Eculizumab (ECU) in Atypical Hemolytic Uremic Syndrome (aHUS) Patients with Progressing Thrombotic Microangiopathy (TMA): 2-Year Data.

aHUS is a rare, life-threatening genetic disease marked by chronic, uncontrolled complement activation leading to TMA and subsequent kidney and vital organ damage. 33%–40% patients (pts) die or progress to end-stage renal disease after the first clinical manifestation. In a phase 2 extension trial (64-week [wk] median ECU duration), pts receiving the terminal complement inhibitor ECU had a highly significant increase in platelet count (98×10⁹/L; P=0.0001)—a measure of TMA improvement—and 4 pts (80%) discontinued prior dialysis by data cutoff. Here we report 2-year (y) results.

Pts ≥12 y with aHUS and progressing TMA enrolled in an open-label, phase 2 trial with long-term extension. Pts had ≥4 plasma exchange/infusion (PE/PI) sessions in the wk before screening. ECU was administered at 900 mg/wk × 4 wk, 1200 mg at wk 5 and 1200 mg q2 wk thereafter.

The 26-wk study enrolled 17 pts, and 13 entered the extension phase. Data analysis was on the intention-to-treat population (n=17). Median time from diagnosis to screening was 10 months (range 0.3–236). Four pts (24%) had no identified complement regulatory factor mutation. Seven pts (41%) had prior renal transplant. All pts had estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² prior to ECU. Median ECU duration was 100 wk (range 2–145).

Suppression of terminal complement activity was sustained at data cutoff. Significant platelet count improvement from baseline was seen at the 2-y data cutoff (P<0.0001; Table), with 15 pts (88%) achieving and maintaining a platelet count ≥150×10⁹/L. Hematologic normalization^a was achieved by 88% of pts for an average duration of 629 days (d). Fifteen pts (88%) achieved TMA event-free status,^b and TMA intervention rate^c decreased from a median 0.88 (range 0.04–1.59) prior to ECU to 0 (range 0–0.31) during ECU treatment. Significant improvements in eGFR were observed throughout the study period (P=0.0008; Table). Earlier intervention with ECU was associated with greater eGFR improvement (P<0.01). Results of a 3-piece linear model demonstrated a flat slope for eGFR change from d −42 to 0, followed by a steep positive slope from d 0 to 28 (P<0.0001), then a continuous increase from d 28 to 860 (P=0.03). Improvements in other renal endpoints, including serum creatinine, proteinuria, and chronic kidney disease (CKD) stage, were observed with ongoing ECU. Significant improvements in quality of life (QOL) were observed. Pts received benefit regardless of the presence or absence of an identified complement mutation. Treatment with ECU was generally well tolerated, with 1 report of a serious adverse event (SAE; hypertension) deemed possibly drug related, which resolved with no change in ECU dosing. Two pts discontinued treatment due to worsening renal function unrelated to ECU.

Long-term ECU therapy inhibited complement-mediated TMA and resulted in significant and continuous time-dependent improvements in renal function. At a median duration of almost 2 y, all pts entering the extension phase remain alive and report better QOL. The low rate of SAEs is consistent with the known safety profile of ECU. These results highlight the ongoing benefit of earlier intervention and long-term treatment with ECU in aHUS.

Greenbaum:Alexion Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau. Legendre:Alexion Pharmaceuticals: Speakers Bureau. Babu:Alexion Pharmaceuticals: Honoraria, Research Funding. Cohen:Alexion Pharmaceuticals Inc.: Research Funding. Bedrosian:Alexion Pharmaceuticals: Employment. Loirat:Alexion Pharmaceuticals: Coordinator of Alexion trials of eculizumab in atypical HUS for France. Honoraria for conferences. Other.