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

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.