Introduction Etentamig (ABBV-383) is a differentiated B-cell maturation antigen (BCMA) x CD3 bispecific antibody (fully humanized IgG4) T-cell engager composed of a bivalent BCMA binding domain with a high avidity and a CD3-binding domain with a low-affinity. The present but silenced-Fc tail retains FcRn binding, leading to an extended half-life that enables less frequent dosing and increased dosing convenience. The optimized monotherapy dosing regimen of etentamig consisting of a 2 mg step-up dose administered on Day 1 followed by administration of 60 mg on Day 4, has shown promising activity and safety in patients with relapsed/refractory multiple myeloma (RRMM; NCT03933735; Rodriguez et al., JCO 2024;42[suppl 16]:7531; Mian et al., Blood 2024;144[suppl 1]:1985). Here, we report population pharmacokinetics (popPK) and pharmacokinetic/pharmacodynamic (PK/PD) simulations and observed clinical data for restarting etentamig therapy following a dosing interruption or delay.

Methods A previously developed popPK model (Polepally et al., Clin Pharmacol Ther 2024; 115 [suppl 1]:S69) was updated with data from Arm A of the phase 1b study NCT05650632 evaluating step-up dose (2 or 4 mg) on Cycle 1 Day 1 (C1D1) with a full dose (60 mg) on C1D4 in patients with RRMM and was used to simulate serum concentration-time profiles after single or multiple doses of etentamig. If the administration of the full dose was delayed beyond 14 days after the administration of the step-up dose, the step-up dose was re-administered as per the study protocol. The simulated mean concentration-time profiles were compared against the maximum concentration attained after administration of the 2 mg step-up dose (threshold concentration). Recommendation regarding the duration of repriming window after dosing delay or interruption was based on the time at which the concentration dropped below the threshold concentration. A supportive PD analysis was conducted using a PK/IL-6 semi-mechanistic model (Wang et al., Blood 2024;144[suppl 1]:1994) to predict IL-6 levels after different dosing delay scenarios and compared against the maximum IL-6 concentrations in the reference regimen (2 mg on C1D1/60 mg C1D4; 60 mg every 4 weeks thereafter). Additionally, we evaluated the clinically observed dosing delays and cytokine release syndrome (CRS) occurrence, if any, upon restarting etentamig therapy.

Results Based on popPK simulations, predicted etentamig mean concentrations after a single dose of 60 mg were predicted to drop below the defined threshold concentration after 16 weeks, increasing to 24 weeks at steady state. Simulated IL-6 profiles using the PK/IL-6 model after various dosing delay scenarios indicated that the maximum IL-6 levels attained upon restarting therapy after 16-24 weeks of delay or interruption were significantly lower than the maximum IL-6 concentrations after administration of the reference regimen. Based on the available clinical data from Arm A of the phase 1b study NCT05650632, no recurrent CRS events were observed beyond Cycle 1. The longest dosing delay observed was 68 days (~10 weeks) after a Cycle 3 dose, and six subjects had dose delays ranging from 27-35 days on or after Cycle 2. In all these cases, treatment was restarted with the full dose (60 mg) without any episode of CRS.

PopPK simulations, IL-6 predictions and observed clinical data are collectively supportive of no repriming in patients with dosing delays or interruptions lasting 16 weeks or less.

Conclusions Based on our popPK and PK/PD simulations and supportive clinical data, patients with dose delays lasting ≤16 weeks following treatment with etentamig full dose are not needed to restart the step-up dose.

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2025
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