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.  Some of the participants in the BIPARK I study were taking anticholinergics (5%) and medicines for Parkinson's disease that are not available in the UK or not included in the NICE guideline on Parkinson's disease, as an option for adjuvant therapy in people with later Parkinson's disease Patients previously treated with entacapone were excluded from the study and so there are no study outcomes for use of opicapone in patients who could not tolerate/did not respond to entacapone

In BIPARK-II, a total of 427 patients were randomised to opicapone (25 mg or 50 mg) or placebo. The study showed a change from baseline in absolute off-time to endpoint at week 15 (primary endpoint) was 64.46 minutes for placebo and 118.77 minutes for opicapone 50mg producing a significant difference of 54.31 minutes (CI 95% 96.18; 12.44, adjusted p=0.0081).

In the open-label (OL) extension studies of BIPARK-I and II (n = 862), the efficacy of opicapone achieved during the initial 14 to 15 week double-blind (DB) treatment phase appeared to be maintained over the course of a subsequent year of treatment.

Safety: In the BIPARK I study, safety outcomes were analysed for all participants who received at least 1 dose of the study medicine (n=599).

The number of participants with treatment-emergent adverse events leading to discontinuation was overall low; opicapone 50 mg was 5 (4%), vs 8 in the placebo group (7%) and 8 in the entacapone group (7%). The most common treatment emergent adverse events leading to discontinuation were diarrhoea, (2 in the entacapone group and 1 in the placebo group), visual hallucinations (1 in the opicapone 5 mg group, 2 in the opicapone 25 mg group, and 2 in opicapone 50 mg group) and dyskinesia (2 in opicapone 5 mg group).

Treatment emergent adverse events were reported in 50% of patients (n=60) in placebo group, 57% (n=69) in the entacapone treatment group and 54% (n=62) in the opicapone 50mg group. • Dyskinesia was the most common reported treatment-emergent adverse event across treatment groups. This was most commonly reported with opicapone 50 mg (16%, n=18), entacapone (8%, n=10) and placebo (4%, n=5) • Other adverse events affecting 5% or more participants taking opicapone 50mg included constipation, hallucination (any type) and insomnia.

The number of participants experiencing at least 1 treatment-emergent adverse event was similar for all doses of opicapone and placebo (between 60 and 62 participants). The number of participants with serious treatment emergent adverse events was greatest for entacapone (n=8), followed by placebo (n=6) and opicapone 50 mg (n=4), statistical analysis was not reported.

Impulse control disorders related to treatment were reported in 10 participants or fewer per group; opicapone 50 mg (n=8), entacapone (n=10) and placebo (n=5). The most commonly reported disorder in all groups was buying disorder. There was no increased suicidality in the opicapone or entacapone groups compared with placebo.

In the 1-year extension phases of BIPARK I and II, there were no new unexpected safety or tolerability concerns

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 3 of 6 identified with opicapone treatment.

The Summary of Product Characteristics (SPC) notes the most common adverse reactions reported were nervous system disorders. Dyskinesia was the most frequently reported treatment-emergent adverse reaction (17.7%). Other adverse reactions described are, but not limited to, psychiatric disorders (abnormal dreams, hallucination, hallucination visual, insomnia), nervous system disorders (dizziness, headache, somnolence), orthostatic hypotension, gastrointestinal disorders (constipation, dry mouth, vomiting), muscle spasms, increased blood creatine phosphokinase.

Patients and care-givers should be made aware that impulse control disorders including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists and/or other dopaminergic treatments. Patients should be monitored regularly for the development of impulse control disorders and review of treatment is recommended if such symptoms develop. SPC notes that for patients who experience progressive anorexia, asthenia and weight decrease within a relatively short period of time, a general medical evaluation including liver function should be considered.

Cost of treatment and Cost Effectiveness:  Opicapone 50mg hard capsules (Ongentys®) is supplied in boxes of 30 capsules (£93.90)  Approximate annual cost compared to standard comparator therapy entacapone is shown in table below. Tolcapone is licensed for adjuvant therapy to levodopa/DDCI in people with Parkinson's disease and motor fluctuations, when other COMT inhibitors are not tolerated or when they have failed and can only be prescribed under specialist supervision only and needs frequent monitoring of liver function. The cost of tolcapone at the lower dose (100mg TDS) is comparable to opicapone but as tolcapone is not considered a first line option and requires monitoring for hepatoxicity it is not included in this analyses for further cost comparisons.

Drug Dose 28-day cost* Approx. annual cost* Opicapone 50mg OD £87.64 £1139.32

Entacapone 200 mg tablet is taken with each levodopa/ £3.45 - £34.53 £44.85 - DDCI dose. (Maximum 10 tablets a day) £448.93

Range: 1 tablet to maximum 10 tablets a day *Prices taken from Drug Tariff August 2019

 1 tablet entacapone costs £0.12 versus 1 tablet opicapone £3.13. NICE evidence summary (ES9) suggests that most patients take entacapone between 4-7 times a day thus the average cost for entacapone per day is estimated at £0.49 - £0.86 and is significantly lower cost than opicapone. Based on dose range from 1-10 tablets with entacapone, a 100% switch to opicapone treatment per year per person can come at an increased cost ranging between approximately £700- £1000.  Entacapone is however also commonly prescribed as a combination product containing levodopa / carbidopa / entacapone making direct costing comparisons difficult to estimate. Low cost branded generic combination products are lower cost than opicapone with levodopa/carbidopa.  Opicapone is being targeted as an oral treatment option after failure or intolerance to entacapone to delay treatment to more invasive, expensive and resource intensive non-oral treatment options including Duodopa®, apomorphine and deep brain stimulation. There are no cost effectiveness studies available at present or budget evaluations on this impact.  No cost-effectiveness studies were found.  All Wales Medicines strategy group have an interim recommendation in place for its use and have only approved with a commercial pricing arrangement in place (details unknown).

The needs of the population  The need of the population appears low as alternative options are available.  NICE CG71 notes that adjuvant treatment of motor symptoms in patients with PD should be based on the offer of a choice of dopamine agonists, MAO-B inhibitors or COMT inhibitors as an adjunct to levodopa taking into account and on discussion with the patient the person's individual clinical circumstances, comorbidities and risks from polypharmacy, the person's individual lifestyle circumstances, preferences, needs and goals.  The availability of opicapone allows for the choice of another COMT inhibitor to entacapone. Because of the risk of potentially fatal, acute liver injury, tolcapone should not be considered as a first-line adjunct therapy.  Opicapone is a once daily drug enabling for some patients a simplified drug regimen and thus potentially increasing compliance. This therefore may be a preferred treatment option for certain patients although combination preparations of entacapone/levodopa/carbidopa are most frequently prescribed.

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 4 of 6

 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  Opicapone appears to offer a better tolerated and safer alternative to tolcapone.

The needs of the community  Specialists anticipate 20 patients per year for Hertfordshire (£14-20) may be eligible for treatment. Costs may be offset by removal of need/delayed use of more invasive, expensive and resource intensive non-oral treatment options including Duodopa®, apomorphine and deep brain stimulation. Opicapone avoids additional costs associated with liver function tests in comparison to tolcapone.  Current primary care prescribing costs for COMT inhibitors including fixed dose combinations is £54k for ENHCCG and £120k HVCCG.

Policy Drivers  A local Hertfordshire wide patient pathway for the treatment of the motor features of Parkinson’s disease is available, whilst no specific drugs are mentioned, the pathway notes the addition of COMT inhibitors when insufficient symptom control/ fluctuations for motor symptoms. (Published 2014)  Not listed as formulary at East and North Herts NHS Hospital Trust or West Hertfordshire Hospitals NHS Trust  NICE guidance for Parkinson’s disease in adults (NG71): adjuvant treatment of motor symptoms; offer a choice of dopamine agonist, MAO-B inhibitors or COMT inhibitors as an adjunct to levodopa for patients with PD who have developed dyskinesia or motor fluctuations and considers that a person's individual clinical circumstances, comorbidities and risks from polypharmacy, the person's individual lifestyle circumstances, preferences, needs and goals need to be taken into account. (Note this was published before availability of opicapone and so did not include evaluation of opicapone.)  NICE evidence summary (ES9) Parkinson’s disease with end-of-dose motor fluctuation: opicapone (March 2017)  SMC (September 2017, SMC no 1281/17): has not recommended opicapone for use in NHS Scotland as the holder of the marketing authorisations has made no application.  AWMSG (February 2019): Opicapone has been recommended for use by the One Wales Interim Commissioning Process, with commercial pricing arrangement in place. Opicapone is restricted for use only after failure of entacapone or in patients who cannot tolerate entacapone or have concordance issues. A full HTA submission to AWMSG is awaited.  Local formulary status: o Not included in West Essex CCG formulary (August 2017): noting ‘opicapone has the same mode of action as entacapone but is twice the price. It is clinically very similar to entacapone. Insufficient evidence to approve the formulary application’. o Included in Cambridge and Peterborough CCG formulary o restricted use North West Anglia Foundation Trust (NWAFT): hospital only use when patients cannot be stabilised on entacapone o Specialist Initiation (CUHFT and NWAFT) for continuation in primary care only for patients with Parkinson’s and motor fluctuations who are eligible for a 2 month trial of opicapone will necessarily first have had a trial of entacapone, and will have experienced the unacceptable adverse effect of persistent diarrhoea causing incontinence, or frequent passing of loose stool disturbing sleep or lifestyle, as defined by Bristol stool chart 6/7, which resolves when stopping entacapone. o Non-formulary at all other Trusts. o Included in Bedfordshire and Luton CCG formulary (December 2017): restricted use at Luton and Dunstable university Hospital. Must be initiated by a Neurologist who specialises in Parkinson’s disease and may be continued by the GP. Second line agent for those patients who do not respond to or tolerate entacapone. o Included in North Central London Joint Formulary Committee recommendations (February 2019): Approved as second-line COMT inhibitor, for patients with Parkinson's Disease and end-of-dose motor fluctuations/OFF periods who do not respond to, or tolerate entacapone. Approval restricted to sites offering advanced PD therapies. Parkinson treatment pathway has not been updated yet to include opicapone specifically.

Equity: No impact anticipated. There is no differential impact expected on one or more equality groups differently to others Age, Disability; Gender reassignment; Marriage & Civil Partnership; Pregnancy & Maternity; Race; Religion & Belief; Sex; Sexual orientation. The recommendations would apply to all patients where opicapone may be indicated. Appropriateness of medicines for individual patients is a clinical decision by the prescribing clinician. Parkinson’s disease is mostly a disease occurring late-middle age. Datasheet advices that opicapone is not contra- indicted in patients ≥85yr old but advised to be used with caution. PD is relatively uncommon in pregnancy. A specific treatment recommendation for PD during pregnancy / breast feeding is outside of the scope of this recommendation document. NHS England is the responsible commissioner for specialist neuroscience services for children include all services provided by Specialist Paediatric Neurosciences Centres. Datasheet notes there is no relevant use of opicapone in the

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 5 of 6 paediatric population with Parkinson's disease and motor fluctuations.

Implementability: No issues identified. If recommended would be AMBER initiation status consistent with other treatments for PD.

References  NICE Guideline (NG71) (19 July 2017); Parkinson’s disease in adults https://www.nice.org.uk/guidance/ng71  Hertfordshire Medicine Management Committee guidance, Patient Pathway for the Treatment of the Motor Features of Parkinson’s Disease (PD) (July 2014), https://www.enhertsccg.nhs.uk/sites/default/files/Pharmacy/Local_Decisions/Parkinsons%20Disease%20Treatment%20Pathway%20HMMC%20a pproved%20July%202012.pdf  Ferreira JJ 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’. Lancet Neurol 2016;15:154-65  Summary of product characteristics, Ongentys 50 mg hard capsules, (last updated 18 Jul 2019), accessed 9/8/2019. Available from: https://www.medicines.org.uk/emc/product/7386  Summary of product characteristics, Entacapone 200 mg Film-Coated Tablets, (last updated 11 Mar 2016), accessed 9/8/2019. Available from https://www.medicines.org.uk/emc/product/3129/smpc  Summary of product characteristics, Tasmar 100 mg film-coated tablets, (last updated 16 Dec 2014), accessed 9/8/2019. Available from https://www.medicines.org.uk/emc/product/3902/smpc  All Wales Medicine Strategy Group; Opicapone (Ongentys®) 50mg capsules, Statement to NHS Wales – Statement of intent (February 2019) http://www.awmsg.org/awmsgonline/app/appraisalinfo/911  Scottish Medicines Consortium; Opicapone 50mg hard capsules (Ongentys®) SMC No 1281/17, Statement of Advice (8 September 2017) https://www.scottishmedicines.org.uk/medicines-advice/opicapone-ongentys-nonsubmission-128117/  West Hertfordshire NHS Hospital Trust formulary. Available from http://www.westhertsformulary.nhs.uk, accessed 9/8/2019  East and North Hertfordshire NHS Hospital Trust formulary. Available from https://www.extranet.enherts-tr.nhs.uk. Accessed 9/8/2019  West Essex CCG formulary, Prescribing formulary central nervous system (3 May 2018) Available from https://westessexccg.nhs.uk/your- health/medicines-optimisation-and-pharmacy/clinical-guidelines-and-prescribing-formularies/04-central-nervous-system/62-prescribing-formulary- central-nervous-system/file  Cambridgeshire and Peterborough formulary. Available from http://www.cambridgeshireandpeterboroughformulary.nhs.uk, accessed 9/8/2019  NCL Joint Formulary Committee, past decisions, JFC tracker. Available from https://www.ncl-mon.nhs.uk/doc/jfc/, accessed 9/8/2019  NCL Medicine Pathways, Guidelines And Position Statements Parkinson’s disease prescribing guidance: ‘Drug therapy for Parkinson’s disease - specialist initiation only’ (April 2015) Available from https://www.ncl-mon.nhs.uk/wp- content/uploads/Guidelines/4_Parkinsons_disease_prescribing_guideline.pdf Accessed 9/8/2019  Bedfordshire and Luton Joint Formulary, Available from http://www.ldhformulary.nhs.uk, accessed 9/8/2019  Bedfordshire and Luton Joint Prescribing Committee Bulletin 262:Opicapone for Parkinson’s Disease (December 2017) Available from http://www.gpref.bedfordshire.nhs.uk/media/201529/opicaponebulletinpathwayupdated_12_4_2018.pdf

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 6 of 6