Drug Design, Development and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Analysis of Renal and Cardiac Outcomes in Male Participants in the Fabry Outcome Survey Starting Agalsidase Alfa Enzyme Replacement Therapy Before and After 18 Years of Age This article was published in the following Dove Press journal: Drug Design, Development and Therapy Rossella Parini 1,2 Purpose: To determine the impact of initiating enzyme replacement therapy (ERT) with 3 agalsidase alfa early in the course of Fabry disease, we evaluated renal and cardiac outcomes Guillem Pintos-Morell Julia B Hennermann 4 for ≤10 years after ERT initiation in males from the Fabry Outcome Survey (FOS). Ting-Rong Hsu 5 Patients and Methods: Male patients from FOS were stratified into three cohorts by age at ERT initiation: ≤18 years (cohort 1), >18 and ≤30 years (cohort 2), and >30 years (cohort 3). Nesrin Karabul 6 Analysis included age at symptom onset, diagnosis, and ERT initiation; ERT duration; FOS- Vasiliki Kalampoki 7 Mainz Severity Score Index (FOS-MSSI); estimated glomerular filtration rate (eGFR); Andrey Gurevich 7 proteinuria level; and left ventricular mass indexed to height (LVMI). Mixed-effect models Uma Ramaswami 8 estimated renal and cardiac outcomes during follow-up between and within cohorts. Findings: The analysis included 560 male patients: 151 (27.0%) in cohort 1, 155 (27.7%) in On behalf of the FOS Study cohort 2, and 254 (45.4%) in cohort 3. Mean±SD duration of ERT for cohorts 1, 2, and 3 was 6.3 Group ±4.3, 8.6±4.9, and 7.9±4.9 years, respectively. Mean±SD baseline FOS-MSSI scores increased 1 Rare Metabolic Diseases Unit, MBBM with age from 9.8±7.2 in cohort 1 to 24.7±11.4 in cohort 3. Cohort 3 showed the lowest baseline Foundation, San Gerardo Hospital, mean±SD value for eGFR (87.1±29.0 mL/min/1.73m2) and highest baseline mean±SD values Reference Centre for Hereditary Metabolic for proteinuria (801.9±952.6 mg/day) and LVMI (56.7±16.0 g/m2.7) among the three cohorts. Disorders (MetabERN), Monza, Italy; 2 TIGET Institute, IRCCS San Raffaele Evaluation of mean annual rates of change in eGFR, proteinuria, and LVMI revealed no Hospital, Milan, Italy; 3Division of Rare significant differences in any parameter for cohort 1. For cohort 2, proteinuria and LVMI Diseases, Reference Centre for Hereditary Metabolic Disorders (MetabERN), remained stable, whereas eGFR significantly deteriorated annually (–1.12 mL/min/1.73m2; University Hospital Vall d’Hebron, P<0.001). Cohort 3 demonstrated significant annual deteriorations in eGFR (–2.60 mL/min/ Autonomous University of Barcelona, 1.73m2; P<0.001), proteinuria (+34.10 mg/day; P<0.001), and LVMI (+0.59 g/m2.7; P=0.001). Barcelona, Spain; 4Villa Metabolica, Department of Pediatric and Adolescent Implications: Renal and/or cardiac disease progression appears attenuated in patients Medicine, University Medical Center, Mainz, starting ERT in childhood or early adulthood versus patients starting ERT in later adulthood. Germany; 5Department of Pediatrics, Taipei These findings support early ERT initiation in Fabry disease. ClinicalTrials.gov identifier: Veterans General Hospital and Faculty of Medicine, National Yang-Ming University, NCT03289065. Taipei, Taiwan; 6Department of Keywords: agalsidase alfa, Fabry disease, enzyme replacement therapy, Fabry Outcome Neuropaediatric and Inborn Metabolic Disorders (Metabolicum Ruhr), University Survey, estimated glomerular filtration rate, left ventricular hypertrophy Children’s Hospital and Centre for Rare Diseases, Ruhr University Bochum, Bochum, Germany; 7Shire, a Takeda company, Zurich, Switzerland; 8Royal Free London NHS Introduction Foundation Trust, London, UK Fabry disease is a progressive, multisystem disease in which nephropathy and cardi- omyopathy are frequent and major complications that can lead to premature death.1–4 Correspondence: Rossella Parini Rare Metabolic Diseases Unit, MBBM The wide variation in phenotypic presentation among patients with Fabry disease may Foundation, San Gerardo Hospital, Via favor misdiagnosis and delay the correct diagnosis and thus treatment.5,6 Enzyme Pergolesi 33, Monza 20900, Italy Email Rossella.parini@unimib.it replacement therapy (ERT) has not been shown to prevent further progression if submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2020:14 2149–2158 2149 DovePress © 2020 Parini 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/terms. http://doi.org/10.2147/DDDT.S249433 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). Parini et al Dovepress initiated during an advanced stage of the disease.7,8 to +3 months around ERT initiation) up to 10 years after Furthermore, evidence-based recommendations promote ERT initiation. Calculation of eGFR was made using the starting ERT early in the disease course for the greatest Counahan-Barratt equation in patients <18 years of age therapeutic benefit.9 and the Chronic Kidney Disease Epidemiology The Fabry Outcome Survey (FOS), sponsored by Collaboration equation in patients ≥18 years of age. Shire, a Takeda company (Zurich, Switzerland), is an Decreased eGFR was defined as <90 mL/min/1.73 m2 international disease registry that has been collecting and was used as a measure of reduced renal function.11 longitudinal data since 2001 on patients with Proteinuria was defined as a protein excretion rate of a confirmed diagnosis of Fabry disease. Until 2016, ≥150 mg/day.12 Increased LVMI was considered as values patients either untreated or treated with agalsidase alfa >50 g/m2.7 and was used as a measure of left ventricular were eligible to participate in the registry. Protocol hypertrophy (LVH).13 amendment 4 (dated June 29, 2016) allowed any patients with Fabry disease, regardless of treatment (ie, no treat- ment or any approved Fabry treatment), to be enrolled. Statistical Analysis The baseline demographic and clinical characteristics were The present analysis included only patients who received compared among the three study cohorts using analysis of ERT with agalsidase alfa. To determine the impact of variance (ANOVA), which constituted the most appropri- starting ERT early in the course of Fabry disease, this ate statistical method for comparing means because it study evaluated renal and cardiac outcomes up to 10 assesses the relative size of variance when more than years after ERT initiation in male patients registered in FOS who started ERT at ≤18 years, >18 and ≤30 years, two groups are being tested. The null hypothesis for an and >30 years of age. ANOVA is that there is no significant difference among the groups, whereas the alternative hypothesis assumes Patients and Methods that there is at least one significant difference among the This was a retrospective study of data from male patients groups. An assumption of normality was assessed in the registered in FOS (data extracted August 2018; current study with the Shapiro–Wilk test, and the Tukey’s ClinicalTrials.gov identifier NCT03289065). FOS was method was used for the post-hoc test. approved by the ethics institutional review boards of Mixed-effects linear regression analysis was used to esti- participating centers (Supplemental File). All participants mate mean values for renal and cardiac outcomes for the or their caregivers gave written informed consent. overall follow-up period within and between cohorts and, Patients were stratified into three cohorts according to subsequently,mean annual changes within each cohort. An age at initiation of ERT with agalsidase alfa: ≤18 years unstructured covariance (patient level) with the fixed effect of age (cohort 1; child), >18 and ≤30 years of age of age at ERT initiation (cohorts 1–3,as listed earlier) and the (cohort 2; young adult), and >30 years of age (cohort 3; random effect of patients and time were implemented in the adult). Baseline demographic and clinical characteristics models. Restricted maximum likelihood estimation was used were recorded, including race; age at symptom onset, to fit the models. P values were calculated using the Wald diagnosis, and ERT initiation; ERT duration; Fabry test. To be included in the mixed-effects linear regression Outcome Survey-Mainz Severity Score Index (FOS- analysis, patients were required to have (1) a minimum of MSSI) results; estimated glomerular filtration rate 3 years of receiving ERT,(2) nonmissing baseline data,(3) (eGFR); proteinuria levels; and left ventricular mass a minimum of 3 years of postbaseline data,(4) a minimum of indexed to height (LVMI). three measurements, and (5) no renal dialysis and/or trans- The FOS-MSSI is a scoring index used to measure plant prior to ERT initiation. For patients with renal dialysis Fabry disease intensity. It consists of general, neurologic, and/or transplant at any time over the course of follow- cardiovascular, and renal components, which are com- up,data were deleted after the timing of renal dialysis and/ bined to calculate the total MSSI score. Scores <20 are or transplant. Data up to a maximum of 10 years after ERT considered mild, 20–40 moderate, and >40 severe.10 initiation were used. Clinical judgment about the score must take the age of The level of statistical significance was set at 0.05. All the patient into account. Renal and cardiac outcomes were analyses were performed using SAS (SAS software ver- analyzed from baseline (defined as within a window of –6 sion 9.4). submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2020:14 2150 DovePress Dovepress Parini et al Results P < 0.001 for each). A comparison of patients in cohorts 2 and 3 also showed significant differences in overall mean Baseline Characteristics values for eGFR (114.1 vs 79.9 mL/min/1.73 m2, respec- A total of 560 male patients registered in FOS received tively), proteinuria (395.5 vs 819.5 mg/day, respectively), ERT with agalsidase alfa and were included in this study. and LVMI (40.0 vs 55.5 g/m2.7, respectively; P < 0.001 for There were 151 (27.0%) patients in cohort 1, 155 (27.7%) each). patients in cohort 2, and 254 (45.4%) patients in cohort 3 For patients in cohort 1, no significant annual (Table 1). Median (range) age at symptom onset was lower changes in eGFR, proteinuria, or LVMI were observed in cohort 1 (7.5 [0.0–16.0] years) than in cohort 2 (8.0 throughout the follow-up period (Table 3). For patients [0.0–17.0] years) or cohort 3 (9.0 [0.0–17.0] years; P = in cohort 2, although proteinuria and LVMI remained 0.017). Age at diagnosis was higher in each successive age stable, eGFR showed a significant annual decline over group and ranged from a median (range) of 11.0 (0.0– the follow-up period (slope, –1.12 mL/min/1.73 m2 18.0) years in cohort 1 to 31.0 (0.0–69.0) years in cohort [95% confidence interval {CI}, –1.77 to –0.47]; 3. Mean ± SD duration of ERT for cohorts 1, 2, and 3 was P < 0.001). For patients in cohort 3, a significant annual 6.3 ± 4.3, 8.6 ± 4.9, and 7.9 ± 4.9 years, respectively. deterioration over the follow-up period was shown for Mean ± SD FOS-MSSI scores at baseline increased with eGFR (slope, –2.60 mL/min/1.73 m2 [95% CI, –3.16 age in each successive cohort, from 9.8 ± 7.2 in cohort 1 to to –2.04]; P < 0.001), proteinuria (slope, +34.10 mg/ 24.7 ± 11.4 in cohort 3. Mean ± SD eGFR for cohorts 1 day [95% CI, 18.48–49.71]; P < 0.001), and LVMI and 2 was 113.8 ± 26.9 and 118.3 ± 20.0 mL/min/1.73 m2, (slope, +0.59 g/m2.7 [95% CI, 0.23–0.95]; P = 0.001). respectively. Mean ± SD proteinuria for cohorts 1 and 2 Figures 1–3 illustrate the estimated annual rates of was 120.6 ± 239.3 and 295.2 ± 476.6 mg/day, respectively. change over the follow-up period for each cohort by Additionally, LVMI for cohorts 1 and 2 was 36.7 ± 7.9 and parameter, showing that the patients in cohort 3 had 40.4 ± 11.0 g/m2.7, respectively. Cohort 3, comprising the worsening rates of change during follow-up for eGFR, oldest patients, showed the lowest baseline mean ± SD proteinuria, and LVMI in comparison with cohorts 1 value for eGFR (87.1 ± 29.0 mL/min/1.73 m2) and highest and 2. baseline mean ± SD values for proteinuria (801.9 ± 952.6 mg/day) and LVMI (56.7 ± 16.0 g/m2.7) among the three cohorts. Discussion The three different age cohorts included in this analysis Totals of 15 (17.0%; n = 88), 11 (10.1%; n = 109), and 70 effectively represent populations at different stages of dis- (46.7%; n = 150) patients in cohorts 1, 2, and 3, respectively, ease progression, as expected and as reflected by the FOS- had pathological eGFR (<90 mL/min/1.73 m2) at baseline; MSSI scores and clinical symptoms. whereas 13 (21.0%; n = 62), 35 (47.9%; n = 73), and 94 We observed that individuals with systemic Fabry dis- (81.0%; n = 116) patients in cohorts 1, 2, and 3, respectively, ease treated with ERT in childhood or early adulthood had pathological proteinuria (≥150 mg/day) at baseline. (cohorts 1 and 2) exhibited a stable eGFR slope or Totals of 3 (6.8%; n = 44), 9 (16.1%; n = 56), and 48 a slight decline in eGFR slope, respectively, and no (64.9%; n = 74) patients in cohorts 1, 2, and 3, respectively, changes in proteinuria slope during the course of the had pathological LVMI (>50 g/m2.7) at baseline. follow-up period. The slopes for eGFR and proteinuria were much more pronounced in cohort 3 compared to Follow-up for ERT cohorts 1 and 2. In a comparison of the cohorts, the overall mean values for Breunig et al reported a worse outcome and greater eGFR and proteinuria did not significantly differ between likelihood of reaching renal and cardiovascular end points patients in cohorts 1 and 2 during the follow-up period for in male and female patients treated with agalsidase alfa ERT, whereas some significant differences were found for who had more severe renal involvement at baseline.14 LVMI (Table 2). However, a comparison of patients in Germain et al also reported an increased likelihood of cohorts 1 and 3 showed significant differences in overall renal disease progression in patients treated with agalsi- mean values for eGFR (117.9 vs 79.9 mL/min/1.73 m2, dase beta who already had higher renal impairment at respectively), proteinuria (210.7 vs 819.5 mg/day, respec- baseline, compared with patients who did not.15 A 10- tively), and LVMI (33.6 vs 55.5 g/m2.7, respectively; year outcome study that included male and female patients submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2020:14 2151 DovePress Parini et al Dovepress Table 1 Demographic and Clinical Characteristics at Baseline in Male Patients with Fabry Disease According to Age at ERT Initiation Characteristics Cohort 1 Cohort 2 Cohort 3 Total P valuea (≤18 Years) (>18 and ≤30 Years) (>30 Years) N = 560 n = 151 n = 155 n = 254 Race <0.001 n 148 155 252 555 White, n (%) 95 (64.2) 132 (85.2) 213 (84.5) 440 (79.3) Black/African American, n (%) 1 (0.7) 0 (0.0) 0 (0.0) 1 (0.2) Asian, n (%) 49 (33.1) 16 (10.3) 34 (13.5) 99 (17.8) Other, n (%) 3 (2.0) 7 (4.5) 5 (2.0) 15 (2.7) Age at symptom onset, y 0.017 n 112 155 254 521 Mean (SD) 7.6 (3.7) 8.5 (4.4) 8.9 (3.7) 8.5 (3.9) Median (Q1, Q3) 7.5 (5.0, 10.0) 8.0 (5.0, 12.0) 9.0 (6.0, 12.0) 8.0 (6.0, 11.0) Range 0.0–16.0 0.0–17.0 0.0–17.0 0.0–17.0 Age at diagnosis, y <0.001 n 146 153 252 551 Mean (SD) 10.4 (4.6) 17.8 (6.7) 29.3 (13.9) 21.1 (13.0) Median (Q1, Q3) 11.0 (8.0, 14.0) 18.0 (14.0, 23.0) 31.0 (17.0, 39.0) 17.0 (11.0, 30.0) Range 0.0–18.0 0.0–28.0 0.0–69.0 0.0–69.0 Age at ERT initiation, y <0.001 n 151 155 254 560 Mean (SD) 13.0 (3.8) 24.1 (3.4) 41.6 (8.2) 29.1 (13.7) Median (Q1, Q3) 13.7 (10.9, 16.1) 24.5 (21.2, 26.9) 40.3 (34.9, 48.2) 27.7 (17.4, 39.4) Range 2.5–18.0 18.0–29.9 30.0–69.2 2.5–69.2 ERT duration, y <0.001 n 151 155 254 560 Mean (SD) 6.3 (4.3) 8.6 (4.9) 7.9 (4.9) 7.6 (4.8) Median (Q1, Q3) 5.5 (2.9, 9.4) 8.4 (4.0, 12.4) 7.0 (3.8, 12.2) 7.1 (3.6, 11.7) Range 0.0–16.3 0.0–17.1 0.0–18.1 0.0–18.1 FOS-MSSI n 145 152 250 547 <0.001 Mean (SD) 9.8 (7.2) 15.1 (8.5) 24.7 (11.4) 18.1 (11.6) Median (Q1, Q3) 8.0 (5.0, 12.5) 13.5 (8.3, 21.5) 23.5 (16.5, 33.5) 16.0 (8.5, 25.5) Range 0.0–35.0 0.0–39.5 1.0–52.5 0.0–52.5 Used at least one ACE inhibitor n 151 155 254 560 Yes, n (%) 20 (13.2) 50 (32.3) 145 (57.1) 215 (38.4) No, n (%) 131 (86.8) 105 (67.7) 109 (42.9) 345 (61.6) Systolic blood pressure, mmHg <0.001 n 91 90 155 336 Mean (SD) 111.6 (14.3) 120.1 (13.0) 125.2 (16.4) 120.1 (16.0) Median (Q1, Q3) 110.0 (104.0, 122.0) 120.0 (110.0, 129.0) 124.0 (115.0, 134.0) 120.0 (110.0, 130.0) Range 74.0–143.0 97.0–155.0 87.0–174.0 74.0–174.0 Diastolic blood pressure, mmHg <0.001 n 91 90 154 335 Mean (SD) 63.8 (10.8) 71.4 (9.6) 75.3 (11.5) 71.1 (11.8) Median (Q1, Q3) 63.0 (59.0, 70.0) 70.0 (64.0, 80.0) 74.0 (70.0, 80.0) 70.0 (63.0, 80.0) Range 40.0–100.0 47.0–98.0 50.0–110.0 40.0–110.0 (Continued) submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2020:14 2152 DovePress Dovepress Parini et al Table 1 (Continued). Characteristics Cohort 1 Cohort 2 Cohort 3 Total P valuea (≤18 Years) (>18 and ≤30 Years) (>30 Years) N = 560 n = 151 n = 155 n = 254 eGFR, mL/min/1.73 m2b,c <0.001 n 88 109 150 347 Mean (SD) 113.8 (26.9) 118.3 (20.0) 87.1 (29.0) 103.7 (29.7) Median (Q1, Q3) 112.4 (96.5, 133.2) 120.9 (109.9, 129.6) 93.1 (62.7, 110.7) 109.1 (85.7, 123.3) Range 48.9–171.1 35.6–163.4 23.2–145.2 23.2–171.1 Proteinuria, mg/dayd <0.001 n 62 73 116 251 Mean (SD) 120.6 (239.3) 295.2 (476.6) 801.9 (952.6) 486.3 (766.1) Median (Q1, Q3) 88.6 (27.0, 142.4) 140.0 (70.0, 220.0) 440.0 (200.0, 1002.5) 180.0 (96.0, 540.0) Range 0.0–1870.0 0.0–2450.0 0.0–4900.0 0.0–4900.0 LVMI, g/m2.7e <0.001 n 44 56 74 174 Mean (SD) 36.7 (7.9) 40.4 (11.0) 56.7 (16.0) 46.4 (15.6) Median (Q1, Q3) 34.9 (32.3, 38.4) 37.9 (33.1, 45.8) 55.6 (45.8, 67.9) 43.2 (34.3, 55.5) Range 22.0–61.0 19.2–76.9 25.8–96.6 19.2–96.6 Notes: aP value, comparing the mean values across the three cohorts, derived from analysis of variance; beGFR values were restricted to between >15 and ≤180 mL/min/ 1.73 m2, values outside this range were considered as missing; ceGFR was calculated using the Counahan-Barratt equation in patients <18 years of age and the Chronic Kidney Disease Epidemiology Collaboration equation in patients ≥18 years of age; dproteinuria values were restricted to between ≥0 and ≤5000 mg/day, values outside this range were considered as missing; eLVMI values were restricted to between >10 and ≤100 g/m2.7, values outside this range were considered as missing. Abbreviations: ACE, angiotensin-converting enzyme; CI, confidence interval; eGFR, estimated glomerular filtration rate; ERT, enzyme replacement therapy; FOS-MSSI, Fabry Outcome Survey-Mainz Severity Score Index; LVMI, left ventricular mass indexed to height; Q, quartile; SD, standard deviation. receiving agalsidase beta ERT found greater benefit from significant decline found with cohort 2 (eGFR slope –1.12), initiating ERT in younger patients with less severe renal which is consistent with the natural yearly decline of disease than in older patients with more severe renal dis- eGFR found in healthy individuals (–0.82 ± 0.22 for ease, in whom disease progression was observed.7 In con- those aged 20–30 years and –1.15 ± 0.12 mL/min/ trast, Beck et al reported a benefit of agalsidase alfa ERT 1.73 m2 per year for those aged >50 years).19 The slope even in male patients with the lowest eGFR values at for cohort 3, however, was more similar to that shown by baseline, as indicated by a slower decline in renal disease Arends et al for patients of approximately the same age.17 progression compared with untreated patients.16 Schiffmann et al reported the natural progression of Owing to the lack of a control group of untreated chronic kidney disease in untreated adult patients with patients, we cannot say with certainty to what extent the Fabry disease and showed that male patients with eGFR favorable slopes in cohorts 1 and 2 may depend on treat- ≥60 mL/min/1.73 m2 and a mean age of 27.3 years had ment. However, the effect of ERT on the natural progres- a rate of eGFR decline of 2.93 mL/min/1.73 m2 per year.18 sion of the disease is easily recognized if we compare the This group of male patients was of approximately the aforementioned findings with those of untreated patients. same age as this study’s cohort 2, in which patients In a 2017 article by Arends et al, the natural history of showed a much slower annual decline of eGFR with Fabry disease was studied in 596 patients from three a slope of –1.12 per year. Schiffman et al also reported European centers; 129 patients with available data were that in a group of patients who were of comparable age to male and had classical Fabry disease.17 The slope of linear this study’s cohort 3 and had progressed to end-stage renal regression reported for eGFR in these patients shows disease, the eGFR slope was –3.85; this contrasts with the a decline starting from 20 years of age; in comparison, eGFR slope of –2.60 observed in cohort 3 in the present the slopes of cohorts 1 and 2 observed in the present study study. Schiffman et al also reported in a subgroup of were fairly stable over the course of the follow-up period. untreated patients with higher proteinuria at baseline Our data analysis also indicated a numerically statistically a decline in eGFR of –6.9. submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2020:14 2153 DovePress 2154 Table 2 Mixed-Effects Linear Regression Analysisa Showing Mean Values of eGFR, Proteinuria, and LVMI for the Overall Follow-Up Period in Each Study Cohort, with a Comparison Parini et al Between the Cohorts Parameter Cohort 1 (≤18 Years) Cohort 2 (>18 and ≤30 Cohort 3 (>30 Years) Cohort 1 vs Cohort 2 Cohort 1 vs Cohort 3 Cohort 2 vs Cohort 3 DovePress Years) nb Mean (95% CI) nb Mean (95% CI) nb Mean (95% CI) Difference (95% CI) P Difference (95% P Difference P Valuec CI) Valuec (95% CI) Valuec eGFR, mL/ 55 117.9 (111.8 to 124.1) 84 114.1 (109.2 to 119.1) 117 79.9 (75.7 to 84.1) 3.8 (–4.1 to 11.7) 0.347 38.1 (30.6 to 45.5) <0.001 34.3 (27.8 to <0.001 min/1.73 m2 40.8) submit your manuscript | www.dovepress.com Proteinuria, 42 210.7 (1.1 to 420.3) 45 395.5 (194.4 to 596.6) 91 819.5 (678.4 to 960.7) –184.8 (–475.3 to 105.7) 0.212 –608.8 (–861.5 to – <0.001 –424.0 (–669.7 <0.001 mg/day 356.1) to –178.3) LVMI, g/m2.7 31 33.6 (29.5 to 37.7) 38 40.0 (36.3 to 43.7) 56 55.5 (52.4 to 58.5) –6.4 (–11.9 to –0.8) 0.024 –21.9 (–27.0 to – <0.001 –15.5 (–20.3 to <0.001 16.8) –10.7) Notes: aAnalysis performed only in patients with (1) a minimum of 3 years of receiving ERT, (2) nonmissing baseline data, (3) a minimum of 3 years of postbaseline data, (4) a minimum of three measurements, and (5) no renal dialysis and/ or transplant prior to ERT initiation; bnumbers at baseline; cP value (calculated using the Wald test) comparing overall mean values between cohorts. Abbreviations: CI, confidence interval; eGFR, estimated glomerular filtration rate; LVMI, left ventricular mass indexed to height. Table 3 Mixed-Effects Linear Regression Analysisa Showing Intercepts (Mean Values at Baseline) and Slopes (Mean Annual Rates of Change) for eGFR, Proteinuria, and LVMI for the Overall Follow-Up Period Parameter Cohort 1 (≤18 Years) Cohort 2 (>18 and ≤30 Years) Cohort 3 (>30 Years) nb Intercept (95% CI) Slope (95% CI) P nb Intercept (95% CI) Slope (95% P nb Intercept Slope (95% P Valuec CI) Valuec (95% CI) CI) Valuec eGFR, mL/min/ 55 116.2 (110.3 to 122.0) 0.44 (–0.42 to 1.30) 0.313 84 118.6 (113.8 to 123.3) –1.12 (–1.77 to <0.001 117 90.2 (86.2 to –2.60 (–3.16 to <0.001 1.73 m2 –0.47) 94.2) –2.04) Proteinuria, mg/ 42 164.8 (–25.9 to 355.6) 12.06 (–13.65 to 37.76) 0.358 45 339.7 (155.5 to 523.8) 14.68 (–7.18 to 0.188 91 689.8 (561.1 to 34.10 (18.48 to <0.001 day 36.54) 818.5) 49.71) LVMI, g/m2.7 31 34.2 (30.2 to 38.2) –0.17 (–0.66 to 0.31) 0.490 38 39.5 (35.9 to 43.2) 0.11 (–0.29 to 0.588 56 53.3 (50.3 to 0.59 (0.23 to 0.001 0.52) 56.3) 0.95) Notes: aAnalysis performed only in patients with (1) a minimum of 3 years of receiving ERT, (2) nonmissing baseline data, (3) a minimum of 3 years of postbaseline data, (4) a minimum of three measurements, and (5) no renal dialysis and/ or transplant prior to ERT initiation; bnumbers at baseline; cP value (calculated using the Wald test) evaluating significance in the annual rate of change within each cohort. Abbreviations: CI, confidence interval; eGFR, estimated glomerular filtration rate; LVMI, left ventricular mass indexed to height. Drug Design, Development and Therapy 2020:14 Dovepress Dovepress Parini et al Figure 1 Estimated regression lines for estimated glomerular filtration rate (eGFR) values over time according to age at enzyme replacement therapy (ERT) initiation. Figure 2 Estimated regression lines for proteinuria values over time according to age at enzyme replacement therapy (ERT) initiation. The current analysis found that in patients with the after 10 years in male patients who had proteinuria before most severe renal disease, the highest proteinuria was agalsidase alfa ERT initiation, whereas no significant observed at baseline and was consistently high throughout changes were seen in patients without baseline the follow-up period. In agreement with a previously proteinuria.20 reported age at onset of proteinuria of 34 ± 10 years,1 LVMI did not progress in cohorts 1 and 2 over the course of significant increases in annual rates of proteinuria were the follow-up period. Although in patients younger than found only in patients in cohort 3, whereas in patients who 30 years of age the prevalence of LVMI is known to be started ERT in childhood or early adulthood, no annual low,21 it is possible that ERT contributed to stabilizing LVMI changes of proteinuria were identified. Kampmann et al in cohorts 1 and 2. In cohort 3, there was evidence of significant reported a significant increase in urinary protein levels deterioration of LVMI over the course of the follow-up period. submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2020:14 2155 DovePress Parini et al Dovepress Figure 3 Estimated regression lines for left ventricular mass indexed to height (LVMI) values over time according to age at enzyme replacement therapy (ERT) initiation. Again, owing to the lack of an untreated control group, it is limited to a maximum of 10 years after ERT initiation, difficult to determine the effect of ERT. However, the slope some male patients in cohort 1 were still young and at an representing the linear regression curve of LVMI in untreated age where the effect of the disease on the heart and kidney is patients shown by Arends et al17 appears to be very different likely to be mild, even if untreated. Lastly, although further from that shown for cohorts 1 and 2 of this analysis in patients analysis of study participants according to phenotype/muta- of approximately the same age. Age at onset of LVH in tion would be informative, it was not practically feasible due untreated patients has been reported to be in the fourth to to a limited availability of genetic data. fifth decade for male patients and the sixth decade for female The current analysis shows that ERT is associated with patients;2,4 however, Wu et al reported LVH even in female attenuation of progressive Fabry disease–related renal and patients <20 years of age.22 Weidemann et al demonstrated cardiac disease in patients who started treatment between 18 progression of cardiac and renal disease in patients with and 30 years of age (cohort 2). Our data reasonably suggest advanced Fabry disease, despite treatment with agalsidase that this effect could be even more pronounced in cohort 1 alfa or beta.8 Germain et al reported that initiating agalsidase (patients starting ERT before 18 years of age), but, owing to beta ERT in male patients ≥40 years of age was associated with the well-known evolution of Fabry disease in the first 3 greater LVH progression compared with male patients ≤30 decades of life and to the lack of a control group, we cannot years of age.23 Kampmann et al found a significant reduction assert the finding. Older patients are generally expected to of LVMI in male patients with LVH at baseline after 1 year of have a worse prognosis in Fabry disease. It is thus true that ERT with agalsidase alfa, which was sustained over 10 years.20 cohort 3 included older patients compared to cohort 1 and There are limitations to these analyses to be considered. cohort 2 and may be at a more advanced disease stage, thus FOS is an observational registry and lacks a control group for reinforcing the idea of early starting treatment to achieve intraregistry data comparisons. Because patients are not ran- a slowing of disease progression. domly enrolled in disease registries, selection bias in favor of those individuals with worse disease may have been intro- Conclusion duced to the data evaluated in this study. Patient numbers in In a small cohort of patients with full sets of long- the three cohorts were relatively small, and some data were itudinal data, the current analysis shows that initiating unavailable for inclusion in the analyses, as is often the case ERT in childhood and young adulthood was associated in rare disease registries. All findings should be interpreted with greater attenuation of progressive Fabry disease– with caution owing to the large amount of missing values, related renal and cardiac disease compared with initiat- especially in cohort 3. Because the analysis period was ing ERT in later adulthood. These results add to and submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2020:14 2156 DovePress Dovepress Parini et al support the growing body of evidence indicating that a Takeda company, provided funding to Excel Medical Affairs greater clinical benefits may be obtained the earlier for support in writing and editing this manuscript. ERT is initiated. Author Contributions Abbreviations All authors contributed to data analysis, drafting or revising ACE, angiotensin-converting enzyme; ANOVA, analysis of the article, gave final approval of the version to be published, variance; CI, confidence interval; eGFR, estimated glomerular and agree to be accountable for all aspects of the work. filtration rate; ERT, enzyme replacement therapy; FOS, Fabry Outcome Survey; FOS-MSSI, Fabry Outcome Survey-Mainz Funding Severity Score Index; LVH, left ventricular hypertrophy; The Fabry Outcome Survey is sponsored by Shire Human LVMI, left ventricular mass indexed to height; Q, quartile. Genetic Therapies, Inc., a Takeda company. Shire International GmbH, a Takeda company, funded this Data Sharing Statement study, was involved in study design, the collection, analy- The datasets, including redacted study protocol, redacted sis, and interpretation of data, the writing of the report, and statistical analysis plan, and individual participants' data the decision to submit the article for publication. behind the results reported in this article, will be available three months after the submission of a request to https:// Disclosure www.shiretrials.com/en/our-commitment-to-transparency Dr Parini reports personal fees and clinical trial participa- /data-sharing-with-researchers by researchers who provide tion from Shire, a Takeda company, and personal fees from a methodologically sound proposal, after de-identification, BioMarin, Chiesi, Sanofi Genzyme, and Ultragenyx, outside in compliance with applicable privacy laws, data protec- the submitted work. Dr Pintos-Morrell reports personal fees tion and requirements for consent and anonymization. from Alexion, Amicus, BioMarin, Kyowa-Kirin, Sanofi Genzyme, and Shire, a Takeda company, outside the sub- Ethics Approval and Consent mitted work. Dr Hennermann reports grants and personal fees from Shire, a Takeda company, and personal fees from Statement Amicus, outside the submitted work. Dr Karabul reports FOS was approved by the ethics institutional review boards of grants and personal fees from Shire, a Takeda company, participating centers (Supplemental File). Further, this registry grants and personal fees from Sanofi Genzyme, and perso- was compliant with relevant global and local regulations and nal fees from BioMarin, outside the submitted work. Ms best practices. Good Pharmacoepidemiological Practice, Good Kalampoki is an employee of and reports stock ownership Research for Comparative Effectiveness principles, and the from Shire, a Takeda company, during the conduct of the relevant principles of the International Conference on study. Dr Gurevich was an employee of Shire, a Takeda Harmonisation Good Clinical Practice (ICH GCP) guidelines company, during the conduct of the study. Dr Ramaswami (ICH E6) were followed as appropriate for an observational reports personal fees and clinical trial participation from registry and consistent with the Declaration of Helsinki. All Amicus, clinical trial participation from Protalix; grants, participants or their caregivers gave written informed consent. personal fees, and clinical trial participation from Sanofi Genzyme; grants, personal fees, and clinical trial participa- Acknowledgments tion from Shire, a Takeda company; and personal fees from Dr Uma Ramaswami is the senior author of this study. The Actelion, Idorsi, and Chiesi, outside the submitted work. authors would like to thank Jaco Botha (Shire International The authors report no other conflicts of interest in this work. GmbH, a Takeda company) for his contribution to the initial statistical analyses, which was supported by Shire, a Takeda company. Under the direction of the authors, Latoya References 1. Branton MH, Schiffmann R, Sabnis SG, et al. Natural history of Fabry M. Mitchell, PhD, CMPP, and Tina Rose, MSc, both of renal disease: influence of alpha-galactosidase A activity and genetic Excel Medical Affairs, provided writing assistance for this mutations on clinical course. Medicine (Baltimore). 2002;81 manuscript. Editorial assistance in the form of formatting, (2):122–138. doi:10.1097/00005792-200203000-00003 2. Mehta A, Ricci R, Widmer U, et al. Fabry disease defined: baseline clinical proofreading, copy editing, and fact-checking also was pro- manifestations of 366 patients in the Fabry Outcome Survey. 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J Am Coll Cardiol. 1995;25 (5):1056–1062. doi:10.1016/0735-1097(94)00540-7 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. Submit your manuscript here: https://www.dovepress.com/drug-design-development-and-therapy-journal submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2020:14 2158 DovePress