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 very potent dental cereblon E3 ligase modulator (CELMoD), were evaluated in escalating single-dose (.03, .1, .3, 1, 2, 4, 6 mg) and multiple-dose (.3 mg once daily for fourteen days, 1 mg once daily for 4 weeks, .3 mg once daily for 4 weeks, or 1 mg once daily for seven days having a 7-day washout, then once daily for 7 more days) studies in healthy subjects (n = 99). Iberdomide exposure elevated inside a dose-proportional manner. Terminal half-existence was 9-13 hrs following a single dose. Iberdomide decreased peripheral CD19 B lymphocytes (Emax , 92.4% EC50 , .718 ng/mL), with modest reductions in CD3 T lymphocytes (Emax , 34.8% EC50 , .932 ng/mL). Lipopolysaccharide-stimulated proinflammatory cytokines (IL-1a, IL-1ß) were reduced, but anti-CD3-stimulated IL-2 and interferon-? were elevated. Iberdomide 1 mg once daily partly decreased T-cell-independent antibody responses to PPV23 but didn’t change tetanus toxoid recall response. Pharmacodynamic data suggest dose-dependent, differential immunomodulatory effects on B and T lymphocytes. Iberdomide was tolerated as much as 6 mg like a single dose and also at .3 mg once daily for 4 days. Grade 3 asymptomatic neutropenia was observed following 1 mg once daily for a 3 week period a 7-day drug holiday alleviated neutropenia. Further analysis of iberdomide in autoimmune and hematological illnesses is warranted.