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Sibeprenlimab APRIL Inhibitor IgAN — ESENeph MCQ

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HardGlomerulonephritisSibeprenlimab APRIL Inhibitor IgANESENeph

A 52-year-old man with IgA nephropathy on maximal RASi and dapagliflozin has persistent proteinuria (uPCR 130 mg/mmol) and eGFR 48 mL/min/1.73m2. His nephrologist is considering adding an agent that targets the upstream immunological pathway. Sibeprenlimab has recently received FDA accelerated approval. What is the target of sibeprenlimab?

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Correct answer: E — A proliferation-inducing ligand (APRIL)

Sibeprenlimab is a first-in-class monoclonal antibody that selectively inhibits APRIL (A Proliferation-Inducing Ligand). APRIL drives the production of galactose-deficient IgA1 (Gd-IgA1) in mucosal B cells — the key upstream pathogenic molecule in IgAN. The VISIONARY phase 3 trial demonstrated ~50% proteinuria reduction at 9 months versus placebo. By blocking APRIL, sibeprenlimab reduces total IgA and Gd-IgA1 levels. This distinguishes it from complement-targeted therapies (iptacopan targets factor B; avacopan targets C5aR) and endothelin antagonists (sparsentan, atrasentan).

Reference: FDA 2025 – Sibeprenlimab Accelerated Approval; Otsuka 2025 – VISIONARY Phase 3 Trial