060: A Phase 1 Study of 5-HT2C Superagonist LP352 Shows Robust Brain Penetration, a Strong Correlation Between Plasma & CSF Pharmacokinetics & QEEG Changes Reflecting Receptor Engagement

Statement of Purpose: LP352 is a potent and highly selective 5-HT2C superagonist being developed for treatment of developmental and epileptic encephalopathies. LP352 elicits a greater response than serotonin at the 5-HT2C receptor, and has no detected activity at receptors associated with significant adverse side effects: 5-HT2B (valvular heart disease and pulmonary arterial hypertension) and 5-HT2A (psychiatric: insomnia, hallucinations, euphoria). Prior clinical pharmacology studies have shown rapid absorption of LP352 after oral administration, with no clinically meaningful food effect. The purpose of this study is to evaluate the relative plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of multiple oral doses of LP352, while assessing the accompanying effects on quantitative EEG (QEEG) activity.

Description of Methods & Materials: Two cohorts of healthy adults (18-55 yr, n=20) received LP352 (3 mg/mL) oral doses of 6 mg and 12 mg TID. Following initial 2 days of up titration, all subjects were then dosed for 8 days at the target doses. Serial plasma samples were obtained after single dose and selected multiple dose days (Days 8, 9 and 10). Serial CSF samples were obtained at steady state (Day 11). Serial EEGs with eyes in open and closed positions were recorded at baseline and Days -1, 1, 3 & 10 and Day 16 (at trough). Protein unbound fraction of LP352 was determined from steady state plasma samples at multiple timepoints. Validated bioanalytical methods were employed for the analysis of LP352 in various clinical samples for calculating standard PK parameters. All QEEG assessments were performed by registered EEG technologists using state-of-the-art recording instruments.

Data & Results: A very strong correlation was observed between LP352 plasma and CSF PK parameters, with r-values of 0.944 for C_max,ss and 0.986 for AUC_tau. The CSF/plasma exposure ratio for AUC_tau ranged between 0.84 to 0.89. LP352 exhibited dose linear PK in plasma and CSF exposure metrics. Circulating plasma contained >99% of protein unbound fraction of LP352. The observed T_max of LP352 ranged between 2.79 to 2.94 hours in brain and 1.05 to 1.20 hours in plasma. This demonstrates that LP352 has negligible protein binding and readily crosses the blood brain barrier, which are highly desirable properties for CNS compounds. Changes in cerebral activity, as measured by QEEG, occurred across multiple spectral bands (e.g., increases in diffuse delta, and decreases in theta, alpha and beta frequency band amplitudes), suggesting effective receptor engagement in the brain. After continuous dosing, such QEEG changes were time- and dose-dependent. TEAEs were mild-to-moderate and consistent with earlier studies; there were no SAEs.

Interpretation, Conclusion or Significance: This novel study in healthy subjects confirms that LP352 readily crosses the blood brain barrier, exhibits dose linear PK not only in the plasma but also in the brain, and leads to changes in cerebral EEG activity suggesting an effect on central 5-HT2C receptors.

Disclosures: Nuggehally Srinivas, Rosa Chan, Dewey McLin, Chad Orevillo and Randall Kaye are employees at Longboard Pharmaceuticals. David Vossler is a consultant for Longboard Pharmaceuticals, Xenon Pharmaceuticals and Biohaven Pharmaceuticals. David Vossler holds a position on the Speaker’s Bureau of SK Life Science and conducts clinical trials for Longboard Pharmaceuticals, SK Life Science and Xenon Pharmaceuticals.