Background
Phase III single-arm open-label study. 97 patients with PNH and evidence of hemolysis (LDH ≥1.5× ULN) but without the transfusion-dependency requirement of TRIUMPH (patients required ≥1 transfusion in the prior 24 months). Median 5 years of PNH symptoms. Designed to demonstrate efficacy in the broader PNH hemolysis population, including patients with thrombocytopenia and modest bone marrow dysfunction. All patients received meningococcal vaccination prior to enrollment.
Interventions and follow up
Regimen: Eculizumab 600 mg IV weekly × 4 (induction), then 900 mg IV every 2 weeks for 52 weeks
Primary endpoint: LDH change from baseline; transfusion avoidance; hemoglobin stabilization
Median follow-up: 52 weeks
Primary endpoint: LDH change from baseline; transfusion avoidance; hemoglobin stabilization
Median follow-up: 52 weeks
Results
LDH reduction: Median −85.4% (P<.001) vs baseline; normalized in 52%
Transfusion avoidance: 51% of patients over 52 weeks
Breakthrough hemolysis: 4.1% of patients
FACIT-Fatigue improvement: +6.4 points (clinically meaningful threshold ≥3 points)
PNH clone size: Unchanged (as expected — eculizumab does not eliminate PNH clones)
Transfusion avoidance: 51% of patients over 52 weeks
Breakthrough hemolysis: 4.1% of patients
FACIT-Fatigue improvement: +6.4 points (clinically meaningful threshold ≥3 points)
PNH clone size: Unchanged (as expected — eculizumab does not eliminate PNH clones)
Adverse events
Common AEs: headache 43%, nasopharyngitis 33%, nausea 20%, fatigue 20%
Serious events/mortality: grade ≥3 AEs 24% (consistent with PNH-related events); no meningococcal infections (all vaccinated); no treatment-related deaths; 2 patients discontinued due to AEs
Serious events/mortality: grade ≥3 AEs 24% (consistent with PNH-related events); no meningococcal infections (all vaccinated); no treatment-related deaths; 2 patients discontinued due to AEs
Conclusions
Eculizumab substantially reduced hemolysis and improved fatigue in non-transfusion-dependent PNH patients with active hemolysis, confirming its benefit across the broader PNH population beyond the most severely affected patients in TRIUMPH.
Key Limitations
Single-arm, open-label design without a concurrent control limits causal inference. 52-week duration leaves long-term durability to extension data. Eculizumab addresses only intravascular (C5-mediated) hemolysis; extravascular C3-mediated hemolysis and persistent anemia can remain, and clone size is unchanged. Heterogeneous baseline transfusion needs complicate interpretation of the transfusion endpoint. Lifelong q2w IV therapy, cost, and meningococcal risk requiring prophylaxis remain practical burdens.
Clinical Context
SHEPHERD, together with TRIUMPH, supported the FDA approval of eculizumab (Soliris) for PNH in 2007 by extending the evidence base to the broader hemolytic PNH population, not just heavily transfused patients. It helped establish C5 inhibition as standard of care for symptomatic hemolytic PNH. Subsequent agents — ravulizumab (q8w C5 inhibitor), pegcetacoplan (C3 inhibitor), and iptacopan (oral factor B inhibitor) — have since broadened options, particularly for patients with persistent extravascular hemolysis.