PACIFIC
(2026)Objective
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).
Study Summary
• Reductions observed across DEE subtypes: Dravet syndrome -74.6%, Lennox-Gastaut syndrome -50.8%, DEE Other -65.5%
• 60.0% of bexicaserin participants achieved ≥50% seizure reduction vs 33.3% with placebo
• Drug-related TEAEs in 65.1% (bexicaserin) vs 33.3% (placebo); 16.3% discontinued during titration and 4.7% during maintenance, most commonly due to somnolence
• Bexicaserin was well tolerated with clinically relevant seizure reductions across a heterogeneous DEE population
Intervention
Oral bexicaserin (5-HT2C receptor superagonist) administered as liquid (orally or via G-tube/PEG) at 6, 9, or 12 mg three times daily during 15-day flexible uptitration, followed by 60-day maintenance on highest tolerated dose, versus placebo.
Inclusion Criteria
Age 12-65 years; diagnosis of DEE (Dravet syndrome, Lennox-Gastaut syndrome, or DEE Other); ≥4 countable motor seizures per 4-week period during 12 weeks before screening and ≥4 during 4-week screening period; taking 1-4 concomitant antiseizure medications at stable doses for ≥4 weeks before screening.
Study Design
Arms: Bexicaserin 6/9/12 mg TID (n=43) vs Placebo (n=9)
Patients per Arm: Bexicaserin n=43; Placebo n=9 (total N=52 safety set; n=44 full analysis set)
Outcome
• Responder rate (≥50% reduction): 60.0% vs 33.3%
• Subgroup reductions: DS -74.6%, LGS -50.8%, DEE Other -65.5%
• Drug-related TEAEs: 65.1% vs 33.3%; somnolence was most common discontinuation reason
• Treatment discontinuations: 7/43 (16.3%) during titration, 2/43 (4.7%) during maintenance
Bottom Line
In this phase 1b/2a trial, bexicaserin was well tolerated and produced clinically meaningful reductions in countable motor seizures (-59.8% vs -17.4% with placebo) across diverse DEE subtypes, supporting the novel inclusive trial design and progression to phase 3 development.
Major Points
- Bexicaserin reduced median countable motor seizure frequency by -59.8% vs -17.4% with placebo across a heterogeneous DEE population.
- Efficacy was consistent across DEE subtypes: Dravet syndrome -74.6%, Lennox-Gastaut syndrome -50.8%, DEE Other -65.5%.
- Responder analysis (≥50% reduction in countable motor seizures): 60.0% with bexicaserin vs 33.3% with placebo.
- Drug-related TEAEs occurred in 65.1% (bexicaserin) vs 33.3% (placebo); somnolence was the most frequent reason for discontinuation.
- Discontinuation rates: 16.3% during titration and 4.7% during maintenance due to TEAEs.
- 85.7% of maintenance participants tolerated the highest dose (12 mg TID); 77.1% sustained it through maintenance.
- The inclusive trial design enrolling DS, LGS, and 'DEE Other' patients may serve as a model to expand access to investigational therapies for previously excluded DEE populations.
- Bexicaserin has progressed to phase 3 development based on these findings.
Study Design
- Study Type
- Phase 1b/2a randomized, double-blind, placebo-controlled, parallel-group, dose-escalation clinical trial
- Randomization
- Yes
- Blinding
- Double-blind (investigators, site staff, participants, caregivers, monitors, sponsor study management, and CRO all blinded)
- Sample Size
- 52
- Follow-up
- 5-week screening/baseline + 15-day flexible uptitration + 60-day maintenance + 5-15-day taper + 30-day follow-up (optional 52-week open-label extension)
- Centers
- 34
- Countries
- United States, Australia
Primary Outcome
Definition: Co-primary endpoints: (1) incidence and severity of treatment-emergent adverse events (TEAEs); (2) median percentage change from baseline in observed countable motor seizure frequency during the treatment period (titration and maintenance)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Median -17.4% change in countable motor seizure frequency | Median -59.8% change in countable motor seizure frequency | - |
Limitations & Criticisms
- Small sample size (N=52) with imbalanced randomization (4:1) limits statistical power and precision of efficacy estimates.
- No formal hypothesis testing performed; reported p-values are nominal and not adjusted for multiple testing.
- Open-label-style exploratory design with no formal sample size calculation.
- Heterogeneous DEE Other group includes diverse etiologies, complicating interpretation of pooled efficacy.
- Short maintenance period (60 days) limits assessment of durability and long-term safety; longer-term data depend on the 52-week OLE.
- Exclusion of patients with cardiovascular/cerebrovascular disease limits generalizability given common DEE comorbidities.
- Caregiver-reported seizure diaries are subject to recall and counting bias, particularly for difficult-to-count seizures.
Citation
Epilepsia. 2026;67(2):646-659.