Background
Phase 3 single-arm multicenter global study (ALXN1210-aHUS-311). N=58 complement-inhibitor-naive adults (≥18 yr) with atypical HUS and active TMA (thrombocytopenia, microangiopathic hemolytic anemia, AKI). Ravulizumab is an engineered anti-C5 antibody (eculizumab variant) with ~4× longer half-life via Fc substitutions and pH-dependent FcRn recycling, enabling q8w vs eculizumab's q2w dosing.
Interventions and follow up
Treatment: Ravulizumab IV weight-based loading dose, then maintenance every 8 wk for 26 wk, with extension phase continuing dosing
Primary endpoint: Complete TMA response (platelet normalization AND LDH normalization AND ≥25% improvement in serum creatinine from baseline)
mFollow up: 26 wk (initial evaluation period)
Primary endpoint: Complete TMA response (platelet normalization AND LDH normalization AND ≥25% improvement in serum creatinine from baseline)
mFollow up: 26 wk (initial evaluation period)
Results
Complete TMA response (primary): 53.6% (30/56 evaluable)
Platelet count normalization: 83.9%
LDH normalization: 76.8%
Serum creatinine ≥25% improvement: 58.9%
eGFR improvement ≥1 CKD stage: 68.1% by day 183
C5 inhibition: complete and immediate in all patients throughout the 8-wk dosing interval
Platelet count normalization: 83.9%
LDH normalization: 76.8%
Serum creatinine ≥25% improvement: 58.9%
eGFR improvement ≥1 CKD stage: 68.1% by day 183
C5 inhibition: complete and immediate in all patients throughout the 8-wk dosing interval
Adverse events
Deaths: 4 (3 within 1 mo of initiation, including 1 excluded post-hoc on eligibility after first dose; none investigator-attributed to treatment)
Common AEs: upper respiratory tract infections, headache, hypertension
Infection prophylaxis: meningococcal prophylaxis required (as with eculizumab)
Breakthrough: no complement breakthrough (incomplete C5 inhibition) within the 8-wk window; no unexpected AEs
Common AEs: upper respiratory tract infections, headache, hypertension
Infection prophylaxis: meningococcal prophylaxis required (as with eculizumab)
Breakthrough: no complement breakthrough (incomplete C5 inhibition) within the 8-wk window; no unexpected AEs
Conclusions
Ravulizumab provides complete, sustained C5 inhibition and achieves complete TMA response in 53.6% of complement-inhibitor-naive adults with aHUS, comparable to historical eculizumab data with the practical advantage of q8w versus q2w dosing.
Key Limitations
Single-arm with no head-to-head eculizumab comparison — non-inferiority inferred from historical/cross-study data. Rare disease, small N=58 and short 26-wk primary window; no direct long-term renal-outcome comparison. Early deaths reflect aHUS severity at presentation.
Clinical Context
Ravulizumab is FDA/EMA-approved for adult and pediatric aHUS, offering q8w maintenance versus eculizumab's q2w schedule with equivalent terminal-complement blockade. Meningococcal vaccination/prophylaxis is mandatory. It is now a preferred long-term anti-C5 option for complement-mediated TMA, reducing infusion burden.