Bexicaserin for the treatment of seizures in developmental and epileptic encephalopathies: A phase 1b/2a trial (PACIFIC)

Objective: This randomized, double-blind, phase 1b/2a clinical trial was designed to evaluate the safety, tolerability, and efficacy of oral bexicaserin versus placebo for the treatment of seizures in adolescents and adults with developmental and epileptic encephalopathies (DEEs). Methods: Eligible participants had a DEE diagnosis, were aged 12–65 years, and were taking 1–4 concomitant antiseizure medications. Randomization to treatment groups (4:1 bexicaserin:placebo) was stratified by type of DEE (Dravet syndrome [DS], Lennox–Gastaut syndrome [LGS], or DEE Other). Following a 28-day baseline period, the treatment period consisted of a 15-day flexible uptitration period (6, 9, or 12 mg three times daily, 5 days each) and a 60-day maintenance period on the highest tolerated dose. Primary end points were safety (adverse events) and change from baseline in countable motor seizure frequency. Results: Forty-three and nine participants were assigned to bexicaserin treatment and placebo, respectively, and received ≥1 dose (safety set); 35 bexicaserin and nine placebo participants completed titration, entered the maintenance period, and had ≥1 seizure measurement during the maintenance period (full analysis set). Twenty-eight of 43 bexicaserin-treated participants (65.1%) and three of nine (33.3%) in the placebo group reported drug-related treatment-emergent adverse events (TEAEs); seven of 43 participants (16.3%) discontinued bexicaserin due to a TEAE during titration and two of 43 (4.7%) during maintenance, most frequently due to somnolence. Median reductions in countable motor seizure frequencies were −59.8% with bexicaserin and −17.4% with placebo; reductions with bexicaserin were observed across DEEs (DS, −74.6%; LGS, −50.8%; DEE Other, −65.5%). The proportion of participants achieving ≥50% reductions during the treatment period (responder analysis) was 60.0% with bexicaserin versus 33.3% with placebo. Significance: Bexicaserin was well tolerated and associated with clinically relevant reductions in countable motor seizure frequencies in participants with a variety of DEEs. This novel trial design may expand treatment access to patients previously excluded from clinical trials.