Comment from Gillian McCrea
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Summary: The commenter advocates for the FDA to consider repurposing specific approved complement inhibitors (anti-C5, factor B, and C3) for the treatment of the thromboinflammatory subset of Long COVID. They argue that complement dysregulation is a documented feature of the disease and propose a biomarker-gated trial for these existing drugs.
Complement Inhibitors for Long COVID
Repurposing approved C5, factor B, and C3 inhibitors for the thromboinflammatory subset | For FDA repurposing / advisory review
The opportunity
Complement dysregulation is now a documented, predictive feature of active Long COVID — and several complement inhibitors are already FDA-approved for other diseases, sitting ready to repurpose.
The mechanism is measured, not assumed
In active Long COVID, C5a and the terminal complement complex are significantly elevated versus controls and normalize on recovery [1]. Autoantibodies and antigen–antibody complexes drive classical-pathway activation, inserting the membrane-attack complex into endothelium and fueling thromboinflammation and vascular damage [2,3] — a direct line from the autoimmune mechanism to tissue injury.
The drugs already exist
Three approved classes can interrupt this cascade: eculizumab / ravulizumab (anti-C5; PNH, aHUS, myasthenia gravis, NMOSD), iptacopan (factor B; PNH, IgA nephropathy, C3 glomerulopathy), and pegcetacoplan (C3; PNH, C3G). The authors of the Long COVID complement work explicitly propose repurposing licensed inhibitors for selected patients [3].
The ask
A biomarker-gated trial (C5a / terminal-complement-high patients) of an approved complement inhibitor. Measurable target, validated drugs, defined responder population.
Sources
1. Cervia-Hasler C, et al. (Boyman). Persistent complement dysregulation with thromboinflammation in active Long Covid. Science. 2024.
2. The role of complement in long COVID pathogenesis. JCI Insight. 2025. PMID 40857408.
3. Complement dysregulation is a predictive and therapeutically amenable feature of Long COVID; Is Long COVID a complement dysregulation disease? Clin Chem. 2024.