Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Bial Portela & Cª, S.A., À Av. da Siderurgia Nacional, 4745-457 S. Mamede do Coronado, Portugal, Tel:+351 22 986 61 00, Fax: +351 22 986 61 90, e-mail: info@bial.com
Pharmacotherapeutic group: Anti-parkinson drugs, other dopaminergic agents
ATC code: N04BX04
Opicapone is a peripheral, selective and reversible catechol-O-methyltransferase (COMT) inhibitor endowed with a high binding affinity (sub-picomolar) that translates into a slow complex dissociation rate constant and a long duration of action (>24 hours) in vivo.
In the presence of a DOPA decarboxylase inhibitor (DDCI), COMT becomes the major metabolising enzyme for levodopa, catalysing its conversion to 3-O-methyldopa (3-OMD) in the brain and periphery. In patients taking levodopa and a peripheral DDCI, such as carbidopa or benserazide, opicapone increases levodopa plasma levels thereby improving the clinical response to levodopa.
Opicapone showed a marked (>90%) and long-lasting (>24 hours) COMT inhibition in healthy subjects after administration of 50 mg opicapone.
At steady state, 50 mg opicapone significantly increased the extent of levodopa systemic exposure approximately 2 fold compared to placebo following a single oral administration of either 100/25 mg levodopa/carbidopa or 100/25 mg levodopa/benserazide administered 12 h after the opicapone dose.
The efficacy and safety of opicapone has been demonstrated in two Phase 3 double-blind, placebo and active (Study 1 only) controlled studies in 1,027 randomized adult patients with Parkinson’s disease treated with levodopa/DDCI (alone or in combination with other antiparkinsonian medicinal products) and end-of-dose motor fluctuations for up to 15 weeks. At screening, the mean age was similar in all treatment groups in both studies, ranging between 61.5 and 65.3 years. Patients had disease severity stages 1 to 3 (modified Hoehn and Yahr) at ON, were treated with 3 to 8 daily doses of levodopa/DDCI and had a daily average OFF-time of at least 1.5 hours. In both studies, 783 patients were treated with 25 mg or 50 mg of opicapone or placebo. In Study 1, 122 patients were treated with 5 mg of opicapone and 122 patients were treated with 200 mg of entacapone (active comparator). The majority of patients treated in both pivotal studies were treated with immediate-release levodopa/DDCI. There were 60 patients in the combined Phase 3 studies who were predominantly using controlled-release levodopa (i.e. >50% of their levodopa/DDCI formulations), 48 of whom were treated solely with controlled-release formulations of levodopa. Although there is no evidence that either the efficacy or safety of opicapone would be affected by use of controlled-release levodopa preparations, the experience with such preparations is limited.
Opicapone demonstrated clinical efficacy superior to placebo during the double-blind treatment, both for the primary efficacy variable used in both pivotal studies, i.e. reduction in OFF-time (Table 2), the proportion of OFF-time responders (i.e. a subject who had a reduction in OFF-time of at least 1 hour from baseline to endpoint) (Table 3) and for most diary-derived secondary endpoints.
The LS mean reduction in absolute OFF-time from baseline to endpoint in the entacapone group was -78.7 minutes. The difference in LS mean change in OFF-time of entacapone to placebo in Study 1 was -30.5 minutes. The difference in LS mean change in OFF-time of opicapone 50 mg to entacapone was -24.8 minutes and non-inferiority of opicapone 50 mg to entacapone was demonstrated (95% confidence interval: -61.4, 11.8).
Table 2. Change in absolute OFF-time and ON-time (minutes) from baseline to endpoint:
| Treatment | N | LS mean | 95% CI | p-value |
|---|---|---|---|---|
| Study 1 | ||||
| Change in OFF-time | ||||
| Placebo | 121 | -48.3 | -- | -- |
| OPC 5 mg | 122 | -77.6 | -- | -- |
| OPC 25 mg | 119 | -73.2 | -- | -- |
| OPC 50 mg | 115 | -103.6 | -- | -- |
| OPC 5 mg – Placebo | -- | -29.3 | -65.5, 6.8 | 0.0558 |
| OPC 25 mg – Placebo | -- | -25.0 | -61.5, 11.6 | 0.0902 |
| OPC 50 mg – Placebo | -- | -55.3 | -92.0, -18.6 | 0.0016 |
| Change in total ON-time without troublesome dyskinesiasa | ||||
| Placebo | 121 | 40.0 | -- | -- |
| OPC 5 mg | 122 | 75.6 | -- | -- |
| OPC 25 mg | 119 | 78.6 | -- | -- |
| OPC 50 mg | 115 | 100.8 | -- | -- |
| OPC 5 mg – Placebo | -- | 35.6 | -2.5, 73.7 | 0.0670 |
| OPC 25 mg – Placebo | -- | 38.6 | 0.2, 77.0 | 0.0489 |
| OPC 50 mg – Placebo | -- | 60.8 | 22.1, 99.6 | 0.0021 |
| Study 2 | ||||
| Change in OFF-time | ||||
| Placebo | 136 | -54.6 | -- | -- |
| OPC 25 mg | 125 | -93.2 | -- | -- |
| OPC 50 mg | 150 | -107.0 | -- | -- |
| OPC 25 mg – placebo | -- | -38.5 | -77.0, -0.1 | 0.0900 |
| OPC 50 mg – placebo | -- | -52.4 | -89.1, -15.7 | 0.0101 |
| Change in total ON-time without troublesome dyskinesiasa | ||||
| Placebo | 136 | 37.9 | -- | -- |
| OPC 25 mg | 125 | 79.7 | -- | -- |
| OPC 50 mg | 150 | 77.6 | -- | -- |
| OPC 25 mg – placebo | -- | 41.8 | 0.7, 82.9 | 0.0839 |
| OPC 50 mg – placebo | -- | 39.7 | 0.5, 78.8 | 0.0852 |
CI = confidence interval; LS mean = least square mean; N = number of non-missing values; OPC = opicapone.
a ON-time without troublesome dyskinesias=ON-time with non-troublesome dyskinesias + ON-time without dyskinesias
Table 3. OFF-time responder rates at endpoint:
| Response type | Placebo (N=121) | Entacapone (N=122) | OPC 5 mg (N=122) | OPC 25 mg (N=119) | OPC 50 mg (N=115) |
|---|---|---|---|---|---|
| Study 1 | |||||
| OFF-time reduction | |||||
| Responders, n (%) | 55 (45.5) | 66 (54.1) | 64 (52.5) | 66 (55.5) | 75 (65.2) |
| Difference to placebo | |||||
| p-value | -- | 0.1845 | 0.2851 | 0.1176 | 0.0036 |
| (95% CI) | -- | (-0.039; 0.209) | (-0.056; 0.193) | (-0.025; 0.229) | (0.065; 0.316) |
| Study 2 | |||||
| OFF-time reduction | |||||
| Responders, n (%) | 65 (47.8) | NA | NA | 74 (59.2) | 89 (59.3) |
| Difference to placebo | |||||
| p-value | -- | -- | -- | 0.0506 | 0.0470 |
| (95% CI) | -- | -- | -- | (0.001; 0.242) | (0.003; 0.232) |
CI = confidence interval; N = total number of patients; n = number of patients with available information; NA = not applicable; OPC = opicapone
Note: A responder was a patient who had a reduction of at least 1 hour in absolute OFF-time (OFF-time responder)
The results of the open-label (OL) extension studies of 1 year duration in 862 patients who continued treatment from the double-blind studies (Study 1-OL and Study 2-OL) indicated maintenance of the effect achieved during DB study periods. In the OL studies, all patients began at a dose of 25 mg opicapone for the first week (7 days), regardless of their prior treatment in the double-blind period. If end-of-dose motor fluctuations were not sufficiently controlled and tolerability allowed, the opicapone dose could be increased to 50 mg. If unacceptable dopaminergic adverse events were seen, the levodopa dose was to be adjusted. If not sufficient to manage the adverse events, the opicapone dose could then be down titrated. For other adverse events, the levodopa and/or opicapone dose could be adjusted.
The European Medicines Agency has waived the obligation to submit the results of studies with opicapone in all subsets of the paediatric population with Parkinson’s disease and motor fluctuations (see section 4.2 for information on paediatric use).
Opicapone presents a low absorption (~20%). Pharmacokinetic results showed that opicapone is rapidly absorbed, with a tmax of 1.0 h to 2.5 h following once-daily multiple-dose administration up to 50 mg opicapone.
In vitro studies over the opicapone concentration range 0.3 to 30 mcg/mL showed that binding of 14C-opicapone to human plasma proteins is high (99.9%) and concentration-independent. The binding of 14C-opicapone to plasma proteins was unaffected by the presence of warfarin, diazepam, digoxin and tolbutamide, and the binding of 14C-warfarin, 2-14C-diazepam, 3H-digoxin and 14C-tolbutamide was unaffected by the presence of opicapone and opicapone sulphate, the major human metabolite.
After oral administration, the apparent volume of distribution of opicapone at a dose of 50 mg was 29 L with an inter-subject variability of 36%.
Sulphation of opicapone appears to be the major metabolic pathway in humans, yielding the inactive opicapone sulphate metabolite. Other metabolic pathways include glucuronidation, methylation and reduction.
The most abundant peaks in plasma after a single-dose of 100 mg 14C-opicapone are metabolites BIA 9-1103 (sulphate) and BIA 9-1104 (methylated), 67.1 and 20.5% of radioactive AUC respectively.
Other metabolites were not found in quantifiable concentrations in the majority of plasma samples collected during a clinical mass balance study.
The reduced metabolite of opicapone (found to be active in non-clinical studies) is a minor metabolite in human plasma and represented less than 10% of total systemic exposure to opicapone.
In in vitro studies in human hepatic microsomes, minor inhibition of CYP1A2 and CYP2B6 was observed. All reductions in activity essentially occurred at the highest concentration of opicapone (10 mcg/mL).
An in vitro study showed opicapone inhibited CYP2C8 activity. A single dose study with opicapone 25 mg showed an average increase of 30% in the rate, but not the extent, of exposure to repaglinide (a CYP2C8 substrate), when the two drugs were co-administered. A second study conducted showed that, at steady state, opicapone 50 mg had no effect on repaglinide systemic exposure.
Opicapone reduced CYP2C9 activity through competitive/mixed type mode of inhibition. However, clinical interaction studies conducted with warfarin showed no effect of opicapone on the pharmacodynamics of warfarin, a substrate of CYP2C9.
In healthy subjects, the opicapone elimination half-life (t1/2) was 0.7 h to 3.2 h following once-daily multiple-dose administration up to 50 mg opicapone. Following once-daily multiple oral doses of opicapone in the dose range of 5 to 50 mg, opicapone sulphate presented a long terminal phase with elimination half-life values ranging from 94 h to 122 h and, as a consequence of this long terminal elimination half-life, opicapone sulphate presented a high accumulation ratio in plasma, with values close of up to 6.6.
After oral administration, the apparent total body clearance of opicapone at a dose of 50 mg was 22 L/h, with an inter-subject variability of 45%.
Following administration of a single oral dose of 14C-opicapone, the main excretion route of opicapone and its metabolites was faeces, accounting for 58.5% to 76.8% of the administered radioactivity (mean 67.2%). The remainder of the radioactivity was excreted in urine (mean 12.8%) and via expired air (mean 15.9%). In urine, the primary metabolite was the glucuronide metabolite of opicapone, while parent drug and other metabolites were generally below the limit of quantification. Overall, it can be concluded that the kidney is not the primary route of excretion. Therefore, it can be presumed that opicapone and its metabolites are mainly excreted in the faeces.
Opicapone exposure increased in a dose proportional manner following once-daily multiple dose administration up to 50 mg opicapone.
In vitro studies have shown that opicapone is not transported by OATP1B1, but is transported by OATP1B3, and efflux transported by P-gp and BCRP. BIA 9-1103, its major metabolite, was transported by OATP1B1 and OATP1B3, and efflux transported by BCRP, but is not a substrate for the P-gp/MDR1 efflux transporter. Effect of opicapone on transporters At clinically relevant concentrations, opicapone is not expected to inhibit OAT1, OAT3, OATP1B1, OATP1B3, OCT1, OCT2, BCRP, P-gp/MDR1, BSEP, MATE1 and MATE2-K transporters as suggested by in vitro and in vivo studies.
The pharmacokinetics of opicapone was evaluated in elderly subjects (aged 65-78 years old) after 7-day multiple-dose administration of 30 mg. An increase in both the rate and extent of systemic exposure was observed for the elderly population when compared to the young population. The SCOMT activity inhibition was significantly increased in elderly subjects. The magnitude of this effect is not considered to be of clinical relevance.
There is no relationship between exposure of opicapone and body weight over the range of 40-100 kg.
There is limited clinical experience in patients with moderate hepatic impairment (Child-Pugh Class B). The pharmacokinetics of opicapone was evaluated in healthy subjects and moderate chronic hepatic impaired patients after administration of a single-dose of 50 mg. The bioavailability of opicapone was significantly higher in patients with moderate chronic hepatic impairment and no safety concerns were observed. However, as opicapone is to be used as adjunctive levodopa-therapy, dose adjustments may be considered based on a potentially enhanced levodopa dopaminergic response and associated tolerability. There is no clinical experience in patients with severe hepatic impairment (Child-Pugh Class C) (see section 4.2).
The pharmacokinetics of opicapone was not directly evaluated in subjects with chronic renal impairment. However, an evaluation with 50 mg opicapone was performed in subjects included in both phase 3 studies with GFR/1.73 m² <60 mL/min (i.e. moderately decreased renal elimination capacity), and using pooled BIA 9-1103 data (major metabolite of opicapone). BIA 9-1103 plasma levels were not affected in patients with chronic renal impairment, and as such, no dose adjustment needs to be considered.
Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
In rats, opicapone did not affect male and female fertility or prenatal development at exposure levels 22 times the therapeutic exposure in humans. In pregnant rabbits, opicapone was less well tolerated resulting in maximum systemic exposure levels around or below the therapeutic range. Although embryo-foetal development was not negatively influenced in rabbits, the study is not considered predictive for human risk assessment.
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