Authors :
Presenting Author: David Vossler, MD – University of Washington School of Medicine, Seattle, WA, USA
Dennis Dlugos, MD, MSCE – Children’s Hospital of Philadelphia (CHOP), Philadelphia, PA, USA
Kate Riney, MB, BCh, BAO, PhD – Neurosciences Unit, Queensland Children’s Hospital, South Brisbane, QLD, Australia; University of Queensland, Brisbane, QLD, Australia
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:
In the randomized, double-blind, Phase 1b/2a PACIFIC trial and open-label extension (OLE), the investigational drug bexicaserin—a highly selective 5-hydroxytriptamine type 2C (5-HT2C) receptor superagonist—was well tolerated, had a favorable safety profile, and demonstrated reductions in countable motor seizure frequency that included clinically meaningful responder rates in participants with any type of developmental and epileptic encephalopathy (DEE; Dravet syndrome, Lennox-Gastaut syndrome, and other DEEs). This post hoc analysis evaluated the effect of bexicaserin over time on reduction of countable motor seizure frequency in the randomized controlled trial (RCT) and OLE, and the sustainability of responses for up to 1 year, including ≥50%, ≥75%, and ≥90% responder rates.
Methods:
Participants were aged ≥12 and ≤65 years at RCT baseline; after completing the 75-day RCT, they could enter the 12-month OLE. Each trial comprised a 15-day flexible titration period (maximum 12 mg TID based on tolerability), followed by a maintenance period. Baseline seizure frequency was determined from the 28-day screening period prior to dosing in the RCT. The median percentage change from baseline in countable motor seizures was assessed during the RCT (bexicaserin vs placebo; after 2, 6, and 8 weeks and end of RCT treatment) and OLE (bexicaserin only; after 1, 6, and 9 months and end of OLE treatment). Time points represent cumulative seizure rates in the RCT or OLE (ie, RCT Weeks 1-2, 1-6; OLE Month 1, 1-6). The sustainability of response was further evaluated as the proportion of participants with ≥50%, ≥75%, and ≥90% seizure frequency reduction during the 12-month OLE.
Results:
Median percentage change from baseline in countable motor seizure frequency with bexicaserin (n=35) diverged from placebo (n=9) by Weeks 1-2 of the RCT (-49.6% vs 1.5%) and was sustained for Weeks 1-6 (-58.0% vs -24.3%), Weeks 1-8 (-60.5% vs -22.0%), and over the entire 75-day RCT treatment period (-59.8% vs -17.4%). In the OLE (n=40), seizure frequency reductions were maintained through 1 year of observation (-59.3%). Responder rates (≥50%, ≥75%, ≥90%) with bexicaserin during the RCT (60%, 31.4%, 11.4%) were maintained in the OLE (55%, 40%, 17.5%), further supporting its sustainability (Figure 1). In contrast, placebo administration yielded a ≥50% response in 33% (n=3/9) of participants in the RCT, with no ≥75% or ≥90% responders.
Conclusions:
Bexicaserin showed a rapid onset in reducing countable motor seizure frequency across DEEs that was sustained over time, with consistent responder rates throughout the RCT and the 1-year OLE. The data suggest that there is no loss of long-term therapeutic benefit of bexicaserin, thereby reinforcing the rationale for the ongoing Phase 3 DEEp program.
Funding:
This study was sponsored by Longboard Pharmaceuticals, Inc, now a part of H. Lundbeck A/S.