The long-acting C5 inhibitor, ravulizumab, is effective and safe in pediatric patients with atypical hemolytic uremic syndrome naïve to complement inhibitor treatment

Abstract

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 or symptoms of kidney to aHUS, of in mean = receiving Birth to yr = yr = to this first infusion of count, median (range), values may be after in median (range), values may be after in creatinine, median (range), values may be after in median (range), values may be after in median (range), values may be after in atypical hemolytic uremic estimated glomerular filtration hemoglobin; intensive care lactate plasma plasma thrombotic patient had 2 races entered (White and American Indian or Alaskan to aHUS, Baseline values may be after in in a aHUS, atypical hemolytic uremic estimated glomerular filtration hemoglobin; intensive care lactate plasma plasma thrombotic Baseline laboratory values are in Table patients the initial evaluation period and entered the extension period. patient because of an adverse the initial evaluation period. a female, anemia and kg and received a dose of ravulizumab on and a maintenance dose of on the this patient had a serum C5 terminal complement a initial the dose for this weight was increased to to serum of ravulizumab and in serum the initial evaluation period and extension the median duration of through the data cut point was (range, weeks. 1 patient was from the extension period. patient had a complete response on and was because of on the for was not to a safety patients had at of the study at the data The primary point of the study was complete response the initial evaluation period (Table the initial evaluation of 18 patients achieved complete response. The median time to complete response all data was (Figure response at week 26 and week evaluation period through week 26 = through week = count in serum from lactate thrombotic in a lactate thrombotic the extension through week 50, an additional 3 patients achieved a complete response complete response in a of one patient did not a complete this patient was the initial evaluation period and had not achieved a response in of the of complete response at point a response in at after the initial was not for this patient to in Overall, platelet normalization and improvement in serum were achieved by in and respectively. By patients had achieved platelet normalization and achieved improvement in serum count normalization was achieved in 17 patients the initial evaluation period and through week The median increase in platelet count from baseline to week 26 was (range, and to week 50, (range, (Figure normalization was achieved in patients the initial evaluation and in 17 patients through week The median in from baseline to week 26 was (range, to and to week 50, (range, to (Figure patients achieved an increase in of from baseline, with a through week 26, and 17 patients through week The increase in from baseline to week 26 was (range, and by week 50, (range, to (Figure improved from baseline, with a median increase in estimated glomerular filtration rate of (range, by week 26 and (range, by week (Figure Of the 6 (28.6%) patients receiving dialysis at baseline, were dialysis by week 26 and all 6 were dialysis by week of the patients dialysis at baseline dialysis the in to a baseline and week was in patients with 2 patients in the same (Figure By week 50, all patients with data had improved (Figure patients had of data at baseline, week 26, and week 9 patients had a improvement 3 D. et and to on the of anemia and Full Text Full Text PDF PubMed Scopus Google Scholar in at week 26 and week with baseline (Figure The median increase in was (range, and 9.0 (range, at week 26 and week 50, respectively. Ravulizumab and terminal complement C5 Figure with C5 at 3 time was in a patient in the to kg received the interim the dose for patients to kg was increased from to with no C5 in to kg patients receiving the patients in the safety analysis (Table with and (Table patients the frequent of which were and both in 2 patients a full of is in Supplementary Table patient a female, a 3 listed by the anemia and which in study on patient was in the weight and received a dose of resulting in serum of ravulizumab of which was the patients study infusion, and one of these patients to ravulizumab on 3 These with study dose and and rate of and the patients in the No or meningococcal infections were of through data (N = resulting in resulting in resulting in study resulting in study study study adverse in a Table frequent adverse (N = in of patients are by the evaluated for safety all patients received ≥1 dose of the study in a adverse in of patients are by the evaluated for safety all patients received ≥1 dose of the study study is the first phase 3 trial the efficacy and safety of ravulizumab, a long-acting C5 inhibitor with a maintenance dosing of 4 to in pediatric patients with dosing of ravulizumab in and terminal complement C5 inhibition, leading to hematologic and improvement of in patients with The primary point was with patients complete response by week response is a point requiring platelet count normalization, normalization, and improvement in serum creatinine, demonstrated at 2 at all this point was in a median time of days. additional 3 the primary point by week 94.4% of patients had a complete of these patients had symptoms of aHUS and achieved platelet normalization and serum response on 18 and respectively. The for response was not the extension period which is the patient achieved the complete response. The patient achieved complete response on patient achieved hematologic response the initial evaluation period on and on did not improve was the initial evaluation period (range, The patient achieved platelet normalization on and normalization on patient dialysis on and for serum which were normalization was in a of patients at week 26 than complete with patients and platelet count normalization by week by week 50, 17 patients had achieved hematologic to other on complement for the treatment of C. P. et complement inhibitor eculizumab in atypical hemolytic-uremic J 2013; PubMed Scopus Google F. M. et complement inhibitor eculizumab in adult patients with atypical hemolytic uremic syndrome: a J 2016; Full Text Full Text PDF PubMed Scopus Google Scholar platelet normalization than other of after the first ravulizumab and data from this clinical trial improvement in efficacy of ravulizumab with treatment is burdensome and a impact on the quality of life of of quality of life children with end-stage a 2018; PubMed Scopus Google A. L.A. et on dialysis children report quality of 2018; PubMed Scopus Google Scholar plasma to of children end-stage kidney disease within 3 years of 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 were receiving dialysis at baseline had dialysis at week 26, were dialysis by week 50, with no patients dialysis the Overall, improved the and all patients improved in by week As chronic kidney disease is not to children years a of this was not clinical for the evaluation and management of chronic kidney 2013; Full Text Full Text PDF Scopus Google Scholar to the of the of other aHUS can also in and M. Ariceta G. et al.An for atypical uraemic syndrome: and a consensus 2013; 33: Google Scholar, A. et al.Eculizumab complement and injury in PubMed Scopus Google Scholar, of atypical hemolytic uremic Nephrol. 2019; PubMed Scopus Google Scholar patients in this study had symptoms at baseline, to the in the clinical trial of ravulizumab in adult patients naïve to complement inhibitor 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 in this trial, to may be to aHUS in an other than the this may symptoms to the of The patients in this trial were at the time of the primary acute of aHUS with by the and the requiring intensive care of care. also a high of patients with of the study, the adult to the the efficacy and safety of ravulizumab in adult patients with aHUS naïve to complement-inhibitor treatment, of patients had symptoms of aHUS the first of patients with in these from an increased of aHUS a resulting in increased of these symptoms to aHUS, an be excluded the of these symptoms was in these and not in pathogenic the rate of patients in this study was high at 7 is a than been to the for naïve to complement inhibition, these patients may been treated with It also been to not all patients to genetic data from the Global aHUS dialysis of plasma exchange/plasma infusion, and the impact in reduced in patients with L.A. C. V. et of and other in patients in the Global aHUS 2020; 5: Full Text Full Text PDF PubMed Scopus Google Scholar In this study, all patients with data had improvement in time at week 26 and week improvement is in patients with a chronic aHUS, and a of treatment with The of a treatment for aHUS can be at a reduced frequency with eculizumab has for a from 26 infusions year to 13 or 7 infusions on body patients and their time at and children may a for may no a with reduced for morbidity to or infections and also the of to may also and reduced and from and an improved quality of life with greater adherence to treatment are to these data from the point to the of reduced dosing frequency on of and reduced from and in children treated with a long-acting factor S. J. G. quality of life in patients treated with 2019; PubMed Scopus Google Scholar It is be in children treated with In of clinical infusions and time in both and in the In patients with aHUS, a analysis in the frequent dosing with ravulizumab time in the resulting for ravulizumab treatment were in the and in with eculizumab P. from atypical hemolytic uremic syndrome patients in the with eculizumab or ravulizumab in an infusion or at 2019; 22 and Full Text Full Text PDF Google Scholar health and with ravulizumab are to be and quality of life resulting from increased time for and is to P. from atypical hemolytic uremic syndrome patients in the with eculizumab or ravulizumab in an infusion or at 2019; 22 and Full Text Full Text PDF Google Scholar patients were in this study at one with under patient the study after of and the study, the to with an increased dose of eculizumab on and In the study of ravulizumab on adults naïve to complement treatment, were in all and were in 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 were and in of patients These data are to those the eculizumab in adults and 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 C. P. et complement inhibitor eculizumab in atypical hemolytic-uremic J 2013; PubMed Scopus Google F. M. et complement inhibitor eculizumab in adult patients with atypical hemolytic uremic syndrome: a J 2016; Full Text Full Text PDF PubMed Scopus Google Scholar in and in the eculizumab trial and to the in the The in children were and and the in this study were and A recently published study the of eculizumab is meningococcal G. et al.Eculizumab in paroxysmal nocturnal and atypical uraemic syndrome: J 2019; PubMed Scopus Google Scholar In the study, no patients treated with ravulizumab meningococcal with eculizumab clinical in no were in this study was the primary point hematologic and parameters to be at 2 at patients the study within of first dose were not to meet this However, this did not a significant impact on the one patient the initial evaluation period this patient the first and did not to for In patients receiving dialysis at baseline were also to meet the point after because of serum to a in time to a complete response in had clinical 2 patients in the analysis were years, of both and data from these patients be with because of the of the in patient and a or was not Ravulizumab and complement C5 inhibition, resulting in improvement in and hematologic parameters 26 and increase in response rate with no unexpected safety with ravulizumab every 4 to weeks patients and with a reduction in treatment The from this study the of ravulizumab in children for of by aHUS for a treatment period of 6

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