PII-145 - POPULATION PHARMACOKINETIC MODELING OF ALNUCTAMAB, A BCMA-BINDING T CELL ENGAGER, TO CHARACTERIZE THE BIOAVAILABILITY AND PHARMACOKINETICS IN PATIENTS WITH RELAPSED AND REFRACTORY MULTIPLE MYELOMA (RRMM)

B. Kiesel¹, M. Osawa¹, C. Godwin¹, K. Hsu¹, I. Boss², E. Thompson¹, Y. Yan¹, M. Masilamani¹, M. Lamba³, A. Gaudy¹; ¹Bristol Myers Squibb, ²Bristol Myers Squibb, , United States, ³Bristol Myers Squibb, Summit, NJ, United States.

Background: Alnuctamab (ALNUC) is a T cell engager (TCE) that binds to B cell maturation antigen (BCMA), a receptor expressed on malignant plasma cells, that is in clinical development for the treatment of multiple myeloma. A population PK (popPK) model was developed to characterize ALNUC PK, characterize SC bioavailability and explore key covariate effects.

Methods: Serum concentrations from 69 IV and 73 SC RRMM patients in the phase 1 trial CC-93269-MM-001 (NCT03486067) were pooled to develop a joint popPK model using a nonlinear mixed-effects method using NONMEM version 7.4. IV doses ranged from 0.5 to 10 mg and SC doses ranged from 3 to 60 mg). Age, weight, sex, and pre-treatment concentrations of soluble BCMA (sBCMA), the cleaved extracellular domain of BCMA with the potential to cause target-mediated reductions in exposure of BCMA targeting agents, were assessed as covariates for impact on PK parameters. Model evaluation included goodness-of-fit criteria and visual predictive checks. Alnuctamab serum concentrations were measured by a validated ligand binding assay.

Results: A 2-compartment linear PK model with first-order absorption (ka) adequately described serum concentrations. Typical of mAbs, the clearance (CL) was slow (0.343 L/d [52.1% IIV]) with an estimated half-life of ~14 days. SC bioavailability was estimated to be 59.6% (78.0% IIV) with a ka of 0.188 1/d (52.7% IIV). The simulated Tmax was 6.01 days. Inclusion of sBCMA as a covariate on clearance significantly improved model fitting.

Conclusion: The popPK model reflects observed ALNUC clinical PK profiles. SC administration had a slow Ka and delayed Tmax relative to IV administration, which contributed to lower frequency of cytokine release syndrome, an expected adverse event of TCEs (Wong et. al. HemaSphere 2023). ALNUC CL appeared to increase with increasing sBCMA concentrations and the inclusion of sBCMA on CL in the model demonstrated a statistically improved model fit. The magnitude of this effect was relatively modest as CL was ~33% lower in subjects with lower sBCMA (at the 5th percentile) relative to the CL in typical subjects at median sBCMA. This model provides a framework to evaluate PK exposure and variability to guide dose selection in future studies of ALNUC.