Eculizumab (ECU) Safety and Efficacy in Atypical Hemolytic Uremic Syndrome (aHUS) Patients with Long Disease Duration and Chronic Kidney Disease (CKD): 2-Year Results

aHUS is a rare, life-threatening genetic disease of chronic, uncontrolled activation of the alternative complement pathway, leading to thrombotic microangiopathy (TMA) and vital organ damage. After the first clinical manifestation, 33%–40% of aHUS patients (pts) will progress to end-stage renal disease (ESRD) or die. Long-term dialysis and high graft rejection rates complicate aHUS management. We previously reported a statistically significant suppression of TMA in a phase 2 trial of the terminal complement inhibitor ECU in pts with persistent aHUS, CKD, and previous chronic plasma exchange/infusion (PE/PI). Here we report 2-year (y) results.

aHUS pts ≥12 y (N=20) treated with chronic PE/PI enrolled in an open-label, phase 2 trial. After 8 weeks (wk) of observation, pts stopped PE/PI and initiated ECU for 26 wk, followed by a long-term ECU treatment extension.

Twenty pts received ECU through wk 26, and 19 pts continued ECU in the extension phase. Data analysis was performed in the intention to treat population (n=19). Median time from diagnosis to screening was 48 months (mo) (range 0.66–286). 50% of pts had baseline (BL) estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m², and 2 of these pts were on chronic dialysis; 8 pts had prior renal transplants. Pts received PE/PI for a median of 10 mo (range 2.4–47) prior to ECU. Median ECU treatment duration was 114 wk (range 2–145). TMA event-free status^a was achieved by 19 pts (95%) for an average duration of 698 days (d). Hematologic normalization^b was achieved or maintained in 18 pts (90%) by wk 26, and sustained to data cutoff. eGFR improved significantly from BL to data cutoff (P=0.05). The proportion of pts with improved renal function (eGFR ≥15 mL/min/1.73 m²) increased from 26 wk (5%) to 1 y (15%) and to 2 y (40%). A flat slope of eGFR change from d −42 to 0, followed by rapid eGFR improvement from d 0 to 28 (P=0.0066) that was maintained through d 860 was demonstrated by a 3-piece linear model. Earlier ECU treatment was associated with greater eGFR improvement (P=0.0013), but pts showed clinical benefit regardless of when ECU was initiated. The proportion of pts with decreases in proteinuria ≥1 grade increased from 26 wk (50%) to 2 y (83%). No pt received PE/PI or progressed to ESRD/dialysis. In a pt subgroup able to show an accepted clinically important difference (n=11), 82% attained significant and sustained improvements in quality of life (QOL). Outcomes were similar in pts with or without an identified complement regulatory factor mutation. Long-term ECU was well tolerated. Most common adverse events (AEs): diarrhea, hypertension and upper respiratory tract infection. Three serious AEs were related to ECU (all resolved with no change in ECU dosing). There were no meningococcal infections. There was 1 pt death due to gastrointestinal bleed after 1.9 y of ECU treatment that was deemed unrelated to drug.

In aHUS pts with substantial renal damage despite prior chronic PE/PI, those expected to reach ESRD and those with renal transplant, long-term ECU treatment was associated with sustained TMA inhibition and continued significant improvements in eGFR and proteinuria. Earlier intervention with ECU resulted in greater improvement in eGFR. All pts eliminated PE/PI and no pt required new dialysis. Long-term ECU treatment was well tolerated and led to significant improvements in QOL in pts with chronic aHUS disease.

Licht:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Muus:Alexion Pharmaceuticals: Sat on advisory board of Alexion Pharmaceuticals. Other. Legendre:Alexion Pharmaceuticals: Speakers Bureau. Herthelius:Alexion Pharmaceuticals: Coordinator of Alexion trials of eculizumab in atypical HUS for France. Honoraria for conferences. Other. Goodship:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Bedrosian:Alexion Pharmaceuticals: Employment, Equity Ownership. Loirat:Alexion Pharmaceuticals: Coordinator of Alexion trials of eculizumab in atypical HUS for France. Honoraria for conferences. Other.