Abstracts

Rationale:
A considerable need exists for new treatment options for adults with pharmacoresistant Dravet syndrome (DS). Many adult patients experience substantial seizure burden, resulting in comorbidities and elevated risk of sudden unexpected death in epilepsy. Fenfluramine (FFA) was recently approved by the US FDA for patients ≥ 2y/o with DS. Although an inclusion criterion for the phase 3 studies was DS patients 2 to 18y/o, several patients turned 18 before the first dose in either the randomized controlled trials (RCTs) or the open-label extension (OLE). The current analysis reports efficacy and safety outcomes from 14 patients who entered the phase 3 program and subsequently turned 18y/o during the trials.
Method:
This case series represents a subset of patients with confirmed DS who participated in 1 of 2 RCTs (NCT02682927/NCT02826863; NCT02926898) and the subsequent OLE (NCT02823145). In the RCTs, following a 4-week baseline, patients were randomized to placebo or FFA (0.2 or 0.7mg/kg/day, Study 1, max 26mg/day; 0.5mg/kg/day, Study 2, dose adjusted for stiripentol, max 17mg/day). After 2-3 weeks’ titration, patients were treated 12 additional weeks. Eligible patients entered the OLE at 0.2mg/kg/day FFA and after 4 weeks were titrated to effect (0.2-0.7mg/kg/day). Study endpoints included the percent change from pre-randomization baseline in convulsive seizure frequency per 28 days (monthly; MCSF).
Results:
Seven patients in the RCTs were 18 or 19y/o at time of first dose (all white; 71% female; 60.6kg median baseline body weight). Four patients in the RCTs were randomized to placebo and 3 to FFA. Median baseline MCSF was 23.3 in the placebo group and 14.7 in the FFA group. Patients treated with FFA experienced substantially greater change from baseline (median -79.9%) than those given placebo (‑16.7%; Figure). All 3 patients treated with FFA achieved a ≥ 50% reduction in MCSF and 2 patients achieved a ≥ 75% reduction, compared to 0 patients in the placebo group for either response. An additional 7 patients turned 18y/o on entry into the OLE and received FFA as adults (Table). Median treatment duration for these 7 patients was 733 days (range 30-905), with MCSF change from baseline in the OLE of -72.6% (range -98.0% to 176.9%). Five of 7 patients (71%) achieved MCSF reduction ≥ 50%. Adverse events (AEs) in ≥ 2 patients in the RCTs included nasopharyngitis and a fall. In the OLE, 1 patient experienced myoclonus, appetite decrease, apathy, and dehydration as serious AEs. No cases of valvular heart disease or pulmonary hypertension were reported in any patient at any time.
Conclusion:
In this case series of adults with DS, FFA treatment resulted in clinically meaningful reduction in MCSF (≥ 50%) in 12 of 14 patients. The safety profile was favorable for adults and matched previous reports in pediatric cohorts. Given the substantial morbidity and mortality of DS, FFA represents a treatment strategy with a favorable benefit-to-risk profile for adults with DS.
Funding:
:Zogenix.