Iberdomide

Iberdomide is a cereblon-modulating protein degrader that binds to cereblon, a substrate recognition component of an E3 ubiquitin ligase complex. Iberdomide engages cereblon and facilitates recruitment, ubiquitination, and proteasomal degradation of the transcription factors, Aiolos and Ikaros, resulting in anti‑tumor and immunomodulatory activity.

In vitro and in vivo, iberdomide treatment showed anti-tumor activity in multiple myeloma (MM) cells and xenografts including in lenalidomide- and pomalidomide-resistant MM cell lines. Immunomodulatory properties of iberdomide include increased secretion of the immune stimulatory cytokines (interleukin-2 and interferon-gamma), inhibition of proinflammatory cytokine release (interleukin-6), enhanced immune mediated killing of MM cells, and prevention of T-cell exhaustion. In vitro, the combination of iberdomide and daratumumab produced an increase in complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) activity of daratumumab against multiple myeloma cells. In vivo, iberdomide showed increased anti-tumor activity in combination with dexamethasone or daratumumab compared to iberdomide, dexamethasone or daratumumab alone.

In patients with relapsed or refractory multiple myeloma, at a dose of 1 mg, iberdomide in combination with daratumumab and dexamethasone decreases B cells, natural killer (NK) cells, and naïve CD8⁺ T cells, and increases effector memory CD8⁺ T cells, HLA-DR expression on CD8⁺ T cells, and Ki-67–positive CD4+ and CD8+ T cells and NK cells.

Iberdomide exposure-response analyses demonstrated no clinically relevant relationship between systemic iberdomide exposure level and efficacy following iberdomide dose of 1 to 1.6 mg (1 to 1.6 times the recommended dosage). Increasing iberdomide exposure was associated with higher risk of Grade 3+ neutropenia and at least 1 dose modification due to treatment-emergent adverse events (TEAE).

Cardiac Electrophysiology

At 2.6-times the mean maximum concentration produced by the recommended iberdomide dosage, a clinically relevant QT interval prolongation was not observed.

Iberdomide pharmacokinetic parameters for patients with multiple myeloma receiving the recommended approved dosage at steady state are presented as mean (% CV), unless otherwise specified.

Iberdomide maximum plasma concentration (C_max) is 6.35 ng/mL (30%) and area under the concentration-time curve (AUC) is 82.6 ng*h/mL (32%). Drug accumulation is approximately two-fold. Iberdomide C_max and AUC are approximately dose-proportional over the dose range of 0.1 mg to 6 mg (0.1 to 6 times the recommended dosage) following a single oral dose in healthy subjects.

Absorption

Iberdomide median (min, max) time to C_max (T_max) at steady state is 2 (2, 10) hours.

Effect of Food

No clinically significant difference in iberdomide PK is expected following administration of iberdomide with food.

Distribution

Iberdomide volume of distribution (V_ss/F) is 415 L (40%). In vitro plasma protein binding is 75% and is not concentration-dependent. In vitro blood-to-plasma ratio is 0.78.

Elimination

Iberdomide terminal elimination half-life (t_1/2) is 37 hours (51%) and apparent oral clearance (CL/F) is 12.3 L/h (38%).

Metabolism

Iberdomide is metabolized primarily by CYP3A.

Excretion

Following a single oral administration of [¹⁴C] iberdomide to healthy subjects, approximately 46% of the dose was eliminated in urine (16% as unchanged drug) and 43% of the dose was eliminated in feces (11% as unchanged drug).

Specific Populations

No clinically significant differences in the pharmacokinetics of iberdomide were observed based on age (36 to 90 years), sex (45% female), race (65% White, 27% Asian, and 4% African American), body weight (37.6 kg to 137 kg), body mass index (16.7 to 49.7 kg/m²), body surface area (1.27 to 2.60 m²), or hepatic impairment (Child-Pugh Class A, B, and C).

Patients with Renal Impairment

Subjects with eGFR less than 30 mL/min/1.73 m² not on dialysis exhibited 1.8-fold higher AUC and comparable C_max compared to healthy subjects.

No clinically significant differences in the pharmacokinetics of iberdomide were observed based on eGFR in patients with eGFR greater than 30 mL/min/1.73 m² or in subjects with eGFR less than 30 mL/min/1.73 m² requiring intermittent hemodialysis. Dialysis clearance (3.07 L/hr) was 16% of total clearance in subjects with kidney failure requiring intermittent hemodialysis.

Drug Interactions Studies

Clinical Studies and Model-Informed Approaches

Strong CYP3A Inhibitors: Itraconazole (strong CYP3A inhibitor) increased iberdomide AUC to 2.4-fold in healthy subjects.

Moderate CYP3A Inhibitors: Fluconazole or diltiazem (moderate CYP3A inhibitors) is predicted to increase iberdomide C_max to 1.5-fold and AUC to 1.7-fold in patients with cancer.

Strong CYP3A Inducers: Rifampin (strong CYP3A inducer) decreased iberdomide C_max to 29% and AUC to 10% in healthy subjects.

Moderate CYP3A Inducers: Efavirenz (moderate CYP3A inducer) is predicted to decrease iberdomide C_max to approximately 50% and AUC to approximately 30% in patients with cancer.

Other Drugs: Coadministration of iberdomide with daratumumab and dexamethasone, mild CYP3A inhibitors and inducers, or P-gp inhibitors is not predicted to have clinically significant effect on iberdomide PK.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Iberdomide does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4. Iberdomide does not induce CYP1A2, CYP2B6, or CYP3A.

Transporter Systems: Iberdomide is a substrate of P-gp and BCRP. Iberdomide is not a substrate of OAT1, OAT3, OATP1B1, OATP1B3, OCT2, or MRP2. Iberdomide does not inhibit P-gp, BCRP, OAT1, OAT3, OATP1B1, OATP1B3, OCT2, MRP2, MATE1, or MATE2-K.