Zilucoplan is effective for ravulizumab-refractory generalized myasthenia gravis with the C5 p.Arg885His variant: a...

Complement inhibition is highly effective for complement-mediated diseases such as paroxysmal nocturnal hemoglobinuria (PNH) and generalized myasthenia gravis (gMG). However, certain C5 variants impair target engagement. In vitro, eculizumab and ravulizumab fail to achieve complete terminal complement blockade, and, in PNH, clinical efficacy is actually compromised in carriers. We report an anti-acetylcholine receptor antibody-positive gMG patient harboring C5 c.2654G>A (p.Arg885His) who exhibited persistent disease activity and only partial suppression of hemolytic complement activity (CH50) during ravulizumab therapy. Switching to zilucoplan, a C5 inhibitor targeting a distinct epitope, produced same-day clinical improvement and sustained remission thereafter, accompanied by undetectable CH50. This is the first report directly demonstrating ravulizumab nonresponse and a robust zilucoplan response in gMG with this variant. Variant-guided selection of complement inhibitors is essential, and pragmatic use of readily available CH50 testing combined with C5 genotyping may help identify potential nonresponders to eculizumab or ravulizumab.