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%; EC50, 0.718 ng/mL), with modest reductions in CD3+ T lymphocytes (E-max, 34.8%; EC50, 0.932 ng/mL). Lipopolysaccharide-stimulated proinflammatory cytokines (IL-1 alpha, IL-1 beta) were reduced, but anti-CD3-stimulated IL-2 and interferon-gamma 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.