The long-acting C5 inhibitor, ravulizumab, is effective and safe in pediatric patients with atypical hemolytic uremic syndrome naïve to complement inhibitor treatment
Authors: Gema Ariceta, Bradley P. Dixon, Seong Heon Kim, Gaurav Kapur, Teri Mauch, Stephan Ortiz, Marc Vallee, Andrew E. Denker, Hee Gyung Kang, Larry A. Greenbaum, Helen Lovell, Melissa Muff-Luett, Kristin Malone, Oluwasegun Adeagbo, Alexandria Wilkerson, Gloria Fraga, Scherezade Sarri, Hae Il Cheong, Yo Han Ahn, Kyoung Hee Han
Journal: Kidney International (2020)

Ravulizumab, a long-acting complement C5 inhibitor engineered from eculizumab, allows extending maintenance dosing from every 2–3 weeks to every 4–8 weeks depending on bodyweight. Here, we evaluated the efficacy and safety of ravulizumab in complement inhibitor-naïve children (under 18 years) with atypical hemolytic uremic syndrome. In this phase III, single-arm trial, ravulizumab was administered every eight weeks in patients 20 kg and over, and four weeks in patients under 20 kg. The primary endpoint was a complete thrombotic microangiopathy response (normalization of platelet count and lactate dehydrogenase, and a 25% or more improvement in serum creatinine) through 26 weeks. Secondary endpoints included change in hematologic parameters and kidney function. 18 patients with a median age of 5.2 years were evaluated. At baseline, symptoms of atypical hemolytic uremic syndrome outside the kidney were present in 72.2% of patients and 38.9% had been in intensive care. Baseline estimated glomerular filtration rate was 22 mL/min/1.73 m2. By week 26, 77.8% of patients achieved a complete thrombotic microangiopathy response; 94.4%, 88.9% and 83.3% of patients achieved platelet normalization, lactate dehydrogenase normalization and a 25% or more improvement in serum creatinine, respectively. By week 50, 94.4% patients had achieved a complete thrombotic microangiopathy response. Median improvement in platelet count was 246 and 213 x109/L through week 26 and week 50, respectively. The median increase above baseline in estimated glomerular filtration rate was 80 and 94 mL/min/1.73m2 through week 26 and week 50, respectively. No unexpected adverse events, deaths, or meningococcal infections occurred. Thus, ravulizumab rapidly improved hematologic and kidney parameters with no unexpected safety concerns in complement inhibitor-naïve children with atypical hemolytic uremic syndrome. Ravulizumab, a long-acting complement C5 inhibitor engineered from eculizumab, allows extending maintenance dosing from every 2–3 weeks to every 4–8 weeks depending on bodyweight. Here, we evaluated the efficacy and safety of ravulizumab in complement inhibitor-naïve children (under 18 years) with atypical hemolytic uremic syndrome. In this phase III, single-arm trial, ravulizumab was administered every eight weeks in patients 20 kg and over, and four weeks in patients under 20 kg. The primary endpoint was a complete thrombotic microangiopathy response (normalization of platelet count and lactate dehydrogenase, and a 25% or more improvement in serum creatinine) through 26 weeks. Secondary endpoints included change in hematologic parameters and kidney function. 18 patients with a median age of 5.2 years were evaluated. At baseline, symptoms of atypical hemolytic uremic syndrome outside the kidney were present in 72.2% of patients and 38.9% had been in intensive care. Baseline estimated glomerular filtration rate was 22 mL/min/1.73 m2. By week 26, 77.8% of patients achieved a complete thrombotic microangiopathy response; 94.4%, 88.9% and 83.3% of patients achieved platelet normalization, lactate dehydrogenase normalization and a 25% or more improvement in serum creatinine, respectively. By week 50, 94.4% patients had achieved a complete thrombotic microangiopathy response. Median improvement in platelet count was 246 and 213 x109/L through week 26 and week 50, respectively. The median increase above baseline in estimated glomerular filtration rate was 80 and 94 mL/min/1.73m2 through week 26 and week 50, respectively. No unexpected adverse events, deaths, or meningococcal infections occurred. Thus, ravulizumab rapidly improved hematologic and kidney parameters with no unexpected safety concerns in complement inhibitor-naïve children with atypical hemolytic uremic syndrome. Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening disease associated with complement dysregulation, characterized by thrombotic microangiopathy (TMA).1Fakhouri F. Zuber J. Fremeaux-Bacchi V. Loirat C. Haemolytic uraemic syndrome.Lancet. 2017; 390: 681-696Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar,2Goodship T.H. Cook H.T. Fakhouri F. et al.Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference.Kidney Int. 2017; 91: 539-551Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar Microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury are hallmarks of aHUS, but aHUS can also affect organs other than the kidneys.1Fakhouri F. Zuber J. Fremeaux-Bacchi V. Loirat C. Haemolytic uraemic syndrome.Lancet. 2017; 390: 681-696Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar Without appropriate treatment, aHUS causes significant morbidity and mortality, with 29% of children requiring dialysis or dying within 1 year and 48% reaching end-stage kidney disease or dying at 3 years, despite plasma therapy.3Noris M. Caprioli J. Bresin E. et al.Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype.Clin J Am Soc Nephrol. 2010; 5: 1844-1859Crossref PubMed Scopus (656) Google Scholar,4Fremeaux-Bacchi V. Fakhouri F. Garnier A. et al.Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults.Clin J Am Soc Nephrol. 2013; 8: 554-562Crossref PubMed Scopus (445) Google Scholar Eculizumab (Alexion Pharmaceuticals Inc., Boston, MA, USA) has been approved for the treatment of aHUS since 2011.5FDAEculizumab (Soliris). 2011.http://wayback.archive-it.org/7993/20170113081126/http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm273089.htmGoogle Scholar,6EMAEU/3/09/653. 2011.https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu309653Google Scholar It has proved highly effective in children with aHUS.7Greenbaum L.A. Fila M. Ardissino G. et al.Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome.Kidney Int. 2016; 89: 701-711Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 8Ito S. Hidaka Y. Inoue N. et al.Safety and effectiveness of eculizumab for pediatric patients with atypical hemolytic-uremic syndrome in Japan: interim analysis of post-marketing surveillance.Clin Exp Nephrol. 2019; 23: 112-121Crossref PubMed Scopus (16) Google Scholar, 9Loirat C. Fakhouri F. Ariceta G. et al.An international consensus approach to the management of atypical hemolytic uremic syndrome in children.Pediatr Nephrol. 2016; 31: 15-39Crossref PubMed Scopus (327) Google Scholar, 10Patriquin C.J. Kuo K.H.M. Eculizumab and beyond: the past, present, and future of complement therapeutics.Transfus Med Rev. 2019; 33: 256-265Crossref PubMed Scopus (30) Google Scholar However, eculizumab treatment regimen involves frequent intravenous infusions (every 2 weeks in patients weighing >10 kg), which can be particularly burdensome for pediatric patients and caregivers. A reduction of dosing frequency may improve the quality of life and adherence to treatment.11Richter A. Anton S.F. Koch P. Dennett S.L. The impact of reducing dose frequency on health outcomes.Clin Ther. 2003; 25 (discussion 2306): 2307-2335Abstract Full Text PDF PubMed Scopus (238) Google Scholar, 12Groth M. Singer S. Niedeggen C. et al.Development of a disease-specific quality of life questionnaire for patients with aplastic anemia and/or paroxysmal nocturnal hemoglobinuria (QLQ-AA/PNH)-report on phases I and II.Ann Hematol. 2017; 96: 171-181Crossref PubMed Scopus (17) Google Scholar, 13Coleman C.I. Limone B. Sobieraj D.M. et al.Dosing frequency and medication adherence in chronic disease.J Manag Care Pharm. 2012; 18: 527-539Crossref PubMed Scopus (264) Google Scholar Ravulizumab, a humanized monoclonal antibody, is a long-acting complement C5 inhibitor recently approved for treatment of aHUS in adults and children.14FDARavulizumab prescribing information. Alexion Pharmaceuticals Inc., Boston, MA2018Google Scholar,15EMA Ravulizumab summary of product characteristics. Alexion Europe SAS, Levalloise-Perret, France2019Google Scholar Ravulizumab was engineered through selective modifications to eculizumab. These modifications included 2 amino acid substitutions made to preserve high binding affinity to C5 at pH 7.4 in blood, but permitting dissociation of C5 from ravulizumab at pH 6.0. Two additional substitutions were made to increase the affinity for neonatal Fc receptor, with all 4 modifications resulting in increased antibody recycling. Overall, these substitutions, while targeting the same C5 epitope, enhanced the duration of terminal complement inhibition, leading to a mean half-life >4 times greater than eculizumab (approximately 51.8 days) because of additional recycling of binding and neutralization of C5 (Supplementary Figure S1).16Sheridan D. Yu Z.X. Zhang Y. et al.Design and preclinical characterization of ALXN1210: a novel anti-C5 antibody with extended duration of action.PloS One. 2018; 13e0195909Crossref PubMed Scopus (88) Google Scholar As such, ravulizumab offers a reduced dosing frequency (every 4–8 weeks based on body weight) relative to eculizumab. The clinical efficacy and safety of ravulizumab in adults with aHUS has been demonstrated in a recently published phase 3 trial report (NCT02949128).17Rondeau E. Scully M. Ariceta G. et al.The long-acting C5 inhibitor, ravulizumab, is effective and safe in adult patients with atypical hemolytic uremic syndrome naïve to complement inhibitor treatment.Kidney Int. 2020; 97: 1287-1296Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar In this study, we assessed the efficacy and safety of ravulizumab in complement-inhibitor treatment-naïve children with aHUS through an initial evaluation period of 26 weeks and an interim data cut point through the extension period. Twenty-one complement-inhibitor naïve children were enrolled, receiving ≥1 dose of ravulizumab, forming the safety set of this analysis (Figure 1). Two patients were excluded from the full analysis set because of ineligibility after treatment (one patient did not meet laboratory criteria for platelet count, lactate dehydrogenase [LDH], and hemoglobin; and the other had a positive Shiga toxin-producing Escherichia coli test), and one patient was excluded because of a protocol violation (did not meet the laboratory criteria for LDH). The full analysis set comprised 18 patients with a median age of 5.2 (range, 0.5–17.3) years (Table 1). Ten patients (55.6%) were female, 9 (50.0%) were White, and the median weight was 16.7 (range, 8.4–69.3) kg. Before ravulizumab treatment, 6 (28.6%) patients had received plasma exchange/plasma infusion. Before the start of screening, 7 (38.9%) patients had been treated in an intensive care unit, for a mean duration of 9.0 (±17.7) days. Extrarenal symptoms of aHUS were present in 13 (72.2%) patients at baseline (Supplementary Table S1). Ten patients were tested using the whole exome sequencing method for genetic variants in complement genes, and 17 were tested for anti-complement factor H (CFH) antibodies. Of those tested with both methods, 9 of 10 (90%) had a pathogenic variant in complement gene and/or anti-CFH antibody (Supplementary Table S2). Pathogenic variants were found in 3 patients (CFH, MCP, and THBD), and CFH antibodies were found in 7 patients (additional pathogenic variants were identified by local genetic analyses; see supplemental information). The median age of first aHUS symptoms was 4.7 (range, 0.8–14.7) years, and the median age at time of first infusion was 5.2 (range, 0.5–17.3) years. Comorbidities in patients in this study are listed in Supplementary Table S3.Table 1Baseline demographics, disease characteristics, and laboratory values (full analysis set)VariableOverall (N = 18)Age at time of first infusion, median (range), yr5.2 (0.5–17.3)Age at time of first infusion category, yr Birth to <22 (11.1) 2–<69 (50.0) 6–<125 (27.8) 12–<182 (11.1)Age at time of first aHUS symptoms, median (range), yr4.7 (0.8–14.7)Sex Male8 (44.4) Female10 (55.6)RaceaOne patient had 2 races entered (White and American Indian or Alaskan Native). American Indian or Alaskan Native1 (5.6) Asian5 (27.5) Black or African American3 (16.7) White9 (50.0) Unknown1 (5.6)Weight at time of first infusion, kg ≥5–<102 (11.1) ≥10–<209 (50.0) ≥20–<303 (16.7) ≥30–<403 (16.7) ≥40–<600 ≥601 (5.6)Pretreatment extrarenal signs or symptoms of aHUS13 (72.2)Any prior kidney transplantbTransplant related to aHUS, December 2014.1 (5.6)Patients who required ICU level of care7 (38.9)Time in ICU, mean (SD), d (n = 9)9.0 (±17.7)Patients receiving dialysis6 (33.3) Birth to <6 yr (n = 11)2 (18.2) 6–<18 yr (n = 7)4 (57.1)Received PE/PI related to this TMA before first infusion of drug6 (28.6)Platelet count, median (range), ×109/LcBaseline values may be after PE/PI in some patients.51.25 (14–125)LDH, median (range), U/LcBaseline values may be after PE/PI in some patients.1963.0 (772–4985)Serum creatinine, median (range), μmol/LcBaseline values may be after PE/PI in some patients.133.0 (35–264)eGFR, median (range), mL/min per 1.73 m2cBaseline values may be after PE/PI in some patients.22.0 (10–84)HGB, median (range), g/LcBaseline values may be after PE/PI in some patients.74.25 (32–106)aHUS, atypical hemolytic uremic syndrome; eGFR, estimated glomerular filtration rate; HGB, hemoglobin; ICU, intensive care unit; LDH, lactate dehydrogenase; PE, plasma exchange; PI, plasma infusion; TMA, thrombotic microangiopathy.Data shown as number (percentage) unless otherwise stated.a One patient had 2 races entered (White and American Indian or Alaskan Native).b Transplant related to aHUS, December 2014.c Baseline values may be after PE/PI in some patients. Open table in a new tab aHUS, atypical hemolytic uremic syndrome; eGFR, estimated glomerular filtration rate; HGB, hemoglobin; ICU, intensive care unit; LDH, lactate dehydrogenase; PE, plasma exchange; PI, plasma infusion; TMA, thrombotic microangiopathy. Data shown as number (percentage) unless otherwise stated. Baseline laboratory values are shown in Table 1. Seventeen patients completed the 26-week initial evaluation period and entered the extension period. One patient discontinued because of an adverse event (AE) during the initial evaluation period. This patient, a 21.6-month-old White female, experienced worsening anemia and hypertensive crisis. She weighed <10 kg and received a loading dose of 300 mg ravulizumab on day 1, and a maintenance dose of 300 mg on day 15. During the loading phase, this patient had a serum C5 level ≥0.5 μg/ml, suggesting incomplete terminal complement inhibition. Following a protocol-specified initial pharmacokinetic (PK)/pharmacodynamic (PD) analysis, the loading dose for this weight category was increased to 600 mg, to ensure adequate target serum concentrations of ravulizumab and corresponding reductions in serum C5. Including the initial evaluation period and extension period, the median duration of follow-up through the current data cut point was 82.6 (range, 3.0–110.6) weeks. Only 1 patient was discontinued from the extension period. This patient had a complete TMA response on day 88 and was discontinued because of physician decision on day 350; the reason for discontinuation was not due to a safety concern. All remaining patients had completed at least 351 days of the study at the data cut. The primary end point of the study was complete TMA response during the initial evaluation period (Table 2). During the 26-week initial evaluation period, 14 of 18 (77.8%) patients achieved complete TMA response. The median time to complete TMA response considering all available data was 30 (95% confidence interval, 22.0–88.0) days (Figure 2).Table 2Complete TMA response at week 26 and week 50VariableInitial evaluation period through week 26 (n = 18)Evaluation through week 50 (n = 18)Complete TMA response14 (77.8)17 (94.4)Platelet count normalization17 (94.4)17 (94.4)LDH normalization16 (88.9)17 (94.4)25% Improvement in serum creatinine from baseline15 (83.3)17 (94.4)Hematologic normalization16 (88.9)17 (94.4)LDH, lactate dehydrogenase; TMA, thrombotic microangiopathy.Data shown as number (percentage). Open table in a new tab LDH, lactate dehydrogenase; TMA, thrombotic microangiopathy. Data shown as number (percentage). During the extension period, through week 50, an additional 3 patients achieved a complete TMA response (resulting complete TMA response in a total of 17/18 [94.4%] patients). Only one patient did not achieve a complete TMA response, as this patient was discontinued during the initial evaluation period (day 21), as mentioned previously, and had not achieved a response in any of the components of complete TMA response at that point (because a response in any component required confirmation at least 28 days after the initial observation, it was not possible for this patient to have responded in any component). Overall, platelet normalization and ≥25% improvement in serum creatinine were achieved by day 8 in 65% and 47% patients, respectively. By day 15, 88% patients had achieved platelet normalization and 53% achieved ≥25% improvement in serum creatinine. Platelet count normalization was achieved in 17 (94.4%) patients during the 26-week initial evaluation period and through week 50. The median increase in platelet count from baseline to week 26 was 246.0 × 109/L (range, 57.5–368.5 × 109/L); and to week 50, 213.0 × 109/L (range, 19.5–471.5 × 109/L) (Figure 3a). LDH normalization was achieved in 16 (88.9%) patients during the 26-week initial evaluation period, and in 17 (94.4%) patients through week 50. The median decrease in LDH from baseline to week 26 was 1851.5 U/L (range, –4713 to –513 U/L); and to week 50, 1825.5 U/L (range, –4724 to –579 U/L) (Figure 3b). Sixteen (88.9%) patients achieved an increase in hemoglobin of ≥20 g/L from baseline, with a confirmatory result through week 26, and 17 patients (94.4%) through week 50. The increase in hemoglobin from baseline to week 26 was 46.5 g/L (range, 26.5–86.0 g/L); and by week 50, 51.5 g/L (range, –19.0 to 80.0 g/L) (Figure 3c). Renal function substantially improved from baseline, with a median increase in estimated glomerular filtration rate (eGFR) of 80.0 (range, 0–222.0) ml/min per 1.73 m2 by week 26 and 94.0 (range, 10–230) ml/min per 1.73 m2 by week 50 (Figure 3d). Of the 6 (28.6%) patients receiving dialysis at baseline, 5 (83.3%) were off dialysis by week 26 and all 6 (100%) were off dialysis by week 50. None of the 12 patients off dialysis at baseline initiated dialysis during the study. Improvement in eGFR (change to a less severe eGFR category between baseline and week 26) was seen in 15 patients (88.2%), with 2 (11.8%) patients remaining in the same category (Figure 4a). By week 50, all 16 patients with evaluable data had improved eGFR category (Figure 4b). Nine patients had evaluable Pediatric Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue data at baseline, week 26, and week 50. All 9 patients (100%) had a clinically meaningful improvement (at least 3 points)18Cella D. Eton D.T. Lai J.S. Peterman A.H. et al.Combining anchor and distribution-based methods to derive minimal clinically important differences on the Functional Assessment of Cancer Therapy (FACT) anemia and fatigue scales.J Pain Symptom Manage. 2002; 24: 547-561Abstract Full Text Full Text PDF PubMed Scopus (573) Google Scholar in Pediatric FACIT-Fatigue score at week 26 and week 50 compared with baseline (Figure 5). The median increase in Pediatric FACIT-Fatigue score was 10.0 (range, 4.0–48.0) and 9.0 (range, 3.0–47.0) at week 26 and week 50, respectively. Ravulizumab showed immediate, complete, and sustained terminal complement C5 inhibition (serum-free C5, <0.5 μg/ml; Figure 6), with individual free C5 outliers noted at only 3 time points. One outlier (day 15 trough; 0.999 μg/ml) was observed in a patient in the ≤5 to <10 kg group who received the original loading dose. Consequently, following prespecified interim PK/PD analysis, the loading dose for enrolled patients ≤5 to <10 kg was increased from 300 to 600 mg, with no free C5 outliers observed in ≤5 to <10 kg patients receiving the updated loading dose. All 21 patients in the safety analysis experienced AEs (Table 3), with pyrexia, headache, nasopharyngitis, diarrhea, and vomiting occurring most frequently (Table 4). Fourteen patients (66.7%) experienced serious AEs (SAEs), the most frequent of which were viral gastroenteritis and abdominal pain, both occurring in 2 patients each (9.5%; a full list of SAEs is shown in Supplementary Table S4). One patient (4.8%), a 21.6-month-old White female, experienced a grade 3 treatment-emergent AE, listed by the investigator as worsening anemia and hypertensive crisis, which resulted in study discontinuation on day 21. This patient was in the lowest weight category (<10 kg) and received a loading dose of 300 mg (as described previously), resulting in predose serum concentration of ravulizumab of 137 μg/ml, which was below the target threshold. Four patients (19.0%) experienced AEs during study drug infusion, and one of these patients experienced nonsevere hypersensitivity to ravulizumab on 3 separate occasions. These cases resolved with study drug dose interruption, diphenhydramine and paracetamol, and slower rate of infusion; and the patients remained in the study. No deaths or meningococcal infections were reported.Table 3Summary of AEs through current data cutAE variableOverall (N = 21)No. (%)EventsAny AE21 (100)369Any SAE14 (66.7)31TEAE resulting in drug discontinuation1 (4.8)2TESAE resulting in drug discontinuation1 (4.8)2TEAE resulting in study discontinuation1 (4.8)2TESAE resulting in study discontinuation1 (4.8)2TEAE during study drug infusion4 (19.0)7TESAE during study drug infusion00Treatment-related AEs10 (47.6)33Meningococcal infections00Deaths00AE, adverse event; SAE, serious AE; TEAE, treatment-emergent AE; TESAE, treatment-emergent SAE. Open table in a new tab Table 4Most frequent treatment-emergent adverse eventsAdverse eventOverall (N = 21)No. (%)EventsPyrexia10 (47.6)22Nasopharyngitis7 (33.3)13Diarrhea7 (33.3)10Vomiting7 (33.3)25Headache7 (33.3)19Abdominal pain6 (28.6)11Hypertension6 (28.6)8Cough5 (23.8)6Rash4 (19.0)5Rhinorrhea4 (19.0)4Myalgia4 (19.0)7Constipation4 (19.0)8Nausea4 (19.0)9Events occurring in >15% of patients listed. Adverse event terms are as reported by the treating investigator. Patients evaluated for safety include all patients who received ≥1 dose of the study drug. Open table in a new tab AE, adverse event; SAE, serious AE; TEAE, treatment-emergent AE; TESAE, treatment-emergent SAE. Events occurring in >15% of patients listed. Adverse event terms are as reported by the treating investigator. Patients evaluated for safety include all patients who received ≥1 dose of the study drug. This study is the first prospective phase 3 trial evaluating the efficacy and safety of ravulizumab, a long-acting C5 inhibitor with a maintenance dosing interval of 4 to 8 weeks, in pediatric patients with aHUS. Weight-based dosing of ravulizumab resulted in immediate, complete, and sustained terminal complement C5 inhibition, leading to hematologic remission and improvement of renal function in patients with aHUS. The primary end point was met, with 14 (77.8%) patients achieving complete TMA response by week 26. Complete TMA response is a stringent end point requiring platelet count normalization, LDH normalization, and ≥25% improvement in serum creatinine, demonstrated simultaneously at 2 separate assessments at least 28 days apart. Considering all available follow-up, this end point was met in a median time of 30 days. An additional 3 patients, described below, met the primary end point by week 50 (overall, 94.4% of patients had a complete TMA response). One of these patients had extrarenal symptoms of aHUS and achieved platelet normalization and serum creatinine response on days 18 and 24, respectively. The LDH criterion for response was not met until during the extension period (day 297), which is when the patient formally achieved the complete TMA response. The second patient achieved complete TMA response on day 351. This patient achieved hematologic response during the initial evaluation period (platelets normalized on day 8, and LDH normalized on day 24). Serum creatinine level did not improve ≥25% until day 351, although it was stable throughout the initial evaluation period (range, 160–235 μmol/L). The third patient achieved platelet normalization on day 71 and LDH normalization on day 104. This patient discontinued dialysis on day 193 and only then became evaluable for serum creatinine criteria, which were subsequently met. Hematologic normalization was observed in a higher proportion of patients at week 26 than complete TMA response, with 16 (88.9%) patients achieving LDH and platelet count normalization by week 26; by week 50, 17 (94.4%) patients had achieved hematologic normalization. Similar to other studies on complement inhibitors for the treatment of aHUS,19Legendre C.M. Licht C. Muus P. et al.Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.N Engl J Med. 2013; 368: 2169-2181Crossref PubMed Scopus (935) Google Scholar,20Fakhouri F. Hourmant M. Campistol J.M. et al.Terminal complement inhibitor eculizumab in adult patients with atypical hemolytic uremic syndrome: a single-arm, open-label trial.Am J Kidney Dis. 2016; 68: 84-93Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar platelet normalization occurred earlier than other components of TMA response, observed 8 days after the first ravulizumab dose; and data from this clinical trial demonstrate improvement in efficacy of ravulizumab with increasing treatment duration. Dialysis is burdensome and debilitating, having a severe impact on the quality of life of children.21El Shafei A.M. Soliman Hegazy I. Fadel F.I. Nagy E.M. Assessment of quality of life among children with end-stage renal disease: a cross-sectional study.J Environ Public Health. 2018; 2018: 8565498Crossref PubMed Scopus (9) Google Scholar,22Splinter A. Tjaden L.A. Haverman L. et al.Children on dialysis as well as renal transplanted children report severely impaired health-related quality of life.Qual Life Res. 2018; 27: 1445-1454Crossref PubMed Scopus (21) Google Scholar With plasma therapy, close to 50% of children develop end-stage kidney disease within 3 years of diagnosis.3Noris M. Caprioli J. Bresin E. et al.Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype.Clin J Am Soc Nephrol. 2010; 5: 1844-1859Crossref PubMed Scopus (656) Google Scholar,4Fremeaux-Bacchi V. Fakhouri F. Garnier A. et al.Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults.Clin J Am Soc Nephrol. 2013; 8: 554-562Crossref PubMed Scopus (445) Google Scholar In this study, 83.3% children who were receiving dialysis at baseline had discontinued dialysis at week 26, and, notably, 100% were off dialysis by week 50, with no patients initiating dialysis during the study. Overall, renal function improved substantially across the cohort, and all patients improved in eGFR category by week 50. As chronic kidney disease staging is not applicable to children aged <2 years as a result of expected physiologic eGFR maturation, this terminology was not applied.23KDIGOKDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.Kidney Int Suppl. 2013; 3: 1-150Abstract Full Text Full Text PDF Scopus (1442) Google Scholar Because TMA leads to the involvement of the microvasculature of other organs, aHUS can also manifest in neurological, gastrointestinal, cardiovascular, and pulmonary systems.24Campistol J.M. Arias M. Ariceta G. et al.An update for atypical haemolytic uraemic syndrome: diagnosis and treatment: a consensus document.Nefrologia. 2013; 33: 27-45PubMed Google Scholar, 25Cofiell R. Kukreja A. Bedard K. et al.Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS.Blood. 2015; 125: 3253-3262Crossref PubMed Scopus (119) Google Scholar, 26Cassandra Formeck A.S.-U. Extra-renal manifestations of atypical hemolytic uremic syndrome.Pediatric Nephrol. 2019; 34: 1337-1348Crossref PubMed Scopus (18) Google Scholar Thirteen (72.5%) patients in this study had extrarenal symptoms at baseline, similar to the proportion reported in the clinical trial of ravulizumab in adult patients naïve to complement inhibitor therapy.17Rondeau E. Scully M. Ariceta G. et al.The long-acting C5 inhibitor, ravulizumab, is effective and safe in adult patients with atypical hemolytic uremic syndrome naïve to complement inhibitor treatment.Kidney Int. 2020; 97: 1287-1296Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar The term "extrarenal symptom," as applied in this trial, refers to any symptom that may be related to aHUS occurring in an organ other than the kidney; this may include symptoms related to the presence of renal failure. The patients in this trial were enrolled at the time of experiencing the primary acute manifestations of aHUS and, thus, presented with severe disease, evidenced by the number hospitalized and the number requiring intensive care unit level of care. Other studies also reported a similar high proportion of patients with extrarenal manifestations of aHUS. For instance, the ALXN1210-aHUS-311 study, the adult equivalent to the current analysis, evaluating the efficacy and safety of ravulizumab in adult patients with aHUS naïve to complement-inhibitor treatment, showed that 92.9% of patients had extrarenal symptoms of aHUS before the first dose. This higher proportion of patients with extrarenal manifestations reported in these recent studies could result from an increased awareness of aHUS as a disease, resulting in increased attribution of these symptoms to aHUS, although an ascertainment bias cannot be excluded as the presence of these symptoms was specifically queried in these trials and not necessarily in earlier ones. Regarding pathogenic variants, the rate of CFH-autoantibody–positive patients in this study was high at 7 (41%). Although it is a higher percentage than expected, it could have been related to the eligibility requirement for being naïve to complement inhibition, as these patients may have been initially treated with alternative therapies. It could also have been due to sampling error, as not all patients consented to genetic testing. Real-world evidence data from the Global aHUS Registry have shown that dialysis requirement, recent hospitalizations, use of plasma exchange/plasma infusion, and TMA have the largest impact in reduced FACIT-Fatigue scores in patients with aHUS.27Greenbaum L.A. Licht C. Nikolaou V. et al.Functional assessment of fatigue and other patient-reported outcomes in patients enrolled in the Global aHUS Registry.Kidney Int Rep. 2020; 5: 1161-1171Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar In this study, all patients with evaluable data had clinically meaningful improvement in FACIT-Fatigue score over time at week 26 and week 50. This improvement is especially important in patients with a chronic disease, such as aHUS, and supports a favorable risk-to-benefit ratio of treatment with ravulizumab. The availability of a long-term treatment for aHUS that can be given at a reduced frequency compared with eculizumab has multiple potential benefits for patients. With a decrease from 26 infusions per year to 13 or 7 infusions (depending on body weight), patients and their caregivers will miss less time at school and work. Moreover, children who may have required a port for vascular access may no longer require a port, with reduced potential for morbidity due to clots or infections and hospital workload. Fewer clinic appointments could also reduce the risk of exposure to nosocomial infections. Children may also feel less sick, and experience reduced fear and pain from repeated venipuncture, and thus have an improved quality of life with potentially greater adherence to treatment regimens, although further studies are required to confirm these hypotheses. Recent data from the hemophilia B literature point to the potential benefit of reduced dosing frequency on burden of therapy and reduced absenteeism from school and work, in children treated with a long-acting recombinant factor IX.28von Mackensen S. Shah J. Seifert W. Kenet G. Health-related quality of life in paediatric haemophilia B patients treated with rIX-FP.Haemophilia. 2019; 25: 45-53Crossref PubMed Scopus (12) Google Scholar It is likely that similar benefits would be seen in children treated with ravulizumab. In terms of clinical benefits, fewer infusions could free up physician and nursing time in both homecare settings and in the clinic. In patients with aHUS, a recent productivity analysis in the United States shows that less frequent dosing with ravulizumab substantially reduces time spent in treatment; the resulting lost productivity costs for ravulizumab treatment were 60% lower in the clinic and 73% lower in home infusing setting, compared with eculizumab treatment.29Levy A.R. Chen P. Tomazos I. Comparing productivity losses from treating atypical hemolytic uremic syndrome patients in the United States with eculizumab or ravulizumab in an infusion clinic or at home [PR05].Value Health. 2019; 22 (Poster and abstract): S841Abstract Full Text Full Text PDF Google Scholar This suggests that health system and societal costs with ravulizumab therapy are likely to be reduced, and quality of life resulting from increased time available for work and school is likely to improve.29Levy A.R. Chen P. Tomazos I. Comparing productivity losses from treating atypical hemolytic uremic syndrome patients in the United States with eculizumab or ravulizumab in an infusion clinic or at home [PR05].Value Health. 2019; 22 (Poster and abstract): S841Abstract Full Text Full Text PDF Google Scholar All patients who were enrolled in this study experienced at least one AE, with just under half (47.6%) experiencing treatment-related AEs. One patient discontinued the study after experiencing SAEs of hypertensive crisis and worsening anemia. After discontinuing the study, the investigator chose to treat her with an increased dose of eculizumab (600 mg) on day 21 and day 23. In the previous study of ravulizumab on adults naïve to complement treatment, AEs were reported in all patients, and SAEs were reported in 51.7%.17Rondeau E. Scully M. Ariceta G. et al.The long-acting C5 inhibitor, ravulizumab, is effective and safe in adult patients with atypical hemolytic uremic syndrome naïve to complement inhibitor treatment.Kidney Int. 2020; 97: 1287-1296Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar The most common SAEs were viral gastroenteritis and abdominal pain, occurring in 9.5% of patients each. These data are similar to those reported across the eculizumab trials in adults and children.7Greenbaum L.A. Fila M. Ardissino G. et al.Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome.Kidney Int. 2016; 89: 701-711Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar,19Legendre C.M. Licht C. Muus P. et al.Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.N Engl J Med. 2013; 368: 2169-2181Crossref PubMed Scopus (935) Google Scholar,20Fakhouri F. Hourmant M. Campistol J.M. et al.Terminal complement inhibitor eculizumab in adult patients with atypical hemolytic uremic syndrome: a single-arm, open-label trial.Am J Kidney Dis. 2016; 68: 84-93Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar Specifically, in children, 90.9% and 59% in the eculizumab trial experienced AEs and SAEs, respectively, similar to the proportions reported in the current study. The most common AEs in eculizumab-treated children were fever, cough, abdominal pain, diarrhea, and respiratory tract infection; and the most common AEs in this study were pyrexia, headache, nasopharyngitis, diarrhea, and vomiting. A recently published 10-year pharmacovigilance study showed that the main risk of eculizumab is meningococcal infection.30Socie G. Caby-Tosi M.P. Marantz J.L. et al.Eculizumab in paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome: 10-year pharmacovigilance analysis.Br J Haematol. 2019; 185: 297-310Crossref PubMed Scopus (86) Google Scholar In the current study, no patients treated with ravulizumab developed meningococcal infections, consistent with previous eculizumab clinical trials in children. Furthermore, no deaths were reported in this study. This study was designed such that the primary end point required hematologic and renal parameters to be met at 2 separate assessments at least 28 days apart. This meant that patients discontinuing the study within 28 days of first dose were not able to meet this end point. However, this did not have a significant impact on the results as only one patient discontinued during the 26-week initial evaluation period (although this patient discontinued during the first 28 days and thus did not participate long enough to have responded for any parameter). In addition, patients receiving dialysis at baseline were also unable to meet the renal end point until after stopping dialysis, because of serum creatinine level requirement. This could have led to a delay in time to achieve a complete TMA response in some patients, although they had earlier clinical improvement. Also, 2 patients in the current analysis were aged <2 years, so interpretation of both continuous and categorical eGFR data from these patients should be approached with caution. Finally, because of the rarity of the condition, limitations in patient enrollment and sample size meant a comparator or control group was not feasible. Ravulizumab provided immediate, complete, and sustained complement C5 inhibition, resulting in rapid improvement in renal and hematologic parameters across 26 weeks, and further increase in response rate over longer duration, with no unexpected safety concerns. Treatment with ravulizumab every 4 to 8 weeks provides patients and caregivers with a meaningful reduction in treatment burden. The results from this study support the use of ravulizumab in children for resolution of TMA caused by aHUS for a minimum treatment period of 6 months.