ZENBEXUS Capsule Ref.[116893] Active ingredients: Iberdomide

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 ZENBEXUS 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 ZENBEXUS 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.

Carcinogenesis

Carcinogenicity studies have not been conducted for iberdomide.

Mutagenesis

Iberdomide was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay but was clastogenic in the in vitro assay using human peripheral blood lymphocytes. Subsequently, iberdomide was negative in the in vivo micronucleus assay and DNA damage in liver (Comet assay) in rats and, therefore, iberdomide is not genotoxic.

Impairment of Fertility

In the 9-month monkey study, animals were treated with oral doses of up to 0.4 mg/kg/day. Testicular hypospermatogenesis and intraluminal cell debris in the epididymis occurred at the high dose of 0.40 mg/kg/day (approximately 3-fold greater than the human exposure at the recommended dose based on AUC at steady state).

In a fertility and early embryonic development toxicity study in rabbits, males and females were treated with oral doses of up to 50 mg/kg and 15 mg/kg, respectively, and were mated with untreated rabbits. Treatment in males began 65 days prior to mating, continued during mating and for up to 81 days post-mating. In females, treatment began 14 days prior to mating, continued during mating and until GD 7. Males treated with ≥5 mg/kg/day (approximately 32-fold greater than the human exposure at the recommended dose based on AUC steady state) had epithelial cell degeneration in seminiferous tubules, cellular debris in epididymal lumen, and abnormal sperm morphology. These effects were reversible after stopping dosing. Due to mortality in males at doses ≥5 mg/kg/day, mating and effects on fertility were not evaluated. Female rabbits had reduced fertility and increased pre- and post-implantation loss at ≥5 mg/kg/day (approximately 50-fold greater than the human exposure at the recommended dose based on AUC at steady state).

The efficacy of ZENBEXUS in combination with daratumumab and hyaluronidase-fihj and dexamethasone (IberDd) compared with daratumumab and hyaluronidase-fihj, bortezomib and dexamethasone (DVd) was evaluated in adult patients with relapsed or refractory multiple myeloma (RRMM) in a phase 3, two-stage, randomized, multicenter open-label study (EXCALIBER-RRMM) (NCT04975997). The study included patients who had previously received one or two prior lines of therapy. Patients who had disease refractory to a prior anti-CD38 monoclonal antibody therapy, or to prior bortezomib were excluded.

Patients received ZENBEXUS in combination with daratumumab and hyaluronidase-fihj and dexamethasone (Dd) as follows:

Dosing in IberDd arm (28-day cycles):

• Iberdomide (oral): 1 mg, Day 1-21;
• Daratumumab and hyaluronidase-fihj (subcutaneous): 1800 mg Cycles 1-2 on Days 1, 8, 15 and 22; Cycles 3-6 on Days 1 and 15; Cycles 7+ on Days 1;
• Dexamethasone (oral): 20 or 40 mg on Days 1, 8, 15 and 22.

Treatment in both arms was administered until disease progression or unacceptable toxicity.

The major efficacy outcome measure was minimal residual disease (MRD) negative complete response (CR) at any time.

A total of 939 patients were randomized to 1 of 3 dose levels of ZENBEXUS in combination with daratumumab and hyaluronidase-fihj and dexamethasone (IberDd) or to daratumumab and hyaluronidase-fihj, bortezomib and dexamethasone (DVd) across stage 1 (n=279), or to ZENBEXUS 1 mg in combination with Dd or DVd in stage 2 (n=660) in EXCALIBER-RRMM. The primary efficacy population for MRD negativity included the first 420 patients randomized to ZENBEXUS 1 mg in combination with Dd in stage 1 and stage 2 (N=207) or (DVd) in stage 1 and stage 2 (N=213).

In the primary efficacy population for MRD negativity, the median age was 68 years (range: 35 to 87); 42% were female; 61% were White, 1% were Black, 35% were Asian, and 2% were Hispanic or Latino. Sixty-three percent had International Staging System (ISS) Stage I, 25% had ISS Stage II and 12% had ISS Stage III disease. High-risk cytogenetics presence of del(17p), t(4;14), or t(14; 16) were present in 22% of patients. Extramedullary disease was present in 11% of patients.

The median number of prior lines of therapy was 1 (range 1 to 2), with 67% who received one prior line of therapy, and 33% who received 2 prior lines of therapy. Ninety percent of patients received prior immunomodulatory agents (70% received prior lenalidomide, 34% received prior thalidomide, and 5% received prior pomalidomide), and 95% received a prior proteasome inhibitor. Four percent of patients received a prior anti-CD38 monoclonal antibody. There is limited data with ZENBEXUS in combination with daratumumab and dexamethasone in patients who have received or are refractory to prior anti-CD38 monoclonal antibody therapy.

The efficacy results are shown in Table 4.

Table 4. Efficacy Results in EXCALIBER-RRMM in the Primary Efficacy Population for MRD Negativity:

Response was based on Independent Review Committee (IRC) assessment per International Myeloma Working Group (IMWG) 2016 criteria.
^* Based on a threshold of 10^-5 using a Hematogenix Next Generation Flow Cytometry assay.
^† The 2-stage combined one-sided p-value based on Miettinen-Nurminen with CMH weights, stratified by number of prior lines (1 vs 2), Age (≤70 vs >70) and ISS staging (I and II vs III).

In the iberdomide arm, among patients who achieved a CR, 89% (85/95) were MRD negative; whereas, in the control arm, among patients who achieved a CR, 83% (44/53) were MRD negative.