Background
Two concurrent prospective phase 2 trials (C08-002 and C08-003). N=37 patients ≥12 yr with atypical hemolytic uremic syndrome (aHUS). Trial 1 (n=17): active TMA with low platelets and renal damage despite plasma exchange/infusion. Trial 2 (n=20): chronic TMA with renal damage but no recent platelet decline despite ongoing plasma therapy. aHUS is a complement-mediated TMA from alternative-pathway dysregulation (CFH, CFI, CD46, C3, CFB, THBD mutations in 50–60%). Eculizumab (Soliris): humanized anti-C5 monoclonal antibody blocking terminal complement.
Interventions and follow up
Treatment: Eculizumab 900 mg IV weekly × 4, then 1200 mg week 5, then 1200 mg every 2 weeks for ≥26 weeks, with open-label extension
Primary endpoint: Trial 1: change in platelet count. Trial 2: TMA event-free status (no platelet drop >25%, no plasma exchange, no new dialysis) at week 26
Median follow-up: 64 weeks (Trial 1), 62 weeks (Trial 2)
Primary endpoint: Trial 1: change in platelet count. Trial 2: TMA event-free status (no platelet drop >25%, no plasma exchange, no new dialysis) at week 26
Median follow-up: 64 weeks (Trial 1), 62 weeks (Trial 2)
Results
Platelet count increase (Trial 1): Mean +73×10^9/L from baseline to week 26; P<.001
TMA event-free status (Trial 2): 80% of patients
Dialysis discontinued (Trial 1): 4/5 patients on dialysis
eGFR: Continuous, time-dependent increase across both trials
Timing effect: Earlier treatment associated with greater eGFR recovery
TMA event-free status (Trial 2): 80% of patients
Dialysis discontinued (Trial 1): 4/5 patients on dialysis
eGFR: Continuous, time-dependent increase across both trials
Timing effect: Earlier treatment associated with greater eGFR recovery
Adverse events
Meningococcal infections: None (all patients vaccinated)
Cumulative toxicity: None through extension
Most common: Headache and nasopharyngitis
Anti-eculizumab antibodies: Not detected
Key safety concern: Encapsulated-organism infection with terminal complement inhibition; meningococcal vaccination mandatory ≥2 weeks before initiation
Cumulative toxicity: None through extension
Most common: Headache and nasopharyngitis
Anti-eculizumab antibodies: Not detected
Key safety concern: Encapsulated-organism infection with terminal complement inhibition; meningococcal vaccination mandatory ≥2 weeks before initiation
Conclusions
Eculizumab inhibited complement-mediated TMA with significant platelet recovery, TMA event-free status, and time-dependent renal improvement in aHUS, establishing complement inhibition as the cornerstone of aHUS treatment.
Key Limitations
Small, open-label, single-arm trials with no control (ethically infeasible given disease severity). N=37 total. Heterogeneous mutation status. Surrogate endpoints (platelets, eGFR). Optimal treatment duration/discontinuation not addressed. Lifelong therapy and infection risk impose ongoing burden.
Clinical Context
Pivotal trials supporting FDA approval of eculizumab (Soliris) for aHUS (2011). Complement C5 inhibition is now first-line for aHUS, replacing plasma exchange; ravulizumab (longer-acting) and meningococcal prophylaxis are standard adjuncts.