Ravulizumab in Atypical Hemolytic Uremic Syndrome: An Analysis of 2-Year Efficacy and Safety Outcomes in 2 Phase 3 Trials

Abstract

Rationale & objective: Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) caused by complement dysregulation. Ravulizumab is a C5i approved for the treatment of aHUS. This analysis assessed long-term outcomes of ravulizumab in adults and pediatric patients with aHUS.

Study design: This analysis reports 2-year data from 2 phase 3, single-arm studies.

Setting & participants: One study included C5i-naïve adults (NCT02949128), and the other included 2 cohorts of pediatric patients (C5i-naïve and those who switched to ravulizumab from eculizumab [pediatric switch patients]; NCT03131219).

Exposure: Patients received intravenous ravulizumab every 4-8 weeks, with the dose depending on body weight.

Outcomes: The primary endpoint in the studies of C5i-naïve patients was complete TMA response, which consisted of platelet count normalization, lactate dehydrogenase normalization, and ≥25% improvement in serum creatinine concentrations from baseline, at 2 consecutive assessments ≥4 weeks apart.

Analytical approach: All analyses used descriptive statistics. No formal statistical comparisons were performed.

Results: In total, 86 and 92 patients were included in efficacy and safety analyses, respectively. Complete TMA response rates over 2 years were 61% and 90% in C5i-naïve adults and pediatric patients, respectively. The median increase in estimated glomerular filtration rate from baseline was maintained over 2 years in C5i-naïve adults (35 mL/min/1.73 m²) and pediatric patients (82.5 mL/min/1.73 m²). Most adverse events and serious adverse events occurred during the first 26 weeks. No meningococcal infections were reported. Improvement in the Functional Assessment of Chronic Illness Therapy - Fatigue score achieved by 26 weeks was maintained over 2 years.

Limitations: Limitations were the small sample of pediatric switch patients and limited availability of genetic data.

Conclusions: Long-term treatment with ravulizumab is well tolerated and associated with improved hematologic and renal parameters and quality of life in adults and pediatric patients with aHUS.

Keywords: Adult; atypical hemolytic uremic syndrome; complement C5 inhibitor; efficacy; hematology; nephrology; pediatric; ravulizumab; safety; thrombotic microangiopathy.

Figure 1

Study design.

Figure 2

Patient disposition in adults naïve to C5i treatment (A), pediatric patients naïve to C5i treatment (B), and pediatric switch patients (C). ^aThe safety analysis set was used for safety analyses and included all patients who received ≥1 infusion of ravulizumab in the initial evaluation period. ^bThe full analysis set was used for analyses of efficacy, demographics, and baseline characteristics and included all patients with confirmed study eligibility and who received ≥1 infusion of ravulizumab in the initial evaluation period, including those later excluded, and ≥1 post-baseline efficacy assessment. Abbreviations: aHUS, atypical hemolytic uremic syndrome; C5i, complement C5 inhibitor; TMA, thrombotic microangiopathy.

Figure 3

Complete TMA response and its components status over time in adults (A) and pediatric patients (B) naïve to C5i treatment up to 2 years. The criteria for complete TMA response were normalization of platelet count, normalization of LDH, and ≥25% improvement in serum creatinine concentrations from baseline. A patient was in the analysis for a specific post-baseline time point if it was possible for the result at that time point to be confirmed. Hematologic normalization included normalization of platelet count and normalization of LDH. Platelet values obtained from the day of a blood transfusion of platelets through 3 days after the transfusion were excluded from all analyses. All serum creatinine values obtained while a patient was on dialysis were excluded from all analyses. When a patient was on dialysis at baseline, then the first valid creatinine value to be used as the baseline value was the first assessment ≥6 days post-dialysis. If a patient was on dialysis during the entire 26-week initial evaluation period, then the baseline creatinine was not calculated. Data from days with ≤1 patient are not shown. Abbreviations: LDH, lactate dehydrogenase; TMA, thrombotic microangiopathy.

Figure 4

Complete TMA response and its components status over time in adults (A) and pediatric patients (B) naïve to C5i treatment at 26 weeks and 2 years. 95% confidence intervals for the proportion were based on exact confidence limits using the Clopper-Pearson method. The criteria for complete TMA response were normalization of platelet count, normalization of LDH, and ≥25% improvement in serum creatinine concentrations from baseline. Patients met all complete TMA response criteria concurrently, and each criterion was met at 2 separate assessments obtained at least 4 weeks (28 days) apart and any measurement in between. The proportion of complete TMA response was based on the responders among treated patients. Hematologic normalization included normalization of platelet count and normalization of LDH. Platelet values obtained from the day of a blood transfusion of platelets through 3 days after the transfusion were excluded from all analyses. All serum creatinine values obtained while a patient was on dialysis were excluded from all analyses. When a patient was on dialysis at baseline, then the first valid creatinine value used as the baseline value was the first assessment ≥6 days post-dialysis. If a patient was on dialysis during the entire 26-week initial evaluation period, then the baseline creatinine was not taken into consideration. Abbreviations: LDH, lactate dehydrogenase; TMA, thrombotic microangiopathy.

Figure 5

Mean observed changes in eGFR up to 2 years for adults naïve to C5i treatment (A), pediatric patients naïve to C5i treatment (B), and pediatric switch patients (C). Values indicate the mean and 95% confidence intervals. Baseline value is defined as the average of the values from the assessments performed before the first study drug infusion (these can include results from screening and the day 1 visit). 10 mL/min/1.73 m² for eGFR is imputed for patients requiring dialysis for acute kidney injury. Abbreviation: eGFR, estimated glomerular filtration rate.

Figure 6

Free C5 concentrations up to 2 years for adults naïve to C5i treatment (A), pediatric patients naïve to C5i treatment (B), and pediatric switch patients (C). Dashed horizontal lines indicate serum-free C5 concentration of 0.5 μg/mL to denote the threshold for complete terminal complement inhibition. The horizontal line in the middle of each box indicates the median, a diamond indicates the mean, and the top and the bottom borders of the box mark the 75th and 25th percentiles, respectively. The whiskers represent the highest and lowest values within 1.5 times the interquartile range from the lower quartile and upper quartile. Outliers are represented by an asterisk beyond the whiskers. In B and C, patients are grouped based on the dose regimen decision day (patients on 4- or 8-week schedules). During the initial evaluation period, dose regimen decision days were screening, day 8, day 57, and day 113. During the extension period, the dose of ravulizumab was based on the patient’s body weight on the preceding decision day. For free C5 values below the limit of quantitation, LLOQ/2 = 0.00915 μg/mL was used. Abbreviation: EOI, end of infusions; LLOQ, lower limit of quantitation.