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

Ravulizumab: A Review in Atypical Haemolytic Uraemic Syndrome

“…A bodyweight-based ravulizumab dosage regimen resulted in immediate and complete terminal complement inhibition (i.e. serum levels of free C5 < 0.5 µg/mL) by the end of the first infusion and throughout the 26-week treatment period in adult [ 19 ] and paediatric [ 20 , 21 ] patients with aHUS. The extent and duration of the pharmacodynamic response was dependent on exposure to ravulizumab in patients with aHUS [ 13 , 14 ].…”

“…The efficacy of ravulizumab was evaluated in two, single-arm, multicentre, 26-week, phase 3 studies in adult (ALXN1210-aHUS-311; hereafter, Study 311) [ 19 ] and paediatric (ALXN1210-aHUS-312; hereafter, Study 312) [ 20 , 21 ] patients with aHUS. Study 311 enrolled patients aged ≥ 18 years (bodyweight ≥ 40 kg) who were naïve to complement inhibitor treatment [ 19 ].…”

“…Study 311 enrolled patients aged ≥ 18 years (bodyweight ≥ 40 kg) who were naïve to complement inhibitor treatment [ 19 ]. Study 312 enrolled patients aged ≤ 18 years of age (bodyweight ≥ 5 kg) who were naïve to complement inhibitor treatment [ 21 ], as well as those who had previously received eculizumab [ 20 ].…”

“…The eculizumab-experienced cohort in Study 312 had to have documented evidence of aHUS and clinical response to eculizumab, as indicated by stable TMA parameters (i.e. platelet count ≥ 150 × 10 9 /L, serum LDH < 1.5 × ULN and estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m 2 ) [ 20 ]. Patients with TMA because of a ADAMTS13 deficiency, Shiga toxin E. coli -related HUS, Streptococcus pneumoniae -related HUS (in Study 311) or drug exposure-related HUS (in Study 312) were among those excluded [ 19 – 21 ].…”

“…Study 312 enrolled 10 eculizumab-experienced patients [ 20 ]. These patients were a median 12.5 years old (median bodyweight 47.8 kg) and had received eculizumab for 98–1701 days.…”