A first-in-human, randomized study of the safety, pharmacokinetics and pharmacodynamics of povetacicept, an enhanced dual BAFF/APRIL antagonist, in healthy adults

Abstract

Therapeutic agents targeting the tumor necrosis factor (TNF) superfamily cytokines B-cell activating factor (BAFF, BLyS) and/or A PRoliferation Inducing Ligand (APRIL) have demonstrated clinical effectiveness in multiple autoimmune diseases, such as systemic lupus erythematosus, lupus nephritis, and immunoglobulin A nephropathy (IgAN). However, their clinical utility can often be limited by incomplete and/or prolonged times to clinical response and inconvenient dosing regimens, which may be improved by more potent dual inhibition of both cytokines. Povetacicept (ALPN-303; TACI vTD-Fc) is a crystallizable fragment (Fc) fusion protein of an engineered transmembrane activator and CAML interactor (TACI) domain which mediates more potent inhibitory activity than wild-type TACI-Fc or BAFF- or APRIL-specific antibodies and demonstrates superior pharmacokinetic and pharmacodynamic activity in multiple preclinical disease models. In this first-in-human study in healthy adults, povetacicept was well-tolerated as single ascending doses of up to 960 mg administered intravenously or subcutaneously. Dose-dependent pharmacokinetics were observed. Coverage of BAFF and APRIL was observed for 2-3 weeks and ≥4 weeks after doses of 80 mg and ≥240 mg, respectively. Maximal pharmacodynamic effects were observed at dose levels ≥80 mg for a single dose, associated with on-target reductions in antibody-secreting cells as well as in all circulating immunoglobulin isotypes, including the IgAN disease-related biomarker galactose-deficient-immunoglobulin A1 (Gd-IgA1), and were superior to results reported for wild-type TACI-Fc. These data strongly support further development of povetacicept for the treatment of B-cell-mediated automimmune diseases.

FIGURE 1

Povetacicept (free and total) serum concentrations versus time following IV or SC dosing. Measurement of dose‐dependent free and total povetacicept serum concentrations after a single administration at doses ranging from 2.4–960 mg (IV) and 80–960 mg (SC). Data are presented as geomean (by cohort) ± SD.

FIGURE 2

Povetacicept administration is associated with dose‐dependent reductions in free BAFF and APRIL. Serum levels of free and total APRIL and BAFF after single doses of povetacicept. Percent change from baseline and percent of baseline data for APRIL and BAFF, respectively are presented as mean (by cohort) ± SD.

FIGURE 3

Povetacicept administration is associated with dose‐dependent reductions in circulating naive B cells and ASCs and increases in memory B cells. Percent change from baseline calculations were performed with frequency data, % naïve of CD19⁺ B cells (a), % CD27⁺ memory of CD19⁺ B cells (b), and % ASC of CD19⁺IgD⁻CD27⁺ B cells (c). Data are represented as mean (by cohort) ± SD.

FIGURE 4

Povetacicept administration is associated with dose‐dependent reductions in all circulating Ig isotypes. Percent change from baseline calculations are presented as mean (by cohort) ± SD.

FIGURE 5

Povetacicept administration is associated with dose‐dependent reductions in galactose‐deficient IgA1 (Gd‐IgA1). Percent change from baseline (upper graphs) and serum concentration data (ng/mL) (lower graphs) are presented as mean (by cohort) ± SD.

FIGURE 6

Povetacicept pharmacokinetics are associated with reciprocal and/or concordant changes in free and total APRIL and BAFF. Comparison of povetacicept (free and total) versus target (free and total APRIL and BAFF) molar concentrations in the 80 mg SC and the 240 mg SC cohorts. Molarity is reported as mean (by cohort).