Drug Design, Development and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Cardio- Renal Outcomes With Long- Term Agalsidase Alfa Enzyme Replacement Therapy: A Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 158.109.91.63 on 26-Mar-2021 10- Year Fabry Outcome Survey (FOS) Analysis This article was published in the following Dove Press journal: Drug Design, Development and Therapy Uma Ramaswami 1 Purpose: Following the publication of 5-year agalsidase alfa enzyme replacement therapy Michael Beck 2 (ERT) outcomes data from the Fabry Outcome Survey (FOS), 10-year data were analyzed. Derralynn Hughes 1 Patients and methods: FOS (ClinicalTrials.gov identifier: NCT03289065) data (April Christoph Kampmann 2 2001 to August 2018) were retrospectively analyzed. Estimated glomerular filtration rate Jaco Botha 3 For personal use only. 4 (eGFR) and left ventricular mass indexed to height (LVMI) were analyzed after treatment Guillem Pintos-Morell start (baseline) for patients with ≥3 measurements, including baseline and year 10. Michael L West 5 Results: Median (range) age (years) of the evaluable treated renal cohort at treatment start Dau-Ming Niu 6 Kathy Nicholls 7,8 was 48.8 (17.9–67.3) for females (n=62), 34.4 (18.0–66.8) for males (n=90). With eGFR ≥60 Roberto Giugliani 9 mL/min/1.73 m2 at baseline, mean (95% CI) rate of eGFR change (eGFR/year) over 10 years was relatively stable in females (n=52; −0.55 [−1.12, +0.01]) and slightly declined in males On behalf of the FOS Study Group (n=79; −1.99 [−2.45, −1.54]). With impaired kidney function (eGFR <60 mL/min/1.73 m2) at 1 baseline, mean (95% CI) eGFR/year was stable in females (n=10; −0.14 [−1.43, +1.15]) and Royal Free London NHS Foundation Trust, Lysosomal Disorders Unit, Institute of slightly declined in males (n=11; −2.79 [−4.01, −1.56]) over 10 years. Median (range) age Immunity and Transplantation, London, UK; (years) of the evaluable treated cardiac cohort at treatment start was 46.7 (3.7–67.3) for 2 Centre for Paediatric and Adolescent Medicine, University Medical Centre, females (n=34), 28.2 (4.0–54.2) for males (n=35). With left ventricular hypertrophy (LVH; University of Mainz, Mainz, Germany; LVMI >48 g/m2.7 in females, >50 g/m2.7 in males) at baseline, mean (95% CI) LVMI/year 3 Department of Biostatistics and slightly increased over 10 years in females (n=18; +1.51 [+0.91, +2.12]) and males (n=14; Programming, Takeda, Zug, Switzerland; 4 Centre for Rare Diseases, University +0.87 (+0.19, +1.55). Without LVH at baseline, mean (95% CI) LVMI/year was stable in Hospital Vall d’Hebron, Barcelona, females (n=16; +0.52 [−0.13, +1.17]) and males (n=21; +0.57 [+0.02, +1.13]) over 10 years. CIBERER-GCV08_IGTP Research Institute Conclusion: Agalsidase alfa-treated patients with 10-year FOS data and preserved kidney and Teaching Unit Germans Trias i Pujol, Universitat Autònoma de Barcelona, function and/or normal LVMI at baseline remained largely stable; those with decreased Badalona, Spain; 5Department of Medicine, kidney function or LVH at baseline experienced modest declines in renal function and/or Dalhousie University, Halifax, Nova Scotia, increases in LVMI. Canada; 6Department of Paediatrics, Taipei Veterans General Hospital, Taipei, Taiwan; Keywords: agalsidase alfa, enzyme replacement therapy, Fabry disease, cardio-renal 7 Department of Nephrology, Royal outcomes Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia; 8 Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia; 9Medical Genetics Service HCPA, Department of Genetics, UFRGS, Introduction and INAGEMP, Porto Alegre, Brazil Fabry disease is a rare X-linked disorder caused by the lack of the lysosomal enzyme α-galactosidase A, which affects glycosphingolipid metabolism. Consequences of this Correspondence: Uma Ramaswami Lysosomal Disorders Unit, Institute of progressive disease include neuropathic pain, angiokeratoma, progressive renal Immunity and Transplantation, 2nd Floor, damage leading to kidney failure, cardiomyopathy, arrhythmia, transient ischemic Royal Free Hospital, Pond Street, London NW3 2QG, UK attacks and/or strokes, and reduced lifespan.1 The advent of enzyme replacement Tel +44 207 794 0500 Ext 22492 therapy (ERT) in 2001 offered the potential for improved outcomes in patients with Fax +44 207 317 7665 Email uma.ramaswami@nhs.net Fabry disease as well as improving pain scores and measures of patient quality of submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2019:13 3705–3715 3705 DovePress © 2019 Ramaswami et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/ http://doi.org/10.2147/DDDT.S207856 terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Powered by TCPDF (www.tcpdf.org) Ramaswami et al Dovepress life.2 Evidence suggests that improved outcomes may be pediatric patients at FOS extract) comprised patients particularly true when treatment is initiated early, before from the evaluable treated cohort with complete longitu- irreversible damage has occurred in target organs such as dinal data, i.e. those who had ≥3 available estimated the kidney and heart.3–7 Fabry-specific therapy is used glomerular filtration rate (eGFR) measurements after together with ancillary therapies for patients with renal or ERT start, including the baseline and year 10 time points cardiac disease, such as angiotensin receptor blockers, (Figure 1). The FOS evaluable treated cardiac cohort Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 158.109.91.63 on 26-Mar-2021 angiotensin-converting enzyme inhibitors, and interventions (n=69; all adults except 10 pediatric patients at FOS aimed at arrhythmia and congestive heart failure.7 entry and 1 pediatric patient at FOS extract) included The Fabry Outcome Survey (FOS), initiated by Shire patients from the evaluable treated cohort with complete (now part of Takeda) in 2001, collects long-term data from longitudinal data, i.e. patients with ≥3 available left ven- patients in 24 countries on the natural history of Fabry tricular mass indexed to height (LVMI) measurements disease and the safety and efficacy of treatment with after ERT start, including the baseline and year 10 time agalsidase alfa.8 A previous evaluation of FOS data from points (Figure 1). patients who had received 5 years of agalsidase alfa ERT Of the patients excluded from the evaluable treated showed this was associated with reduced morbidity and cohorts, 3 patients were excluded from the renal and mortality.9 The current objective was to perform an addi- cardiac cohorts due to switching to another treatment tional retrospective analysis of data extracted from FOS in (type not specified; as entered by the investigator as free August 2018 to assess cardiac and renal outcomes in text) before their 10-year data could be collected. For personal use only. patients who had received agalsidase alfa ERT over a 10- FOS (ClinicalTrials.gov identifier: NCT03289065) has year period. been approved by the ethics institutional review boards of participating centers (Supplemental File). Further, this reg- istry was compliant with relevant global and local regula- Materials And Methods tions and best practices. Good Pharmacoepidemiological Patients Practice, Good Research for Comparative Effectiveness The FOS all treated 10-year cohort (n=388) comprised all principles, and the relevant principles of the International children and adults followed in FOS who initiated agalsi- Conference on Harmonisation Good Clinical Practice dase alfa ERT 0.2 mg/kg intravenously every other week (ICH GCP) guidelines (ICH E6) were followed as appro- either before or during entry into FOS and received it for a priate for an observational registry. All participants gave minimum of 10 years before data extraction on August 3, written informed consent. 2018. Of 350 patients (n=38 missing) in the all-treated cohort, we identified that 197 (56.3%) patients within the Assessments cohort were carrying mutations related to classic Fabry eGFR was calculated only in patients aged ≥18 years at the disease and 35 (10.0%) patients were carrying mutations time of assessment, using serum creatinine level and an equa- related to late-onset Fabry disease; 118 (33.7%) patients tion derived from the Modification of Diet in Renal Disease were of unknown phenotype. study.10 LVMI was calculated using the Devereux formula The FOS evaluable treated cohort (n=363) was defined from measurements obtained by echocardiography.11 as the subset of patients who did not receive other ERT Left ventricular hypertrophy (LVH) was defined as LVMI prior to FOS entry, had a known agalsidase alfa ERT start >48 g/m2.7 in females and LVMI >50 g/m2.7 in males.12,13 date and did not have a kidney transplant or receive LVMI slopes over 10 years were analyzed by sex and base- dialysis before the start of treatment; this cohort included line LVH status, and left ventricular posterior wall thickness 44 pediatric (<18 years of age) and 319 adult (≥18 years of in diastole (PWTD) slopes over 10 years were analyzed by age) patients at FOS entry, and 53 pediatric and 310 adult sex and baseline eGFR <60 or ≥60 mL/min/1.73 m2. patients at ERT start. Patients were excluded if they received other ERT before FOS entry (n=11) or had Statistical Analysis begun dialysis or had a kidney transplant prior to ERT The statistical analysis was performed using SAS® soft- initiation (n=14; Figure 1). ware version 9.3 (SAS Institute Inc., Cary, NC, USA). The FOS evaluable treated renal cohort (n=152; all Descriptive statistics were calculated for demographic adults except 1 pediatric patient at FOS entry but no and outcome data. For continuous variables, 95% submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2019:13 3706 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Ramaswami et al Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 158.109.91.63 on 26-Mar-2021 For personal use only. Figure 1 Flow diagram of participants included in the evaluable treated renal cohort and the evaluable treated cardiac cohort. Abbreviations: eGFR, estimated glomerular filtration rate; ERT, enzyme replacement therapy; FOS, Fabry Outcome Survey; LVMI, left ventricular mass index. confidence intervals (CIs) for means were computed Results using t-distribution. Average slope estimates for renal Evaluable Treated Renal Cohort and cardiac parameters, together with standard errors The evaluable treated renal cohort consisted of 152 (SEs) and 95% CIs, were calculated using a mixed patients: 62 females with a median (range) age at treat- model with random intercept and slope, without any ment start of 48.8 (17.9–67.3) years and 90 males with a assumptions on the within-patient covariance structure median (range) age at treatment start of 34.4 (18.0–66.8) (unstructured covariance matrix). years (Table 1). The median (range) time from treatment Mixed models for eGFR and LVMI included time from start to data extraction from FOS was 12.5 (10.1–17.1) treatment start as covariate, sex and baseline renal (eGFR years in females and 14.4 (10.1–18.4) years in males <60 or ≥60 mL/min/1.73 m2) or cardiac (LVH or no LVH) (Table 1). Use of angiotensin-converting enzyme inhibi- status as factors, and all corresponding interactions. Mixed tors and/or angiotensin receptor blockers was recorded in model for PWTD included time from treatment start, sex, 41 of 62 (66.1%) females and 73 of 87 (83.9%) males baseline eGFR level (<60 or ≥60 mL/min/1.73 m2), and all (Table 1). Decreased kidney function (stage 3 or 4 chronic interactions. In evaluable treated cardiac cohort patients kidney disease, as patients on dialysis or having received a with baseline eGFR >90 mL/min/1.73 m2 and urinary renal transplant were excluded) at baseline, defined as protein <0.5 g/day, the model for eGFR included time eGFR <60 mL/min/1.73 m2, was seen in 10 of 62 from treatment start as covariate, sex as a factor, and (16.1%) females and 11 of 90 (12.2%) males. Baseline interaction of sex with time variable. urinary protein data were available for 115 of 152 (76%) submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2019:13 3707 DovePress Powered by TCPDF (www.tcpdf.org) Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 158.109.91.63 on 26-Mar-2021 For personal use only. Powered by TCPDF (www.tcpdf.org) 3708 Ramaswami et al Table 1 Demographic And Clinical Characteristics At Treatment Start For The Evaluable Treated Renal And Cardiac Cohorts DovePress Characteristic Evaluable Treated Renal Cohort Evaluable Treated Cardiac Cohort Female Male Total Female Male Total Patients, n 62 90 152 34 35 69 White race, n (%) 60 (96.8) 85 (94.4) 145 (95.4) 30 (88.2) 33 (94.3) 63 (91.3) submit your manuscript | www.dovepress.com Median (range) age at treatment start, years 48.75 (17.9–67.3) 34.35 (18.0–66.8) 39.95 (17.9–67.3) 46.70 (3.7–67.3) 28.20 (4.0–54.2) 38.80 (3.7–67.3) Median (range) time from start of ERT to FOS 12.50 (10.1–17.1) 14.40 (10.1–18.4) 13.30 (10.1–18.4) 12.75 (10.1–16.5) 14.30 (10.2–17.1) 13.60 (10.1–17.1) data extraction, years Mean (SD) blood pressure at baseline in adult patients, mm Hg Systolic 125.0 (17.9) n=55 125.1 (15.4) n=81 125.1 (16.4) n=136 123.7 (17.4) n=30 122.5 (11.2) n=33 123.1 (14.4) n=63 Diastolic 73.3 (12.0) n=55 75.2 (11.8) n=81 74.4 (11.9) n=136 72.6 (10.7) n=30 72.9 (11.8) n=33 72.8 (11.2) n=63 Mean (SD) total FOS-MSSI score 20.48 (8.43) n=62 21.48 (10.16) n=90 21.08 (9.48) n=152 21.04 (9.99) n=34 21.57 (10.09) n=35 21.31 (9.97) n=69 Patients who received ACE/ARB medications, n (%) 41 (66.1) n=62 73 (83.9) n=87 114 (76.5) n=149 23 (67.6) n=34 26 (74.3) n=35 49 (71.0) n=69 Patients with urinary protein ≥1.0 g/24 hrs at 3 (6.7) n=45 9 (12.9) n=70 12 (10.4) n=115 3 (11.5) n=26 5 (17.9) n=28 8 (14.8) n=54 baseline, n (%) Mean (SD) baseline eGFR, mL/min/1.73 m2 80.40 (17.99) n=62 95.00 (29.68) n=90 89.04 (26.49) n=152 NA NA NA Patients in eGFR category <60 mL/min/1.73 m2 10 (16.1) n=62 11 (12.2) n=90 21 (13.8) n=152 6 (20.0) n=30 4 (14.8) n=27 10 (17.5) n=57 at baseline, n (%) Mean (SD) baseline LVMI, g/m2.7 NA NA NA 52.21 (16.99) n=34 49.13 (16.92) n=35 50.65 (16.90) n=69 Patients with LVH at baseline, n (%) 25 (58.1) n=43 23 (48.9) n=47 48 (53.3) n=90 18 (52.9) n=34 14 (40.0) n=35 32 (46.4) n=69 Mean (SD) baseline PWTD, mm NA NA NA 11.6 (2.5) n=34 11.1 (3.2) n=35 11.3 (2.9) n=69 Abbreviations: ACE, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; eGFR, estimated glomerular filtration rate; ERT, enzyme replacement therapy; FOS, Fabry Outcome Survey; LVH, left ventricular hypertrophy; LVMI, left ventricular mass index; MSSI, Mainz severity score index; NA, not available; PWTD, left ventricular posterior wall thickness in diastole. Drug Design, Development and Therapy 2019:13 Dovepress Dovepress Ramaswami et al patients in the evaluable treated renal cohort and indicated 46.7 (3.7–67.3) years and 35 males with a median (range) age urinary protein ≥1.0 g/24hrs was present in 3 of 45 (6.7%) at treatment start of 28.2 (4.0–54.2) years (Table 1). The females and 9 of 70 (12.9%) males (Table 1). median (range) time from treatment start to data extraction The mean (95% CI) eGFR measurements (mL/min/1.73 from FOS was 12.8 (10.1–16.5) years in females and 14.3 2 m ) at baseline and year 10, respectively, were 80.4 (75.8, 85.0) (10.2–17.1) years in males (Table 1). Baseline LVH was and 79.1 (74.1, 84.0) in females and 95.0 (88.8, 101.2) and 77. present in 18 (52.9%) females and 14 (40.0%) males Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 158.109.91.63 on 26-Mar-2021 5 (70.1, 84.9) in males (Figure 2). Stratification by baseline (Table 1). renal function (Figure 3) showed that patients with eGFR ≥60 The mean (95% CI) LVMI measurements (g/m2.7) at mL/min/1.73 m2 at baseline had a relatively stable mean (95% baseline and year 10, respectively, were 52.2 (46.3, 58.1) CI) eGFR slope (mL/min/1.73 m2/year) of −0.55 (−1.12, and 58.8 (48. 7, 68.9) in females and 49.1 (43.3, 54.9) and +0.01) for females (n=52) throughout the 10-year treatment 52.0 (43.2, 60.8) in males (Figure 4). period and a small negative slope for males (n=79) of −1.99 Stratification by the presence or absence of LVH at base- (−2.45, −1.54). Among those with impaired kidney function line (Figure 5) showed that in patients without LVH at base- (eGFR <60 mL/min/1.73 m2) at baseline, the mean (95% CI) line, cardiac mass remained stable in females and in males; eGFR slope (mL/min/1.73 m2/year) throughout the 10-year the mean (95% CI) LVMI slopes (g/m2.7/year) throughout the treatment period for females (n=10) was stable at −0.14 (−1.43, 10-year treatment period were +0.52 (−0.13, +1.17) for +1.15) and showed a modest decline for males (n=11), −2.79 females (n=16) and +0.57 (+0.02, +1.13) for males (n=21). (−4.01, −1.56). For the renal cohort (n=152), blood pressure Among those with LVH at baseline, mean (95% CI) LVMI For personal use only. values were available for 136 patients at baseline; however, the (g/m2.7/year) had slight positive slopes throughout the 10- follow-up data for blood pressure were missing for many year treatment period of +1.51 (+0.91, +2.12) for females patients meaning that a blood pressure change could not be (n=18) and +0.87 (+0.19, +1.55) for males (n=14). adequately analyzed. Stratification by baseline eGFR (Figure 6) showed that in patients with baseline eGFR <60 mL/min/1.73 m2, the Evaluable Treated Cardiac Cohort mean (95% CI) slope (mm/year) of PWTD over the 10- The evaluable treated cardiac cohort consisted of 69 patients: year treatment period was +0.01 (−0.12, +0.15) for 34 females with a median (range) age at treatment start of females (n=6) and +0.03 (−0.11, +0.18) for males (n=4). Among those with baseline eGFR ≥60 mL/min/1.73 m2, the mean (95% CI) slope was +0.10 (+0.01, +0.18) for 120 Females females (n=24) and +0.11 (+0.03, +0.19) for males (n=23). Males Among cardiac cohort patients without renal involvement eGFR MDRD (mL/min/1.73 m2) (ie, eGFR >90 mL/min/1.73 m2 and urinary protein <0.5 g/ 100 day) at baseline (6 of 34 [17.6%] females and 10 of 35 [28.6%] males), the mean (95% CI) LVMI measurements (g/m2.7) at baseline and year 10, respectively, were 43.3 80 (27.1, 59.5) and 45.9 (22.9, 69.0) in females (n=6) and 39.3 (34.1, 44.5) and 43.2 (36.3, 50.1) in males (n=10; Figure 7). 60 Discussion 0 1 2 3 4 5 6 7 8 9 10 Our current analysis of a subset of the FOS population Years of treatment showed that during 10 years of agalsidase alfa ERT, renal Treatment year 0 1 2 3 4 5 6 7 8 9 10 function was relatively stable in females and showed mod- Females, n 62 58 53 56 51 53 54 52 49 54 62 est decreases in males; these observations should be con- Males, n 90 80 83 78 81 77 83 72 78 71 90 sidered in the context of the natural history of Fabry disease as described in the literature. Schiffmann et al14 published a Figure 2 Mean (95% CI) eGFR MDRD (mL/min/1.73 m2) over a 10-year duration of enzyme replacement therapy for female and male populations in the evaluable retrospective chart review of 168 female and 279 male treated renal cohort*. *Data shown are cross-sectional values. untreated patients examined between 1944 and 2002 in Abbreviations: eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease. North America and Europe, with only approximately one- submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2019:13 3709 DovePress Powered by TCPDF (www.tcpdf.org) Ramaswami et al Dovepress Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 158.109.91.63 on 26-Mar-2021 For personal use only. Figure 3 Individual profiles and average slope estimates for eGFR over time for the evaluable renal cohort (n=152) for the: (A) female population, baseline eGFR ≥60 mL/ min/1.73 m2; (B) female population, baseline eGFR <60 mL/min/1.73 m2; (C) male population, baseline eGFR ≥60 mL/min/1.73 m2; (D) male population, baseline eGFR <60 mL/min/1.73 m2. Full interaction model: [age] × [sex] × [baseline] category. Abbreviations: eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease; SEM, standard error of the mean. 80 third of these patients receiving angiotensin receptor block- Females Males ers or angiotensin-converting enzyme inhibitors. Among those with baseline eGFR <60 mL/min/1.73 m2 (calculated from serum creatinine measurements with the abbreviated 60 LVMI (g/m2.7) Modification of Diet in Renal Disease [MDRD] equation), the mean eGFR change was −2.1 and −6.8 mL/min/1.73 m2/year, respectively, in females and males. Among those 40 with baseline eGFR ≥60 mL/min/1.73 m2, the mean eGFR change was −0.9 and −3.0 mL/min/1.73 m2/year, respec- tively, in females and males. Male patients and those with 20 hypertension, baseline proteinuria, or impaired renal func- 0 1 2 3 4 5 6 7 8 9 10 tion at baseline had a more rapid loss of renal function. Years of treatment A FOS analysis by Mehta et al of adults who received 5 Treatment year 0 1 2 3 4 5 6 7 8 9 10 years of agalsidase alfa showed mean annual eGFR changes Females, n 34 29 22 25 26 23 23 21 23 19 34 of −0.89 and −3.17 mL/min/1.73 m2 in females and males, Males, n 35 30 29 29 29 26 25 24 24 25 35 respectively.15 The authors noted these declines in eGFR Figure 4 Mean (95% CI) LVMI (g/m2.7) over a 10-year duration of enzyme replace- (calculated from serum creatinine measurements with the ment therapy for female and male populations in the evaluable treated cardiac MDRD equation) were slower than those reported for the cohort*. *Data shown are cross-sectional values. Abbreviations: LVMI, left ventricular mass index. natural history of the disease and were similar to those submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2019:13 3710 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Ramaswami et al Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 158.109.91.63 on 26-Mar-2021 For personal use only. Figure 5 Individual profiles and average slope estimates for LVMI over time for the evaluable cardiac cohort (n=69) for the (A) female population, LVH at baseline; (B) female population, no LVH at baseline; (C) male population, LVH at baseline; (D) male population, no LVH at baseline. Abbreviations: LVH, left ventricular hypertrophy; LVMI, left ventricular mass index; SEM, standard error of the mean. expected with age in females and approximately 2 to 3 proteinuria. The effect of these medications on proteinuria times greater than those expected with age in males. has been described in patients with various proteinuric Among the patients with baseline eGFR ≥130 mL/min/ conditions;17,18 this is also expected in Fabry disease. 1.73 m2, ~86% had eGFR within the normal range after 5 The effects of these medications on eGFR slope is less years of ERT, and among patients with baseline eGFR consistent in the literature and may be related to protei- classified as chronic kidney disease stages 1 to 3, mean nuria reduction rather than a direct effect of the medica- annual changes in eGFR were between −1.53 and −2.63 tions. The patients in the Nowak report had a median mL/min/1.73 m2, with renal function stabilization or baseline eGFR of 92 mL/min/1.73 m2 in females and 96 improvement in 56.5% to 75.0% of the patients, and slowed mL/min/1.73 m2 in males (calculated using the serum decline of eGFR in 68.8% to 89.1%. creatinine-based Chronic Kidney Disease-Epidemiology Nowak et al recently published results from prospec- Collaboration [CKD-EPI(cr)] equation);16 our FOS evalu- tive disease progression modeling of renal function in able treated renal cohort had a mean baseline eGFR of adults with classical Fabry disease.16 During a median 80.4 mL/min/1.73 m2 in females and 95.0 mL/min/1.73 m2 follow-up of 9 years in 21 treated females and 24 treated in males. males (most received agalsidase alfa), female patients had Germain et al published a 10-year analysis of patients a stable renal function (eGFR slope, −0.07 mL/min/1.73 receiving agalsidase beta ERT stratified by baseline renal m2/year) and males had a change in eGFR of −3.07 mL/ involvement.3 The study included data collected from 50 min/1.73 m2/year. There was no clear effect of angiotensin males and 2 females enrolled in a phase 3 clinical trial and receptor blockers or angiotensin-converting enzyme inhi- an open-label extension study, as well as subsequent data bitors on the eGFR slope, but there was an effect on after the patients entered the Fabry Registry. Overall, submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2019:13 3711 DovePress Powered by TCPDF (www.tcpdf.org) Ramaswami et al Dovepress Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 158.109.91.63 on 26-Mar-2021 For personal use only. Figure 6 Individual profiles and average slope estimates for left ventricular PWTD over time for the evaluable cardiac cohort (n=69) for the (A) female population, baseline eGFR ≥60 mL/min/1.73 m2; (B) female population, baseline eGFR <60 mL/min/1.73 m2; (C) male population, baseline eGFR ≥60 mL/min/1.73 m2; (D) male population, baseline eGFR <60 mL/min/1.73 m2. Abbreviations: eGFR, estimated glomerular filtration rate; PWTD, left ventricular posterior wall thickness in diastole; SEM, standard error of the mean. 160 patients in the Germain et al study were younger at treat- Females Males ment start (mean age, 30.1 years) than those in our FOS evaluable renal cohort (mean age, 40.2 years), and had a 120 higher eGFR (calculated using the serum creatinine-based CKD-EPI(cr) equation) at baseline (mean, 116.6 mL/min/ LVMI (g/m2.7) 80 1.73 m2) than patients in our FOS evaluable renal cohort (mean, 89.0 mL/min/1.73 m2). Germain et al classified patients as having low or high baseline renal involvement: 40 low renal involvement was defined by a urinary protein-to- creatinine ratio of ≤0.5 g/g and <50% sclerotic glomeruli 0 in renal biopsies collected during the first 6 months of the 0 1 2 3 4 5 6 7 8 9 10 study, while high renal involvement was defined by a Years of treatment urinary protein-to-creatinine ratio of >0.5 g/g or ≥50% Treatment year 0 1 2 3 4 5 6 7 8 9 10 sclerotic glomeruli. The mean eGFR slope was −1.89 Females, n 6 4 4 3 4 4 2 1 4 2 6 and −6.82 mL/min/1.73 m2/year over 10 years among Males, n 10 8 9 9 8 7 7 7 8 8 10 patients classified as having low (n=32) or high (n=20) renal involvement, respectively, at baseline. We stratified Figure 7 Mean (95% CI) LVMI (g/m2.7) over a 10-year duration of enzyme replace- ment therapy for female and male patients with baseline eGFR >90 mL/min/1.73 m2 our FOS evaluable renal cohort by baseline eGFR ≥60 or and urinary protein <0.5 g/day in the evaluable treated cardiac cohort. <60 mL/min/1.73 m2. In our analyses of those with higher Abbreviations: eGFR, estimated glomerular filtration rate; LVMI, left ventricular mass index. baseline eGFR, renal function was relatively stable (slope submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2019:13 3712 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Ramaswami et al estimate, −0.55) in 52 females and showed modest Several limitations of our study should be considered. declines (slope estimate, −1.99) in 79 males over 10 Observational studies, including analysis of patient registry years of ERT; our analysis of those with impaired renal data, provide important real-world evidence that complements function at baseline showed a steady eGFR (slope esti- the limited information available from randomized controlled mate, −0.14) in 10 females and a modest decline (slope trials in rare diseases. However, with registry data in general, it estimate, −2.79) in 11 males. Taken together, patients is difficult to ensure comprehensive data capture, assessments Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 158.109.91.63 on 26-Mar-2021 treated with agalsidase alfa or beta over 10 years show may not be standardized across multiple sites, and there is the better preservation of renal function when ERT was started possibility of patient enrollment bias as patients with more with earlier kidney disease characterized by higher base- severe symptoms or who are receiving treatment are more line eGFR and less proteinuria. likely to be enrolled in a registry. This retrospective analysis Our current FOS analysis showed that during 10 years of 10-year FOS patient registry data did not include compar- of agalsidase alfa ERT, LVMI had relatively small isons with untreated patients from the same registry because increases among patients with LVH at baseline and was there were too few untreated patients to match by sex, age, stable among patients without LVH at baseline. The and/or disease severity. The patients in the FOS registry were observed increases in LVMI were less than those reported not randomly selected, possibly giving rise to selection and/or in an untreated population, in which LVMI was shown to ascertainment bias. For example, male patients may have been increase at a rate of 2.31 g/m2.7/year in females and identified and treated earlier than females, whereas treatment start may have in some cases been delayed in females until 4.07 g/m2.7/year in males.13 In addition, patients without For personal use only. organ involvement was established (as suggested by lower renal involvement and LVH at baseline who received eGFR at baseline). Although the serum creatinine-based agalsidase alfa ERT over 10 years in FOS had stable CKD-EPI(cr) equation may provide a more accurate estima- cardio-renal outcomes, which would be beneficial in pre- tion at eGFR >60 mL/min/1.73 m2, the MDRD equation is venting early organ manifestation of the disease. In a 10- widely used,20 allowing comparison with more studies, and year analysis by Kampmann et al of patients receiving was used in the FOS 5-year analysis. However, proteinuria and agalsidase alfa at a single FOS site,19 males with baseline its effect on eGFR slopes were also not fully investigated in LVMI ≥50 g/m2.7 had statistically significant reductions this analysis. There was no centralized reading of echocardio- in LVMI from baseline at years 1, 2, 3, 5, and 10, while grams in the FOS cohorts. There is the possibility of bias females had similar improvements in LVMI at years 1, 2, associated with the censoring of patients who stopped agalsi- and 3. Reflecting our findings, in patients with baseline dase alfa treatment. The relatively small sample size, espe- LVMI <50 g/m2.7, LVMI was not significantly changed cially in subgroups, could affect the precision and robustness from baseline over 10 years of ERT.19 The patient popu- of estimates, and the lack of data regarding Fabry disease lation, management, and follow-up in our current FOS phenotype, proteinuria, and blood pressure control may limit 10-year multicenter analysis were less homogeneous than the generalizability of our observations. The relationship of the in the single-center report by Kampmann et al, but our surrogate endpoints in this analysis to clinical endpoints is not overall treatment outcomes were similar and appear con- clear. By the nature of the analysis, the clinical endpoints may sistent with the single-center experience. be enriched in people who died or stopped ERT. Our current analysis also showed that over 10 years of ERT, in patients with minimal renal involvement at base- Conclusion line, LVMI was stable over 10 years, between 43.3 and The current analysis of a cohort of FOS provides evidence 45.9 g/m2.7 in females and between 39.3 and 43.2 g/m2.7 in supporting the benefits of agalsidase alfa ERT over 10 males. This finding is in agreement with the results years. Patients with preserved kidney function and/or nor- reported by Germain et al, in which the mean slopes of mal LVMI at baseline remained largely stable during 10 left posterior wall thickness over 10 years of agalsidase years of ERT, whereas those patients with reduced eGFR beta ERT were +0.08 mm/year and +0.10 mm/year in and/or evidence of LVH at baseline experienced modest patients with low and high Fabry disease renal involve- declines in renal function and/or increases in LVMI that ment, respectively, at baseline.3 Compared with the popu- were less than expected based on natural history data. These lation in the Germain et al report, our cohort had similar or findings suggest that early treatment, before substantial greater overall disease severity at baseline. organ damage has occurred, may improve outcomes. submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2019:13 3713 DovePress Powered by TCPDF (www.tcpdf.org) Ramaswami et al Dovepress Acknowledgments consulting fees, honoraria for lectures, and travel grants Under the direction of the authors, Margit Rezabek, DVM, from Alexion, Amicus, BioMarin, and Shire, during the PhD, Sally Hassan, PhD, CMPP, and Latoya M. Mitchell, conduct of the study. He is also a member of the SC of PhD, CMPP, employees of Excel Medical Affairs, provided FOS and has received honoraria for compensation of the writing assistance for this publication. Editorial assistance time spent on SC meetings. Michael West has received con- in formatting, proofreading, copy editing, and fact checking sulting fees from GlaxoSmithKline, AvroBio and Shire; has Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 158.109.91.63 on 26-Mar-2021 was also provided by Excel Medical Affairs. Statistical performed contract research for Alexion, Genzyme, Idorsia support was provided by Patrick Engrand, PhD, of and Shire; has received speaker honoraria from Excelsior, Clinical Research Services – ICC, under contract to Shire. Genzyme, Shire, and Sumitomo; honoraria for serving on a This paper was presented at the WORLDSymposium 2016 data and safety monitoring board for Amicus; and honoraria as a poster presentation with interim findings. The poster’s for advisory boards from Actelion, Genzyme, and Shire. He abstract was published in Ramaswami U, et al Mol Genet is also a member of the SC of FOS and has received honor- Metab 2016;117(2):S98. https://doi.org/10.1016/j.ymgme. aria for compensation of the time spent on SC meetings. Dau- 2015.12.416. Ming Niu has received travel and research grants and speaker honoraria from Genzyme and Shire. He is also a member of the SC of FOS and has received honoraria for compensation Funding of the time spent on SC meetings. Kathy Nicholls reports The Fabry Outcome Survey is sponsored by Shire Human grants from Melbourne Health, during the conduct of the For personal use only. Genetic Therapies, Inc., a member of the Takeda group of study and has received research support from Amicus, companies. Shire International GmbH, a member of the Genzyme, and Shire, outside the submitted work. She is Takeda group of companies, provided funding to Excel also a member of the SC of FOS and has received honoraria Medical Affairs for support in writing and editing this for compensation of the time spent on SC meetings. Roberto manuscript and participated in data collection and analysis. Giugliani has received consulting fees, fees for non-CME/CE services, investigator fees, and support for travel expenses to Disclosure attend scientific meetings from Actelion, Amicus, Armagen, Uma Ramaswami has received travel and research grants and BioMarin, GC Pharma, Inventiva, JCR Pharmaceuticals, honoraria for lectures and advisory boards from Amicus, Lysogene, RegenxBio, Sanofi-Genzyme, Shire, Sobi and Chiesi, Genzyme, and Shire (now a member of the Takeda Ultragenyx. He is also a member of the SC of FOS and has group of companies). She is also a member of the steering received honoraria for compensation of the time spent on SC committee (SC) of FOS, a registry of Fabry disease spon- meetings. The authors report no other conflicts of interest in sored by Shire/Takeda, and has received honoraria for com- this work. pensation of the time spent on SC meetings. Michael Beck has received consulting fees from Genzyme and Shire. He is References also a member of the SC of FOS and has received honoraria 1. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30. for compensation of the time spent on SC meetings. doi:10.1186/1750-1172-5-30 Derralynn Hughes has received travel and research grants 2. Ramaswami U, Wendt S, Pintos-Morell G, et al. Enzyme replacement therapy with agalsidase alfa in children with Fabry disease. Acta and honoraria for speaking and advisory boards from Paediatr. 2007;96(1):122–127. doi:10.1111/j.1651-2227.2007.00029.x Amicus, Genzyme, Protalix, and Shire. She also reports 3. Germain DP, Charrow J, Desnick RJ, et al. Ten-year outcome of personal fees from Takeda, Sanofi, and Amicus, outside the enzyme replacement therapy with agalsidase beta in patients with Fabry disease. J Med Genet. 2015;52(5):353–358. doi:10.1136/jmed- submitted work. She is also a member of the SC of FOS and genet-2014-102797 has received honoraria for compensation of the time spent on 4. Hughes DA. Fabry disease: will markers of early disease enable early treatment and better outcomes? Curr Opin Cardiol. 2016;31(4):434– SC meetings. Christoph Kampmann has received consulting 439. doi:10.1097/HCO.0000000000000308 fees from Amicus, BioMarin, Gore, and Shire and honoraria 5. Ortiz A, Abiose A, Bichet DG, et al. Time to treatment benefit for adult patients with Fabry disease receiving agalsidase beta: data from for lectures and travel and research grants from BioMarin, the Fabry Registry. J Med Genet. 2016;53(7):495–502. doi:10.1136/ Shire, and Gore. He is also a member of the SC of FOS and jmedgenet-2015-103486 has received honoraria for compensation of the time spent on 6. Weidemann F, Niemann M, Breunig F, et al. Long-term effects of enzyme replacement therapy on Fabry cardiomyopathy: evidence for a SC meetings. Jaco Botha is an employee of Takeda and a better outcome with early treatment. Circulation. 2009;119(4):524– Takeda stock owner. Guillem Pintos-Morell has received 529. doi:10.1161/CIRCULATIONAHA.108.794529 submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2019:13 3714 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Ramaswami et al 7. Oder D, Nordbeck P, Wanner C. Long term treatment with enzyme 15. Mehta A, Beck M, Elliott P, et al. Enzyme replacement therapy with replacement therapy in patients with Fabry disease. Nephron. agalsidase alfa in patients with Fabry’s disease: an analysis of registry 2016;134(1):30–36. doi:10.1159/000448968 data. Lancet. 2009;374(9706):1986–1996. doi:10.1016/S0140-6736(09) 8. Giugliani R, Niu DM, Ramaswami U, et al. A 15-year perspective of 61493-8 the Fabry Outcome Survey. J Inborn Errors Metab Screen. 2016;4:1– 16. Nowak A, Koch G, Huynh-Do U, Siegenthaler M, Marti HP, Pfister 12. doi:10.1177/2326409816666298 M. Disease progression modeling to evaluate the effects of enzyme 9. Beck M, Hughes D, Kampmann C, et al. Long-term effectiveness of replacement therapy on kidney function in adult patients with the agalsidase alfa enzyme replacement in Fabry disease: a Fabry classic phenotype of Fabry disease. Kidney Blood Press Res. 2017;42 Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 158.109.91.63 on 26-Mar-2021 Outcome Survey analysis. Mol Genet Metab Rep. 2015;3:21–27. (1):1–15. doi:10.1159/000464312 doi:10.1016/j.ymgmr.2015.02.002 17. Kunz R, Friedrich C, Wolbers M, Mann JF. Meta-analysis: effect of 10. Levey AS, Coresh J, Bolton K, et al. K/DOQI clinical practice monotherapy and combination therapy with inhibitors of the renin guidelines for chronic kidney disease: evaluation, classification, and angiotensin system on proteinuria in renal disease. Ann Intern Med. stratification. Am J Kidney Dis. 2002;39(2 Suppl 1):S1–266. 2008;148(1):30–48. doi:10.7326/0003-4819-148-1-200801010-00190 11. Linhart A, Kampmann C, Zamorano JL, et al. Cardiac manifestations of 18. Xu R, Sun S, Huo Y, et al. Effects of ACEIs versus ARBs on Anderson-Fabry disease: results from the international Fabry Outcome proteinuria or albuminuria in primary hypertension: a meta-analysis Survey. Eur Heart J. 2007;28(10):1228–1235. doi:10.1093/eurheartj/ of randomized trials. Medicine (Baltimore). 2015;94(39):e1560. ehm153 doi:10.1097/MD.0000000000000874 12. de Simone G, Devereux RB, Daniels SR, Koren MJ, Meyer RA, 19. Kampmann C, Perrin A, Beck M. Effectiveness of agalsidase alfa enzyme Laragh JH. Effect of growth on variability of left ventricular mass: replacement in Fabry disease: cardiac outcomes after 10 years’ treatment. assessment of allometric signals in adults and children and their Orphanet J Rare Dis. 2015;10:125. doi:10.1186/s13023-015-0338-2 capacity to predict cardiovascular risk. J Am Coll Cardiol. 1995;25 20. Kilbride HS, Stevens PE, Eaglestone G, et al. Accuracy of the (5):1056–1062. doi:10.1016/0735-1097(94)00540-7 MDRD (Modification of Diet in Renal Disease) study and CKD- 13. Kampmann C, Linhart A, Baehner F, et al. Onset and progression of EPI (CKD Epidemiology Collaboration) equations for estimation of the Anderson-Fabry disease related cardiomyopathy. Int J Cardiol. 2008;130(3):367–373. doi:10.1016/j.ijcard.2008.03.007 GFR in the elderly. Am J Kidney Dis. 2013;61(1):57–66. doi:10.1053/ For personal use only. 14. Schiffmann R, Warnock DG, Banikazemi M, et al. Fabry disease: j.ajkd.2012.06.016 progression of nephropathy, and prevalence of cardiac and cere- brovascular events before enzyme replacement therapy. Nephrol Dial Transplant. 2009;24(7):2102–2111. doi:10.1093/ndt/gfp031 Drug Design, Development and Therapy Dovepress Publish your work in this journal Drug Design, Development and Therapy is an international, peer- been accepted for indexing on PubMed Central. The manuscript reviewed open-access journal that spans the spectrum of drug design management system is completely online and includes a very quick and development through to clinical applications. Clinical outcomes, and fair peer-review system, which is all easy to use. Visit http://www. patient safety, and programs for the development and effective, safe, dovepress.com/testimonials.php to read real quotes from published and sustained use of medicines are a feature of the journal, which has also authors. 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