Complement Inhibition in IgAN: Interpreting the APPLAUSE Trial

This episode, "Complement Inhibition in IgAN: Interpreting the APPLAUSE Trial," features the panel weighing a landmark trial.

Dr. Parikh asks Dr. Fervenza to interpret the phase 3 APPLAUSE trial of iptacopan versus standard of care. Dr. Fervenza calls it a good study but offers a vivid metaphor. Blocking complement, he says, is like putting up a shield while someone keeps throwing stones at your house. It slows progression but does not stop whoever is throwing the stones. He argues the field is past the era of merely slowing disease and should aim to stop it. Dr. Rovin responds to the data: a roughly 3 milliliter GFR slope change, 38% proteinuria reduction, and 38% hematuria reduction versus 16% on placebo. He admits he underestimated complement's role and pushed for these studies in lupus, yet IgA nephropathy was tested first. He describes his own ASN data showing urinary complement activation products correlated with damage and the S lesion, not activity. He had hoped complement inhibition would rapidly clear inflammation, but the correlation surprised him. Dr. Rovin cites older experimental studies suggesting complement inhibition may protect the tubulointerstitium long term. He says he still pictures using it acutely for a clearly inflammatory lesion, then withdrawing it, since complement is a natural defense. He notes the same duration questions apply to B-cell therapy. Dr. Mehdi adds that non-canonical complement effects on fibrosis regeneration are being appreciated. He describes his own candidate patient: someone inflamed, seemingly progressive, in whom he wants to avoid steroids. The panel summarizes a shared view. They would target the immune cascade up front and reserve complement blockade for acute inflammation, while watching whether it slows fibroinflammatory progression over time.

In "Endothelin Receptor Antagonists in IgAN: The ALIGN Trial and Access," the panel examines endothelin receptor antagonists and the ALIGN trial, weighing dual blockade against cost and access.