Long-Term Efficacy and Safety of the Long-Acting Complement C5 Inhibitor Ravulizumab for the Treatment of Atypical Hemolytic Uremic Syndrome in Adults

Abstract

Introduction: Atypical hemolytic uremic syndrome (aHUS) is a rare, complex, multisystem disease of dysregulated complement activity, characterized by progressive thrombotic microangiopathy (TMA), acute kidney injury, and multiorgan dysfunction, which often progresses to chronic kidney disease. Results from the prospective clinical trial of ravulizumab (NCT02949128) reveal rapid resolution of TMA in patients with aHUS, with sustained efficacy and safety in a 26-week initial evaluation period.

Methods: The aim of this analysis was to characterize the long-term efficacy and the safety profile of ravulizumab in adults with aHUS who had completed the initial evaluation period of the trial. Complete TMA response, hematologic and kidney functions, and safety were evaluated for all patients available for follow-up in the extension period (median follow-up: 76.7 weeks; range: 0.6-118.3). This trial included a total of 58 patients, 49 of whom entered the extension period.

Results: A total of 4 additional patients achieved complete TMA response during the follow-up period. Normalization of platelet count, serum lactate dehydrogenase (LDH), and hemoglobin observed in the 26-week initial evaluation period was sustained until the last available follow-up, as were the improvements in the estimated glomerular filtration rate (eGFR) and patient quality of life. All efficacy endpoints were correlated with the sustained inhibition of complement C5. Most adverse events (AEs) occurred early during the initial evaluation period and decreased substantially during the extension period. No patient developed a meningococcal infection or died during the extension period.

Conclusion: This analysis reveals that ravulizumab administered every 8 weeks is efficacious with an acceptable safety profile for the long-term treatment of adults with aHUS and provides additional clinical benefit beyond 6 months of treatment.

Keywords: atypical hemolytic uremic syndrome; complement; hemolytic uremic syndrome; kidney failure; ravulizumab; thrombotic microangiopathy.

Figure 1

Patient disposition. Of the 8 patients who discontinued the study, 1 discontinued owing to protocol violation (the patient received frozen plasma, a prohibited procedure), 5 because of their own (patient) decision, and 2 because of the physician’s decision. An additional 3 patients discontinued the study drug during the extension period but remained enrolled in the study. Of these 3 patients, 2 discontinued the drug owing to physician’s decision and 1 because of their own (patient) decision. aHUS, atypical hemolytic uremic syndrome; STEC, Shiga toxin-producing Escherichia coli; TMA, thrombotic microangiopathy.

Figure 2

Kaplan–Meier graph depicting the time to complete TMA response. Patients who did not have a response were censored on the day of the last study visit or at study discontinuation. ∗Patient achieved initial complete TMA response measurement at day 169; however confirmatory measurement was not achieved until the extension period (day 239). BL, baseline; TMA, thrombotic microangiopathy.

Figure 3

Observed laboratory values over time. (a) platelet count; (b) lactate dehydrogenase; (c) hemoglobin. Data are shown as mean (error bars, 95% confidence interval).

Figure 4

Observed eGFR values over time. eGFR, estimated glomerular filtration rate. Data are shown as mean (SD; error bars, 95% confidence interval).

Figure 5

FACIT-Fatigue score over time. Data are shown as mean (error bars, 95% confidence interval). FACIT, Functional Assessment of Chronic Illness Therapy.