Eculizumab (ECU) Inhibits Thrombotic Microangiopathy (TMA) and Improves Renal Function In Adult Patients (Pts) With Atypical Hemolytic Uremic Syndrome (aHUS)
Authors: Fakhouri Fadi , Hourmant Maryvonne , Cataland Spero R. , Espinosa Mario , Gaber A. Osama , Menne Jan , Minetti Enrico , Provot Francois , Rondeau Eric , Ruggenenti Piero , Weekers Laurent , Ogawa Masayo , Bedrosian Camille L. , Legendre Christophe 
Published: October 2019

Abstract

Introduction
aHUS is a rare, genetic, life-threatening disease of uncontrolled, chronic complement activation leading to TMA and severe end-organ damage. During the first clinical manifestation, end-stage renal disease (ESRD) or death occurs in approximately 33 to 40% of patients, and within one year of diagnosis, up to 65% have permanent renal damage, ESRD, or die despite receiving plasma exchanges/plasma infusions (PE/PI). Many aHUS pts are also misdiagnosed as TTP, which also results in poor outcomes with PE/PI. Hence, early diagnosis and effective treatment are critical to halt and/or prevent systemic complement-mediated damage. Ecu, a terminal complement inhibitor, is approved for the treatment of aHUS. Herein, we report safety and efficacy results of Ecu from the largest prospective study in aHUS to date.

Methods
This was an open-label, single-arm, Phase 2 trial of Ecu in adult aHUS pts. Inclusion criteria included platelet count <150 x109/L and LDH ≥1.5 ULN. Pts with STEC-HUS (shiga toxin + E. coli) and severe ADAMTS13 deficiency (<5%) were excluded. An identified complement gene mutation was not required for admission. The primary endpoint was complete TMA response at 26 wks (normalization of platelets and LDH, and ≥25% improvement in serum creatinine from baseline (BL) on 2 consecutive measurements ≥4 wks apart).

Results
41 pts enrolled and 38 (93%) received 26 wks of treatment (Table). 30 pts (73%) were newly diagnosed, with a median of 2 wks to the first dose of Ecu. 6 pts (15%) had no PE/PI during the current clinical manifestation. At wk 26, 30 pts (73%) achieved complete TMA response, 36 (88%) achieved hematologic normalization, and 40 (98%) achieved platelet count normalization. Mean increase in platelet count from BL was 119x109/L (P<0.0001). Mean eGFR increase from BL was 26.1 mL/min/1.73 m2 (P<0.0001). Platelet count (Fig 1) and eGFR (Fig 2) increased significantly from BL through wk 26. Of 24 pts on dialysis at BL, 20 (83%) discontinued dialysis by wk 26. Two pts not on dialysis at BL initiated and remained on dialysis through 26 wks. QoL significantly improved. Ecu was generally safe and well tolerated. Two pts had meningococcal infections, one of whom continued Ecu. No pts died.

Conclusions
Ecu normalized hematologic parameters and significantly improved renal function and QoL. The results of this prospective study confirm that Ecu inhibits complement-mediated TMA in adult aHUS pts, and point to the importance of early and accurate diagnosis, including ADAMTS13 testing. Due to high morbidity and mortality in aHUS despite PE/PI, recent guidelines recommend Ecu as first-line treatment in adults once an unequivocal diagnosis is made. The current data validate this treatment approach. This study is ongoing.

Disclosures:
Weekers: Roche, Novartis, Astellas: Grant Support Other, Research Funding. Ogawa:Alexion Pharmaceuticals: Employment. Bedrosian:Alexion Pharmaceuticals: Employment.