Background
Two simultaneous phase III open-label RCTs of ravulizumab vs eculizumab in PNH. Study 301 (n=246): complement-naive adults with LDH ≥1.5× ULN and ≥1 PNH symptom, randomized 1:1 × 183 days. Study 302 (n=195): patients on stable eculizumab ≥6 months, randomized 1:1 to switch to ravulizumab vs continue eculizumab × 183 days. Ravulizumab is a long-acting C5 inhibitor with pH-dependent recycling enabling q8w dosing vs eculizumab q2w.
Interventions and follow up
Arm A: Ravulizumab weight-based IV (loading then maintenance) every 8 weeks
Arm B: Eculizumab 600 mg IV weekly × 4, then 900 mg every 2 weeks
Primary endpoint: Study 301 coprimary — transfusion avoidance AND LDH normalization (pre-specified non-inferiority margins); Study 302 — percent change in LDH
Median follow-up: 183 days (both studies)
Arm B: Eculizumab 600 mg IV weekly × 4, then 900 mg every 2 weeks
Primary endpoint: Study 301 coprimary — transfusion avoidance AND LDH normalization (pre-specified non-inferiority margins); Study 302 — percent change in LDH
Median follow-up: 183 days (both studies)
Results
Study 301 — Transfusion avoidance: 73.6% (ravulizumab) vs 66.1% (eculizumab); difference +6.8% (95% CI −4.7, 18.1) — non-inferior
Study 301 — LDH normalization: 53.6% vs 49.4%; OR 1.19 (95% CI 0.80, 1.77) — non-inferior
Study 301 — Breakthrough hemolysis: 4.0% vs 10.7%
Study 302 — LDH change: difference 9.21% (95% CI −0.42, 18.84) — non-inferior; no increase in breakthrough hemolysis in switching arm
Study 301 — LDH normalization: 53.6% vs 49.4%; OR 1.19 (95% CI 0.80, 1.77) — non-inferior
Study 301 — Breakthrough hemolysis: 4.0% vs 10.7%
Study 302 — LDH change: difference 9.21% (95% CI −0.42, 18.84) — non-inferior; no increase in breakthrough hemolysis in switching arm
Adverse events
Common AEs: headache most frequent (Study 301: 26.8% ravulizumab vs 25.0% eculizumab); safety profiles similar across arms in both studies
Serious events/mortality: grade ≥3 AEs similar between arms; no meningococcal infections in either study; no discontinuations due to AEs in Study 302
Serious events/mortality: grade ≥3 AEs similar between arms; no meningococcal infections in either study; no discontinuations due to AEs in Study 302
Conclusions
Ravulizumab q8w was non-inferior to eculizumab q2w across all efficacy endpoints in both complement-naive and eculizumab-switching PNH patients, offering equivalent efficacy with substantially reduced infusion frequency (from 26 to 6.5 infusions per year).
Key Limitations
Both trials were designed for non-inferiority, not superiority, so they do not establish ravulizumab as more effective than eculizumab. Open-label design introduces potential bias, partly mitigated by objective LDH and transfusion endpoints. The 183-day duration limits assessment of long-term efficacy and durability. Like eculizumab, ravulizumab inhibits only terminal complement (C5) and does not address extravascular C3-mediated hemolysis or persistent anemia, nor does it modify PNH clone size.
Clinical Context
FDA approved ravulizumab (Ultomiris) for PNH in December 2018; EMA approval followed in 2019. Its q8w dosing schedule markedly reduces infusion burden versus eculizumab q2w and has made it a preferred terminal C5 inhibitor for many PNH patients. For patients with persistent anemia from extravascular hemolysis on C5 inhibition, proximal inhibitors — pegcetacoplan (C3) and iptacopan (oral factor B) — provide additional options. Crovalimab offers an alternative C5 inhibitor with q4w SC dosing.