A Phase 1 Dose‐Escalation, Food Effect, and Drug–Drug Interaction Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the MALT1 Inhibitor, SGR‐1505, in Healthy Volunteers

Abstract SGR‐1505 is a novel small‐molecule inhibitor of MALT1, a key mediator of NF‐κB signaling implicated in the pathogenesis of B‐cell malignancies. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of SGR‐1505 in healthy volunteers. In this four‐part, open‐label study, 73 participants received single or multiple oral doses of SGR‐1505 (25–225 mg). A food effect study assessed SGR‐1505 exposure with and without a high‐calorie, high‐fat meal. The CYP3A4 drug–drug interaction potential of SGR‐1505 was evaluated by co‐administration with posaconazole, a strong CYP3A4 inhibitor. SGR‐1505 was rapidly absorbed (median T max 2–4 h) with a dose‐proportional increase in exposure up to 100 mg. Twice daily dosing at 100 mg over 10 days resulted in a 1.6‐fold increase in both C max and AUC and a 2.5‐fold increase in C trough compared to once daily dosing at 150 mg. A high‐fat, high‐calorie meal increased SGR‐1505 C max 1.6‐fold and AUC 1.3‐fold compared to the fasted state. Co‐administration with posaconazole increased SGR‐1505 exposure 3‐fold. SGR‐1505 inhibited ex vivo stimulated T‐cell derived IL‐2 production in a concentration‐dependent manner. Most adverse events were mild. Asymptomatic, reversible indirect hyperbilirubinemia occurred, consistent with inhibition of UGT1A1. SGR‐1505 was well‐tolerated and exhibited favorable pharmacokinetic and pharmacodynamic properties, supporting further clinical development.