Authors :
Presenting Author: Pavel Klein, MD – Mid-Atlantic Epilepsy and Sleep Center, Bethesda, MD, USA
Terrence J. O'Brien, MB, BS, MD, FRACP, FRCPE, FAHMS, FAES – Monash University, Melbourne, VIC, Australia
Dennis Dlugos, MD, MSCE – Children’s Hospital of Philadelphia (CHOP), Philadelphia, PA, USA
Nadine Knowles, MS – H. Lundbeck A/S, Copenhagen, Denmark
Tolga Uz, PhD – H. Lundbeck A/S, Copenhagen, Denmark
Randall Kaye, MD – Longboard Pharmaceuticals (now a part of H. Lundbeck A/S), La Jolla, CA, USA
Sidsel Jensen, MSc, PhD – H. Lundbeck A/S, Copenhagen, Denmark
Shikha Polega, PharmD – H. Lundbeck A/S, Copenhagen, Denmark
Rationale:
Developmental and epileptic encephalopathies (DEEs) are the most severe epilepsies, characterized by treatment-resistant seizures, background epileptiform activity, and developmental slowing or regression.1 Despite polytherapy with multiple antiseizure medications (ASMs), efficacy beyond the addition of a second agent is limited in refractory epilepsies like DEEs.2,3 Onset of seizures usually occurs in infancy or childhood, and patients often cycle through numerous ASMs as they age.4,5 Bexicaserin is a highly selective 5-hydroxytryptamine type 2C (5-HT2C) receptor superagonist under investigation to treat seizures associated with DEEs. Results from the Phase 1b/2a PACIFIC randomized controlled trial (RCT) with bexicaserin showed a meaningful reduction in countable motor seizure frequency and a favorable safety profile in participants aged 12-65 years with any type of DEE. This post hoc analysis examined concomitant ASM use in this highly treatment-resistant population and evaluated bexicaserin efficacy stratified by number of concomitant ASMs.
Methods:
Participants with DEEs (Dravet syndrome, Lennox-Gastaut syndrome, or other DEEs) were eligible for RCT enrollment if they were nonresponsive to their current, stable ASM regimen; suboptimal response was confirmed by the inclusion criterion of ≥4 countable motor seizures observed during the 28-day screening period. Reduction in countable motor seizure frequency with bexicaserin vs placebo was evaluated for subgroups stratified by concomitant ASM use (3, 4, or ≥5 ASMs).
Results:
Participants (bexicaserin, n=35; placebo, n=9) received a median of 3 concomitant ASMs during the RCT; 34 participants (77.3%) received ≥3 ASMs and 10 (22.7%) were taking 1-2 ASMs. Overall, the median change from baseline in countable motor seizure frequency was -59.8% with bexicaserin vs -17.4% with placebo. Subgroup analysis showed consistent efficacy with bexicaserin across concomitant ASM regimen sizes: 3 ASMs, -61% vs -17.4% (n=9 vs 5); 4 ASMs, -49.9% vs 167.4% (n=16 vs 1); and ≥5 ASMs, -52% vs 43.6% (n=2 vs 1).
Conclusions:
In this post hoc analysis of participants with any type of DEE who received ≥3 concomitant ASMs, reductions in countable motor seizure frequency with bexicaserin were comparable to previously reported aggregate data. These findings suggest that bexicaserin remains effective in highly refractory populations, including those with suboptimal seizure control beyond the addition of a second ASM, and support progression to the recently initiated Phase 3 DEEp program.
1. Scheffer I, et al. Epilepsia. 2025;66:1014-1023.
2. Kwan P, Brodie MJ. N Eng J Med. 2000;342:314-319.
3. Chen Z, et al. JAMA Neurol. 2017;75(3):279-286.
4. Wirrell EC, et al. Epilepsia. 2022;63(7):1761-1777.
5. Cross JH, et al. Epilepsia. 2024;65(5):1224-1239.
Funding:
This study was sponsored by Longboard Pharmaceuticals, Inc., now a part of H. Lundbeck A/S.