Bexicaserin Shows Promise for Developmental Epileptic Encephalopathies in Phase 1b/2a PACIFIC Extension

Ngoc Minh D. Le, MD, a pediatric neurologist in San Diego, California and senior medical director at Longboard

In the phase 1b/2a PACIFIC open-label extension (OLE) study, new findings showed that crossover from placebo to treatment with investigational Bexicaserin (Longboard Pharmaceuticals) resulted in significant and sustained reductions in total seizures among patients with developmental and epileptic encephalopathies (DEEs). Investigators concluded that these data further support phase 3 development for the highly selective 5-HT2c receptor superagonist.¹

The open-label extension, which featured 41 patients (32 on bexicaserin; 9 on placebo) with DEEs across 34 sites, included a 15-day flexible titration period (maximum dose of 12 mg TID, based on tolerability), followed by up to 1 year of maintenance treatment. Presented at the 2024 American Epilepsy Society (AES) Annual Meeting, held December 6-10 in Los Angeles, California, the analysis focused on the 9 patients previously randomized to placebo who then switched to bexicaserin for a 6-month period in the OLE.

Led by Ngoc Minh D. Le, MD, a pediatric neurologist in San Diego, California and senior medical director at Longboard, patients who switched to bexicaserin experienced a –57.3% reduction in countable motor seizures (CMS) and a –61.2% reduction in total seizures. Within this group, which showed no issues in titrating to their maximum tolerated dose, 55.6% of participants demonstrated at least a 50% reduction in the frequency of CMS.

The study comprised of 20 patients with Lennox-Gastaut syndrome (LGS), 3 with Dravet syndrome (DS), and 18 with other DEEs. In the analysis, bexicaserin maintained its safety profile, with no new serious adverse events (AEs) reported in the OLE. Overall, investigators noted that the placebo-to-bexicaserin cohort’s seizure reductions highlight the therapeutic’s consistent across DEE subgroups, giving weight to future, larger-scale studies.

Bexicaserin, a selective 5-HT2c receptor superagonist, is thought to modulate GABAergic neurotransmission, suppressing central hyperexcitability. In the original PACIFIC trial, 52 participants aged 12-65 years old with a DEE diagnosis were included to evaluate the safety, tolerability, efficacy, and pharmacokinetics of oral bexicaserin in 3 doses (6 mg, 9 mg, and 12 mg) vs placebo. Following a 5-week screening period and baseline evaluations, study participants initiated a dose titration over a 15-day period and subsequently continued on the highest tolerated dose throughout the maintenance period of 60 days.²

Of the 52 participants enrolled in the study, 43 were randomly assigned bexicaserin (DS: n = 4; LGS: n = 24; other DEE: n = 15) and 9 to placebo. Despite patients being allowed to remain on a contemporary, stable polytherapy regimen of up to 4 antiseizure medications, results showed a median decrease of 53.3% in CMS for those on the investigational agent (n = 35) vs a 20.8% decrease for those on placebo (n = 9). In specific subgroups, the median motor seizure frequency decreased by 72.1% in DS, 48.1% in LGS, and 61.2% in other DEEs, with placebo-adjusted reductions of 27.3% and 28.6% in LGS and other DEEs, respectively.

At the time of the announced PACIFIC data, Randall Kaye, chief medical officer at Longboard, said in a statement that, "These exciting PACIFIC Study results underscore our belief that bexicaserin’s differentiated profile will translate into a clinically and commercially best-in-class product and has the potential to redefine the standard of care in DEEs. We are pleased to see such strong seizure reduction across a wide range of DEE syndromes with varying etiologies coupled with favorable safety and tolerability results."²

Tracy Dixon-Salazar, PhD

Tracy Dixon-Salazar, PhD, executive director at the LGS Foundation, also wrote in a statement, "The remarkable results from the PACIFIC Study give hope to patients and their loved ones who are in dire need of research and novel therapies in these severe syndromes. A tremendous unmet need remains not only for those living with LGS, but for the many other DEE patients who have not received the attention they deserve, and I applaud this innovative and inclusive approach that is designed to get therapies quickly and safely to even more people."²

In September, Longboard initiated a global phase 3 study dubbed DEEp SEA (NCT06660394) that will assess the therapeutic potential of bexicaserin in patients with DS aged 2 years of age and older. The trial aims to include approximately 160 participants between the ages of 2 and 65 years old who will undergo a 5-week screening period, 3-week dose titration phase, and 12-week maintenance period. Following the maintenance period, eligible participants will be given the opportunity to enroll in the 52-week DEEp Open-Label Extension. Of note, the phase 3 DEEp SEA study is part of a broader DEEp program which will take place across 80 sites globally and include around 480 participants with a range of DEEs.³

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REFERENCES
1. Le NM, Smith S, Weberg M, Polega S. Bexicaserin’s Safety, Tolerability and Efficacy in a Cohort of Participants with Developmental and Epileptic Encephalopathies: Interim Results of a Phase 1b/2a PACIFIC Study Open-label Extension (OLE). Presented at: 2024 AES Annual Meeting; December 6-10; Los Angeles, CA. ABSTRACT 1.509
2. Longboard Pharmaceuticals Announces Positive Topline Data from the PACIFIC Study, a Phase 1b/2a Clinical Trial, for Bexicaserin (LP352) in Participants with Developmental and Epileptic Encephalopathies (DEEs). News release. Longboard Pharmaceuticals. January 2, 2024. Accessed December 4, 2024. https://ir.longboardpharma.com/news-releases/news-release-details/longboard-pharmaceuticals-announces-positive-topline-data
3. Longboard Pharmaceuticals Initiates Phase 3 DEEp SEA Study Evaluating Bexicaserin in Dravet Syndrome. News release. September 26, 2024. Accessed December 4, 2024. https://ir.longboardpharma.com/news-releases/news-release-details/longboard-pharmaceuticals-initiates-phase-3-deep-sea-study