Evaluation of Prolactin as a Useful Pharmacodynamic Tool to Assess Engagement of Central 5-HT2C Receptors by LP352, a Potent and Selective 5-HT2C Agonist
Abstract number :
1.29
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2022
Submission ID :
2204440
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:25 AM
Authors :
Rosa Chan, PhD – Longboard Pharmaceuticals; Dewey McLin, PhD – Longboard Pharmaceuticals; Randall Kaye, MD – Longboard Pharmaceuticals
Rationale: Converging lines of human and animal evidence support the hypothesis that prolactin elevations in response to serotonergic agonists reflect drug-induced activation of 5-HT2C receptors in the central nervous system (CNS). Therefore, serum prolactin may represent a useful pharmacodynamic tool for evaluating the engagement of central 5-HT2C receptors in the brain by serotonergic agonists. LP352 is a potent and selective 5-HT2C receptor agonist; it displays a binding affinity of 44 nM at the human 5-HT2C receptor and shows >227-fold selectivity for the 5-HT2C receptor versus 5-HT2A and 5-HT2B. LP352 is being developed for the treatment of childhood onset and adult refractory motor seizures, conditions for which serotonergic agonists have been shown efficacious.
Methods: Serum prolactin levels of LP352 were evaluated in first in human single (SAD) and multiple (MAD) ascending dose studies. Both studies were randomized, double blind, placebo-controlled studies in healthy human volunteers. The SAD study contained 6 arms: single oral doses of 1, 3, 6, 12, or 24 mg (n=6) or placebo (n=10). The MAD study contained 5 arms: 3, 6, 12, or 18 mg LP352 three times daily (TID) (n=6) or placebo (n=8). Prolactin serum concentrations were summarized by timepoint and dose. Predose serum prolactin values on Day 1 were considered the baseline values. Fold change from baseline was calculated against the maximum prolactin level at 2 hours post dose on Day 1 and Day 14.
Results: Prolactin demonstrated an acute dose-dependent increase at 2 hours following single LP352 doses (1 mg to 24 mg) (Figure 1), as well as after the first dose of the 14-day multiple dose regimen (3 mg TID to 18 mg TID) (Figure 2A). In addition, Day 14 evaluation of prolactin did not demonstrate any differences between LP352 and placebo (Figure 2B). No subject reported an adverse event that could be attributed to hyperprolactinemia (e.g., galactorrhea, gynecomastia).
Conclusions: These data indicate that, at doses studied in humans, LP352 engages central 5-HT2C receptors at physiologically relevant concentrations and support the suitability of prolactin as a biomarker of 5-HT2C agonism in the early period of dosing. The attenuation of response on Day 14 suggests that the prolactin increase elicited by LP352 activation of 5-HT2C receptors is transient.
Funding: Sponsored by Longboard Pharmaceuticals
Anti-seizure Medications