Comparative effectiveness of fenfluramine versus cannabidiol in their licensed indications for the treatment of seizures in Dravet Syndrome: a systematic review and network meta-analysis

PurposeFenfluramine and cannabidiol are licensed as add-on therapies for the treatment of seizures in Dravet syndrome (DS); however, there are no comparative trials of these therapies. We assessed the comparative effectiveness of fenfluramine (with/without concomitant stiripentol) versus cannabidiol (with/irrespective of concomitant clobazam, using robust indirect comparison methods. MethodsWe systematically searched for randomised controlled trials (RCTs) of licensed regimens published up to 30 November 2021. Outcomes of interest were placebo-adjusted reductions from baseline in monthly convulsive seizure frequency (MCSF), the odds of achieving [&ge;]25%, [&ge;]50%, [&ge;]75% and 100% reductions from baseline in MCSF, and the odds of experiencing serious treatment-emergent adverse events (TEAEs). Comparative efficacy and safety were assessed using Bayesian network meta-analysis (NMA). PROSPERO registration: CRD42021296141. ResultsWe identified five relevant placebo-controlled RCTs (three for fenfluramine; two for cannabidiol; N=667). All licensed regimens of fenfluramine and cannabidiol significantly reduced MCSF compared with standard of care. When indirectly comparing fenfluramine 0.7mg/kg/day (without concomitant stiripentol) and fenfluramine 0.4mg/kg/day (with concomitant stiripentol) versus cannabidiol 10mg/kg/day, irrespective of clobazam use, the mean differences in placebo-adjusted reduction from baseline in MCSF were 47.3% (95%CrI: 18.9, 64.7) and 35.1% (1.0, 57.5), respectively, and versus cannabidiol 10mg/kg/day plus clobazam were 37.2% (2.0, 59.7) and 23.5% (-20.2, 51.3), respectively. For these outcomes, and for the proportion of patients achieving [&ge;]25%, [&ge;]50% and [&ge;]75% reductions in MCSF, Bayesian treatment ranking indicated [&ge;]99% probability that fenfluramine is the most effective therapy versus <1% probability for cannabidiol 10 or 20mg/kg/day (maximum recommended dose), with/irrespective of concomitant clobazam. Fenfluramine regimens had lower odds of serious TEAEs. ConclusionNMA using RCT data indicates fenfluramine provides superior convulsive seizure control compared to cannabidiol across all licensed dose regimens and is comparatively well-tolerated. Fenfluramine may meet the need for a highly effective and tolerable add-on therapy to control seizures in DS. O_TEXTBOXWhat is already known on this topicO_LIFenfluramine (Fintepla(R)) is a recently licensed add-on therapy to standard of care antiepileptic drugs for the treatment of seizures in Dravet syndrome. C_LIO_LICannabidiol (Epidiolex(R)/Epidyolex(R)) is also licensed for this use. In Europe cannabidiol is only licensed for use with concomitant clobazam. C_LIO_LIThere are no direct comparative data to inform on the relative efficacy and safety of these therapies in the management of seizures in Dravet syndrome. No indirect comparisons have been conducted across the full licensed dose regimens of these therapies. C_LI What this study addsO_LIBased on NMA using RCT data, fenfluramine provides superior convulsive seizure control in Dravet syndrome compared with cannabidiol across all licensed dose regimens, and is comparatively well tolerated. C_LIO_LIFenfluramine may meet the need for a highly effective and tolerable add-on therapy to control seizures in Dravet syndrome C_LI C_TEXTBOX