Safety, Pharmacokinetics, and Pharmacodynamics of Subcutaneous Sibeprenlimab in Healthy Participants

Abstract Sibeprenlimab blocks the cytokine “A Proliferation‐Inducing Ligand” (APRIL), which may play a key role in immunoglobulin A nephropathy pathogenesis. A phase 1 study of subcutaneous (SC) sibeprenlimab evaluated preliminary safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy participants. This was an open‐label, single‐ascending‐dose study. Twelve participants in each of 4 sequential dosing cohorts received 1 SC dose of sibeprenlimab (200 mg [1×1 mL injection], 400 mg [2×1 mL injections], 400 mg [1×2 mL injection], or 600 mg [1 mL+2 mL injections]) and underwent 16‐week follow‐up for adverse events, pharmacokinetics, and pharmacodynamics (serum APRIL, immunoglobulin [Ig] levels). Sibeprenlimab in single SC doses of 200‐600 mg was slowly absorbed into the systemic circulation, with a median time to maximum serum concentration of approximately 6‐10.5 days, and a mean elimination half‐life of approximately 8‐10 days. Serum APRIL, IgA, IgM, and, to a lesser extent, IgG decreased in a dose‐dependent and reversible manner. Maximal reduction in serum IgA was approximately 60% at the 400‐ and 600‐mg doses and 40% at 200 mg. Serum APRIL rapidly decreased to near the lower limit of quantification, and duration of suppression was dose‐dependent, with near complete suppression until weeks 4‐6 at the 400‐mg dose and week 8 at the 600‐mg dose. Adverse events occurred in 30/48 (62.5%) participants; none were serious or led to study discontinuation. Sibeprenlimab rapidly and sustainably reduced target APRIL and Ig biomarkers in a dose‐dependent and reversible manner, with acceptable preliminary safety and pharmacokinetics.