PII-065 - POPULATION PHARMACOKINETICS (POPPK) OF ABBV-383, A B-CELL MATURATION ANTIGEN (BCMA) × CD3 BISPECIFIC T-CELL-REDIRECTING ANTIBODY, IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM).

A. Polepally¹, J. Badillo², M. Rinas³, A. Ahsan¹, O. Bueno⁴, C. Talati⁴, R. Menon⁴, B. Engelhardt³; ¹Abbvie Inc., North Chicago, IL, USA, ²AbbVie Inc., Ludwigshafen, Germany, ³AbbVie Inc.,, Ludwigshafen, Germany, ⁴AbbVie Inc.,, North Chicago, IL, USA.

Background: ABBV-383 is a fully human, silenced Fc region IgG4 monoclonal, BCMA × CD3 T-cell–engaging bispecific antibody with 2 BCMA-binding domains and a low-affinity CD3-binding domain. The objectives of this analysis were to develop popPK models to characterize 'total' (unbound and bound to soluble BCMA [sBCMA]) and 'free' (unbound and partially bound to sBCMA) ABBV-383 PK and identify patient-specific covariates affecting exposures.

Methods: ABBV-383 serum 'total' and 'free' PK data (n=215) from a Phase 1 dose escalation and expansion study (NCT03933735) were used to build two separate nonlinear mixed-effects models in NONMEM 7.5. The dataset consisted of 6093 'total' and 6085 'free' concentrations from dosing cohorts of 0.025 mg Q3W to 120 mg Q3W and 60 mg Q4W. Patient-specific covariates (demographics, baseline albumin, baseline sBCMA, time varying sBCMA, renal/hepatic functions, baseline disease/performance characteristics, and number of prior therapies) were tested on relevant clearance and volume parameters.

Results: ABBV-383 'total' and 'free' PK were adequately described by two compartment models with linear elimination. The clearance (CL) estimates of 'total' and 'free' ABBV-383 were 0.205 L/day and 0.346 L/day with inter-individual variabilities (%CV) of 49% and 78%, respectively. The mean terminal half-lives (t1/2,ꞵ) and steady-state volumes of distribution (Vss) derived using the popPK model estimated clearances (CL and Q) and volumes (Vc and Vp) were approximately 27 days and 7.7 L for 'total' ABBV-383, and 17 days and 7.9 L for 'free' ABBV-383, respectively. The clearances and volumes were allometrically scaled using body weight. Higher baseline sBCMA appeared to reduce 'free' PK exposures only and not impact 'total' PK exposures. Sex and IgG MM disease type were other significant covariates in 'total' PK model only. None of the other tested covariates influenced 'total' and 'free' ABBV-383 PK.

Conclusion: The two separate two compartment popPK models adequately described 'total' and 'free' ABBV-383 PK data. Although covariates influenced 'total' PK, the effects on 'free' PK were considered most relevant given the pharmacological relevance of 'free' ABBV-383. These current models can be used to conduct simulations or to evaluate the ABBV-383 exposure-response relationships with efficacy and safety endpoints.