A novel approach for first-in-human dose selection using population dose-response modelling to find a minimum anticipated biological effect level.

Abstract

Aims: Choice of first-in-human dose has critical implications for the safety of Phase I participants as well as the likelihood of reaching the therapeutic dose range during escalation. In this analysis, we present a population concentration-response modelling approach for selecting the Phase I starting dose for a novel stimulator of interferon response cGAMP interactor 1 (STING) agonist, SNX281.

Methods: Given the immune agonist mechanism of SNX281, we opted to select the starting dose according to the minimum anticipated biological effect level (MABEL). To determine the MABEL concentration, we fitted a population concentration-response model to cytokine induction data from an ex vivo whole blood assay. We selected a whole blood assay to obviate the need for free fraction scaling for this highly protein-bound drug. We used the population concentration-response model to estimate the lower 10th percentile for the 10% maximal interferon-β response concentration of SNX281, which was chosen as the MABEL concentration. We translated the ex vivo MABEL concentration to a human MABEL dose using a human pharmacokinetic projection based on allometric scaling from preclinical species.

Results: The human dose-peak concentration relationship projection fell within 2-fold of the clinical result. After the application of a safety factor, the MABEL dose was applied in the clinic and did not demonstrate dose-limiting toxicities.

Conclusions: Our novel population modelling-based MABEL strategy for first-in-human dose selection resulted in successful clinical translation of a small molecule STING agonist.