PI-059 - EARLY CLINICAL PK/PD MODELING AND SIMULATION OF ALPN-303, A POTENT DUAL BAFF/APRIL ANTAGONIST, TO SUPPORT FIRST-IN-DISEASE CLINICAL TRIALS IN SYSTEMIC LUPUS ERYTHEMATOSUS AND OTHER B CELL-RELATED DISEASES.

R. Davies¹, S. Dillon¹, R. Sanderson¹, A. Chunyk¹, M. Marino², S. Peng¹; ¹Alpine Immune Sciences, Seattle, WA, USA, ²Mark T. Marino Consulting LLC, San Diego, CA, USA.

Background: ALPN-303 is an engineered TACI vTDTM-Fc fusion protein with potent inhibitory activity against the BAFF and APRIL B cell cytokines. This study was undertaken to support dose selection for upcoming first-in-disease clinical trials in SLE and other BAFF/APRIL-related autoimmune diseases, based on the PK/PD relationship in an ongoing FIH study in healthy adults (NCT05034484).

Methods: PK/PD models (direct and time-delayed) were fit to exposure and PD data. Monte Carlo simulations of these models were used to predict the APRIL target coverage and decreases in IgA, IgG, and IgM to estimate the impact of ALPN-303 in repeat-dose studies.

Results: Based on Monte Carlo simulations of the PK/PD models, the 240 mg dose provided 95% APRIL target coverage for 28 days and saturated the observed decreases in Ig at steady state in 97.5% of the simulations. The 80 mg dose was able to provide greater than 75% target coverage for 28 days in greater than 50% of the simulations. This dose was able to saturate the decrease in IgA and IgG in 97.5% of simulations, while it saturates the IgM decrease in greater than 50% of the simulations.

Conclusion: Based on predictions from PK/PD models, 80 and 240 mg SC Q4W will be recommended doses for ALPN-303 in the treatment of SLE and other B-cell related diseases.

PK/PD model simulation results of 240 mg Q4W on APRIL target coverage and decreases in immunoglobulins with repeat dosing