Investigational Encephalopathy Agent LP352 Safe and Effective in Phase 1 Trial

Longboard Pharmaceuticals plans to initiate a phase 1b/2a trial to determine the efficacy of the 5-HT2c receptor superagonist in patients with developmental and epileptic encephalopathies.

Favorable tolerability, safety, pharmacokinetics (PK) and pharmacodynamics (PD) were observed in the multiple ascending dose (MAD) portion of the phase 1 clinical trial of LP352 in healthy patients, Longboard Pharmaceuticals announced. The company also announced plans for a phase 1b/2a trial in adult patients with developmental and epileptic encephalopathies (DEEs), anticipated to begin enrollment in the first quarter of 2022.1

The phase 1 trial evaluated escalating doses of LP352. The agent is a centrally acting, 5-HT2C receptor superagonist that is hoped to be used to treat seizures associated with epileptic disorders such as Dravet syndrome (DS), Lennox-Gastaut syndrome, tuberous sclerosis complex, and CDKL5 deficiency disorder. 

"We are very pleased that we achieved the goals of this trial, which were to explore the safety, tolerability, PK and PD of LP352 at several dose levels and determine the optimal expected dose range for our upcoming efficacy trial. We are encouraged by the initial safety and tolerability characteristics of LP352 observed in the trial and that it appears to have a potent effect on the 5-HT2c pathway," Phil Perera, MD, MBA, chief medical officer, Longboard Pharmaceuticals, said in a statement.1 "We believe LP352 has the potential to reduce seizures in a broad range of severe and devastating, treatment-resistant epilepsies, and we look forward to advancing the program in patients living with these debilitating disorders."

READ MORE: Epilepsy Among Major Risk Factors for Sudden Unexplained Death

The first-in-human, randomized, placebo-controlled, double-blind, 4-part phase 1 trial included a total of 83 patients, divided into the MAD and single-ascending dose groups. Those in the MAD group (n = 43) were given up to the maximum of 5 doses of LP352, which is intended suppress central hyperexcitability associated with seizures by regulating GABA inhibition. 

Two days after the final dose of the maximum planned dose was administered, 1 serious adverse event (AE) of anxiety was reported. Of the mild to moderate AEs reported, headache was the most common, with AEs similar to those expected from serotonergic drugs and central nervous system (CNS) effects.

Investigators observed increases of prolactin that were both dose and exposure-dependent, which may offer proof of engagement with the central 5-HT2c receptor. Exposure (Cmax and AUCtau) were also observed to be dose-dependent. Preclinical trials of LP352 found an insignificant effect on 5-HT2B and 5-HT2A receptor subtypes, both of which can trigger adverse effects. The treatment aims to reduce seizures in patients with DEE, as it has more selectivity for the 5-HT2C receptor subtype.

Longboard Pharmaceuticals also has additional treatments in the pipeline for CNS disorders. For the potential treatment of neurodegenerative diseases with microglial activation causing neuroinflammation, the company is evaluating LP143, a centrally acting full cannabinoid type 2 receptor agonist. For the treatment of CNS neuroinflammatory diseases, LP659, a centrally acting, sphingosine-1-phosphate receptor subtypes 1 and 5 modulator, is also in development.

Lorcaserin, a selective serotonin 5-HT2c receptor agonist, is another potential therapy in development by Eisai for patients with DS, with the company announcing the phase 3 MOMENTUM1 clinical trial (also known as Study 304; NCT04572243) in September 2020.2 Originally approved under the name Belviq, the weight-loss medication was voluntarily withdrawn in February 2020 following data from a cardiovascular safety study, CAMELLIA-TIMI 61, which found an increased occurrence of cancer in patients taking the drug.3 The drug was then being used for off-label treatment in patients with DS. 

REFERENCES
1. Longboard Pharmaceuticals successfully completes LP352 multiple ascending dose portion of phase 1 clinical trial in health volunteers, plans to initiate phase 1b/2a clinical trial. News release. Longboard Pharmaceuticals. September 8, 2021. Accessed September 13, 2021. https://www.biospace.com/article/releases/longboard-pharmaceuticals-successfully-completes-lp352-multiple-ascending-dose-portion-of-phase-1-clinical-trial-in-healthy-volunteers-plans-to-initiate-phase-1b-2a-clinical-trial/
2. Eisai initiates phase 3 MOMENTUM 1 clinical trial (Study 304) of lorcaserin in Dravet syndrome. News release. Eisai. September 30, 2020. Accessed September 13, 2021. https://eisai.mediaroom.com/2020-09-30-Eisai-Initiates-Phase-3-MOMENTUM-1-Clinical-Trial-Study-304-of-Lorcaserin-in-Dravet-Syndrome
3. Bohula EA, Wiviott SD, McGuire DK, et al. Cardiovascular safety of lorcaserin in overweight or obese patients. N Engl J Med. 2018;379(12):1107-1117. doi:10.1056/NEJMoa1808721