid illness, the most common were and gamma-glutamyl transferase (GGT) using the musculoskeletal and connective tissue disorders (e.g. last observation carried forward (LOCF) approach to osteoporosis and osteoarthritis) and psychiatric dis- account for missing data. orders (e.g. anxiety, depression). Finally, we performed post-hoc subgroup analysis comparing the double-blind safety of opicapone in Double-blind phase the elderly (aged 70 years) and non-elderly (<70 ≥ years old) populations. In the double-blind studies, 63.3% (n = 322) of patients in the opicapone groups reported a TEAE RESULTS compared to 57.2% (n = 147) in the placebo group. Most TEAEs were mild or moderate in intensity. Patient disposition and baseline characteristics The only TEAEs which occurred in≥ 5% of patients in either opicapone group and were more common Of the 1027 patients randomized to the two double- with active treatment versus placebo were: dyskine- blind studies, 766 patients took a dose of relevant sia, constipation, insomnia and dry mouth (Table 2). study medication (509 patients received opicapone Most TEAEs occurred early (Fig. 2) and were mostly 25 mg or 50 mg, 257 received placebo) and were transient. Dyskinesia was the most frequent TEAE, included in the double-blind analysis (Fig. 1). The but the incidence of severe cases was low (opi- open label analysis included all 848 patients enrolled capone 1.2% vs. placebo 0.8%) and most dyskinetic to open-label treatment who took at
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