PI-059 - CASDATIFAN (AB521) PHARMACOKINETICS IS SIMILAR WHEN ADMINISTERED AS CAPSULES OR TABLETS AND IS UNAFFECTED BY FOOD

M. Ghasemi¹, H. Huang¹, K. Liao¹, E. Paterson¹, P. Foster¹, J. Chen¹, B. Agoram¹; ¹Arcus Biosciences, Hayward, CA, USA.

Background: Casdatifan (AB521), an orally bioavailable small molecule inhibitor of HIF-2α, potently inhibits transcription of HIF-2α-dependent genes in cell lines and preclinical species. The objective of this study was to evaluate the relative bioavailability of casdatifan tablet and capsule formulations and the effect of food on the pharmacokinetics (PK) of the tablet formulation in healthy participants.

Methods: In a Phase 1, open-label, randomized, single-dose, 3-treatment, 3-period, 3-way crossover study ARC-28 (NCT05999513), 24 healthy participants on Day 1 of each treatment period received a single oral dose of 100 mg casdatifan capsules under fasting conditions, or 100 mg casdatifan tablets under fasting or fed (high-fat meal) conditions. Plasma PK samples for casdatifan were taken predose and up to 168 hours postdose in each period. There was a washout period of 7 days between the casdatifan doses. PK parameters, including total exposure (AUC from time zero to the last measurable concentration [AUC0-t] and AUC from time zero extrapolated to infinity [AUC0-inf]), maximum concentration (Cmax), and time to reach maximum concentration (Tmax) were calculated for each participant in each period and the parameter ratios were calculated.

Results: Total exposure of casdatifan (AUC0-t and AUC0-inf) administered as tablets is generally equivalent to capsules with the 90% confidence interval (CI) of exposure ratio lying within 80% to 125%. The upper bound of the 90% CIs for Cmax (109.71-126.43%) slightly exceeded the upper limit of this reference range (80-125%), but this is unlikely to be clinically significant. In addition, the total exposure of casdatifan (AUC0-t and AUC0-inf) in tablets with or without food was equivalent (GMR of 97.98% and 98.04%), while food resulted in a 23% reduced Cmax and delayed Tmax (4.0 h vs 2.0 h).

Conclusion: Overall, casdatifan PK, when administered as tablets or capsules, were generally equivalent and food had a minimal effect on casdatifan exposure. Casdatifan can be administered irrespective of food intake.