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

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.