The long-acting C5 inhibitor, ravulizumab, is efficacious and safe in pediatric patients with atypical hemolytic uremic syndrome previously treated with eculizumab

Abstract

Background: Atypical hemolytic uremic syndrome (aHUS) is a rare, complement-mediated disease associated with poor outcomes if untreated. Ravulizumab, a long-acting C5 inhibitor developed through minimal, targeted modifications to eculizumab was recently approved for the treatment of aHUS. Here, we report outcomes from a pediatric patient cohort from the ravulizumab clinical trial (NCT03131219) who were switched from chronic eculizumab to ravulizumab treatment.

Methods: Ten patients received a loading dose of ravulizumab on Day 1, followed by maintenance doses administered initially on Day 15, and then, every 4-8 weeks thereafter, depending on body weight. All patients completed the initial evaluation period of 26 weeks and entered the extension period.

Results: No patients required dialysis at any point throughout the study. The median estimated glomerular filtration rate values remained stable during the trial: 99.8 mL/min/1.73m² at baseline, 93.5 mL/min/1.73m² at 26 weeks, and 104 mL/min/1.73m² at 52 weeks. At last available follow-up, all patients were in the same chronic kidney disease stage as recorded at baseline. Hematologic variables (platelets, lactate dehydrogenase, and hemoglobin) also remained stable throughout the initial evaluation period and up to the last available follow-up. All patients experienced adverse events; the most common were upper respiratory tract infection (40%) and oropharyngeal pain (30%). There were no meningococcal infections reported, no deaths occurred, and no patients discontinued during the study.

Conclusions: Overall, treatment with ravulizumab in pediatric patients with aHUS who were previously treated with eculizumab resulted in stable kidney and hematologic parameters, with no unexpected safety concerns when administered every 4-8 weeks.

Trial registration: Trial identifiers: Trial ID: ALXN1210-aHUS-312 Clinical trials.gov : NCT03131219 EudraCT number: 2016-002499-29 Graphical abstract.

Keywords: Atypical hemolytic uremic syndrome; Children; Complement; Eculizumab; Hemolytic uremic syndrome; Ravulizumab; Thrombotic microangiopathy.

Graphical abstract

Fig. 1

Study design with dosing schedule

Fig. 2

Change in eGFR over time, for the initial evaluation and the extension period (full analysis set). eGFR estimated glomerular filtration rate

Fig. 3

Mean (95% CI) observed values over time during the initial evaluation period and the extension period (full analysis set) for platelet count (a), lactate dehydrogenase (LDH) (b), and hemoglobin (c). CI confidence interval, LDH lactate dehydrogenase

Fig. 4

Free C5 concentrations over time (PK/PD analysis set). A dashed line is drawn at 0.5 ug/ml free C5 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 border and the bottom border of the boxes 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. Patients weighing < 20 kg (a) and patients weighing ≥ 20 kg (b). PD pharmacodynamic, PK pharmacokinetic