154: Early Clinical Pharmacokinetic/Pharmacodynamic Modeling & Simulation of Povetacicept, a Potent Dual BAFF/APRIL Antagonist, to Support First-in-Disease Clinical Trials in Autoimmune Glomerulonephritis & Cytopenias

Statement of Purpose: To use PK/PD modeling to predict pharmacokinetics (PK) and pharmacodynamics (PD) of povetacicept (ALPN-303) after repeat dosing to support dose selection for upcoming first-in-disease clinical trials.

Description of Methods & Materials: Povetacicept is an engineered transmembrane activator and CAML interactor (TACI) vTD™-Fc fusion protein with potent inhibitory activity against the B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) B cell cytokines. PK/PD models (direct and indirect) were fit to exposure and PD data for a single ascending dose study in healthy volunteers. Monte Carlo simulations of these models were used to predict the APRIL and BAFF target coverage and decreases in serum immunoglobulins (Igs) (IgA, IgG, and IgM) to estimate the impact of povetacicept in repeat-dose studies, and to evaluate multiple dose regimens.

Data & Results: Povetacicept exposure is best described by a PK model with parallel linear and nonlinear clearance. APRIL and Ig concentrations are best described by direct and indirect models with a saturable effect, respectively. The dynamic profile of free and total BAFF concentrations over time were characterized to predict target coverage after multiple dosing. APRIL simulations show that dose regimens of 80 and 240 mg subcutaneous (SC) once every 4 weeks (Q4W) have greater than 75% and 95% target coverage for 3 and 4 weeks at steady state, respectively. IgA, IgG and IgM simulations show that 80 mg SC Q4W and 240 mg SC Q4W and Q8W have saturated reductions of these immunoglobulins. IgG simulations predict that with dose regimens of 80 and 240 mg SC Q4W, fewer than 1% of patients will have reductions in IgG that would result in hypogammaglobulinemia ( < 1.5 g/L IgG). Free BAFF simulations show similar dynamic time profile to those previously reported for other dual APRIL/BAFF inhibitors. Since total BAFF concentrations exhibit large increases ( >100x) within 14 days, the ratio of free to total BAFF was used to assess BAFF target coverage. Similar to APRIL, BAFF target coverage was predicted to be dose dependent. The povetacicept dose regimens of 80 and 240 mg SC Q4W are anticipated to provide adequate APRIL target coverage while minimizing the risk of hypogammaglobulinemia (Figure 1).

Interpretation, Conclusion or Significance: Simulations of these PK/PD models support investigating the dose regimens of 80-240 mg SC Q4W in future studies.

Disclosures: Rupert H. Davies, Stacey R. Dillon, Russell J. Sanderson, Allison G. Chunyk, and Stanford L. Peng own stock options in and are employees of Alpine Immune Sciences, Inc. Jeffrey R. Proctor is a paid consultant of Alpine Immune Sciences, Inc.