Ravulizumab in Atypical Hemolytic Uremic Syndrome: Final Analysis of Efficacy and Safety Outcomes in Two Phase 3 Trials

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Background: Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy (TMA) caused by complement dysregulation. Ravulizumab (RAV) is a complement C5 inhibitor (C5i) approved for the treatment of aHUS. Methods: This analysis reports final efficacy and safety data from two phase 3, single-arm clinical trials of C5i-naive adults (NCT02949128) and pediatric patients (pts) (NCT03131219) who were C5i-naive or switched to RAV from eculizumab (pediatric switch pts). Intravenous RAV was administered every 4–8 weeks, depending on body weight, in pts with aHUS. The primary endpoint was complete TMA response (platelet count normalization, lactate dehydrogenase normalization, and ≥25% improvement in serum creatinine from baseline, at two consecutive assessments ≥4 weeks apart). The primary endpoint evaluation was at Week 26; the extension period was up to 4.5 years or product approval/registration (whichever occurred first). Results: 54 pts completed the study (C5i-naive adults: n=28; C5i-naive pediatric pts: n=16; pediatric switch pts: n=10). The median (interquartile range) treatment duration was 130 (49–178) weeks for C5i-naive adults, 131 (15–160) weeks for C5i-naive pediatric pts, and 114 (114–123) weeks for pediatric switch pts. Among pts with available genetic data, 12/45 (27%) C5i-naive adults, 10/17 (59%) C5i-naive pediatric pts, and 6/10 (60%) pediatric switch pts had complement abnormalities and entered the extension. In C5i-naive adults (n=56), complete TMA response rates were 54% at Week 26 and 64% at end of study. In C5i-naive pediatric pts (n=20), complete TMA response rates were 75% at Week 26 and 90% at end of study. Among C5i-naive adults and pediatric pts, mean eGFR gradually improved up to Week 26 and remained stable until the end of the study. Most adverse events and serious adverse events were Grade 1 or 2 and occurred up to Week 26. No meningococcal infections were reported. Conclusion: This final analysis over a median of 114–131 weeks demonstrated that continuation of RAV treatment is associated with sustained control of aHUS and clinical benefit through improvement and long-term preservation of renal function, with no unexpected safety concerns. Funding: Commercial Support - Alexion, AstraZeneca Rare Disease.

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