PII-094 - A PHASE 1, SINGLE ASCENDING DOSE (SAD) STUDY OF FOOD EFFECT AND DRUG-DRUG INTERACTION (DDI) EFFECTS OF PH-MODIFYING AGENTS ON INCB099280 PHARMACOKINETICS (PK), A PROGRAMMED DEATH-LIGAND 1 (PD-L1) INHIBITOR, IN HEALTHY PARTICIPANTS

X. Gong, E. Cimino, C. Leonetti-Whalen, P. Wang, X. Chen, N. Punwani; Incyte Research Institute.

Background: A SAD, food effect, and DDI study was conducted to evaluate PK, safety, and tolerability of INCB099280 (PD-L1 inhibitor) tablets in healthy participants.

Methods: In the SAD study, 36 adult participants were randomized (3:1) to a single dose of oral INCB099280 (25, 75, or 150 mg) or to placebo. The effect of a high- or medium-fat meal was assessed using a 2-way crossover design, with 12 participants in each cohort receiving a single dose of INCB099280 150 mg orally with or without food. DDI effects of pH-modifying agents were assessed using a fixed-sequence design in 13 or 12 participants receiving a single dose of INCB099280 150 mg orally with and without famotidine (histamine type 2 [H2] antagonist) and esomeprazole (PPI), respectively. Serial PK samples were collected predose and up to 96 hours postdose. PK parameters were derived by noncompartmental analysis.

Results: In the fasted state, INCB099280 was absorbed with a median tmax of 4 hours, after which plasma concentrations declined in a multiphasic manner, with a mean terminal t½ of ~10-12 hours. Single-dose exposures increased slightly more than dose proportionally from 25 to 150 mg and dose proportionally from 75 to 150 mg. Plasma Cmax and AUC∞ exhibited moderate to high interindividual variability. Administration of INCB099280 after a high-fat meal significantly delayed median tmax by 2 hours (P=0.0020) and decreased Cmax and AUC∞ by 57% and 43%, respectively. Administration of INCB099280 after a medium-fat meal significantly delayed median tmax by 3 hours (P=0.00390) and decreased Cmax and AUC∞ by 36% and 26%, respectively. Administration of INCB099280 with famotidine did not impact INCB099280 exposure, whereas esomeprazole decreased Cmax and AUC∞ by 65% and 57%, respectively. No serious adverse events (AEs) were reported. All treatment-emergent AEs were mild or moderate, with no dose- or treatment-dependent trends observed.

Conclusion: INCB099280 PK was impacted by food. INCB099280 may be dosed concomitantly with H2 antagonists without dose adjustment, but should not be dosed concomitantly with PPIs. Single doses of INCB099280 were generally safe and well tolerated in healthy participants. These exposure and safety results support further evaluation of INCB099280 in clinical studies.