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

Area of Science:

• Pharmacology
• Immunology
• Clinical Trial Design

Background:

• First-in-human (FIH) dose selection is critical for Phase I participant safety and achieving therapeutic dose ranges.
• Novel small molecule stimulator of interferon response cGAMP interactor 1 (STING) agonists require robust dose selection strategies.

Purpose of the Study:

• To present a population concentration-response modeling approach for selecting the FIH starting dose of SNX281, a novel STING agonist.
• To establish a methodology for determining the minimum anticipated biological effect level (MABEL) for FIH dose selection.

Main Methods:

• A population concentration-response model was fitted to ex vivo whole blood assay data measuring cytokine induction.
• The MABEL was defined as the lower 10th percentile of the concentration eliciting 10% maximal interferon-β response.
• Ex vivo MABEL was translated to a human MABEL dose using allometric scaling of preclinical pharmacokinetic data.

Main Results:

• The population modeling approach successfully predicted the human dose-peak concentration relationship within 2-fold of clinical findings.
• The MABEL dose, adjusted by a safety factor, was administered in Phase I trials without dose-limiting toxicities.

Conclusions:

• A novel population modeling-based MABEL strategy facilitated the successful clinical translation of a small molecule STING agonist.
• This approach enhances the safety and efficiency of FIH dose selection for immunomodulatory agents.