Fenfluramin (1) – Fintepla®

• Clinical trials
  • Study 1 (a combination of studies 1501 and 1502) is a randomised, placebo-controlled, double-blind Phase III study with a parallel-group design (1:1:1) designed to investigate the efficacy and safety of fenfluramine 0.7 mg/kg/day and fenfluramine 0.2 mg/kg/day compared with placebo in children and adolescents with Dravet syndrome.
  • Study 1504 had a similar design: in this study, patients were randomised 1:1 to receive 0.4 mg/kg/day of fenfluramine or placebo.
  • Study 1503 is a single-arm, multicentre, ongoing, open-label Phase III extension study into which children and adolescents aged between 2 and 18 years can be enrolled following completion of studies 1501, 1502 and 1504.

Individuals aged 2 years and over with seizures associated with Dravet syndrome

• Overall, there is a hint of a considerable additional benefit.
• In its overall assessment of the available results on patient-relevant endpoints, the G-BA classifies the extent of the additional benefit of fenfluramine for the treatment of individuals aged 2 years and over with seizures associated with Dravet syndrome, as ‘considerable’ on the basis of the criteria set out in Section 5(8), sentences 1 and 2, in conjunction with Section 5(7), sentence 1, number 4 of the AM-NutzenV.
• The strength of the evidence is classified as ‘hint’, as no data on adult patients were provided, the study duration for the present therapeutic indication is to be regarded as short, and the size of the study population is to be regarded as small.
• mortality
  • No deaths occurred in studies 1 and 1504.
• Morbidity – frequency of convulsive seizures
  • In both studies (Study 1 and 1504), a statistically significant difference was observed between the study arms in favour of fenfluramine, based on the change in the frequency of convulsive seizures between the baseline period and the titration and maintenance phases.
  • As a sensitivity analysis, the difference between the groups in the change from baseline was calculated for the maintenance phases and also yielded statistically significant differences in favour of fenfluramine in both studies.
  • In addition to the between-group differences, responder analyses were conducted. These consistently showed statistically significant differences in favour of fenfluramine for responders with a reduction in convulsive seizures of ≥ 25, ≥ 50 and ≥ 75.
  • A significant advantage in favour of fenfluramine over placebo was also observed for the endpoint ‘increase in the frequency of convulsive seizures > 0 per cent’, which was likewise confirmed by a meta-analysis.
• Morbidity – frequency of non-convulsive seizures
  • In the analysis of the endpoint ‘change in non-convulsive seizures’ (focal seizures without a clear motor component, absence seizures or atypical absence seizures, myoclonic seizures and other unclassified seizures), only those patients who had already reported non-convulsive seizures at baseline were included.
  • A statistically significant difference was observed in Study 1, but not in Study 1504.
• Morbidity – Clinical Global Impression (CGI-I)
  • In both studies, there was a statistically significant difference between the study arms in the proportions of participants showing improvement compared with those showing no change or deterioration, in favour of fenfluramine.
  • A meta-analysis confirmed these results.
  • The assessment of deterioration in the Clinical Global Impression (CGI-I) showed no significant difference between the fenfluramine and placebo study arms.
• Morbidity – Executive function assessed using BRIEF / BRIEF-P
  • With regard to the BRIEF, a statistically significant difference between fenfluramine and placebo in changes from baseline was observed only in Study 1, both for the total score and for the underlying indices.
  • Neither Study 1 nor Study 1504 showed statistically significant changes from baseline in the total score of the BRIEF-P.
• quality of life
  • In Study 1, a statistically significant between-group difference was observed for the total PedsQL score; however, its clinical relevance remains unclear based on Hedges’ g.
  • Neither Study 1504 nor the pooled analysis showed any difference between the study arms. Overall, therefore, no difference relevant to the benefit assessment can be identified.
• Side effects
  • Only minor numerical differences were observed with regard to serious and severe adverse events (AEs) as well as AEs leading to discontinuation of the study medication.
  • In its submission, the pharmaceutical manufacturer provided stratified relative risks at the individual study level and for the corresponding meta-analyses for the endpoints ‘serious AEs’ and ‘AEs of particular interest’. The pooled results showed no significant differences between the study arms.
• Overall assessment
  • For the benefit assessment of fenfluramine for the treatment of individuals aged 2 years and over with seizures associated with Dravet syndrome, results are available from the 14- and 15-week randomised, double-blind and placebo-controlled treatment phases of Study 1 and Study 1504.
  • No deaths occurred in the studies. No conclusions regarding additional benefit can be drawn for the mortality category.
  • In the morbidity category, a reduction in seizure frequency in this therapeutic indication is an important therapeutic goal and is of high clinical relevance. For the clinically relevant endpoints in this therapeutic indication – frequency of convulsive seizures and a 75%, 50 per cent and 25 per cent, as well as an increase in the frequency of convulsive seizures of more than 0 per cent, a statistically significant advantage of fenfluramine over placebo was demonstrated in both studies. The results regarding clinical health status, assessed by the carer using the CGI-I, support this finding. An improvement in health status was noted significantly more frequently in the fenfluramine arms of both studies. For the endpoint of executive function as measured by the BRIEF, a statistically significant advantage was observed in Study 1, but not in Study 1504. No relevant effects were observed for the other morbidity endpoints relevant to the assessment (non-convulsive seizures, executive function as measured by the BRIEF-P). The advantages in the morbidity endpoint category are assessed as considerable overall.
  • In the quality of life category, the analyses of the PedsQL questionnaire revealed no statistically significant advantages of fenfluramine overall. In the side effects category, no significant differences were found for serious AEs or AEs of particular interest; no evaluable data are available for severe AEs or therapy discontinuations due to AEs.

Courtesy translation only, please refer to the German original.