First‐in‐Human, Single‐ and Multiple‐Ascending‐Dose Studies in Healthy Subjects to Assess Pharmacokinetics, Pharmacodynamics, and Safety/Tolerability of Iberdomide, a Novel Cereblon E3 Ligase Modulator

Pharmacokinetics, pharmacodynamics, and safety/tolerability of iberdomide (CC‐220), a highly potent oral cereblon E3 ligase modulator (CELMoD), were evaluated in escalating single‐dose (0.03, 0.1, 0.3, 1, 2, 4, 6 mg) and multiple‐dose (0.3 mg once daily for 14 days, 1 mg once daily for 28 days, 0.3 mg once daily for 28 days, or 1 mg once daily for 7 days with a 7‐day washout, then once daily for 7 more days) studies in healthy subjects (n = 99). Iberdomide exposure increased in a dose‐proportional manner. Terminal half‐life was 9‐13 hours after a single dose. Iberdomide decreased peripheral CD19+ B lymphocytes (E(max), 92.4%; EC(50), 0.718 ng/mL), with modest reductions in CD3+ T lymphocytes (E(max), 34.8%; EC(50), 0.932 ng/mL). Lipopolysaccharide‐stimulated proinflammatory cytokines (IL‐1α, IL‐1β) were reduced, but anti‐CD3‐stimulated IL‐2 and interferon‐γ were increased. Iberdomide 1 mg once daily partially decreased T‐cell‐independent antibody responses to PPV23 but did not change tetanus toxoid recall response. Pharmacodynamic data suggest dose‐dependent, differential immunomodulatory effects on B and T lymphocytes. Iberdomide was tolerated up to 6 mg as a single dose and at 0.3 mg once daily for 4 weeks. Grade 3 asymptomatic neutropenia was observed following 1 mg once daily for 21 days; a 7‐day drug holiday alleviated neutropenia. Further investigation of iberdomide in autoimmune and hematological diseases is warranted.