Manager, Clinical Pharmacology Arcus Biosciences, Pennsylvania, United States
Disclosure(s):
Nicole Rivera Rosario: No relevant disclosure to display
Objectives: Casdatifan is a potent and selective small molecule inhibitor of HIF-2α, being developed for the treatment of clear cell renal cell carcinoma. The primary objective of this analysis was to assess the relationship between plasma casdatifan concentrations and the change from baseline in Fridericia-corrected QT (ΔQTcF). The second objective was to identify categorical outliers for QTcF and ΔQTcF.
Methods: Data from phase-1 studies ARC-14, ARC-20 and ARC-28 were used in this analysis. Time-matched casdatifan concentrations and triplicate ECG recordings were available over a wide range of concentrations including at a 1.5-fold higher exposure than those achieved at current intended Ph3 dose of 100 mg once daily. Triplicate ECG data were obtained pre-dose and at different time points post-dose following single and multiple dosing with casdatifan. In total, there were 1857 evaluable PK-ECG matched observations from 153 subjects. The effects of heart rate (HR) on QT were corrected based on Fridericia method (ie, QTcF = QT×(HR/60)1/3). A concentration-QTcF linear mixed effects model-based analysis and graphical visualization of data was performed. The concentration-QTcF model had: 1) ΔQTcF as the dependent variable; 2) fixed effect parameters as intercept (baseline QTcF) and slope(s), influence of baseline on intercept, treatment versus placebo; 3) plasma concentrations of casdatifan as the explanatory variable; and 4) additive random effects on intercept per subject. A supratherapeutic exposure was simulated at 3-fold to estimate the predicted casdatifan effect at higher concentrations of up to 3000 ng/mL in a virtual population representative of cancer patients, to further characterize the risk in a real-world setting (e.g., overdose or drug-drug interaction). Categorical outliers for QTcF and ∆QTcF were summarized by treatment group in frequency tables for prespecified intervals.
Results: No significant increase or decrease in heart rate was observed when pooled data was evaluated with respect to casdatifan concentrations and time. The assumption of linearity between concentration and ΔQTcF was not violated and the trend line indicated no drug effect. The results of linear mixed effects modeling analysis demonstrated that casdatifan does not have any clinically concerning QTcF prolongation effect (the upper bound of the 90% prediction interval of the predicted effect is < 20 msec) and an effect on ΔQTcF exceeding 20 msec can be excluded within the observed range of plasma concentrations of casdatifan, and up to ~3000 ng/mL. Only CTCAE grade 1 QTcF prolongation was observed in 65 of 1634 (4%) observations or 17 of 187 (9%) subjects.
Conclusions: Overall, the potential of casdatifan to cause QT changes appears to be low. In conclusion, the effect of casdatifan on the QTcF interval was minimal and not clinically significant.
