HERTFORDSHIRE MEDICINES MANAGEMENT COMMITTEE (HMMC) OPICAPONE CAPSULES FOR THE TREATMENT OF PARKINSONS DISEASE (PD) IN ADULT PATIENTS RECOMMENDED FOR RESTRICTED USE (AMBER INITIATION) Name: generic What it is Indication Date Decision NICE / SMC (trade) decision status Guidance last revised Opicapone 50mg Peripheral, Licensed as adjunctive October 2019 Final NICE TA: not hard capsules selective and therapy to available ® (Ongentys ) reversible catechol- preparations of NICE guidance 0-methyltransferase levodopa/ DOPA for Parkinson’s (COMT) inhibitor decarboxylase disease in adults inhibitors in adult (NG71) patients with SMC not Parkinson's disease recommended and end-of-dose motor AWMSG fluctuations who recommended cannot be stabilised on those combinations HMMC recommendation: Opicapone 50mg capsules, within licensed indications, is recommended for restricted use as AMBER initiation as a second line COMT inhibitor in adult patients with PD with end-of-dose motor fluctuations who are intolerant of entacapone and where the next step of treatment would be the non-oral treatment options or tolcapone. Background Information: Opicapone is the third COMT inhibitor licensed in the UK with the recommended dose of 50 mg as an adjunct to levodopa/DDCI inhibitors. It should be taken once-daily at bedtime, at least one hour before or after levodopa combinations. In certain patients, this may enable a simplified drug regimen which may potentially improve compliance. Some patients taking a complicated PD drug regimen may find it easier to add a single tablet such as opicapone and keep their familiar levodopa doses over the day. In contrast, entacapone has to be taken with each levodopa dose, which may be up to 10 times daily. Combination products containing different fixed doses of levodopa, carbidopa and entacapone are available to aid compliance, but these may not be suitable for those requiring more flexible levodopa dosing regimens. The more potent tolcapone is administered three-times daily. Tolcapone is however considered second- line adjuvant therapy when other COMT inhibitors are not tolerated or have failed due to the risk of serious hepatic reactions and consequently requiring frequent monitoring of liver function. It can only be prescribed and supervised by physicians experienced in the management of advanced Parkinson's disease. Opicapone, with an approximate annual cost of £1,139 per patient, is significantly more costly to entacapone (single ingredient product cost varies from £45-£449/pa, depending on the dose taken) and similar in price to tolcapone (at the dose of 100mg TDS). Opicapone enhances the effects of levodopa. To reduce levodopa-related dopaminergic adverse reactions (e.g. dyskinesia, hallucinations, nausea, vomiting and orthostatic hypotension), it is often necessary to adjust levodopa dosage within the first days to first weeks after initiating the treatment. No dose adjustment is needed for elderly patients, but caution must be exercised in patients ≥ 85 years of age as there is limited experience in this age group. No dose adjustment is needed in people with renal impairment or mild hepatic impairment. There is limited clinical experience in patients with moderate hepatic impairment (caution must be exercised in these patients and dose adjustment may be necessary based on a potentially enhanced levodopa dopaminergic response and associated tolerability). There is no clinical experience in patients with severe hepatic impairment. Overall opicapone appears well tolerated with the SPC noting the most commonly reported adverse event being dyskinesia (very common (≥ 1/10). In comparison, the datasheet for entacapone notes dyskinesia This HMMC recommendation is based upon the evidence available at the time of publication. The recommendation will be reviewed upon request in the light of new evidence becoming available. Page 1 of 6 as well as nausea as very common side effects. In one of the main studies (BIPARK-I), dyskinesia was more frequently reported with opicapone 50mg than entacapone. BIPARK-I showed the main clinical benefits of opicapone 50mg daily up to 15 weeks were reduced off- time of 60.8 minutes and an increase in on-time without troublesome dyskinesia of 62.6 minutes compared to placebo. Opicapone 50mg was shown to be non-inferior to entacapone 200mg for reducing off time. The effect was maintained at 1 year in an open- label extension study. ASSESSMENT AGAINST THE ETHICAL FRAMEWORK Evidence of Clinical Effectiveness: The efficacy of opicapone has been mainly evaluated in two randomised, controlled, double-blind, multinational phase 3 studies BIPARK-I and BIPARK-II. BIPARK-I (Ferreira et al. ‘Opicapone as an adjunct to levodopa in patients with Parkinson’s disease and end of dose motor fluctuations: a randomised, double blind controlled trial.’ Patients: A total of 600 patients, aged 30-83 years with PD and end-of- dose motor fluctuations. Notably key exclusion included previous use of entacapone. Intervention: opicapone (5 mg, 25 mg or 50 mg once daily) – only results for the licensed 50mg dose are reported below Comparator: placebo or entacapone 200 mg (active comparator) with every levodopa intake. BIPARK I study evaluated the superiority of opicapone to placebo and also the non-inferiority of opicapone to entacapone 200 mg. Primary outcome: The primary outcome was the change from baseline to study end in the absolute time in the off state as assessed by using daily participant diaries. At 14 to 15 weeks, the mean change from baseline in absolute time in the off state to study end was largest in the opicapone 50 mg group (−116.8 minutes), followed by entacapone (−96.3 minutes) and the placebo group (−56.0 minutes) in the intention to treat [ITT] analysis. The mean difference in change from baseline between opicapone 50 mg and placebo was −60.8 minutes (95% confidence interval [CI] −97.2 to −24.2, p=0.0015) demonstrating superiority to placebo. In the non-inferiority analysis, the mean difference in the absolute time in the off state with opicapone 50 mg compared with entacapone was −26.2 minutes (95% CI −63.8 to 11.4, p=0.0051). Based on the non- inferiority margin of 30 min, opicapone 50mg was found to be non-inferior to entacapone. [per-protocol analysis]). Secondary outcomes: Responder rates for the off and on state (percentage of participants achieving a 1 hour or more reduction in absolute time in the off state or 1 hour or more increase in the absolute time in the on state): There was a statistically significant higher responder rate for the off and on state in the opicapone 50 mg group when compared with placebo (70% versus 48%, p=0.001 and 65% versus 46%, p=0.003). No statistically significant difference was found for entacapone when compared with placebo or with opicapone 50 mg for these outcomes (p>0.05). Total time in on state at the end of the study treatment: The least squares mean difference in the total time in the on state at the end of the study when compared with placebo was found to be the greatest with opicapone 50 mg at 71.9 minutes (95% CI 35.0 to 108, p=0.0001), followed by entacapone at 52.6 minutes (95% CI 16.1 to 89.1, p=0.005). There was no statistically significant difference when opicapone 50 mg was compared with entacapone for this outcome (p=0.30). Motor symptoms without troublesome dyskinesia: There was a statistically significant improvement in on time without troublesome dyskinesia by approximately 60 minutes with opicapone 50 mg when compared with placebo (95% CI 23.8 to 101.4, p=0.002). There was no statistically significant difference when opicapone 50 mg was compared with entacapone for this outcome (p=0.45). Opicapone 50mg/day was associated with greater improvements in both patient and Clinicians and Patient’s Global Impression of Change than placebo. No statistically significant differences were observed between opicapone and placebo in health-related quality of life, motor scores or daily activity scores. Study strengths and limitations The NICE evidence summary (ES9) for opicapone notes the following strengths and limitations of BIPARKI: This HMMC recommendation is based upon the evidence available at the time of publication. The recommendation will be reviewed upon request in the light of new evidence becoming available. Page 2 of 6 BIPARK I was a double-blind, placebo and active-controlled study, which included a total of 600 participants across 106 centres in 19 European countries (excluding UK) and Russia. Participants may not reflect UK population and routine clinical practice The primary efficacy outcome measure ‘the reduced time in off state’ is, according to the EPAR for opicapone, noted as a valid and clinically relevant measure of efficacy The baseline participant clinical characteristics, demographics and treatment history were similar between the treatment groups The active control group received entacapone 200 mg with each levodopa dose. Entacapone is the most commonly used COMT inhibitor in practice for end-of-dose motor fluctuations and so was an appropriate comparator Masking of the opicapone and placebo was carefully maintained in the study. Due to the double-blind nature of this study, patients took the same number of tablets irrespective of the treatment they were randomised to. Therefore, tablet burden could not be assessed. Different study populations were used to test for superiority versus placebo (ITT analysis) and non-inferiority versus entacapone (per-protocol analysis). Both analyses support the efficacy of opicapone 50 mg compared with placebo and non-inferiority of opicapone 50 mg to entacapone. Dose adjustments of levodopa were allowed between baseline and up to 3 weeks according to clinical response in the BIPARK I study, but the baseline dose was not to be exceeded and adjustments were not allowed after the first 3 weeks. This does not reflect routine practice, as the dose of levodopa can be adjusted when adjunctive therapy is started The BIPARK I study was carried out over a short period of up to 15 weeks and excluded a broad population of people with Parkinson's disease.