Authors :
Presenting Author: Sheryl Vermudez, PhD – Longboard Phamaceuticals, Inc.
Celina Zerbinatti, PhD – Longboard Pharmaceuticals, Inc.
Anne Danks, PhD – Longboard Pharmaceuticals, Inc.
Marco Peters, PhD – Longboard Pharmaceuticals, Inc.
Rationale:
Sudden unexpected death in epilepsy (SUDEP) is a rare, yet devastating event for patients with developmental and epileptic encephalopathies (DEEs). DEEs are the most severe group of epilepsies characterized by drug-resistant seizures, epileptiform abnormalities, and developmental slowing or regression. Poor seizure control and brainstem dysfunction are two main contributors of SUDEP. The brainstem is enriched with transcript levels of 5-HT2C receptors, and accordingly, Htr2c knockout mice are susceptible to both seizures and SUDEP. Bexicaserin (also known as LP352), a potent and highly selective 5-HT2C receptor superagonist, is currently in development for the treatment of seizures in patients with DEEs. Given recent preclinical and clinical data (PACIFIC Study, LP352-201, NCT05364021) demonstrating bexicaserin’s anticonvulsant activity, the effect of bexicaserin in a mouse model of SUDEP was evaluated.
Methods:
Mixed-sex 23-24-day-old DBA/1 mice were presented with a 110-120 dB tone (audiogenic stimulus) to induce generalized tonic-clonic seizures, which progress from wild running to clonic and tonic seizures, and respiratory arrest, a measurable correlate of SUDEP. Prior to drug testing, mice underwent a priming phase that consisted of 3 consecutive days of a single tone presentation per day to induce seizures and respiratory arrest. Mice that exhibited respiratory arrest were resuscitated using a rodent respirator. Epileptic mice were defined as those showing respiratory arrest on days 2 and 3 of the 3-day priming period. These mice were subsequently used for the testing phase on day 4, which involved oral administration of vehicle or bexicaserin, followed by a tone presentation at specified timepoints (0.5, 6 or 24 hours) post-treatment. The incidence of and latency to seizure types and respiratory arrest were recorded.
Results:
Vehicle-treated mice exhibited a 100% incidence of all seizure types and respiratory arrest at all timepoints post-treatment (0.5, 6 or 24 hours). Bexicaserin treatment dose-dependently decreased incidence of all seizure types and prevented respiratory arrest in all mice at 6 hours post-dose (p < 0.01 vs vehicle). Bexicaserin also increased latency to all seizure types and respiratory arrest at 6 hours post-dose (p < 0.001 vs vehicle). A similar dose-dependent partial drug effect was observed at 0.5 hours post-dose (p < 0.05 vs vehicle). The incidence of seizures and respiratory arrest returned to baseline following drug washout at 24 hours post-dose.