56 Clinical Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship Confirms Best-in-class Potential of Casdatifan (AB521), a Small Molecule Inhibitor of HIF-2α Being Developed in Renal Cancer
Authors: Ghasemi Mohammad , Khosravan Reza , Kim Ji Yun , Seitz Lisa , Foster Paul , Agoram Balaji 
Published: August 2024

Abstract

Background
Casdatifan, 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 analysis was to develop an understanding of the relationship between clinical dose, casdatifan PK, erythropoietin (EPO), a PD biomarker for peripheral (non-tumor) HIF-2α inhibition, and hemoglobin and to use this information to guide dose selection in future clinical trials.

Methods
Casdatifan plasma concentrations, serum EPO concentration, and hemoglobin data were obtained from 79 healthy participants in two Phase 1 studies, ARC-14 (NCT05117554) and ARC-28 (NCT05999513), and from 71 patients with clear cell renal cell carcinoma (ccRCC) and other solid tumors in an ongoing Phase 1 study, ARC-20 (NCT05536141). The available PK and PD data were collected following single oral doses of casdatifan ranging from 3 mg to 100 mg in healthy participants, and multiple oral doses of casdatifan ranging from 15 mg to 150 mg once daily (QD) in healthy participants and cancer patients. Serial PK, EPO, and Hb data were gathered in all study participants pre-dose till end of treatment. The population PKPD model was developed using mixed effects methodology with NONMEM software to relate dose, PK, and PD (EPO and Hb) data.

Results
Casdatifan showed dose-proportional increases in plasma exposure over the 3-150 mg dose range after single and multiple doses. Casdatifan PK was also invariant over time in patients with an approximately 2.0-fold accumulation at steady-state compared to first dose. The mean terminal half-life of casdatifan was approximately 24 h. The PK was similar in healthy participants and cancer patients. Dose-dependent reduction in EPO was observed after single and multiple doses in healthy participants and patients.
A two-compartment model with first-order absorption adequately described the casdatifan plasma PK across the dose range tested. The effect of casdatifan plasma concentrations on EPO production rate was modeled using an inhibitory function.
Analysis of the casdatifan dose-PD (EPO suppression) relationship indicated that casdatifan 20 mg once daily provided a similar level of EPO suppression in patients as belzutifan 120 mg daily (benchmark peripheral PD). Furthermore, due to the dose-proportional PK of casdatifan, the selected dose (100 mg daily) for further development results in plasma levels approximately 5 times higher than those associated with the benchmark peripheral PD.

Conclusions
Casdatifan exhibits dose-linear and time-invariant PK in the dose range 15-150 mg. Dose-dependent reduction in EPO levels, consistent with the mechanism of action of HIF-2α inhibition, was seen after casdatifan administration. A PKPD analysis of available data indicated that 20 mg daily dose of casdatifan would result in similar EPO effect as the registered dose of belzutifan. Available PKPD data and analyses indicated best-in-class properties of casdatifan.