Safety, pharmacokinetics, and pharmacodynamics of sofnobrutinib, a novel non-covalent BTK inhibitor, in healthy subjects: First-in-human phase I study.

Bruton's tyrosine kinase (BTK) is a potential therapeutic target for allergic and autoimmune diseases. This first-in-human phase I study evaluated safety, pharmacokinetic, and pharmacodynamic profiles of sofnobrutinib (formerly AS-0871), a highly selective, orally available, non-covalent BTK inhibitor, in healthy adult subjects. Single ascending doses (SAD; 5-900 mg) and multiple ascending doses (MAD; 50-300 mg twice daily [b.i.d.] for 14 days [morning dose only on Day 14]) of sofnobrutinib were tested. In the entire study, all adverse events (AEs) were mild or moderate, and no apparent dose-proportional trend in severity or frequency was observed. No serious treatment-emergent AEs, cardiac arrythmias, or bleeding-related AEs were reported. In the SAD part, sofnobrutinib exhibited approximately dose-dependent systemic exposures up to 900 mg with rapid absorption (median time to maximum concentration of 2.50-4.00 h) and gradual decline (mean half-lives of 3.7-9.0 h). In the MAD part, sofnobrutinib showed low accumulation after multiple dosing (mean accumulation ratios of ≤1.54) and reached a steady state on ≤Day 7. Single dosing of sofnobrutinib rapidly and dose-dependently suppressed basophil and B-cell activations in ex vivo whole blood assays. Multiple dosing of sofnobrutinib achieved 50.8%-79.4%, 67.6%-93.6%, and 90.1%-98.0% inhibition of basophil activation during the dosing interval of 50, 150, and 300 mg b.i.d., respectively. Based on pharmacokinetic-pharmacodynamic analysis, half-maximal inhibitory concentration (IC) of sofnobrutinib for basophil activation was 54.06 and 57.01 ng/mL in the SAD and MAD parts, respectively. Similarly, IC for B-cell activation was 187.21 ng/mL. These data support further investigation of sofnobrutinib in allergic and autoimmune diseases.