Complement-driven haemolytic disorders have seen an explosion of targeted therapies, transforming paroxysmal nocturnal haemoglobinuria (PNH) in particular from a disease controlled by intravenous infusions into one increasingly managed with oral drugs.
PNH: terminal and proximal complement inhibition
The terminal C5 inhibitors remain a backbone — eculizumab, the long-acting ravulizumab, and now crovalimab, a subcutaneous, self-administered C5 inhibitor approved in 2024. But the bigger shift is toward proximal complement inhibition, which addresses the residual extravascular haemolysis that C5 blockade can leave behind. Pegcetacoplan, a C3 inhibitor, was superior to eculizumab for raising haemoglobin and reducing transfusions in the PEGASUS trial (approved 2021). Iptacopan, an oral factor B inhibitor, provides effective oral monotherapy (approved 2023), and danicopan, an oral factor D inhibitor, is approved (2024) as an add-on to a C5 inhibitor for patients with clinically significant extravascular haemolysis. PNH now offers a menu of mechanisms, several of them oral.
Cold agglutinin disease
For cold agglutinin disease, sutimlimab, a monoclonal antibody against C1s that blocks the classical complement pathway, raised haemoglobin and normalized haemolysis markers with early, sustained fatigue improvement (approved 2022) — the first therapy specifically targeting this disorder's mechanism.
Further reading: PEGASUS pegcetacoplan (Hillmen et al., NEJM 2021); sutimlimab in cold agglutinin disease (Röth et al., NEJM 2021); iptacopan and danicopan PNH programs (2023–2024 approvals).