Eculizumab prevents thrombotic microangiopathy in patients with atypical haemolytic uraemic syndrome in a long-term observational study

Eculizumab prevents thrombotic microangiopathy in patients with atypical haemolytic uraemic... Clinical Kidney Journal, 2018, 1–10 doi: 10.1093/ckj/sfy035 Original Article OR I G I N AL A R T I C L E Eculizumab prevents thrombotic microangiopathy in patients with atypical haemolytic uraemic syndrome in a long-term observational study 1 2 3 4, Jan Menne , Yahsou Delmas , Fadi Fakhouri , John F. Kincaid *, 5 6 4, 7 Christoph Licht , Enrico E. Minetti , Chris Mix *, Franc ¸ois Provo ˆt , 8 9 4 10 Eric Rondeau , Neil S. Sheerin , Jimmy Wang , Laurent E. Weekers and Larry A. Greenbaum 1 2 Klinik fu ¨ r Nieren- und Hochdruckerkrankungen, Hannover, Germany, CHU de Bordeaux, Bordeaux, France, 3 4 5 CHU de Nantes, Nantes, France, Alexion Pharmaceuticals, Inc., New Haven, CT, USA, The Hospital for Sick 6 7 Children, Toronto, Ontario, Canada, Azienda Ospedaliero Universitaria Careggi, Florence, Italy, CHU de Lille, 8 9 Lille, France, Ho ˆ pital Tenon and Universite ´ Paris VI, Paris, France, Institute of Cellular Medicine, University 10 11 of Newcastle upon Tyne, Newcastle upon Tyne, UK, CHU de Lie ` ge, Lie ` ge, Belgium and Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, GA, USA Correspondence and offprint requests to: Jan Menne; E-mail: menne.jan@mh-hannover.de *Former employee. ABSTRACT Background. Eculizumab, a terminal complement inhibitor, is approved for atypical haemolytic uraemic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA). Methods. In five parent studies, eculizumab effectively prevented TMA and improved renal and haematologic outcomes in patients with aHUS; therefore, these patients could enrol in this long-term, prospective, observational and multicentre study. The primary endpoint was the TMA manifestation rate off and on eculizumab post-parent study. Post hoc analyses evaluated rates during labelled versus non-labelled dosing regimens, and in those with versus without identified complement abnormalities. Serious targeted treatment-emergent adverse events (TEAEs) were evaluated. Results. Of 87 patients in the current study, 39 and 76 had off- and on-treatment periods, respectively; 17 (44%) with off periods reinitiated eculizumab. TMA manifestation rate per 100 patient-years was 19.9 off and 7.3 on treatment [hazard ratio (HR), 4.7; P¼ 0.0008]; rates were highest off treatment and lowest during labelled regimens. TMA manifestations with hospitalizations/ serious AEs occurred more frequently off versus on treatment. TMA rates were higher among patients with identified complement abnormalities (HR, 4.5; P¼ 0.0082). Serious targeted TEAEs occurred at similar rates off and on treatment. Conclusions. As expected, patients with aHUS have increased risk of TMA manifestations after discontinuation of eculizumab or in the setting of non-labelled eculizumab dosing. Collectively, results show that maintaining eculizumab treatment minimizes risk of TMA, particularly in patients with identified complement abnormalities. Future studies are Received: 7.12.2017. Editorial decision: 2.4.2018 V The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy035/4996707 by Ed 'DeepDyve' Gillespie user on 12 July 2018 2| J. Menne et al. needed to further characterize TMA and longer term outcomes on labelled or non-labelled eculizumab regimens and after discontinuation of treatment. Keywords: atypical haemolytic uraemic syndrome, complement, discontinuation, eculizumab, observational study, thrombotic microangiopathy discontinued from the parent study or were on eculizumab at the INTRODUCTION time of enrolment. Patients could withdraw from the current study Atypical haemolytic uraemic syndrome (aHUS) is a rare, genetic, at any time. The protocol was approved by an institutional review potentially life-threatening disease predominantly caused by board or independent ethics committee at each participating cen- uncontrolled activation of the alternative complement pathway tre and the study was conducted in accordance with International [1–3]. Abnormalities in complement genes or autoantibodies to Council for Harmonisation Guidelines and the Declaration of complement proteins are identified in50–70% of patients Helsinki. All patients and/or parents/guardians provided written [2, 3]. Complement dysregulation leads to persistent cleavage of informed consent before entry into the current study. C5 to the prothrombotic, pro-inflammatory anaphylatoxin C5a The current study consequently includes both prospective and to C5b, which initiates formation of the prothrombotic and and retrospective data collection. Retrospective data were cytolytic C5b-9 and ultimately causes injury, activation and obtained from the date each patient ended participation in the lysis of endothelial cells, leucocytes and platelets [1, 4]. The parent study until the date of signed informed consent for the resultant thrombotic microangiopathy (TMA) is typically current study. All patients who received at least one infusion of characterized by microangiopathic haemolytic anaemia, throm- eculizumab during the parent study and had signed consent bocytopaenia and acute renal failure, and frequently includes forms for the current study were included in the analysis. extrarenal complications [2, 3]. Identification of complement abnormalities occurred during the Patients who remain untreated are at lifelong risk of renal parent studies and included analysis of complement factor I impairment or failure, organ dysfunction and premature death (CFI), complement factor B (CFB), complement factor H (CFH), [2, 3]. Eculizumab (Soliris , Alexion Pharmaceuticals, Inc., New membrane cofactor protein (MCP) and C3 mutations, comple- Haven, CT, USA), a humanized monoclonal antibody that inhib- ment factor H-related proteins 1-3 (CFHR1-3) deletions/polymor- its C5a, C5b and C5b-9 formation by binding to C5, is the first phisms and CFH autoantibodies [7, 9–11]. Patients received and only approved treatment for patients with aHUS [5, 6]. The meningococcal vaccination in the parent studies [7, 9, 10] and efficacy and safety of eculizumab have been demonstrated in were revaccinated according to country guidelines. The cut-off four prospective, multicentre clinical studies [7–10] and a retro- date for this interim analysis was 28 March 2015. spective study [11]. TMA manifestations were neither defined nor collected uni- Current regulatory guidance notes potential risk of TMA fol- formly in the parent studies; thus, this analysis includes out- lowing discontinuation of eculizumab [5, 6]. Additional evidence comes reported in this ongoing observational study only (i.e. for TMA manifestations occurring after discontinuation is lim- beginning at the end of the parent study). Data were collected ited to case studies [12–25], two retrospective studies [26, 27] four times annually in both the retrospective and prospective and a small prospective observational study [28, 29]. Together, portions of the current study. TMA manifestations were documented in 26/82 patients (32%) who discontinued eculizumab [12–29]. An analysis [30] from the eculizumab clinical trial programme determined that severe Treatment TMA manifestations occurred in 12/61 patients (20%) who chose After completion of the parent study and entry into the current to discontinue treatment. study, the labelled dosing regimen of eculizumab was defined This is the single largest prospective, observational study of as that specified in the prescribing information approved by the consequences following eculizumab discontinuation in regulatory authorities [5, 6], and other dosing schedules (i.e. de- aHUS. In an interim analysis, TMA manifestation rates off and creased or increased dosages, shortened or extended dosing on eculizumab in patients with aHUS were evaluated. Post hoc intervals) were permitted and classified as non-labelled regi- analyses based on a revised, more stringent definition of TMA, mens. In this study, the first on-treatment period was defined during labelled versus non-labelled regimens and by comple- as: from the date of the first infusion in the current study (i.e. ment abnormality status, also were conducted. In addition, the beginning at the end of the parent study) through 3 weeks after safety of long-term eculizumab is reported. the last infusion of eculizumab, or until the patient discontin- ued from the study, or data cut-off (whichever occurred first). The first off-treatment period was defined as: from 3 weeks af- MATERIALS AND METHODS ter the last infusion of eculizumab within the current study un- til the patient restarted eculizumab therapy, discontinued from Study design and patients the study or data cut-off (whichever occurred first). Subsequent on- and off-treatment periods were defined similarly. Patient This is a long-term, prospective, observational and multicentre study (NCT01522170) of patients with aHUS who were treated groups were not mutually exclusive; individual patients could be represented in both groups. with eculizumab in any of five previous clinical studies (parent studies): four prospective studies (NCT00844545/NCT00844844 and NCT00838513/NCT00844428 [7, 8], NCT01193348 [9], Endpoints NCT01194973 [10]) and one retrospective study (NCT01770951 [11]). Patients who participated in a parent study were eligible Primary endpoint was the rate of TMA manifestations (defined for the current study, regardless of whether they completed or in Table 1) in the current study off and on treatment. Post hoc Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy035/4996707 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Eculizumab for TMA prevention in aHUS | 3 Table 1. Per-protocol definition of TMA manifestations (any1 listed criteria) Type/severity Criteria Laboratory value The occurrence of a change in 1 laboratory value : a c change only Platelet count decrease 25% compared with baseline and <LLN Increase in SCr or LDH level 25% compared with baseline and >ULN Clinical signs and Clinical signs and symptoms of TMA considered definitely related to aHUS, including: symptoms of TMA Thrombosis Seizure Decreased renal function Proteinuria (new or worse compared with baseline and >1þ or >30 mg/dL) Haematuria (new or worse compared with baseline and >50 RBC/HPF) Increased haemolytic anaemia Biopsy-proven TMA Other (e.g. extrarenal TMA manifestations including confusion, cardiovascular abnormalities, pericarditis, gastrointestinal symptoms and diarrhoea) Intervention The patient received PE/PI, dialysis, blood transfusions or renal transplant due to a TMA manifestation As determined by changes in laboratory parameters with ongoing follow-up. Measurements were required to be confirmed by a second measurement28 days apart with no interruption. Baseline was defined for each on period as the last laboratory value during the preceding off period, and for each off period as the last value during the preceding on period. As determined at the discretion of the investigator. HPF, high-powered field; LDH, lactate dehydrogenase; LLN, lower limit of normal; PE/PI, plasma exchange/plasma infusion; RBC, red blood cells; SCr, serum creatinine; ULN, upper limit of normal. analyses evaluated TMA manifestation rates off and on treat- eight patients (21%) who discontinued eculizumab and 14 (29%) ment when TMA manifestations based on only a single labora- on ongoing eculizumab. A median (range) of 11.0 (0.0–230.0) tory value change were excluded; in patients receiving labelled plasma exchanges or plasma infusions were used by the overall compared with non-labelled eculizumab regimens; and in population before eculizumab initiation, including 7.0 (0.0–64.0) patients with and without identified complement abnormali- in patients who discontinued eculizumab and 13.3 (0.0–230.0) in ties. Safety endpoints included assessment of serious targeted patients who never discontinued eculizumab. Dialysis was re- treatment-emergent adverse events (TEAEs; predefined as inci- quired by 29/87 patients (33%) before parent study enrolment, dence of serious infection, meningococcal infection, sepsis, re- and use was more frequent in those who discontinued eculizu- nal impairment or leucopaenia), as well as any serious AE (SAE). mab (39%) compared with those who never discontinued eculi- zumab (29%). Including parent studies, patients had a total median (range) of 45.9 (1.3–86.9) months of eculizumab expo- Statistical methods sure. In the current study, median (range) follow-up was 20.1 Time to first TMA manifestation was defined as time from the (0.7–79.5) months off and 26.1 (0.7–64.2) months on treatment. start of the current study (i.e. end of the parent study) to first Compared with patients who continued on eculizumab, TMA manifestation during the current study. Patients who did those who discontinued had a shorter interval from initial aHUS not have a TMA manifestation were censored at data cut-off or diagnosis, as well as the most recent pretreatment TMA mani- study discontinuation, whichever occurred first. Time to first festation, to first-ever eculizumab dose in the parent study. TMA manifestation was analysed using Cox proportional haz- Patients who discontinued also presented with lower estimated ards models with treatment status as a time-dependent explan- glomerular filtration rates (eGFRs) and were more frequently di- atory variable and complement abnormality status as a alysis dependent at initiation of eculizumab (Table 2). covariate. Hazard ratios (HRs) and P values were obtained for Non-labelled eculizumab regimens were received by 33/87 comparisons off and on treatment and between identified and patients (38%) during the current study. Of these, 11 always re- no identified complement abnormality subgroups. ceived non-labelled doses and 22 had periods of labelled and non-labelled regimens. Median (range) duration of therapy was 25.7 (0.5–60.4) months during labelled and 14.3 (0.4–64.3) months RESULTS during non-labelled regimens. Dosing higher than labelled Patients and exposure accounted for 0.4% of the total patient-years for non-labelled regimens. Overall, 130 patients were enrolled in the parent studies. By the data cut-off for this analysis, 87 patients had enrolled in the cur- rent study. Of these, 39 (45%) had off-treatment periods whereas TMA manifestations 76 (87%) had on-treatment periods. Seventeen patients (44%) with off-treatment periods reinitiated eculizumab; of these, 14 When using the per-protocol definition (Table 1), 28 TMA (82%) remained on therapy once they reinitiated (Figure 1). Age, manifestations occurred. This included 14 TMA manifestations frequency of complement abnormalities and kidney transplant in 11/39 patients (28%) off treatment and 14 TMA manifesta- status were not different between patients with ongoing eculi- tions in 10/76 patients (13%) on treatment (Tables 3 and 4). zumab therapy versus those who discontinued (Table 2). TMA manifestation rate per 100 patient-years was 19.9 off and Twenty-two patients (25%) had renal transplants, including 7.3 on treatment (63% lower; HR, 4.7; P ¼ 0.0008; Table 5). Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy035/4996707 by Ed 'DeepDyve' Gillespie user on 12 July 2018 4| J. Menne et al. FIGURE 1: Patient disposition. Patients treated with non-labelled and labelled regimens had manifestations occurred in 2/76 patients (3%) on treatment. TMA manifestation rates of 12.1 and 5.2 per 100 patient-years, The TMA manifestation rate per 100 patient-years was 15.6 off respectively (39% and 74% lower, respectively, versus off and 1.0 on treatment (94% decrease; HR, 16.8; P ¼ 0.0010) treatment). (Table 5). Characteristics of TMA manifestations TMA manifestations by complement abnormality status TMA manifestations off treatment were more frequently associ- The majority of patients who reported TMA manifestations as ated with multiple laboratory criteria for TMA, clinical signs and defined per protocol had complement abnormalities (Tables 3 symptoms of TMA, interventions, SAEs and/or hospitalizations and 4), particularly in those with CFH [10/17 (59%)] and CFI (Tables 3 and 4). Eleven of 14 TMA manifestations (79%) in mutations [4/17 (24%)]. Rates were higher for patients with iden- patients off treatment included multiple laboratory TMA criteria tified complement abnormalities compared with no identified and/or an intervention, compared with 2/14 TMA manifesta- complement abnormalities (HR, 4.5; P¼ 0.0082). tions (14%) on treatment. Patients required hospitalization dur- ing 9/14 TMA manifestations (64%) off treatment and 3/14 TMA Safety manifestations (21%) on treatment. Overall, treatment with eculizumab was well tolerated. The oc- currence of serious targeted TEAEs during the current study was TMA manifestation rate excluding TMAs based on similar off and on treatment (Table 6). Two patients from the par- single laboratory value changes ent retrospective study reported meningococcal infections during An abnormality in a single laboratory value may not be the current study; both were determined to be probably related to considered as TMA clinically; therefore, a post hoc analysis was eculizumab. Both patients were treated and recovered while con- performed to better reflect TMA evaluation in clinical practice. tinuing eculizumab on schedule. Diagnoses/underlying condi- TMA defined by a change from baseline in a single laboratory tions associated with reported serious targeted TEAEs of renal value occurred in 3/14 TMA manifestations (21%) off treatment impairment that did not meet criteria for TMA included new kid- and 12/14 TMA manifestations (86%) on treatment (Tables 3 ney transplant, renal graft rejection, multiorgan failure, dehydra- and 4). When using this definition, 11 TMA manifestations tion, infection and interstitial tubulopathy. One adult patient, occurred in 8/39 patients (21%) off treatment and two TMA who received non-labelled dosing during the current study, Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy035/4996707 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Eculizumab for TMA prevention in aHUS | 5 Table 2. Demographic and baseline clinical characteristics in the parent studies Ongoing eculizumab Discontinued Total Characteristic (n¼ 48) (n¼ 39) (n¼ 87) Age at first-ever infusion of eculizumab, years Median (range) 24.0 (0.0–65.0) 21.0 (0.0–80.0) 22.0 (0.0–80.0) <12, n (%) 13 (27) 11 (28) 24 (28) 12 to <18, n (%) 6 (13) 5 (13) 11 (13) 18, n (%) 29 (60) 23 (59) 52 (60) Age at entry to current study, years Median (range) 27.5 (2.5–67.6) 25.1 (1.6–81.6) 26.0 (1.6–81.6) <12, n (%) 10 (21) 11 (28) 21 (24) 12 to <18, n (%) 3 (6) 0 (0) 3 (3) 18, n (%) 35 (73) 28 (72) 63 (72) Female, n (%) 30 (63) 23 (59) 53 (61) Complement gene mutation or autoantibody, n (%) 31 (65) 20 (51) 51 (59) CFH 12 (25) 8 (21) 20 (23) CFH autoantibodies 6 (13) 1 (3) 7 (8) C3 6 (13) 1 (3) 7 (8) CD46 (MCP) 2 (4) 5 (13) 7 (8) CFI 3 (6) 4 (10) 7 (8) C3, CFHR3-CFHR1 1 (2) 0 1 (1) CD46 (MCP), CFI 1 (2) 0 1 (1) CFB 0 1 (3) 1 (1) Identified CFHR1, CFHR3 deletion 0 1 (3) 1 (1) Time from last pretreatment aHUS manifestation to 2.3 (0.0–47.4) 0.5 (0.0–19.2) 0.9 (0.0–47.4) first-ever dose of eculizumab, median (range), months Family history of aHUS, n (%) 8 (17) 8 (21) 16 (18) Time from aHUS diagnosis to first-ever dose of 18.4 (0.0–313.3) 0.9 (0.0–178.1) 4.0 (0.0–313.3) eculizumab, median (range), months History of TMA manifestations, n (%) Single 29 (60) 27 (69) 56 (64) Multiple 19 (40) 12 (31) 31 (36) Prior renal transplant, n (%) 14 (29) 8 (21) 22 (25) PE/PI sessions per patient, median (range) 13.3 (0.0–230.0) 7.0 (0.0–64.0) 11.0 (0.0–230.0) Dialysis at baseline , n (%) 14 (29) 15 (39) 29 (33) d 2 eGFR at baseline, median (range), mL/min/1.73 m 21.2 (8.4–128.3) 12.1 (5.3–105.5) 18.9 (5.3–128.3) Includes patients with additional abnormalities [i.e. C3, CD46 (MCP), CFI, CFHR1, CFHR3, and CFHR3-CFHR1]. Includes patients with additional abnormalities (i.e. CFHR1, CFHR3, CFHR3-CFHR1). Dialysis at baseline was defined as any dialysis that occurred within 7 days prior to or 14 days following the first eculizumab dose in the parent study. d 2 eGFR was defined as 10 mL/min/1.73 m when a patient was on dialysis. PE/PI, plasma exchange/plasma infusion. died due to severe intensive care complications and severe multi- agreed-upon definition of TMA based upon a single laboratory organ dysfunction after gastrointestinal haemorrhage, lithiasic value in clinical practice. TMA manifestations off treatment were cholecystitis and severe sepsis, which were determined to be associated with multiple laboratory criteria, clinical sequelae (e.g. unrelated to eculizumab. renal impairment and acute renal failure), SAEs, hospitalizations and/or required interventions (e.g. transfusion) in 13/14 cases (93%). In contrast, TMA manifestations on treatment typically comprised changes in single laboratory values with no clinical DISCUSSION signs/symptoms. Therefore, post hoc analyses were conducted to Results from this interim analysis of a non-randomized, pro- provide insights using a more stringent TMA definition that we spective observational study demonstrate that rates of TMA believe more closely defines TMA in the setting of aHUS. When manifestations in patients with aHUS were 2.7-fold higher off TMA manifestations based only on changes in single laboratory compared with on eculizumab (63% lower), despite longer values were excluded, the rate off treatment was 15.6-fold higher follow-up on treatment. TMA manifestation rates were lowest than on treatment. These results taken together could suggest during labelled dosing regimens (74% lower than off treatment), worse outcomes for patients who discontinue eculizumab, al- higher during non-labelled regimens (39% lower than off treat- though it is possible that changes in single laboratory values may ment) and highest off treatment. signal subclinical disease processes. The per-protocol definition of TMA manifestations was broad, Patients with identified complement abnormalities had sta- including changes in laboratory values, clinical signs and symp- tistically significantly higher TMA rates than patients with no toms of TMA related to aHUS, and/or interventions related to identified abnormalities. CFH and CFI mutations were predomi- TMA. Thus, reported TMA per this definition represented varying nant among patients who experienced TMA, regardless of treat- degrees of clinical deterioration. Importantly, there is no single, ment status. This finding is consistent with previous Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy035/4996707 by Ed 'DeepDyve' Gillespie user on 12 July 2018 6| J. Menne et al. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy035/4996707 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 3. Reported TMA manifestations in patients off treatment with eculizumab Patient demographics and clinical characteristics Eculizumab therapy Eculizumab Duration of duration discontinuation TMA Criteria before before TMA manifestation achieved for Patient age Complement discontinuation manifestation based on single TMA SAE/ Eculizumab b c Patient Sex (years) abnormality (months) (months) lab criterion manifestation hospitalization reinitiation 1 Male 9 CFH 6 1.3 No "SCr, "LDH No Yes 2 Male 11 CFI 517 No "SCr, "LDH, #platelets Yes Yes 0.7 3.7 No "SCr, "LDH, #platelets, transfusion Yes Yes 3 Male 4 CFH 14 2.5 No #Platelets, #renal function, No Yes "haemolytic anaemia 4 Male 38 CFH 27 2.6 Yes "SCr Yes Yes 5 Female 25 MCP 37 5 No "SCr, "LDH, #Hb, #haptoglobin, Yes Yes renal impairment 6 Female 39 CFI 37 7 Yes #Platelets Yes Yes 7 Female 84 None identified 3 28 No "LDH, #platelets Yes No 3 42 No Signs of reactivation of TMA No No with clinical repercussion 8 Male 26 MCP 618 No "SCr, transfusion Yes No 634 No "SCr, transfusion Yes Yes 9 Male 27 None identified 50 2 No #Haptoglobin Yes Yes 10 Female 73 CFH autoantibodies, 34 17 Yes "SCr No No CFHR1-3 11 Female 20 CFH, C3 62No #Platelets, acute No Yes renal failure During the current study only (i.e. excluding the parent study). Before or during TMA manifestation. Seventeen of 39 patients (43.6%) reinitiated eculizumab after discontinuation of therapy. Median (range) time to reinitiation was 2.6 (0.7–69.3) months. Fourteen of 17 patients (82%) continue on therapy after reinitiation. Hb, haemoglobin; LDH, lactate dehydrogenase; SCr, serum creatinine. Eculizumab for TMA prevention in aHUS | 7 Table 4. Reported TMA manifestations in patients on treatment with eculizumab Patient demographics and clinical characteristics Eculizumab therapy Treatment TMA manifestation Criteria achieved Patient age Complement duration Labelled based on single lab for TMA SAE/ b c Patient Sex (years) abnormality (months) regimen criterion manifestation hospitalization 1 Female 4 None identified 26 No Yes "SCr No 2 Female 31 CFH 28 Yes Yes #Platelets Yes 3 Female 44 CFH 20 Yes Yes "LDH No 4 Female 12 CFH 59 Yes Yes "SCr No 5 Female 44 CFI 19 Yes Yes #Platelets Yes 6 Male 27 MCP 51 Yes Yes "LDH No 60 No Yes "LDH No 7 Male 49 CFI 39 Yes No Dialysis Yes 8 Female 10 CFH 56 No Yes "SCr No 61 No No "SCr, #platelets, No "Proteinuria 9 Male 15 CFH 41 No Yes #Platelets No 44 No Yes "SCr No 53 No Yes "SCr No 10 Male 20 None identified 3 Yes Yes "LDH No During the current study only (i.e. excluding the parent study). No TMA manifestations occurred while patients received dosing higher than approved by regulatory authorities. Before or during TMA manifestation. The patient’s first on-treatment period was 19 months, followed by an off-treatment period of 31 months and another on-treatment period of 10 months. LDH, lactate dehydrogenase; SCr, serum creatinine. Table 5. TMA manifestation rates Excluding single laboratory Eculizumab treatment status Eculizumab dosing change criterion Off On Non-labelled Labelled Off On treatment treatment regimen regimen treatment treatment Parameter (n ¼ 39) (n ¼ 76) (n¼ 33) (n ¼ 65) (n ¼ 39) (n ¼ 76) Patients with manifestation, n (%) 11 (28) 10 (13) 4 (12) 7 (11) 8 (21) 2 (3) Total number of manifestations 14 14 7 7 11 2 Total patient-years 70.5 192.8 57.9 135.0 70.5 192.8 TMA manifestation rate/ 19.9 7.3 12.1 5.2 15.6 1.0 100 patient-years Fold change in rate 2.7 Ref 2.3 Ref 15.6 Ref Per cent change compared Ref 63 39 74 Ref 94 with off treatment (%) c d HR (P value) 4.7 (P¼ 0.0008) Ref 1.3 (P¼ 0.7000) Ref 16.8 (P¼ 0.0010) Ref Off treatment compared with on treatment (overall) or non-labelled compared with labelled regimen for the same analysis. On treatment (overall), non-labelled or labelled regimen compared with off treatment for the same analysis. HRs were based on Cox proportional hazards model of time to first TMA manifestation, with treatment status as a time-dependent explanatory variable and comple- ment abnormality status as a covariate. Compared with the labelled dosing regimen of eculizumab. Ref, reference value. observational studies of the natural history of aHUS [2, 3]. In a eculizumab discontinuation, reinforce previous findings that small observational study, Ardissino et al. [28, 29] also noted patients who discontinued eculizumab were at greater risk for particular risk for TMA in patients who chose to discontinue TMA compared with patients on treatment, and particularly eculizumab with CFH mutations, and CFI mutations to a lesser those with identified complement abnormalities. In this study, extent. In a retrospective study of eculizumab discontinuation patients without identified abnormalities were at a signifi- in a French cohort (n ¼ 38) [27], all 12 patients (32%) with TMA cantly lower yet distinct risk for TMA after eculizumab discon- post-eculizumab discontinuation had rare or novel CFH or MCP tinuation. However, genetic analyses were performed during variants; both were independent risk factors for TMA following the parent studies several years ago; thus, it is possible that discontinuation. However, patients with transplant, on novel mutations not known at that time have been left chronic dialysis or ‘secondary’ aHUS were excluded from the unrecognized. French cohort. Results of the current analysis, which are from Overall, characteristics of patients with TMA manifestations the single largest prospective study of TMA risk following were highly heterogeneous with respect to age, treatment Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy035/4996707 by Ed 'DeepDyve' Gillespie user on 12 July 2018 8| J. Menne et al. Table 6. Serious targeted TEAEs reported in the current study associated with new kidney transplantation and existing graft failure. Two patients reported meningococcal infections during Off treatment On treatment the current study. Both recovered and there were no changes TEAE (n¼ 39) (n¼ 76) in eculizumab dosing. Frequency of meningococcal infections [2/87 patients (2%)] is similar to that from the overall parent trial Any serious targeted TEAEs, 15.6 (11) 14.0 (27) programme of eculizumab in aHUS [two cases/100 total patients rate per 100 patient-years (2%)] [7–10]. Overall, the reported meningococcal infection rate Renal impairment 11.3 (8) 8.3 (16) in patients treated with eculizumab is 0.3 events/100 patient- Infection, other 2.8 (2) 2.1 (4) Infection, septic 1.4 (1) 2.1 (4) years [33]. Regulatory guidance for eculizumab includes in- Infection, meningococcal 0.0 (0) 1.0 (2) creased susceptibility to meningococcal infection [5, 6]. Patients Leucopaenia 0.0 (0) 0.5 (1) should be counselled in order to fully understand potential ben- efits and risks of treatment, early signs of meningococcal dis- Data are presented as n (%). ease and processes for seeking immediate medical care. Risks of Data were obtained retrospectively between the end of the parent study and potentially severe complications, including meningococcal in- enrolment in the current study for patients off treatment and on treatment. fection, should be considered during the decision-making pro- TEAEs of renal impairment were evaluated and reported by each investigator, cess regarding initiating treatment or discontinuing and no set definition was used. eculizumab. Long-term evaluations of the eculizumab safety profile will be included in future analyses from the Global aHUS duration and duration of eculizumab before onset of TMA. Registry [34]. An important study limitation was its open-label and obser- Age, frequency of complement abnormalities and kidney transplant status did not differ between patients who discon- vational nature. Voluntary patient enrolment into this prospec- tive study may have introduced selection bias because data are tinued versus remained on eculizumab. However, patients who discontinued appeared to have poorer renal function not available for patients who completed a parent study but did not consent to enrolment in the current study. In this analysis, at baseline in the parent study and initiated eculizumab more rapidly. Such patients may have had clinically significant 43/130 patients (33%) who enrolled in one of the parent studies had not continued into the current study. During the parent and renal improvement with eculizumab, since they initiated treatment in a rapid manner [31], followed by the clinical deci- current studies, which together included a median exposure of 45.9 months, withdrawal of eculizumab due to an AE was sion to discontinue treatment after recovery. Discontinuation of therapy was not randomized, potentially allowing selection uncommon. One adult patient died due to multiorgan failure following a reduced dosing regimen. One paediatric patient dis- bias for continuing versus discontinuing eculizumab. In the previously cited studies [26–28], not all patients with aHUS continued eculizumab in the parent study due to agitation [9]. Three patients with previous renal transplants and poor renal were included. In the current study, all patients who met in- clusion criteria for the parent studies (including those with di- function (eGFR<30 mL/min/1.73 m ) at the start of treatment discontinued eculizumab following reports of renal impairment alysis and renal transplants) were allowed to enrol. Further studies are needed to identify patient characteristics poten- in the current study; of these, one later restarted eculizumab and the other two received additional renal transplants. tially associated with increased risk for TMA after eculizumab discontinuation. Additional studies are needed to further understand patient and physician rationale for discontinuing and reinitiating Notably, 17/39 patients (44%) reinitiated eculizumab follow- ing a period of discontinuation, including 9/11 patients (82%) treatment. Taken together, findings from this interim analysis suggest who had TMA manifestations while off treatment. After reini- tiation, 14/17 patients (82%) continued eculizumab. Longer term that patients with aHUS have an increased risk for TMA mani- festations after discontinuation of eculizumab or during non-la- evaluation may provide additional insight as to clinical out- comes associated with therapy stops and restarts. belled regimens compared with labelled eculizumab dosing. These results support current regulatory guidance [5, 6] in not- Collectively, the current results reinforce the need for ongo- ing treatment with eculizumab to minimize risk of TMA in ing potential risk for TMA following discontinuation of eculizu- mab. Evidence demonstrates that patients had a 63–94% lower patients with aHUS, particularly those with an identified com- plement abnormality. Although thorough genetic testing risk of TMA on eculizumab therapy, depending on the definition used. Future analyses will allow for further characterization of informs prognosis, additional considerations when optimizing treatment strategy include the patient’s unique clinical situa- TMA and evaluation of longer term outcomes on labelled or non-labelled regimens of eculizumab and after therapy tion, age, TMA and family histories, as well as recognition of the complex and unpredictable nature of aHUS. For individual discontinuation. patients in whom discontinuation of eculizumab is being con- sidered, clinicians would be well advised to consult an expert ACKNOWLEDGEMENTS centre in the field while ensuring that the patient: (i) has been The authors wish to thank the study investigators, and the treated for a sufficiently long period to ensure maximal organ patients and their families, for their participation in this function recovery; (ii) can be monitored closely for signs and/or clinical trial (aHUS Observational Long Term Follow-Up: symptoms of TMA; and (iii) has immediate access to eculizumab NCT01522170). so treatment can be restarted at the first signs and/or symp- toms of TMA [27, 32]. As was observed in the parent studies [7–10], eculizumab FUNDING was generally well tolerated in the current study. Rates of seri- This interim analysis was funded by Alexion ous targeted TEAEs, including infections, reported off and on treatment were similar. In particular, rates of renal impairment Pharmaceuticals, Inc. Medical writing/editorial support were relatively high both off and on treatment, but commonly was provided by Kristen W. Quinn, PhD, of Peloton Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy035/4996707 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Eculizumab for TMA prevention in aHUS | 9 Advantage, LLC, Parsippany, NJ, with funding from Alexion REFERENCES Pharmaceuticals, Inc. Alexion Pharmaceuticals, Inc. 1. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. provided financial support for the conduct of the research N Engl J Med 2009; 361: 1676–1687 and preparation of the article. 2. Noris M, Caprioli J, Bresin E et al. Relative role of genetic com- plement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol CONFLICT OF INTEREST STATEMENT 2010; 5: 1844–1859 This interim analysis was sponsored by Alexion 3. Fremeaux-Bacchi V, Fakhouri F, Garnier A et al. Genetics and outcome of atypical hemolytic uremic syndrome: a nation- Pharmaceuticals, Inc. J.M. receives lecture and/or advisory wide French series comparing children and adults. Clin J Am fees from Alexion Pharmaceuticals, Inc., AstraZeneca, Berlin- Soc Nephrol 2013; 8: 554–562 Chemie, Daiichi Sankyo, Boehringer Ingelheim and Novartis. 4. Noris M, Mescia F, Remuzzi G. STEC-HUS, atypical HUS and F.F. received fees for participation in advisory boards, experts’ TTP are all diseases of complement activation. Nat Rev meetings and/or teaching courses from Alexion Nephrol 2012; 8: 622–633 Pharmaceuticals, Inc. J.F.K. was a stockholder and employee 5. US Food and Drug Administration. Soliris (eculizumab) of Alexion Pharmaceuticals, Inc. when the study was con- [Prescribing Information]. New Haven, CT: Alexion Pharma- ducted. C.L. has received grant/research support and/or con- ceuticals, Inc., 2017 sultancy fees from Achillion Pharmaceuticals, Inc., Alexion 6. European Medicines Agency. Soliris (eculizumab) [Summary of Pharmaceuticals, Inc. and CSL Behring; has received hono- Product Characteristics]. Paris, France: Alexion Europe SAS, raria from Alexion Pharmaceuticals, Inc. and CSL Behring; has submitted patents for CSL Behring and Finnegan, 7. Legendre CM, Licht C, Muus P et al. Terminal complement in- Henderson, Farabow, Garrett & Dunner; is a member of the hibitor eculizumab in atypical hemolytic-uremic syndrome. Editorial Boards for Kidney International, Nephrology Dialysis N Engl J Med 2013; 368: 2169–2181 Transplantation and Pediatric Nephrology;is a Steering 8. Licht C, Greenbaum LA, Muus P et al. 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NCT00844844), Eculizumab in Adolescent Patients With Am J Kidney Dis 2016; 68: 84–93 Plasma Therapy-Sensitive aHUS (C08-003; NCT00844428), and 11. Vilalta R, Al-Akash S, Davin J et al. Eculizumab therapy for Eculizumab in Pediatric Patients With Atypical Hemolytic- pediatric patients with atypical hemolytic uremic syndrome: Uremic Syndrome (C10-003; NCT01193348) clinical studies for efficacy and safety outcomes of a retrospective study [ab- Alexion Pharmaceuticals, Inc. E.E.M. has participated in the stract 1155]. Haematologica 2012; 97 (Suppl 1): 479 C10-004 adult interventional study (NCT01194973) and in the 12. Chatelet V, Fremeaux-Bacchi V, Lobbedez T et al. Safety and C11-003 observational, follow-up study (NCT01522170) of long-term efficacy of eculizumab in a renal transplant pa- atypical haemolytic uraemic syndrome patients for Alexion tient with recurrent atypical hemolytic-uremic syndrome. Pharmaceuticals, Inc. C.M. was a stockholder and employee Am J Transplant 2009; 9: 2644–2645 of Alexion Pharmaceuticals, Inc. when the study was con- 13. Alachkar N, Bagnasco SM, Montgomery RA. Eculizumab for ducted. F.P. has received honoraria from Alexion the treatment of two recurrences of atypical hemolytic ure- Pharmaceuticals, Inc. E.R. has received fees for participation mic syndrome in a kidney allograft. Transpl Int 2012; 25: in advisory boards, experts’ meetings and/or teaching e93–e95 14. Cayci FS, Cakar N, Hancer VS et al. Eculizumab therapy in a courses from Alexion Pharmaceuticals, Inc. N.S.S. has re- child with hemolytic uremic syndrome and CFI mutation. ceived research funding from GlaxoSmithKline plc. J.W. is a Pediatr Nephrol 2012; 27: 2327–2331 stockholder and employee of Alexion Pharmaceuticals, Inc. 15. Carr R, Cataland SR. 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Current evidence on in pregnancy-associated atypical hemolytic uremic syn- the discontinuation of eculizumab in patients with atypical drome: insights for optimizing management. J Nephrol 2015; haemolytic uraemic syndrome. Clin Kidney J 2017; 10: 310–319 28: 641–645 31. Vande Walle J, Delmas Y, Ardissino G et al. Improved renal 24. Wetzels JF, van de Kar NC. Discontinuation of eculizumab recovery in patients with atypical hemolytic uremic syn- drome following rapid initiation of eculizumab treatment. maintenance treatment for atypical hemolytic uremic syn- drome. Am J Kidney Dis 2015; 65: 342 J Nephrol 2017; 30: 127–134 25. Toyoda H, Wada H, Miyata T et al. Disease recurrence after 32. Loirat C, Fakhouri F, Ariceta G et al. An international consen- early discontinuation of eculizumab in a patient with atypi- sus approach to the management of atypical hemolytic ure- cal hemolytic uremic syndrome with complement C3 I1157T mic syndrome in children. Pediatr Nephrol 2016; 31: 15–39 mutation. J Pediatr Hematol Oncol 2016; 38: e137–e139 33. Drug Safety and Risk Management Advisory Committee. 26. Sheerin NS, Kavanagh D, Goodship TH et al. A national spe- Briefing Document for Soliris (eculizumab). Cheshire, CT: cialized service in England for atypical haemolytic uraemic Alexion Pharmaceuticals, Inc., 2014 syndrome-the first year’s experience. QJM 2016; 109: 27–33 34. Licht C, Ardissino G, Ariceta G et al. The global aHUS registry: 27. Fakhouri F, Fila M, Provo ˆt F et al. Pathogenic variants in com- methodology and initial patient characteristics. BMC Nephrol plement genes and risk of atypical hemolytic uremic 2015; 16: 207 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy035/4996707 by Ed 'DeepDyve' Gillespie user on 12 July 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

Eculizumab prevents thrombotic microangiopathy in patients with atypical haemolytic uraemic syndrome in a long-term observational study

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Clinical Kidney Journal, 2018, 1–10 doi: 10.1093/ckj/sfy035 Original Article OR I G I N AL A R T I C L E Eculizumab prevents thrombotic microangiopathy in patients with atypical haemolytic uraemic syndrome in a long-term observational study 1 2 3 4, Jan Menne , Yahsou Delmas , Fadi Fakhouri , John F. Kincaid *, 5 6 4, 7 Christoph Licht , Enrico E. Minetti , Chris Mix *, Franc ¸ois Provo ˆt , 8 9 4 10 Eric Rondeau , Neil S. Sheerin , Jimmy Wang , Laurent E. Weekers and Larry A. Greenbaum 1 2 Klinik fu ¨ r Nieren- und Hochdruckerkrankungen, Hannover, Germany, CHU de Bordeaux, Bordeaux, France, 3 4 5 CHU de Nantes, Nantes, France, Alexion Pharmaceuticals, Inc., New Haven, CT, USA, The Hospital for Sick 6 7 Children, Toronto, Ontario, Canada, Azienda Ospedaliero Universitaria Careggi, Florence, Italy, CHU de Lille, 8 9 Lille, France, Ho ˆ pital Tenon and Universite ´ Paris VI, Paris, France, Institute of Cellular Medicine, University 10 11 of Newcastle upon Tyne, Newcastle upon Tyne, UK, CHU de Lie ` ge, Lie ` ge, Belgium and Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, GA, USA Correspondence and offprint requests to: Jan Menne; E-mail: menne.jan@mh-hannover.de *Former employee. ABSTRACT Background. Eculizumab, a terminal complement inhibitor, is approved for atypical haemolytic uraemic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA). Methods. In five parent studies, eculizumab effectively prevented TMA and improved renal and haematologic outcomes in patients with aHUS; therefore, these patients could enrol in this long-term, prospective, observational and multicentre study. The primary endpoint was the TMA manifestation rate off and on eculizumab post-parent study. Post hoc analyses evaluated rates during labelled versus non-labelled dosing regimens, and in those with versus without identified complement abnormalities. Serious targeted treatment-emergent adverse events (TEAEs) were evaluated. Results. Of 87 patients in the current study, 39 and 76 had off- and on-treatment periods, respectively; 17 (44%) with off periods reinitiated eculizumab. TMA manifestation rate per 100 patient-years was 19.9 off and 7.3 on treatment [hazard ratio (HR), 4.7; P¼ 0.0008]; rates were highest off treatment and lowest during labelled regimens. TMA manifestations with hospitalizations/ serious AEs occurred more frequently off versus on treatment. TMA rates were higher among patients with identified complement abnormalities (HR, 4.5; P¼ 0.0082). Serious targeted TEAEs occurred at similar rates off and on treatment. Conclusions. As expected, patients with aHUS have increased risk of TMA manifestations after discontinuation of eculizumab or in the setting of non-labelled eculizumab dosing. Collectively, results show that maintaining eculizumab treatment minimizes risk of TMA, particularly in patients with identified complement abnormalities. Future studies are Received: 7.12.2017. Editorial decision: 2.4.2018 V The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy035/4996707 by Ed 'DeepDyve' Gillespie user on 12 July 2018 2| J. Menne et al. needed to further characterize TMA and longer term outcomes on labelled or non-labelled eculizumab regimens and after discontinuation of treatment. Keywords: atypical haemolytic uraemic syndrome, complement, discontinuation, eculizumab, observational study, thrombotic microangiopathy discontinued from the parent study or were on eculizumab at the INTRODUCTION time of enrolment. Patients could withdraw from the current study Atypical haemolytic uraemic syndrome (aHUS) is a rare, genetic, at any time. The protocol was approved by an institutional review potentially life-threatening disease predominantly caused by board or independent ethics committee at each participating cen- uncontrolled activation of the alternative complement pathway tre and the study was conducted in accordance with International [1–3]. Abnormalities in complement genes or autoantibodies to Council for Harmonisation Guidelines and the Declaration of complement proteins are identified in50–70% of patients Helsinki. All patients and/or parents/guardians provided written [2, 3]. Complement dysregulation leads to persistent cleavage of informed consent before entry into the current study. C5 to the prothrombotic, pro-inflammatory anaphylatoxin C5a The current study consequently includes both prospective and to C5b, which initiates formation of the prothrombotic and and retrospective data collection. Retrospective data were cytolytic C5b-9 and ultimately causes injury, activation and obtained from the date each patient ended participation in the lysis of endothelial cells, leucocytes and platelets [1, 4]. The parent study until the date of signed informed consent for the resultant thrombotic microangiopathy (TMA) is typically current study. All patients who received at least one infusion of characterized by microangiopathic haemolytic anaemia, throm- eculizumab during the parent study and had signed consent bocytopaenia and acute renal failure, and frequently includes forms for the current study were included in the analysis. extrarenal complications [2, 3]. Identification of complement abnormalities occurred during the Patients who remain untreated are at lifelong risk of renal parent studies and included analysis of complement factor I impairment or failure, organ dysfunction and premature death (CFI), complement factor B (CFB), complement factor H (CFH), [2, 3]. Eculizumab (Soliris , Alexion Pharmaceuticals, Inc., New membrane cofactor protein (MCP) and C3 mutations, comple- Haven, CT, USA), a humanized monoclonal antibody that inhib- ment factor H-related proteins 1-3 (CFHR1-3) deletions/polymor- its C5a, C5b and C5b-9 formation by binding to C5, is the first phisms and CFH autoantibodies [7, 9–11]. Patients received and only approved treatment for patients with aHUS [5, 6]. The meningococcal vaccination in the parent studies [7, 9, 10] and efficacy and safety of eculizumab have been demonstrated in were revaccinated according to country guidelines. The cut-off four prospective, multicentre clinical studies [7–10] and a retro- date for this interim analysis was 28 March 2015. spective study [11]. TMA manifestations were neither defined nor collected uni- Current regulatory guidance notes potential risk of TMA fol- formly in the parent studies; thus, this analysis includes out- lowing discontinuation of eculizumab [5, 6]. Additional evidence comes reported in this ongoing observational study only (i.e. for TMA manifestations occurring after discontinuation is lim- beginning at the end of the parent study). Data were collected ited to case studies [12–25], two retrospective studies [26, 27] four times annually in both the retrospective and prospective and a small prospective observational study [28, 29]. Together, portions of the current study. TMA manifestations were documented in 26/82 patients (32%) who discontinued eculizumab [12–29]. An analysis [30] from the eculizumab clinical trial programme determined that severe Treatment TMA manifestations occurred in 12/61 patients (20%) who chose After completion of the parent study and entry into the current to discontinue treatment. study, the labelled dosing regimen of eculizumab was defined This is the single largest prospective, observational study of as that specified in the prescribing information approved by the consequences following eculizumab discontinuation in regulatory authorities [5, 6], and other dosing schedules (i.e. de- aHUS. In an interim analysis, TMA manifestation rates off and creased or increased dosages, shortened or extended dosing on eculizumab in patients with aHUS were evaluated. Post hoc intervals) were permitted and classified as non-labelled regi- analyses based on a revised, more stringent definition of TMA, mens. In this study, the first on-treatment period was defined during labelled versus non-labelled regimens and by comple- as: from the date of the first infusion in the current study (i.e. ment abnormality status, also were conducted. In addition, the beginning at the end of the parent study) through 3 weeks after safety of long-term eculizumab is reported. the last infusion of eculizumab, or until the patient discontin- ued from the study, or data cut-off (whichever occurred first). The first off-treatment period was defined as: from 3 weeks af- MATERIALS AND METHODS ter the last infusion of eculizumab within the current study un- til the patient restarted eculizumab therapy, discontinued from Study design and patients the study or data cut-off (whichever occurred first). Subsequent on- and off-treatment periods were defined similarly. Patient This is a long-term, prospective, observational and multicentre study (NCT01522170) of patients with aHUS who were treated groups were not mutually exclusive; individual patients could be represented in both groups. with eculizumab in any of five previous clinical studies (parent studies): four prospective studies (NCT00844545/NCT00844844 and NCT00838513/NCT00844428 [7, 8], NCT01193348 [9], Endpoints NCT01194973 [10]) and one retrospective study (NCT01770951 [11]). Patients who participated in a parent study were eligible Primary endpoint was the rate of TMA manifestations (defined for the current study, regardless of whether they completed or in Table 1) in the current study off and on treatment. Post hoc Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy035/4996707 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Eculizumab for TMA prevention in aHUS | 3 Table 1. Per-protocol definition of TMA manifestations (any1 listed criteria) Type/severity Criteria Laboratory value The occurrence of a change in 1 laboratory value : a c change only Platelet count decrease 25% compared with baseline and <LLN Increase in SCr or LDH level 25% compared with baseline and >ULN Clinical signs and Clinical signs and symptoms of TMA considered definitely related to aHUS, including: symptoms of TMA Thrombosis Seizure Decreased renal function Proteinuria (new or worse compared with baseline and >1þ or >30 mg/dL) Haematuria (new or worse compared with baseline and >50 RBC/HPF) Increased haemolytic anaemia Biopsy-proven TMA Other (e.g. extrarenal TMA manifestations including confusion, cardiovascular abnormalities, pericarditis, gastrointestinal symptoms and diarrhoea) Intervention The patient received PE/PI, dialysis, blood transfusions or renal transplant due to a TMA manifestation As determined by changes in laboratory parameters with ongoing follow-up. Measurements were required to be confirmed by a second measurement28 days apart with no interruption. Baseline was defined for each on period as the last laboratory value during the preceding off period, and for each off period as the last value during the preceding on period. As determined at the discretion of the investigator. HPF, high-powered field; LDH, lactate dehydrogenase; LLN, lower limit of normal; PE/PI, plasma exchange/plasma infusion; RBC, red blood cells; SCr, serum creatinine; ULN, upper limit of normal. analyses evaluated TMA manifestation rates off and on treat- eight patients (21%) who discontinued eculizumab and 14 (29%) ment when TMA manifestations based on only a single labora- on ongoing eculizumab. A median (range) of 11.0 (0.0–230.0) tory value change were excluded; in patients receiving labelled plasma exchanges or plasma infusions were used by the overall compared with non-labelled eculizumab regimens; and in population before eculizumab initiation, including 7.0 (0.0–64.0) patients with and without identified complement abnormali- in patients who discontinued eculizumab and 13.3 (0.0–230.0) in ties. Safety endpoints included assessment of serious targeted patients who never discontinued eculizumab. Dialysis was re- treatment-emergent adverse events (TEAEs; predefined as inci- quired by 29/87 patients (33%) before parent study enrolment, dence of serious infection, meningococcal infection, sepsis, re- and use was more frequent in those who discontinued eculizu- nal impairment or leucopaenia), as well as any serious AE (SAE). mab (39%) compared with those who never discontinued eculi- zumab (29%). Including parent studies, patients had a total median (range) of 45.9 (1.3–86.9) months of eculizumab expo- Statistical methods sure. In the current study, median (range) follow-up was 20.1 Time to first TMA manifestation was defined as time from the (0.7–79.5) months off and 26.1 (0.7–64.2) months on treatment. start of the current study (i.e. end of the parent study) to first Compared with patients who continued on eculizumab, TMA manifestation during the current study. Patients who did those who discontinued had a shorter interval from initial aHUS not have a TMA manifestation were censored at data cut-off or diagnosis, as well as the most recent pretreatment TMA mani- study discontinuation, whichever occurred first. Time to first festation, to first-ever eculizumab dose in the parent study. TMA manifestation was analysed using Cox proportional haz- Patients who discontinued also presented with lower estimated ards models with treatment status as a time-dependent explan- glomerular filtration rates (eGFRs) and were more frequently di- atory variable and complement abnormality status as a alysis dependent at initiation of eculizumab (Table 2). covariate. Hazard ratios (HRs) and P values were obtained for Non-labelled eculizumab regimens were received by 33/87 comparisons off and on treatment and between identified and patients (38%) during the current study. Of these, 11 always re- no identified complement abnormality subgroups. ceived non-labelled doses and 22 had periods of labelled and non-labelled regimens. Median (range) duration of therapy was 25.7 (0.5–60.4) months during labelled and 14.3 (0.4–64.3) months RESULTS during non-labelled regimens. Dosing higher than labelled Patients and exposure accounted for 0.4% of the total patient-years for non-labelled regimens. Overall, 130 patients were enrolled in the parent studies. By the data cut-off for this analysis, 87 patients had enrolled in the cur- rent study. Of these, 39 (45%) had off-treatment periods whereas TMA manifestations 76 (87%) had on-treatment periods. Seventeen patients (44%) with off-treatment periods reinitiated eculizumab; of these, 14 When using the per-protocol definition (Table 1), 28 TMA (82%) remained on therapy once they reinitiated (Figure 1). Age, manifestations occurred. This included 14 TMA manifestations frequency of complement abnormalities and kidney transplant in 11/39 patients (28%) off treatment and 14 TMA manifesta- status were not different between patients with ongoing eculi- tions in 10/76 patients (13%) on treatment (Tables 3 and 4). zumab therapy versus those who discontinued (Table 2). TMA manifestation rate per 100 patient-years was 19.9 off and Twenty-two patients (25%) had renal transplants, including 7.3 on treatment (63% lower; HR, 4.7; P ¼ 0.0008; Table 5). Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy035/4996707 by Ed 'DeepDyve' Gillespie user on 12 July 2018 4| J. Menne et al. FIGURE 1: Patient disposition. Patients treated with non-labelled and labelled regimens had manifestations occurred in 2/76 patients (3%) on treatment. TMA manifestation rates of 12.1 and 5.2 per 100 patient-years, The TMA manifestation rate per 100 patient-years was 15.6 off respectively (39% and 74% lower, respectively, versus off and 1.0 on treatment (94% decrease; HR, 16.8; P ¼ 0.0010) treatment). (Table 5). Characteristics of TMA manifestations TMA manifestations by complement abnormality status TMA manifestations off treatment were more frequently associ- The majority of patients who reported TMA manifestations as ated with multiple laboratory criteria for TMA, clinical signs and defined per protocol had complement abnormalities (Tables 3 symptoms of TMA, interventions, SAEs and/or hospitalizations and 4), particularly in those with CFH [10/17 (59%)] and CFI (Tables 3 and 4). Eleven of 14 TMA manifestations (79%) in mutations [4/17 (24%)]. Rates were higher for patients with iden- patients off treatment included multiple laboratory TMA criteria tified complement abnormalities compared with no identified and/or an intervention, compared with 2/14 TMA manifesta- complement abnormalities (HR, 4.5; P¼ 0.0082). tions (14%) on treatment. Patients required hospitalization dur- ing 9/14 TMA manifestations (64%) off treatment and 3/14 TMA Safety manifestations (21%) on treatment. Overall, treatment with eculizumab was well tolerated. The oc- currence of serious targeted TEAEs during the current study was TMA manifestation rate excluding TMAs based on similar off and on treatment (Table 6). Two patients from the par- single laboratory value changes ent retrospective study reported meningococcal infections during An abnormality in a single laboratory value may not be the current study; both were determined to be probably related to considered as TMA clinically; therefore, a post hoc analysis was eculizumab. Both patients were treated and recovered while con- performed to better reflect TMA evaluation in clinical practice. tinuing eculizumab on schedule. Diagnoses/underlying condi- TMA defined by a change from baseline in a single laboratory tions associated with reported serious targeted TEAEs of renal value occurred in 3/14 TMA manifestations (21%) off treatment impairment that did not meet criteria for TMA included new kid- and 12/14 TMA manifestations (86%) on treatment (Tables 3 ney transplant, renal graft rejection, multiorgan failure, dehydra- and 4). When using this definition, 11 TMA manifestations tion, infection and interstitial tubulopathy. One adult patient, occurred in 8/39 patients (21%) off treatment and two TMA who received non-labelled dosing during the current study, Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy035/4996707 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Eculizumab for TMA prevention in aHUS | 5 Table 2. Demographic and baseline clinical characteristics in the parent studies Ongoing eculizumab Discontinued Total Characteristic (n¼ 48) (n¼ 39) (n¼ 87) Age at first-ever infusion of eculizumab, years Median (range) 24.0 (0.0–65.0) 21.0 (0.0–80.0) 22.0 (0.0–80.0) <12, n (%) 13 (27) 11 (28) 24 (28) 12 to <18, n (%) 6 (13) 5 (13) 11 (13) 18, n (%) 29 (60) 23 (59) 52 (60) Age at entry to current study, years Median (range) 27.5 (2.5–67.6) 25.1 (1.6–81.6) 26.0 (1.6–81.6) <12, n (%) 10 (21) 11 (28) 21 (24) 12 to <18, n (%) 3 (6) 0 (0) 3 (3) 18, n (%) 35 (73) 28 (72) 63 (72) Female, n (%) 30 (63) 23 (59) 53 (61) Complement gene mutation or autoantibody, n (%) 31 (65) 20 (51) 51 (59) CFH 12 (25) 8 (21) 20 (23) CFH autoantibodies 6 (13) 1 (3) 7 (8) C3 6 (13) 1 (3) 7 (8) CD46 (MCP) 2 (4) 5 (13) 7 (8) CFI 3 (6) 4 (10) 7 (8) C3, CFHR3-CFHR1 1 (2) 0 1 (1) CD46 (MCP), CFI 1 (2) 0 1 (1) CFB 0 1 (3) 1 (1) Identified CFHR1, CFHR3 deletion 0 1 (3) 1 (1) Time from last pretreatment aHUS manifestation to 2.3 (0.0–47.4) 0.5 (0.0–19.2) 0.9 (0.0–47.4) first-ever dose of eculizumab, median (range), months Family history of aHUS, n (%) 8 (17) 8 (21) 16 (18) Time from aHUS diagnosis to first-ever dose of 18.4 (0.0–313.3) 0.9 (0.0–178.1) 4.0 (0.0–313.3) eculizumab, median (range), months History of TMA manifestations, n (%) Single 29 (60) 27 (69) 56 (64) Multiple 19 (40) 12 (31) 31 (36) Prior renal transplant, n (%) 14 (29) 8 (21) 22 (25) PE/PI sessions per patient, median (range) 13.3 (0.0–230.0) 7.0 (0.0–64.0) 11.0 (0.0–230.0) Dialysis at baseline , n (%) 14 (29) 15 (39) 29 (33) d 2 eGFR at baseline, median (range), mL/min/1.73 m 21.2 (8.4–128.3) 12.1 (5.3–105.5) 18.9 (5.3–128.3) Includes patients with additional abnormalities [i.e. C3, CD46 (MCP), CFI, CFHR1, CFHR3, and CFHR3-CFHR1]. Includes patients with additional abnormalities (i.e. CFHR1, CFHR3, CFHR3-CFHR1). Dialysis at baseline was defined as any dialysis that occurred within 7 days prior to or 14 days following the first eculizumab dose in the parent study. d 2 eGFR was defined as 10 mL/min/1.73 m when a patient was on dialysis. PE/PI, plasma exchange/plasma infusion. died due to severe intensive care complications and severe multi- agreed-upon definition of TMA based upon a single laboratory organ dysfunction after gastrointestinal haemorrhage, lithiasic value in clinical practice. TMA manifestations off treatment were cholecystitis and severe sepsis, which were determined to be associated with multiple laboratory criteria, clinical sequelae (e.g. unrelated to eculizumab. renal impairment and acute renal failure), SAEs, hospitalizations and/or required interventions (e.g. transfusion) in 13/14 cases (93%). In contrast, TMA manifestations on treatment typically comprised changes in single laboratory values with no clinical DISCUSSION signs/symptoms. Therefore, post hoc analyses were conducted to Results from this interim analysis of a non-randomized, pro- provide insights using a more stringent TMA definition that we spective observational study demonstrate that rates of TMA believe more closely defines TMA in the setting of aHUS. When manifestations in patients with aHUS were 2.7-fold higher off TMA manifestations based only on changes in single laboratory compared with on eculizumab (63% lower), despite longer values were excluded, the rate off treatment was 15.6-fold higher follow-up on treatment. TMA manifestation rates were lowest than on treatment. These results taken together could suggest during labelled dosing regimens (74% lower than off treatment), worse outcomes for patients who discontinue eculizumab, al- higher during non-labelled regimens (39% lower than off treat- though it is possible that changes in single laboratory values may ment) and highest off treatment. signal subclinical disease processes. The per-protocol definition of TMA manifestations was broad, Patients with identified complement abnormalities had sta- including changes in laboratory values, clinical signs and symp- tistically significantly higher TMA rates than patients with no toms of TMA related to aHUS, and/or interventions related to identified abnormalities. CFH and CFI mutations were predomi- TMA. Thus, reported TMA per this definition represented varying nant among patients who experienced TMA, regardless of treat- degrees of clinical deterioration. Importantly, there is no single, ment status. This finding is consistent with previous Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy035/4996707 by Ed 'DeepDyve' Gillespie user on 12 July 2018 6| J. Menne et al. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy035/4996707 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 3. Reported TMA manifestations in patients off treatment with eculizumab Patient demographics and clinical characteristics Eculizumab therapy Eculizumab Duration of duration discontinuation TMA Criteria before before TMA manifestation achieved for Patient age Complement discontinuation manifestation based on single TMA SAE/ Eculizumab b c Patient Sex (years) abnormality (months) (months) lab criterion manifestation hospitalization reinitiation 1 Male 9 CFH 6 1.3 No "SCr, "LDH No Yes 2 Male 11 CFI 517 No "SCr, "LDH, #platelets Yes Yes 0.7 3.7 No "SCr, "LDH, #platelets, transfusion Yes Yes 3 Male 4 CFH 14 2.5 No #Platelets, #renal function, No Yes "haemolytic anaemia 4 Male 38 CFH 27 2.6 Yes "SCr Yes Yes 5 Female 25 MCP 37 5 No "SCr, "LDH, #Hb, #haptoglobin, Yes Yes renal impairment 6 Female 39 CFI 37 7 Yes #Platelets Yes Yes 7 Female 84 None identified 3 28 No "LDH, #platelets Yes No 3 42 No Signs of reactivation of TMA No No with clinical repercussion 8 Male 26 MCP 618 No "SCr, transfusion Yes No 634 No "SCr, transfusion Yes Yes 9 Male 27 None identified 50 2 No #Haptoglobin Yes Yes 10 Female 73 CFH autoantibodies, 34 17 Yes "SCr No No CFHR1-3 11 Female 20 CFH, C3 62No #Platelets, acute No Yes renal failure During the current study only (i.e. excluding the parent study). Before or during TMA manifestation. Seventeen of 39 patients (43.6%) reinitiated eculizumab after discontinuation of therapy. Median (range) time to reinitiation was 2.6 (0.7–69.3) months. Fourteen of 17 patients (82%) continue on therapy after reinitiation. Hb, haemoglobin; LDH, lactate dehydrogenase; SCr, serum creatinine. Eculizumab for TMA prevention in aHUS | 7 Table 4. Reported TMA manifestations in patients on treatment with eculizumab Patient demographics and clinical characteristics Eculizumab therapy Treatment TMA manifestation Criteria achieved Patient age Complement duration Labelled based on single lab for TMA SAE/ b c Patient Sex (years) abnormality (months) regimen criterion manifestation hospitalization 1 Female 4 None identified 26 No Yes "SCr No 2 Female 31 CFH 28 Yes Yes #Platelets Yes 3 Female 44 CFH 20 Yes Yes "LDH No 4 Female 12 CFH 59 Yes Yes "SCr No 5 Female 44 CFI 19 Yes Yes #Platelets Yes 6 Male 27 MCP 51 Yes Yes "LDH No 60 No Yes "LDH No 7 Male 49 CFI 39 Yes No Dialysis Yes 8 Female 10 CFH 56 No Yes "SCr No 61 No No "SCr, #platelets, No "Proteinuria 9 Male 15 CFH 41 No Yes #Platelets No 44 No Yes "SCr No 53 No Yes "SCr No 10 Male 20 None identified 3 Yes Yes "LDH No During the current study only (i.e. excluding the parent study). No TMA manifestations occurred while patients received dosing higher than approved by regulatory authorities. Before or during TMA manifestation. The patient’s first on-treatment period was 19 months, followed by an off-treatment period of 31 months and another on-treatment period of 10 months. LDH, lactate dehydrogenase; SCr, serum creatinine. Table 5. TMA manifestation rates Excluding single laboratory Eculizumab treatment status Eculizumab dosing change criterion Off On Non-labelled Labelled Off On treatment treatment regimen regimen treatment treatment Parameter (n ¼ 39) (n ¼ 76) (n¼ 33) (n ¼ 65) (n ¼ 39) (n ¼ 76) Patients with manifestation, n (%) 11 (28) 10 (13) 4 (12) 7 (11) 8 (21) 2 (3) Total number of manifestations 14 14 7 7 11 2 Total patient-years 70.5 192.8 57.9 135.0 70.5 192.8 TMA manifestation rate/ 19.9 7.3 12.1 5.2 15.6 1.0 100 patient-years Fold change in rate 2.7 Ref 2.3 Ref 15.6 Ref Per cent change compared Ref 63 39 74 Ref 94 with off treatment (%) c d HR (P value) 4.7 (P¼ 0.0008) Ref 1.3 (P¼ 0.7000) Ref 16.8 (P¼ 0.0010) Ref Off treatment compared with on treatment (overall) or non-labelled compared with labelled regimen for the same analysis. On treatment (overall), non-labelled or labelled regimen compared with off treatment for the same analysis. HRs were based on Cox proportional hazards model of time to first TMA manifestation, with treatment status as a time-dependent explanatory variable and comple- ment abnormality status as a covariate. Compared with the labelled dosing regimen of eculizumab. Ref, reference value. observational studies of the natural history of aHUS [2, 3]. In a eculizumab discontinuation, reinforce previous findings that small observational study, Ardissino et al. [28, 29] also noted patients who discontinued eculizumab were at greater risk for particular risk for TMA in patients who chose to discontinue TMA compared with patients on treatment, and particularly eculizumab with CFH mutations, and CFI mutations to a lesser those with identified complement abnormalities. In this study, extent. In a retrospective study of eculizumab discontinuation patients without identified abnormalities were at a signifi- in a French cohort (n ¼ 38) [27], all 12 patients (32%) with TMA cantly lower yet distinct risk for TMA after eculizumab discon- post-eculizumab discontinuation had rare or novel CFH or MCP tinuation. However, genetic analyses were performed during variants; both were independent risk factors for TMA following the parent studies several years ago; thus, it is possible that discontinuation. However, patients with transplant, on novel mutations not known at that time have been left chronic dialysis or ‘secondary’ aHUS were excluded from the unrecognized. French cohort. Results of the current analysis, which are from Overall, characteristics of patients with TMA manifestations the single largest prospective study of TMA risk following were highly heterogeneous with respect to age, treatment Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy035/4996707 by Ed 'DeepDyve' Gillespie user on 12 July 2018 8| J. Menne et al. Table 6. Serious targeted TEAEs reported in the current study associated with new kidney transplantation and existing graft failure. Two patients reported meningococcal infections during Off treatment On treatment the current study. Both recovered and there were no changes TEAE (n¼ 39) (n¼ 76) in eculizumab dosing. Frequency of meningococcal infections [2/87 patients (2%)] is similar to that from the overall parent trial Any serious targeted TEAEs, 15.6 (11) 14.0 (27) programme of eculizumab in aHUS [two cases/100 total patients rate per 100 patient-years (2%)] [7–10]. Overall, the reported meningococcal infection rate Renal impairment 11.3 (8) 8.3 (16) in patients treated with eculizumab is 0.3 events/100 patient- Infection, other 2.8 (2) 2.1 (4) Infection, septic 1.4 (1) 2.1 (4) years [33]. Regulatory guidance for eculizumab includes in- Infection, meningococcal 0.0 (0) 1.0 (2) creased susceptibility to meningococcal infection [5, 6]. Patients Leucopaenia 0.0 (0) 0.5 (1) should be counselled in order to fully understand potential ben- efits and risks of treatment, early signs of meningococcal dis- Data are presented as n (%). ease and processes for seeking immediate medical care. Risks of Data were obtained retrospectively between the end of the parent study and potentially severe complications, including meningococcal in- enrolment in the current study for patients off treatment and on treatment. fection, should be considered during the decision-making pro- TEAEs of renal impairment were evaluated and reported by each investigator, cess regarding initiating treatment or discontinuing and no set definition was used. eculizumab. Long-term evaluations of the eculizumab safety profile will be included in future analyses from the Global aHUS duration and duration of eculizumab before onset of TMA. Registry [34]. An important study limitation was its open-label and obser- Age, frequency of complement abnormalities and kidney transplant status did not differ between patients who discon- vational nature. Voluntary patient enrolment into this prospec- tive study may have introduced selection bias because data are tinued versus remained on eculizumab. However, patients who discontinued appeared to have poorer renal function not available for patients who completed a parent study but did not consent to enrolment in the current study. In this analysis, at baseline in the parent study and initiated eculizumab more rapidly. Such patients may have had clinically significant 43/130 patients (33%) who enrolled in one of the parent studies had not continued into the current study. During the parent and renal improvement with eculizumab, since they initiated treatment in a rapid manner [31], followed by the clinical deci- current studies, which together included a median exposure of 45.9 months, withdrawal of eculizumab due to an AE was sion to discontinue treatment after recovery. Discontinuation of therapy was not randomized, potentially allowing selection uncommon. One adult patient died due to multiorgan failure following a reduced dosing regimen. One paediatric patient dis- bias for continuing versus discontinuing eculizumab. In the previously cited studies [26–28], not all patients with aHUS continued eculizumab in the parent study due to agitation [9]. Three patients with previous renal transplants and poor renal were included. In the current study, all patients who met in- clusion criteria for the parent studies (including those with di- function (eGFR<30 mL/min/1.73 m ) at the start of treatment discontinued eculizumab following reports of renal impairment alysis and renal transplants) were allowed to enrol. Further studies are needed to identify patient characteristics poten- in the current study; of these, one later restarted eculizumab and the other two received additional renal transplants. tially associated with increased risk for TMA after eculizumab discontinuation. Additional studies are needed to further understand patient and physician rationale for discontinuing and reinitiating Notably, 17/39 patients (44%) reinitiated eculizumab follow- ing a period of discontinuation, including 9/11 patients (82%) treatment. Taken together, findings from this interim analysis suggest who had TMA manifestations while off treatment. After reini- tiation, 14/17 patients (82%) continued eculizumab. Longer term that patients with aHUS have an increased risk for TMA mani- festations after discontinuation of eculizumab or during non-la- evaluation may provide additional insight as to clinical out- comes associated with therapy stops and restarts. belled regimens compared with labelled eculizumab dosing. These results support current regulatory guidance [5, 6] in not- Collectively, the current results reinforce the need for ongo- ing treatment with eculizumab to minimize risk of TMA in ing potential risk for TMA following discontinuation of eculizu- mab. Evidence demonstrates that patients had a 63–94% lower patients with aHUS, particularly those with an identified com- plement abnormality. Although thorough genetic testing risk of TMA on eculizumab therapy, depending on the definition used. Future analyses will allow for further characterization of informs prognosis, additional considerations when optimizing treatment strategy include the patient’s unique clinical situa- TMA and evaluation of longer term outcomes on labelled or non-labelled regimens of eculizumab and after therapy tion, age, TMA and family histories, as well as recognition of the complex and unpredictable nature of aHUS. For individual discontinuation. patients in whom discontinuation of eculizumab is being con- sidered, clinicians would be well advised to consult an expert ACKNOWLEDGEMENTS centre in the field while ensuring that the patient: (i) has been The authors wish to thank the study investigators, and the treated for a sufficiently long period to ensure maximal organ patients and their families, for their participation in this function recovery; (ii) can be monitored closely for signs and/or clinical trial (aHUS Observational Long Term Follow-Up: symptoms of TMA; and (iii) has immediate access to eculizumab NCT01522170). so treatment can be restarted at the first signs and/or symp- toms of TMA [27, 32]. As was observed in the parent studies [7–10], eculizumab FUNDING was generally well tolerated in the current study. Rates of seri- This interim analysis was funded by Alexion ous targeted TEAEs, including infections, reported off and on treatment were similar. In particular, rates of renal impairment Pharmaceuticals, Inc. Medical writing/editorial support were relatively high both off and on treatment, but commonly was provided by Kristen W. Quinn, PhD, of Peloton Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy035/4996707 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Eculizumab for TMA prevention in aHUS | 9 Advantage, LLC, Parsippany, NJ, with funding from Alexion REFERENCES Pharmaceuticals, Inc. Alexion Pharmaceuticals, Inc. 1. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. provided financial support for the conduct of the research N Engl J Med 2009; 361: 1676–1687 and preparation of the article. 2. Noris M, Caprioli J, Bresin E et al. Relative role of genetic com- plement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol CONFLICT OF INTEREST STATEMENT 2010; 5: 1844–1859 This interim analysis was sponsored by Alexion 3. 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Clinical Kidney JournalOxford University Press

Published: May 16, 2018

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