Abstracts

Rationale:
Fenfluramine (FFA) has demonstrated the ability to provide durable and profound reductions in monthly convulsive seizure frequency (MCSF) in patients with Dravet syndrome treated for up to 2 years, with 37% of patients experiencing a ≥ 75% reduction in MCSF—a degree of seizure frequency reduction associated with clinically meaningful improvement in executive functions. (Bishop KI et al. AES 2019: 2.438) Here we report an updated analysis of the safety and efficacy of FFA in an ongoing open-label extension (OLE) study, with treatment duration of up to 3 years.
Method:
Patients who completed phase 3 controlled studies were eligible to enroll in the OLE study (NCT02823145). All patients initiated FFA at 0.2 mg/kg/day regardless of what dose they previously received in the core studies. At the end of 4 weeks, doses were titrated to effect and tolerability, up to 0.7 mg/kg/day (maximum 26 mg/day) or 0.4 mg/kg/day (maximum 17 mg/day), in patients also receiving stiripentol. Seizure frequency was captured via hand-held e-diary. Effectiveness and safety were assessed at each office visit (monthly for the first 3 months, then every 3 months).
Results:
As of October 14, 2019, 330 patients were enrolled and had received ≥ 1 dose of FFA. At the time of entry into the study, mean±SD age of patients was 9.0±4.6 years and 180/330 (54.5%) were male. Median duration of treatment was 631 days (range: 7-1086), with a total of 282 patients with > 12 months and 128 patients with > 24 months of FFA exposure in the OLE. Reasons for discontinuation included lack of efficacy (14.5%) and adverse events (3.3%). The most common concomitant antiepileptic drugs (AEDs) were valproate (80.6%), clobazam (72.7%), stiripentol (29.4%), topiramate (25.5%), and levetiracetam (25.5%). Median percent MCSF reduction from baseline (in the core studies) compared to most recent visit was -64.5% (P< 0.001) (Figure 1). Over the entire analysis period, 63.4% of patients had clinically meaningful (≥ 50%) MCSF reductions and 38.2% experienced profound (≥ 75%) MCSF reductions; 3 patients were seizure-free during their entire time in the OLE (Figure 2). The most common (≥ 15%) adverse events included pyrexia (28.2%), nasopharyngitis (27.3%), decreased appetite (23.0%), decreased blood glucose (19.4%), diarrhea (18.2%), seizure (16.7%), echocardiogram abnormal (19.4%) limited to nonpathologic trace/physiologic regurgitation, and upper respiratory tract infection (15.5%). No cases of valvular heart disease (VHD) nor pulmonary artery hypertension (PAH) were observed during the entire OLE treatment period.