Opicapone 50mg capsules

There has been a steadily growing armamentarium of drugs for the symptomatic treatment of Parkinson's disease (PD). Consequently, as various various pharmaceutical agents are used, it has become more difficult to perform and compare clinical trials with different medication regimens. Given that levodopa remains the gold standard treatment, conversion factors have been proposed to calculate l-dopa equivalent doses (LEDs) for each drug to facilitate comparison of medication regimens. Adding up LEDs of each drug leads to a daily total LED that is artificial but feasible and—if used as a standard scheme—comparable internationally. Since the last widely accepted proposal of LEDs for PD drugs by Tomlinson et al.,1 there has been no update. We hereby propose LED conversion factors for opicapone and safinamide, which are currently missing, but urgently needed, in ongoing clinical trials and observational studies. Opicapone is a new peripheral catechol-O-methyl transferase (COMT) inhibitor. Tomlinson et al. have proposed a conversion ratio, rather than a conversion factor, for inhibitors of COMT activity, by considering the mode of action of these drugs in terms of prolongation of the duration of the coadministered l-dopa treatment. The suggested ratio for entacapone is 0.33 × LD (coadministered l-dopa dose); the suggested ratio for tolcapone is LD × 0.5, respectively.1 For opicapone, we suggest a ratio higher than for entacapone, given that our literature search (see Supporting Information S1) and clinical experience suggest that opicapone is slightly more efficacious than entacapone.2 However, there are no intriguing data suggesting that opicapone might be more efficient than tolcapone3; we therefore propose using the same ratio for calculating the LED of opicapone as is used for tolcapone (LD × 0.5). Safinamide is mainly a reversible monoamine oxidase-B (MAO-B) inhibitor. Other proposed mechanisms likely play no relevant additional role concerning l-dopa equivalence. For safinamide, we propose an LED of 100 mg, independently of the actual administered dose, given that full reversible inhibition of MAO-B activity is already reached in the lowest commercially available preparations of safinamide.4 In the previous scheme,1 this would make safinamide equivalent to 1 mg of rasagiline and 10 mg of oral selegiline. All existing LED proposals (including our current additions) are based on clinical experience and empirical approaches. They pooled together studies by individual researchers, which provided sparse and inconsistent data. Consequently, these proposals are neither objective nor inherently scientific. To the best of our knowledge, there has not been a thorough evaluation so far. There needs to be a critical retrospective discussion on whether calculating LED reflects what we ought to measure and whether conclusions drawn from these calculations are valid. This pseudo-validity remains the major limitation of calculating LEDs. In conclusion, we believe that our proposed conversions fit reasonably well into the previous scheme of conversion factors (Table 1) and still sufficiently reflect the potential of both drugs. However, they follow the same limitations as the previous proposals.1 Prospectively, the LED conversion factor scheme needs a global reassessment with an attempt to use more objective measurements (using validated rating scales, adjusting for placebo, etc.) and thereby allowing the inclusion of new agents. We thank Anne-Marie Williams for language editing and formatting the manuscript. We thank Joaquim Ferreira for his valuable input and for reviewing an earlier version of the manuscript (including detailed results and conclusions of our literature search). (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript: A. Writing of the First Draft, B. Review and Critique. S.S.: 1A, 1B, 1C, 2A, 2B B.M.: 1C, 2B C.T.: 1A, 2B Ethical Compliance Statement: The authors confirm that the approval of an institutional review board or patient consent was not required for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest. Financial Disclosures for previous 12 months: S.S. has received salaries from the EU Horizon 2020 research and innovation program under grant agreement No. 634821 and from the Deutsche Forschungsgemeinschaft (DFG) under grant agreement No. MO 2088/5-1. B.M. has received honoraria for consultancy from Roche, Biogen, UCB, and Sun Pharma Advanced Research Company. B.M. is a member of the executive steering committee of the Parkinson Progression Marker Initiative and PI of the Systemic Synuclein Sampling Study of the Michael J. Fox Foundation for Parkinson's Research and has received research funding from the Deutsche Forschungsgemeinschaft (DFG), EU (Horizon2020), Parkinson Fonds Deutschland, Deutsche Parkinson Vereinigung, and the Michael J. Fox Foundation for Parkinson's Research. C.T. has received honoraria for consultancy from Britannia and Roche and for educational lectures from UCB. She has received research grants from the Michael J. Fox Foundation for Parkinson's Research and the EU (Horizon2020). She holds patents for the treatment of dyskinesia in PD with oxycodone/naloxone and the PDSS-2 Scale as well as publishing royalties for a book for PD patients published in Schattauer Verlag, Germany, 2015. Supporting Information Material S1. Methods, results, and references for literature search. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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BACKGROUND: Catechol-O-methyl transferase (COMT) inhibitors are routinely used to manage motor fluctuations in Parkinson's disease (PD). We assessed the effect of opicapone on motor symptom severity in levodopa-treated patients without motor complications. METHODS: This was a randomized, double-blind, 24-week, placebo-controlled study of opicapone 50 mg as adjunct to levodopa (NCT04978597). Levodopa-treated patients without motor complications were randomized to 24 weeks of double-blind treatment with adjunct opicapone 50 mg or matching placebo. The primary efficacy endpoint was the mean change from baseline to week 24 in Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) total score. RESULTS: A total of 355 patients were randomized (opicapone 50 mg n = 177, placebo n = 178) and 322 (91%) completed the double-blind period. The adjusted mean [95% CI] change from baseline to week 24 in MDS-UPDRS-III subscore was -6.5 [-7.9, -5.2] in the opicapone group versus -4.3 [-5.7, 3.0] in the placebo group resulting in a significant difference of -2.2 [-3.9, -0.5] favoring opicapone (p = 0.010). There was no difference in the incidence of patients who developed motor complications (5.5% with opicapone vs. 9.8% with placebo) and the incidence of adverse events considered related to study medication was similar between groups (opicapone 10.2% vs. placebo 13.5%). CONCLUSIONS: Treatment with once-daily adjunct opicapone was well tolerated, improved motor severity, and did not induce the development of motor complications. These results support the clinical usefulness of opicapone in the management of PD patients without motor complications.

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BACKGROUND: Levodopa-carbidopa intestinal gel infusion (LCIG) is an effective therapy for advanced Parkinson's disease (PD). Opicapone (OPC) is an enzyme inhibitor that enhances the bioavailability of levodopa in the brain. OBJECTIVES: This study evaluates the effect of Opicapone addition in PD-LCIG patients, assessing its impact on motor fluctuations and dyskinesias. Secondly, the study analyses the impact of OPC on non-motor symptoms, LCIG dosage, and peripheral neuropathy. METHODS: In this pilot study, 22 PD patients on LCIG were randomized to receive OPC or not, based on persistent or reemergent fluctuations. The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Unified Dyskinesia Rating Scale (UDysRS), Montreal Cognitive Assessment (MoCA), electroneurography (ENG), LCIG doses, homocysteine, vitamin B12, and folic acid levels were measured at baseline (T0) and after 12 months (T1). RESULTS: Eleven patients added OPC (addOPC group), while 11 maintained standard treatment (nOPC group). At baseline, both groups had similar disease duration and severity. At T1, the addOPC group showed significant: (i) improvement in motor fluctuations evaluated by the MDS-UPDRS part IV; (ii) reduction in dyskinesias (UDyRS); (iii) decrease in LCIG infusion rate; (iv) improvement in motor and non-motor symptoms (MDS-UPDRS parts I-III); (v) increase in Vitamin B12. No significant differences were observed in the ENG data, and no serious adverse events occurred. Four addOPC patients (36%) discontinued OPC after 15 ± 2 months, mainly due to hallucinations. CONCLUSIONS: OPC addition appeared well tolerated and beneficial in reducing motor fluctuations, dyskinesia, and LCIG dose. Randomized controlled trials are needed to confirm these findings.

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Background: In levodopa‐treated individuals with Parkinson’s disease (PD) and end‐of‐dose motor fluctuations, the BIPARK‐I randomized controlled trial (RCT) demonstrated that opicapone is noninferior to entacapone in reducing OFF‐time. Furthermore, the BIPARK‐II RCT demonstrated that opicapone is well tolerated and significantly reduces OFF‐time compared with placebo. This study developed a cost‐effectiveness model (CEM) of opicapone compared with entacapone from the perspective of the English National Health Service (NHS) and personal social services (PSS). Methods: The CEM used a Markov model with three health states, including “<25% OFF‐time,” “≥25% OFF‐time,” and “dead,” as individuals spending less than 25% of their awake time experiencing OFF‐time have previously been shown to have a significantly improved health‐related quality of life and to accumulate fewer healthcare costs. The CEM had a 25‐year time horizon, expressed costs as 2021/22 Great British Pounds (GBPs), and health outcomes as quality‐adjusted life years (QALYs). Both costs and health outcomes were discounted at 3.5% annually, and a cost‐effectiveness threshold of £20,000 per QALY was used. Probabilistic sensitivity analysis (PSA) considered parameter uncertainty. Results: The deterministic base case indicates that an individual treated with opicapone accrues fewer costs and more QALYs compared with each entacapone comparator and, therefore, is considered cost‐effective. The PSA indicates that the probability that opicapone is cost‐effective ranges from 87.2% to 98.0%, depending on the choice of entacapone comparator. Conclusions: Opicapone is cost‐effective when compared with entacapone for levodopa‐treated PD patients experiencing end‐of‐dose motor fluctuations. Trial Registration: ClinicalTrials.gov identifier: NCT01568073

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INTRODUCTION: In BIPARK-1 and BIPARK-2, addition of once-daily opicapone to levodopa/carbidopa significantly reduced daily "OFF"-time relative to placebo in adults with Parkinson's disease (PD) and motor fluctuations. Diary data from these studies were pooled and analyzed post hoc to characterize "OFF"-times around nighttime sleep and to explore the effects of opicapone 50 mg. METHODS: "OFF" before sleep (OBS), "OFF during the nighttime sleep period" (ODNSP), early morning "OFF" (EMO), and duration of nighttime sleep and awake periods were analyzed descriptively at baseline. Mean changes from baseline to Week 14/15 (end of double-blind treatment) were analyzed using two-sided t-tests in participants with data for both visits. RESULTS: At baseline, 88.3 % (454/514) of participants reported having OBS (34.0 %), ODNSP (17.1 %), or EMO (79.6 %). Those with ODNSP had substantially shorter mean duration of uninterrupted sleep (4.4 h) than the overall pooled population (7.1 h). At Week 14/15, mean decrease from baseline in ODNSP duration was significantly greater with opicapone than with placebo (-0.9 vs. -0.4 h, P < 0.05). In participants with ODNSP at baseline, the decrease in total time spent awake during the night-time sleep period was significantly greater with opicapone than with placebo (-1.0 vs. -0.4 h, P < 0.05), as was the reduction in percent time spent awake during the night-time sleep period (-12.8 % vs. -4.5 %, P < 0.05). CONCLUSION: "OFF"-times around nighttime sleep were common in BIPARK-1 and BIPARK-2. Opicapone may improve sleep by decreasing the amount of time spent awake during the night in patients with PD who have night-time sleep period "OFF" episodes.

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BACKGROUND: Increasing levodopa (L-dopa)/dopa decarboxylase inhibitor (DDCI) daily dose or adding a catechol-O-methyltransferase (COMT) inhibitor to levodopa/DDCI therapy are strategies used to manage wearing-off symptoms in Parkinson's disease (PD) patients. OBJECTIVES: To evaluate the COMT inhibitor opicapone versus an additional dose of levodopa to treat early wearing-off in PD patients. METHODS: ADOPTION was a randomized, parallel-group, open-label, Phase 4 study conducted in Korea. At baseline, eligible patients were randomized (1:1) to opicapone 50 mg (n = 87) or L-dopa 100 mg (n = 81) (added to current L-dopa/DDCI therapy) for 4 weeks. The main efficacy endpoint was change from baseline to end of study in absolute off time. Other endpoints included changes in on time, in Movement Disorder Society-Unified Parkinson's Disease Rating Scale and 8-item PD Questionnaire scores, and the Clinical and Patient Global Impression of Improvement/Change. RESULTS: The adjusted mean in absolute off time was significantly greater for opicapone 50 mg than for L-dopa 100 mg (-62.1 vs. -16.7 minutes; P = 0.0015). Opicapone-treated patients also reported a greater reduction in the percentage of off time (P = 0.0015), a greater increase in absolute on time (P = 0.0338) and a greater increase in the percentage of on time (P = 0.0015). There were no significant differences in other secondary endpoints. The L-dopa equivalent daily dose was significantly higher in the opicapone group (750.9 vs. 690.0 mg; P = 0.0247), when a 0.5 conversion factor is applied. CONCLUSIONS: Opicapone 50 mg was more effective than an additional 100 mg L-dopa dose at decreasing off time in patients with PD and early wearing-off.

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BACKGROUND: The wearing-off phenomenon is a key driver of medication change for patients with Parkinson's disease (PD) treated with levodopa. Common first-line options include increasing the levodopa dose or adding a catechol-O-methyltransferase (COMT) inhibitor, but there are no trials comparing the efficacy of these approaches. We evaluated the effectiveness of adjunct opicapone versus an additional 100 mg levodopa dose in PD patients with early wearing-off using pooled data from 2 randomized studies. METHODS: The ADOPTION study program included two similarly designed 4-week, open-label studies conducted in South Korea (NCT04821687) and Europe (NCT04990284). Patients with PD, treated with 3-4 daily doses of levodopa therapy and with signs of early wearing-off were randomized (1:1) to adjunct opicapone 50 mg or an additional dose of levodopa 100 mg. Patient-level data from the two studies were pooled. RESULTS: The adjusted mean [SE] change from baseline to week 4 in absolute OFF time (key endpoint) was - 62.8 min [8.8] in the opicapone group and - 33.8 min [9.0] in the levodopa 100 mg group, the difference significantly favoring opicapone (- 29.0 [- 53.8, - 4.2] min, p = 0.02). Significant differences in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III subscore (- 4.1 with opicapone vs - 2.5 with levodopa 100 mg), also favored opicapone (- 1.7 [- 3.3, - 0.04], p < 0.05). Dyskinesia was the most frequently reported adverse event (opicapone 7.2% vs. levodopa 100 mg 4.2%). CONCLUSIONS: In these short-term trials, introducing adjunct opicapone was more effective at reducing OFF time than adding another 100 mg levodopa dose in PD patients with early signs of wearing-off.

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Background While sleep disturbances are among the most frequent non-motor symptoms of Parkinson's disease (PD), there is a lack of evidence to support its treatment. Objective To evaluate the efficacy of opicapone 50 mg in treating sleep disturbances in patients with PD and end-of-dose motor fluctuations. Methods OASIS was an exploratory, open-label, single-arm clinical trial in PD patients with end-of-dose motor fluctuations and associated sleep disturbances. The primary endpoint was change from baseline to week 6 in Parkinson's Disease Sleep Scale 2 (PDSS-2). Secondary endpoints included functional motor and non-motor assessments (Movement Disorder Society [MDS]-Unified Parkinson's Disease Rating Scale [UPDRS], MDS-Non-motor Scale [NMS], 8-item PD Questionnaire [PDQ-8], 16-item PD Fatigue Scale [PFS-16], ON/OFF home diary), Clinical and Patient Global Impression of Change (CGI-C; PGI-C) and adverse events. Results At week 6, there was a significant reduction of −7.9 points (95%CI −13.6, −2.2; p = 0.0099) in PDSS-2 total score, with a significant mean change of −4.7 in the PDSS-2 domain of disturbed sleep (95%CI: −7.2, −2.3; p = 0.0009). Significant reductions were also observed in PFS-16 (−9.6; p = 0.0211), MDS-NMS total score (−28.9; p = 0.0015), MDS-UPDRS-III (−6.3; p = 0.0253), MDS-UPDRS-IV (−1.2; p = 0.0044) and PDQ-8 (−14.2; p = 0.0051). Absolute OFF-time was reduced (−142.1 min). Most patients (93.3%) and most clinicians (80.0%) reported improvements on PGI-C and CGI-C, respectively. Opicapone was well tolerated. Conclusions Adding opicapone 50 mg to levodopa/DDCI therapy in patients with PD and motor fluctuations and sleep disturbances improved both sleep disturbances and OFF time in these patients.

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BACKGROUND: Opicapone (OPC) is a third-generation, selective peripheral COMT inhibitor that improves peripheral L-DOPA bioavailability and reduces OFF time and end-of-dose motor fluctuations in Parkinson's disease (PD) patients. OBJECTIVES: In this study, we objectively assessed the effects of adding OPC to L-DOPA on bradykinesia in PD through kinematic analysis of finger movements. METHODS: We enrolled 20 treated patients with PD and motor fluctuations. Patients underwent two experimental sessions (L-DOPA, L-DOPA + OPC), separated by at least 1 week. In each session, patients were clinically evaluated and underwent kinematic movement analysis of repetitive finger movements at four time points: (i) before their usual morning dose of L-DOPA (T0), (ii) 30 min (T1), (iii) 1 h and 30 min (T2), and (iv) 3 h and 30 min after the L-DOPA intake (T3). RESULTS: Movement velocity and amplitude of finger movements were higher in PD patients during the session with OPC compared to the session without OPC at all the time points tested. Importantly, the variability of finger movement velocity and amplitude across T0-T3 was significantly lower in the L-DOPA + OPC than L-DOPA session. CONCLUSIONS: This study is the first objective assessment of the effects of adding OPC to L-DOPA on bradykinesia in patients with PD and motor fluctuations. OPC, in addition to the standard dopaminergic therapy, leads to significant improvements in bradykinesia during clinically relevant periods associated with peripheral L-DOPA dynamics, i.e., the OFF state in the morning, delayed-ON, and wearing-OFF periods.

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