eslicarbazepine acetate 800mg tablet (Zebinix) SMC No. (592/09) Eisai Ltd 8 October 2010 The Scottish Medicines Consortium (SMC) has completed its assessment of the above product and advises NHS Boards and Area Drug and Therapeutic Committees (ADTCs) on its use in NHS Scotland. The advice is summarised as follows: ADVICE : following a re-submission eslicarbazepine acetate (Zebinix) is accepted for restricted use within NHS Scotland. Indication under review: as adjunctive therapy in adults with partial-onset seizures with or without secondary generalisation. SMC restriction: patients with highly refractory epilepsy who have been heavily pre-treated and remain uncontrolled with existing anti-epileptic drugs. Eslicarbazepine acetate reduces seizure frequency compared to placebo over a 12-week maintenance period. Direct comparative data versus other anti-epileptic drugs are unavailable, particularly comparisons with other cheaper agents with a very similar mode of action. This SMC advice takes account of the benefits of a Patient Access Scheme (PAS) that improves the cost-effectiveness of eslicarbazepine acetate. This SMC advice is contingent upon the continuing availability of the PAS in Scotland. Overleaf is the detailed advice on this product. Chairman Scottish Medicines Consortium Published 08 November 2010 1 Indication Adjunctive therapy in adults with partial-onset seizures with or without secondary generalisation Dosing Information 400mg once daily for one to two weeks then 800mg once daily. Based on individual response the dose may be increased to 1,200mg once daily. Eslicarbazepine acetate must be added to existing anticonvulsant therapy. Product availability date 21 April 2009 (launch date 21 October 2009) Summary of evidence on comparative efficacy Eslicarbazepine acetate, a dibenzazepine antiepileptic drug (AED) in the same pharmacological class as carbamazepine and oxcarbazepine, is metabolised to the active form, eslicarbazepine. Eslicarbazepine is the active metabolite of oxcarbazepine. This submission requests that SMC consider the use of eslicarbazepine acetate in patients with highly refractory epilepsy who have been heavily pre-treated with existing AED combinations. Three phase III studies recruited adults experiencing simple or complex partial-seizures with or without secondary generalisation for at least 12 months who had at least four seizures per four- week period, despite treatment with one or two AED. The second study permitted concomitant treatment with one to three AED. After an eight-week baseline period, which was single-blind placebo-controlled in the first study and observational in the others, patients who continued to have at least four seizures per four-week period with no seizure-free interval greater than 21 days were randomised equally to double-blind treatment with eslicarbazepine acetate 400mg, 800mg or 1,200mg once daily or placebo for twelve weeks following a two-week dose titration. The third study did not include an eslicarbazepine acetate 400mg per day treatment arm. Following completion of double-blind treatment patients could enter open-label extension studies where they received eslicarbazepine acetate titrated to clinical response for one year. In the intention-to-treat (ITT) population, which comprised all patients who received at least one dose of study drug and had at least one post-baseline seizure frequency efficacy assessment, the primary outcome, four-week seizure frequency during the 12-week maintenance period, was compared to placebo for each eslicarbazepine acetate treatment arm by analysis of covariance (ANCOVA) that modelled seizure frequency as a function of baseline seizure frequency and treatment. The results presented as least square mean (LS mean) are detailed in the table below and indicate a significant reduction in four-week seizure frequency with eslicarbazepine acetate 800mg and 1,200mg, but not 400mg, daily doses compared to placebo. ANCOVA analysis of integrated data from ITT populations of the studies indicated significant differences compared to placebo for eslicarbazepine acetate 800mg and 1,200mg daily. 2 Table: ANCOVA derived LS means (95% confidence intervals) seizure frequency per 28- days during 12-week maintenance within ITT population Study Placebo ESL 400mg ESL 800mg ESL 1,200mg A N=102 N=99 N=98 N=98 7.6 6.7 5.7 5.4 (6.8 to 8.6) (6.0 to 7.7) (5.0 to 6.5)* (4.6 to 6.1)* B N=100 N=96 N=100 N=97 9.8 8.7 7.1 7.0 (8.7 to 11.1) (7.7 to 9.9) (6.2 to 8.2)* (6.0 to 8.1)* C N=84 N=84 N=77 7.3 - 5.7 5.5 (6.3 to 8.5) (4.9 to 6.7)** (4.6 to 6.5)* ESL= eslicarbazepine acetate ; *significant difference versus placebo; ** p=0.048 versus placebo Compared to placebo, the proportion of patients experiencing a response (reduction of at least 50% in seizure frequency during the 12-week maintenance period compared with baseline) was significantly greater with eslicarbazepine acetate 1,200mg in all three studies and an integrated analysis of these and was significantly greater with eslicarbazepine acetate 800mg in studies A and B and the integrated analysis. In the integrated analyses eslicarbazepine acetate 400mg, 800mg, 1,200mg and placebo were associated with response rates of 23%, 36%, 44% and 22%, respectively, and 3%, 3.8%, 8% and 2% of patients in the respective groups were seizure- free during the maintenance period. Of the 857 patients who completed the double-blind phases of the three phase III studies 97% entered open-label extensions and 73% of these patients completed one year’s treatment with eslicarbazepine acetate median daily dose of 800mg. In the ITT population (all patients who had received at least one dose of study drug and had at least one efficacy assessment in the open- label phase), mean relative reductions from baseline in seizure frequency during weeks 41 to 52 were 41%, 39% and 58% for studies A, B and C respectively. During the double-blind treatment phase there were no major changes in the quality of life in epilepsy inventory-31 (QUOLIE-31) mean scores from randomisation to last visit for any of the subscales or the overall score in either the placebo or eslicarbazepine acetate groups. Other data were also assessed but remain commercially confidential.* Summary of evidence on comparative safety In the double-blind phases of the three phase III studies the incidence of treatment-emergent adverse effects increased with increasing doses of eslicarbazepine acetate 400mg, 800mg and 1,200mg: 60.7%, 62.7% and 67.5%, in the respective groups and 46.4% with placebo. The dose-dependent increase was also seen for possibly-related adverse effects (38.3%, 47.2% and 55% in the respective groups and 24.9% with placebo) and adverse effects leading to discontinuation of study medication (8.7%, 11.6%, 19.3% in the respective groups and 4.5% with placebo). There was a higher, but not dose related, incidence of serious adverse effects in the eslicarbazepine acetate groups (3.7%) compared to the placebo group (4.5%), with 3 incidences in the eslicarbazepine acetate 400mg, 800mg and 1,200mg groups of 4.6%, 3.5% and 3.2%, respectively. There are no direct comparative data. However, the European Medicines Agency (EMA) review of eslicarbazepine acetate notes that in general the profile of at least possibly related treatment- emergent adverse effects appears similar to oxcarbazepine and some (e.g. headache, diplopia, nausea and vomiting) appear to occur less frequently compared to the known frequencies with oxcarbazepine. However, conclusive results could only be provided from active comparator studies. Summary of clinical effectiveness issues Efficacy is reported as LS mean seizure frequency during the maintenance period. The figures are derived from complex processing of seizure frequency data. In the integrated analysis of the three phase III studies median four-week seizure frequencies with placebo and eslicarbazepine acetate 400mg, 800mg and 1,200mg were 7.0, 8.0, 7.7 and 8.0, respectively, at baseline and 6.4, 5.9, 5.0 and 4.6, respectively, during the maintenance period. The EMA noted that in responder analyses in the three phase III studies and integrated analysis patients who discontinued treatment prematurely during one of the treatment periods were still categorised as treatment responders for that particular period when their seizure frequency was reduced by 50% or more before discontinuation. Supplementary analyses in which patients who discontinued were regarded as non-responders were consistent with the original analyses. The EMA also noted that the frequency and character of the major protocol violations of study C raised doubts about the reliability of the study results. However, when it was excluded from the integrated analysis the outcomes were not significantly different from the overall integrated analysis. The manufacturer wishes to position eslicarbazepine acetate for use in patients who have failed to respond to numerous AED. However, available efficacy data are derived from studies in which some patients may have received only one previous AED. Information on patients’ lifetime previous AED use was not recorded in these studies, therefore it is not possible to estimate efficacy within the subgroup of patients who have failed to respond to numerous AEDs. An indirect comparison was provided to support an assumption used in the economic analysis - that eslicarbazepine acetate 800mg daily is associated with a slightly higher response rate than lacosamide 400mg daily. The wide credible limits around relative risk and odds ratios indicate that it did not establish eslicarbazepine acetate or lacosamide as being more effective than the other. Of note, the indirect comparison did not adjust for differences across study populations. On average patients in the eslicarbazepine acetate studies, compared to those in the lacosamide studies, had lower baseline four-week seizures frequencies, with medians ranging from 6.7 to 9 and 9.9 to 16.5, respectively.