Full text

Turn on search term navigation

1. Introduction

Fabry disease (FD) is a rare, X-linked lysosomal storage disease caused by variants in the α-galactosidase A gene (GLA) that result in deficient α-galactosidase A enzyme (α-Gal A) activity [1]. This deficiency results in the systemic accumulation of glycosphingolipids in lysosomes and leads to heterogeneous, progressive manifestations, including renal failure, cardiomyopathy, and cerebrovascular disease, together with a significant reduction in life expectancy [1,2,3,4]. The severe ‘classic’ FD phenotype presents with multisystemic involvement, whereas ‘non-classic’ or ‘late-onset’ FD phenotypes may be restricted to a single organ, usually the heart [5,6]. The rate of disease progression can vary substantially among patients [7].

Treatment for FD involves the replacement or augmentation of α-Gal A function. Several approved therapies are available, including enzyme replacement therapy (ERT) with agalsidase alfa [8], agalsidase beta [9,10], or more recently, pegunigalsidase alfa (a pegylated form of the α-Gal A enzyme) [11,12], and oral chaperone therapy with migalastat [13,14] for patients with amenable GLA variants. Beyond these therapies, research into the treatment of FD continues to advance, with several emerging therapies under investigation in clinical trials. These include gene therapy to address the genetic defect responsible for the α-Gal A deficiency, and substrate reduction therapy, a novel approach intended to modulate the metabolic pathways involved in glycosphingolipid synthesis [15,16].

The purpose of this systematic literature review (SLR) was to identify and summarize the literature relating to the clinical efficacy (based on clinical trial data) and real-world effectiveness (based on data from observational studies) of available and emerging treatments for FD. Specific topics of interest were the impact of treatment on cardiovascular, renal, cerebrovascular, and disease severity outcomes.

2. Methods

2.1. Search Strategy

The SLR search strategy and reporting was fully compliant with the 2020 Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines [17]. The protocol was prospectively registered in the International Prospective Register of Systematic Reviews in Health and Social Care (PROSPERO, ID number CRD42023394203) on 26 January 2023. Searches of MEDLINE (in-process and other non-indexed citations), EMBASE, and the Cochrane library databases were conducted on 28 November 2022 and repeated using the same criteria on 17 June 2024. Search strings are shown in Supplementary Table S1. The population of interest was patients with FD of any age, sex, race, or ethnicity who received any approved or experimental disease-specific treatment for FD. Searches were restricted to English but were not limited by year or region. Case reports were excluded. Proceedings from the following key congresses (from 2020 to 2024) were also searched for relevant abstracts and posters: the Lysosomal Diseases Gordon Research Conference (GRC), the Society for the Study of Inborn Errors of Metabolism (SSIEM) annual symposium, the We’re Organizing Research on Lysosomal Diseases (WORLD) symposium, the International Congress of Inborn Errors of Metabolism (ICIEM), and the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) annual conference.

2.2. Data Collection, Extraction, and Bias Assessment

Relevant abstracts and titles were identified by a single reviewer based on the criteria outlined in Supplementary Table S2. Articles meeting the inclusion criteria, or for which eligibility was unclear, were revisited for a full-text review by another single reviewer to confirm eligibility. Systematic reviews were included for full-text review to identify potentially relevant studies in their reference lists. Remaining uncertainties regarding eligibility were addressed by a separate reviewer. Relevant data from eligible publications were extracted to populate predefined summary tables, with all data being checked by a second reviewer. Extracted data included the study design, country, number of patients, baseline demographics, length of follow-up, treatment details, outcomes of interest (see below), funding information, and author conclusions. Publications were classified and summarized using the following categories: agalsidase alfa single-arm studies, agalsidase beta single-arm studies, mixed or non-specified ERT or other treatment single-arm studies, comparator studies, and studies examining the effects of switching between treatments (switch studies). For each included study, a risk of bias assessment was performed using the RoB2 tool for randomized trials, the Risk Of Bias In Non-randomized Studies—of Interventions (ROBINS-I) tool for non-randomized studies, or the Joanna Biggs Institute (JBI) critical appraisal checklist for systematic reviews and research synthesis (for meta-analyses).

2.3. Outcome Measures

The SLR strategy aimed to identify literature relating to the clinical efficacy and real-world effectiveness of different treatments for FD. Outcomes of interest were renal outcomes (glomerular filtration rate [GFR] and proteinuria); cardiovascular outcomes (left ventricular mass index [LVMI]/left ventricular mass [LVM] and other cardiac structure outcomes); cerebrovascular outcomes (white matter lesions [WMLs], stroke, transient ischemic attack [TIA], and other cerebrovascular outcomes); and the Mainz Severity Score Index (MSSI), a scoring system developed to measure the severity of general, neurological, cardiovascular, and renal signs and symptoms of FD. The SLR also identified safety outcomes data (adverse events and serious adverse events); these have not been included here owing to the heterogeneous nature of safety reporting across the included clinical studies.

3. Results

A flow diagram summarizing the search and screening process is presented in Figure 1. Overall, 1881 articles were identified from the electronic databases. An additional 20 relevant publications were identified in congress searches. After removing duplicates and non-eligible studies, 234 publications remained, covering a total of 225 studies. Most studies were real-world, observational studies (n = 150; 67%); the remaining studies were clinical trials (n = 71; 32%) and meta-analyses (n = 2; 1%). Geographically, study locations were wide-ranging, with the largest number conducted in Germany (n = 25) or across multiple countries (n = 70; Supplementary Figure S1). Most studies included only adults (n = 172; 74%). In studies that reported clinical outcomes, the number of included patients ranged from six [18,19] to 2051 [20]. Seven studies included over 500 patients [20,21,22,23,24,25,26]. The pharmaceutical industry funded 122 (54%) studies (41 studies were not industry funded; funding was not reported in the remaining 62 studies identified).

Overall, 187 studies included ERT with agalsidase alfa and/or agalsidase beta, 30 studies included treatment with migalastat, and 11 studies included second-generation ERT with pegunigalsidase alfa. Of the publications on single-arm studies (i.e., those without a comparator arm), 37 investigated the effects of agalsidase alfa, and 25 examined the effects of agalsidase beta. In addition, 23 publications examined mixed or non-specified ERT and 21 examined other treatments (including second-generation ERT) in single-arm studies. Overall, 32 publications compared various treatment regimens with each other or with untreated or placebo-treated patients. Only three studies compared the effects of agalsidase alfa and agalsidase beta [27,28,29]. In total, 20 publications examined the effects of switching between different treatments; this excluded investigations in which the effects of the switch were not reported as outcomes [30,31,32,33,34,35,36,37]. A summary of the risk of bias assessments is shown in Supplementary Table S3. Studies reported in congress publications were more likely to have a high risk of bias or lack information than studies reported in journal articles.

3.1. Renal Outcomes

FD causes glycosphingolipid accumulation and damage throughout the glomerular, vascular, and interstitial compartments of the kidney, resulting in progressive decline in kidney function and increased proteinuria [38]. Publications reporting GFR outcomes (reported as GFR, estimated GFR [eGFR], or measured GFR) presented data from single-arm studies of agalsidase alfa (n = 29) [26,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66], agalsidase beta (n = 19) [23,30,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83], mixed or non-specified ERT (n = 13) [31,35,36,84,85,86,87,88,89,90,91,92,93], other treatments (n = 18) [94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111], comparator studies (n = 21) [27,28,29,33,108,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127], and switch studies (n = 13) [128,129,130,131,132,133,134,135,136,137,138,139,140]. An overview of the GFR outcome data from agalsidase alfa and agalsidase beta single-arm studies and the comparator studies is presented in Table 1. Key results from the other types of studies are provided in Supplementary Table S4.

Treatment duration in the identified agalsidase alfa single-arm studies ranged from 26 weeks [51] to 20 years [40] (Table 1A). In 16 studies with follow-up durations of less than 5 years, treatment with agalsidase alfa demonstrated a renoprotective effect, stabilizing renal function (i.e., no statistically significant change in eGFR over the follow-up period) [39,44,46,48,49,50,51,54,56,58,59,60,61,62,63,64,65,66]. In 10 longer-term studies (>5 years), mixed results were reported [26,40,42,43,45,47,52,53,55,57]. In a retrospective, observational study, eGFR values remained stable over 10 years of treatment [47]. In a 10-year, prospective clinical study, weekly infusions of agalsidase alfa at a dose of 0.2 mg/kg were found to be beneficial for patients whose kidney function had declined with standard every-other-week dosing [53,57]. However, this study included small numbers of patients (n = 12). In two larger Fabry Outcome Survey (FOS) studies (n > 150), with longer follow-up periods (median treatment duration ≥ 12 years), agalsidase alfa treatment stabilized eGFR in patients with preserved kidney function (eGFR ≥ 60 mL/min/1.73 m2) or low proteinuria (≤0.5 g/24 h) at baseline [42,43]. In contrast, patients with impaired renal function (eGFR < 60 mL/min/1.73 m2) or high proteinuria (>0.5 g/24 h) at baseline continued to show declines in eGFR during treatment, although these declines were less than expected based on FD natural history data [42,43]. In a large, retrospective cohort study (n = 560) with a mean treatment duration of 7.6 years, patients who initiated agalsidase alfa treatment after 18 and 30 years of age had significant annual declines in mean (95% confidence interval [CI]) eGFR over the follow-up period (−1.12 [−1.77, −0.47] and −2.60 [−3.16, −2.04] mL/min/1.73 m2, respectively), whereas those who initiated treatment in childhood (≤18 years old) did not have significant annual changes in mean eGFR (−0.44 [−0.42, 1.30] mL/min/1.73 m2) [26]. In the longest agalsidase alfa study reported (in a congress publication), which included 66 patients from the FOS registry who had received agalsidase alfa for at least 19 years, the mean (standard deviation [SD]) annual rate of eGFR decline was −2.04 (0.36) mL/min/1.73 m2 (n = 48) [40].

Treatment duration in single-arm studies of agalsidase beta reporting GFR outcomes ranged from 22.7 months [68] to 10 years [82] (Table 1A). In total, 17of 19 identified studies reported a stabilizing effect of agalsidase beta on kidney function [23,30,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83], which varied based on factors, such as baseline GFR (based on clearance of 93Technetium DTPA [68] and eGFR [72]) and level of renal involvement [23,70,82]. In a long-term analysis (median treatment duration: 10 years) of patients with classic FD who participated in a phase 3 clinical trial of agalsidase beta, its extension study, and the Fabry Registry (n = 52), patients with low renal involvement at baseline (urine protein-to-creatinine ratio [UPCR] ≤ 0.5 g/g and <50% sclerotic glomeruli on kidney biopsy) had a mean annual eGFR decline of −1.89 mL/min/1.73 m2 [82]. In contrast, those with high renal involvement (UPCR > 0.5 g/g or ≥50% sclerotic glomeruli on kidney biopsy) had a mean annual eGFR decline of −6.82 mL/min/1.73 m2 despite treatment [82]. In patients from the Fabry Registry who initiated agalsidase beta treatment at a young age (5–30 years old; median follow-up: ≥5 years), annual eGFR decline was modest for both males (−1.18 mL/min/1.73 m2; n = 117) and females (−0.92 mL/min/1.73 m2; n = 59) with low renal involvement (UPCR ≤ 0.5 g/g or urine albumin-to-creatinine ratio [UACR] ≤ 0.3 g/g) at baseline, whereas males with high renal involvement (UPCR > 0.5 g/g or UACR > 0.3 g/g) showed a greater annual decline in eGFR (−2.39 mL/min/1.73 m2; n = 23) [23].

Single-arm studies evaluating mixed or non-specified ERT also demonstrated the importance of early initiation of ERT for better long-term renal outcomes (Supplementary Table S4). In a retrospective cohort of adults receiving ERT (n = 293; median follow-up: 6.8 years), those with lower eGFR at baseline had an increased risk of having a first renal event (hazard ratio [per −10 mL/min/1.73 m2]: 5.57, p = 0.02) [31]. In single-arm studies of other treatments, 12 studies (13 publications) specifically evaluated the effects of migalastat [14,97,98,99,100,101,103,104,105,106,108,109,110], four examined second-generation ERT with pegunigalsidase alfa [94,95,96,107], and one explored the effects of a lentivirus-mediated gene therapy [102] on eGFR in patients with FD. Renal function remained stable in most migalastat studies (follow-up periods ranged from 6 months to 7 years) [98,99,100,101,105,106,108,110,111]. In a prospective, observational study of migalastat treatment over 24 months (n = 59), mean (SD) eGFR significantly decreased from 98.6 (15.2) to 90.4 (14.7) mL/min/1.73 m2 (p = 0.0317) in females and from 99.8 (22.6) to 92.4 (24.0) mL/min/1.73 m2 (p = 0.0028) in males [103,104]. In the four studies that examined the effects of pegunigalsidase alfa (n = 15–30), eGFR remained stable over follow-up periods of 3 to 72 months [94,95,96,107]. In the single study of lentivirus-mediated gene therapy, five patients were infused with autologous lentivirus-transduced, CD34+-selected, hematopoietic stem/progenitor cells engineered to express α-Gal A [102]. Patients had a transient increase in eGFR during the active treatment phase, although eGFR returned to baseline levels and remained stable after gene therapy (follow up: 12–33 months), except for one patient who displayed progressive chronic kidney disease with significant proteinuria at baseline [102].

In total, 12 studies reporting on GFR outcomes compared active treatments with no treatment or placebo [33,108,112,114,115,116,117,120,121,122,123,124,126], 10 studies directly compared different active treatments [27,28,29,108,113,114,115,119,122,125,127] (two studies included active comparator groups and untreated groups [112,114]), and two compared different doses of the same treatment [33,118] (Table 1B). Overall, studies that included patients who received no treatment or placebo indicated that approved treatments for FD generally resulted in stabilization of GFR outcomes, although study designs, patient populations, and follow-up times varied considerably. In a comparison of FOS registry data (n = 740; median treatment duration: 5.4 years) and published findings for untreated patients with FD, treatment with agalsidase alfa slowed eGFR decline in male patients with low eGFR (<60 mL/min/1.73 m2) at baseline [112]. A stabilizing effect of ERT on eGFR was also observed in patients with FD following kidney transplantation [113,114,115]. Three studies (two cohort studies and one randomized controlled open-label trial) directly compared agalsidase alfa and agalsidase beta with respect to effects on eGFR; no significant differences between the two treatments were identified [27,28,29]. In the largest of these studies, there was no significant difference in the slope of eGFR between patients treated with agalsidase alfa (n = 248) or agalsidase beta (n = 139) over a median follow-up period of 4.9 years. This finding was seen regardless of baseline eGFR (≥60 or <60 mL/min/1.73 m2) and after adjusting for additional factors including sex, phenotype, and baseline proteinuria [29]. In the phase 3 BALANCE trial, pegunigalsidase alfa showed noninferiority to agalsidase beta based on the rate of eGFR decline over 24 months in adults with deteriorating renal function at baseline (linear eGFR slope more negative than −2 mL/min/1.73 m2/year; n = 52) [127].

Ten studies (17 publications) assessed the effects of switching from one FD treatment to another on GFR outcomes (Supplementary Table S4), of which six studies (seven publications) focused on patients switching from agalsidase beta to agalsidase alfa following an agalsidase beta supply shortage from June 2009 to January 2012 [128,131,132,133,136,137,138]. Four studies showed mild deterioration in eGFR after switching from the standard dosing of agalsidase beta to agalsidase alfa (n = 22–38) [131,132,133,138]. However, all of these studies were observational and nonrandomized; therefore, treatment groups were not homogeneous. Two other studies demonstrated maintenance of eGFR in patients following the switch from agalsidase beta to agalsidase alfa (n = 71 and 11) [128,136,137]. In the phase 3 BRIDGE trial (n = 20), pegunigalsidase alfa slowed progression of kidney disease (mean eGFR slope was −5.90 mL/min/1.73 m2/year with agalsidase alfa compared with −1.19 mL/min/1.73 m2/year 12 months after switching to pegunigalsidase alfa) [139]. The small number of patients means the data could be influenced by a few patients. There was no difference in GFR outcomes in studies in which patients were switched from ERT to migalastat [129,130,134,135,140].

Identified studies reporting on proteinuria in patients receiving FD treatments (42 studies in 44 publications) are shown in Supplementary Table S5. Overall, the majority of studies showed little to no effect of treatment on proteinuria in patients with FD, although improvements in at least one proteinuria outcome were reported in four out of the six studies in children [33,51,76,81]. However, supportive treatment with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) is standard practice for any patient with proteinuric kidney disease, and has been shown to provide sustained reductions in proteinuria and stabilization of kidney function in a small study of patients with severe FD [79]. The differing use of supportive treatments with ACEi and ARB may have affected the results from other studies and cannot be independently assessed. The additional effect of sodium-glucose co-transporter-2 inhibitors combined with ERT on proteinuria and renal outcomes in FD remains to be established.

Table 1

Overview of GFR data from (A) single-arm agalsidase alfa or agalsidase beta studies and (B) comparator studies.

(A)
Author YearStudy Identifier N Treatment Duration Key Results
Agalsidase alfa single-arm studies
Beck 2004 [39]FOS 150 Mean [max]: 17 [56] months

Observational study using data from FOS

In patients with a baseline GFR between 60 and 90 mL/min/1.73 m2 (n = 104), GFR was stable following 1 year (n = 57) and 2 years (n = 30) of treatment

Patients with a baseline GFR between 30 and 60 mL/min/1.73 m2 (n = 46) also had stable GFR at 1 year (n = 26) and 2 years (n = 18) of treatment
Cybulla 2022 [43]FOS 193 Mean/median (SD) [range]: 12.6/11.9 (5.0) [5.0, 21.6] years

Observational study using male patient data from FOS

eGFR (mL/min/1.73 m2)

◦. Low proteinuria (n = 114): intercept (SE), 9.67 (4.00); slope (SE), −1.61 (0.28); p < 0.0001

◦. High proteinuria (n = 51): intercept (SE), 4.15 (3.69); slope (SE), −3.62 (0.42); p < 0.0001

◦. p (high vs. low proteinuria) < 0.0001
Feriozzi 2009 [44]FOS 165 3 years

Observational study using data from FOS

eGFR remained stable in men with stage III disease; in those with stage I or II renal disease, there was a small but significant decrease in eGFR (p < 0.01)

The mean decrease in eGFR in all male patients (n = 115) was 2.66 ± 5.07 mL/min/1.73 m2/year

The decline in eGFR (SD) was numerically larger in patients with urine protein levels > 500 mg/24 h (n = 14) −3.98 (7.86) mL/min/1.732/year than in patients with urine protein levels <500 mg/24 h (n = 40) −1.68 (3.59) mL/min/1.732/year
Feriozzi 2012 [45]FOS 208 Mean [range]: 7.4 [5.0, 11.2] years

Observational study using data from FOS

Mean (95% CI) yearly change in eGFR was −2.2 (−2.8, −1.7) mL/min/1.73 m2 in men (n = 134) and −0.7 (−1.4, 0.0) mL/min/1.73 m2 in women (n = 74)
Giugliani 2023 * [40]FOS 66 Median [IQR]: 20.03 [19.55, 20.64] years

Observational study using data from FOS

Baseline eGFR: 99.35 (27.07) mL/min/1.73 m2

Annual rate of change: mean (SE), −2.04 (0.36) mL/min/1.73 m2 (n = 48)

Mean reduction: males (n = 38), −2.27 mL/min/1.73 m2; females (n = 10), −1.24 mL/min/1.73 m2

Statistical significance values not reported
Goker-Alpan 2016 [46] 14 Median [range]: 54.5 [54.0, 59.0] weeks

An open-label trial of agalsidase alfa in children

Mean (95% CI) change from baseline at week 55 of 0.15 (−11.39, 11.70) mL/min/1.73 m2 (median, 0.72 [−27.5, 35.9] mL/min/1.73 m2)
Hughes 2011 [48]FOS 250 ≥4 years

Observational study using data from FOS

Median [10–90th percentile] eGFR (MDRD) at baseline (mL/min/1.73 m2): women, 71.8 [56.5–87.6]; men, 88.2 [41.1–137.0]

Median [10–90th percentile] eGFR (MDRD) at 4 years (mL/min/1.73 m2): women (n = 41), 69.6 [44.8–91.1], p = 0.007 vs. baseline;

men (n = 105), 80.3 [34.2–119.7], p < 0.001 vs. baseline
Kampmann 2015 [47] 45 Median [range]: 10.8 [9.6, 12.5] years

Single-center observational study in Germany

Among patients (8 males, 5 females) with pretreatment eGFR ≥ 90 mL/min/1.73 m2, the mean annual decline in eGFR over 10 years was not statistically significant

In patients with poorer renal function (10 males, 11 females), eGFR seemed to improve in the first 3 years of ERT

After 10 years, however, eGFR values were not significantly changed regardless of renal function before ERT
Kleinert 2006 [64]FOS 60 >2 years

Observational study using data from FOS

Median [10th–90th percentile] eGFR (mL/min/1.73 m2): baseline: 88 [49–126] (n = 54); 1 year: 86; 2 years: 84
Mehta 2009 [65]FOS 181 Mean (SD): 3.1 (2.1) years

Observational study using data from FOS

All patients: mean (SD) eGFR (mL/min/1.73 m2)

◦. Year 1 (n = 121); baseline: 85.46 (29.21); year-end: 82.31 (29.12); change: −3.15 (13.01); annualized: −3.15; p = 0.01

◦. Year 2 (n = 143); baseline: 86.17 (27.65); year-end: 79.03 (29.47); change: −7.14 (16.82); annualized: −3.57; p = 0.001

◦. Year 3 (n = 137); baseline: 87.51 (28.63); year-end: 76.77 (27.01); change: −10.74 (14.91); annualized: −3.58; p = 0.001

◦. Year 5 (n = 150); baseline: 87.04 (28.80); year-end: 74.75 (28.65); change: −12.29 (18.40); annualized: −2.46; p = 0.001

Men: mean (SD) eGFR (mL/min/1.73 m2)

◦. Year 1 (n = 80); baseline: 94.02 (30.56); year-end: 90.30 (31.02); change: −3.72 (14.84); annualized: −3.72; p = 0.028

◦. Year 2 (n = 99); baseline: 93.23 (28.37); year-end: 85.58 (31.60); change: −7.65 (19.05); annualized: −3.83; p = 0.0001

◦. Year 3 (n = 92); baseline: 96.26 (29.01); year-end: 82.65 (27.91); change: −13.61 (14.66); annualized: −4.54; p < 0.0001

◦. Year 5 (n = 103); baseline: 94.71 (29.77); year-end: 78.84 (31.08); change: −15.87 (20.04); annualized: −3.17; p < 0.0001

Women: mean (SD) eGFR (mL/min/1.73 m2)

◦. Year 1 (n = 41); baseline: 68.76 (16.81); year-end: 66.71 (16.33); change: −2.05 (8.45); annualized: −2.05; p = NS

◦. Year 2 (n = 44); baseline: 70.28 (17.81); year-end: 64.30 (16.46); change: −5.98 (10.27); annualized: −2.99; p = 0.0004

◦. Year 3 (n = 45); baseline: 69.61 (17.49); year-end: 64.74 (20.59); change: −4.87 (13.80); annualized: −1.62; p = 0.02

◦. Year 5 (n = 47); baseline: 70.23 (17.37); year-end: 65.80 (19.96); change: −4.44 (10.72); annualized: −0.89; p = 0.007

Hyperfiltration (≥130 mL/min/1.73 m2): mean (SD) eGFR (mL/min/1.73 m2)

◦. Year 1 (n = 11); baseline: 144.49 (13.40); year-end: 131.13 (21.61); change: −13.35; annualized: −13.35; p = 0.05

◦. Year 2 (n = 12); baseline: 139.64 (8.75); year-end: 118.04 (43.46); change: −21.60; annualized: −10.80; p = NS

◦. Year 3 (n = 13); baseline: 142.47 (13.19); year-end: 114.36 (16.56); change: −28.11; annualized: −9.37; p = 0.001

◦. Year 5 (n = 14); baseline: 143.50 (13.25); year-end: 108.07 (20.26); change: −35.43; annualized: −7.09; p = 0.001

CKD Stage 1 (90–129 mL/min/1.73 m2): mean (SD) eGFR (mL/min/1.73 m2)

◦. Year 1 (n = 35); baseline: 107.06 (11.15); year-end: 103.94 (18.37); change: −3.12; annualized: −3.12; p = NS

◦. Year 2 (n = 47); baseline: 106.89 (10.34); year-end: 99.06 (19.38); change: −7.83; annualized: −3.91; p = 0.01

◦. Year 3 (n = 45); baseline: 107.63 (10.34); year-end: 95.37 (19.49); change: −12.26; annualized: −4.09; p = 0.001

◦. Year 5 (n = 48); baseline: 107.06 (10.30); year-end: 93.93 (23.48); change: −13.13; annualized: −2.63; p = 0.001

CKD Stage 2 (60–89 mL/min/1.73 m2): mean (SD) eGFR (mL/min/1.73 m2)

◦. Year 1 (n = 55); baseline: 73.61 (8.59); year-end: 72.21 (12.32); change: −1.39; annualized: −1.39; p = NS

◦. Year 2 (n = 60); baseline: 74.16 (8.73); year-end: 69.33 (14.03); change: −4.83; annualized: −2.41; p = 0.001

◦. Year 3 (n = 58); baseline: 73.25 (8.54); year-end: 66.84 (13.71); change: −6.40; annualized: −2.13; p = 0.001

◦. Year 5 (n = 64); baseline: 73.98 (8.74); year-end: 66.33 (17.26); change: −7.64; annualized: −1.53; p = 0.001

CKD Stage 3 (30–59 mL/min/1.73 m2): mean (SD) eGFR (mL/min/1.73 m2)

◦. Year 1 (n = 19); baseline: 48.78 (8.23); year-end: 45.92 (9.88); change: −2.87; annualized: −2.87; p = 0.05

◦. Year 2 (n = 23); baseline: 49.76 (7.93); year-end: 45.23 (9.82); change: −4.54; annualized: −2.27; p = 0.01

◦. Year 3 (n = 21); baseline: 49.77 (8.31); year-end: 41.07 (10.19); change: −8.70; annualized: −2.90; p = 0.001

◦. Year 5 (n = 23); baseline: 49.76 (7.93); year-end: 39.53 (14.50); change: −10.23; annualized: −2.05; p = 0.001

CKD Stage 4 (15–29 mL/min/1.73 m2): mean (SD) eGFR (mL/min/1.73 m2)

◦. Year 1 (n = 1); baseline: 28.78; year-end: 34.60; change: +5.81; annualized: +5.81; p = NA

◦. Year 2 (n = 1); baseline: 28.78; year-end: 29.29; change: +0.50; annualized: +0.25; p = NA

◦. Year 3 (n = 0); data: NR

◦. Year 5 (n = 1); baseline: 28.78; year-end: 37.05; change: +8.27; annualized: +1.65; p = NA
Parini 2020 [26]FOS 560 Mean (SD): 7.6 (4.8) years

Observational study using data from FOS

Overall mean eGFR (mL/min/1.73 m2): cohort 1: ≤18 years, 117.9; cohort 2: 18–30 years, 114.1; cohort 3: >30 years, 79.9

Changes during follow-up

◦. Cohort 1: ≤ 18 years; no significant annual changes in eGFR slope (95% CI) −0.44 mL/min/1.73 m2 (−0.42, 1.30) proteinuria was observed throughout the follow-up period

◦. Cohort 2: 18–30 years; although proteinuria remained stable, eGFR showed a significant annual decline over the follow-up period: eGFR slope (95% CI), −1.12 mL/min/1.73 m2 (−1.77, −0.47; p < 0.001)

◦. Cohort 3: >30 years; a significant annual deterioration over the follow-up period was shown for eGFR (slope (95% CI), −2.60 mL/min/1.73 m2 (−3.16, −2.04; p < 0.001)
Pastores 2007 [49] 22 Median [range]: 42 [11, 65] weeks

A phase 2, multi-center, open-label study

Patients with FD and ESRD undergoing dialysis or who had a history of kidney transplantations were treated with agalsidase alfa

After 26 weeks of agalsidase alfa therapy, mean (SEM) eGFR increased slightly to 71.6 (8.0) mL/min/1.73 m2 (n = 10) from 64.5 (6.0) mL/min/1.73 m2 (n = 12), which approached statistical significance in this relatively small cohort of patients (p = 0.07)
Pintos-Morell 2023 [41]FOS 285 Mean (SD): Early initiators group: 11.2 (5.7) years; Late initiators group: 11.8 (5.8) years

Observational study using data from FOS

Rates of annual eGFR change; mean (SE)

◦. Early-initiators (<25 years at treatment start) group (n = 40): −1.45 (0.52) mL/min/1.73 m2/year; p = 0.0054

◦. Late-initiators (≥25 years at treatment start) group (n = 103): −2.84 (0.32) mL/min/1.73 m2/year; p < 0.0001

The rate of eGFR change was significantly slower in the early initiators compared with the late initiators group; p = 0.0234
Ramaswami 2011 [50]FOS 8 Mean (SD): 4.2 (1.9) years

Observational study in children using data from FOS

Study of patients in the FOS registry who received their first dose of agalsidase alfa before reaching the age of 7 years

Mean (SD) baseline eGFR (mL/min/1.73 m2): 124.4 (25.7); final eGFR, 112.7 (21.79)
Ramaswami 2012 [66]FOS 98 ≥6 months

Observational study in pediatric patients (<18 years old) using data from FOS

Mean (SD) eGFR at baseline and 12 months (n = 40): 96.8 (26.5) and 94.2 (21.2) mL/min/1.73 m2

Mean (SD) eGFR at baseline and 24 months (n = 45): 93.2 (26.1) and 92.5 (25.2) mL/min/1.73 m2
Ramaswami 2019 [42]FOS 152 Median [range]: Evaluable treated renal cohort (n = 152) 13.3 [10.1, 18.4] years;Females (n = 62) 12.5 [10.1, 17.1] years;Males (n = 90): 14.4 [10.1, 18.4] years

Observational study in children using data from FOS

Pediatric patients who had received agalsidase alfa ERT over a 10-year period

Mean (SD) baseline eGFR (mL/min/1.73 m2): evaluable treated renal cohort, 89.04 (26.49)

Number of patients (%) in eGFR category <60 mL/min/1.73 m2: evaluable treated renal cohort, 21/152 (13.8%)

Mean [95% CI] eGFR at year 10 (mL/min/1.73 m2): females 79.1 [74.1, 84.0]; males 77.5 [70.1, 84.9]

Mean [95% CI] eGFR slope in patients in eGFR category ≥ 60 mL/min/1.73 m2 at baseline: females (n = 52), −0.55 [−1.12, 0.01]; males (n = 79), −1.99 [−2.45, −1.54]

Mean [95% CI] eGFR slope in patients in eGFR category <60 mL/min/1.73 m2 at baseline: females (n = 10), −0.14 [−1.43, 1.15]; males (n = 11), −2.79 [−4.01, −1.56]
Ries 2006 [51] 24 26 weeks

Open-label study in pediatric patients

Study in pediatric patients with FD (between 6.5 and 18 years of age) naive to ERT

Mean (SEM) baseline eGFR was 121 (5.0) mL/min/1.73 m2

7 patients had eGFR > 135 mL/1.73 m2

2 patients showed evidence of kidney dysfunction defined as eGFR between 60 and 89 mL/min/1.73 m2

Mean (SEM) eGFR did not change significantly during the treatment (mL/min/1.73 m2): 9 weeks, 119.2 (3.6); 17 weeks, 120.0 (3.9); and 26 weeks, 116.0 (3.9)

The eGFR of patients with possible hyperfiltration (eGFR > 135 mL/min/1.73 m2) returned to the reference range
Sasa 2019 [52] 493 Mean [range]:3.5 [0.0, 7.9] years;<0.5: (n = 35);>0.5–1: (n = 31);>1–2: (n = 48);>2–3: (n = 69);>3–4: (n = 86);>4–5: (n = 132);>5–6: (n = 55);>6–7: (n = 20);>7–8: (n = 17)

A post-marketing surveillance study in Japan

Mean (SD) yearly change in eGFR (mL/min/1.73 m2)

◦. Males (classic phenotype): year 0.5, 1.00 (p = 0.619); year 1, −1.03

(p = 0.289); year 2, −1.79 (p = 0.002); year 3, −2.09 (p = 0.001); year 4, −2.04 (p = 0.000); year 5, −2.50 (p = 0.000); year 6, −2.88 (p = 0.124); year 7, −0.44 (p = 0.814)

◦. Males (non-typical variant): year 0.5, −1.17 (p = 0.718); year 1, −1.24

(p = 0.544); year 2, −1.73 (p = 0.103); year 3, −2.04 (p = 0.028); year 4, −1.47 (p = 0.057); year 5, −0.95 (p = 0.447); year 6, −1.54 (p = 0.084); year 7, NR

◦. Females: year 0.5, −1.81 (p = 0.328); year 1, −1.61 (p = 0.059); year 2, −1.44 (p = 0.008); year 3, −1.02 (p = 0.020); year 4, −1.10 (p = 0.028); year 5, −1.89 (p = 0.009); year 6, −1.95 (p = 0.021); year 7, −2.64 (p = 0.078)
Schiffmann 2006 [54] 25 ≤54 months

Open-label extension study for male patients

Assessment of long-term renal effects and practicality of home infusions of agalsidase alfa

Data reported for 24/25 patients: 12 had stage I renal disease (eGFR, ≥ 90 mL/min/1.73 m2) at baseline, 8 had stage II (eGFR, 60–89 mL/min/1.73 m2), and 4 had stage III (GFR, 30–59 mL/min/1.73 m2) renal disease

Overall population: after 48 months, eGFR declined to 75.1 (32.7) mL/min/1.73 m2, p = 0.039 vs. baseline, mostly owing to changes in patients with stage 3 CKD
Schiffmann 2007 [53], Schiffmann 2015 [57] 12 ≤10 years

Open-label single-center study in the US

Long-term prospective clinical trial assessing the effects of EOW versus weekly agalsidase alfa infusions in patients who experienced ongoing decline in renal function of EOW dosing

Before therapy with agalsidase alfa, mean (SD) eGFR was 77.8 (30.4) mL/min/1.73 m2

During EOW dosing, the mean (SD) rate of change of eGFR was −8.0 (2.8) mL/min/1.73 m2/year (−0.67 (0.23) mL/min/1.73 m2/month)

During 2 years of weekly dosing (following EOW dosing), the mean rate of change of eGFR slowed to −3.3 ± 4.7 mL/min/1.73 m2/year (−0.27 ± 0.40 mL/min/1.73 m2/month); p = 0.01

After 10 years of follow-up, mean (SD) slope on agalsidase alfa every 2 weeks was −7.92 (2.88) and 3.84 (4.08) mL/min/1.73 m2/year on weekly enzyme infusions (p = 0.01)
Schiffmann 2013 [56] 73 12 months

Data pooled from three randomized, double-blind, placebo-controlled trials and their open-label extension studies

25 patients had stage II/III renal disease (baseline eGFR 30–90 mL/min/1.73 m2

Mean (SD) eGFR at baseline was 92.6 (32.4) mL/min/1.73 m2 and remained stable at 92.1 (32.4) at 12 months
Schiffmann 2014 [55] 17 Mean (SD):6.5 (0.6) years

Open-label multi-center extension study for pediatric patients

Evaluating safety and efficacy of long-term agalsidase alfa ERT in children with FD

Pediatric patients with FD (7–17 years of age at study enrollment) received agalsidase alfa

Mean (SD) baseline eGFR was 123.29 (16.00) mL/min/1.73 m2

Most individuals showed relatively stable eGFR over time
Schwarting 2006 [58]FOS 20 2 years

Observational study using data from FOS

eGFR (mL/min/1.73 m2), median [10th–90th percentile]

◦. Baseline: CKD stage 2 (n = 12), 70 [63–83]; CKD stage 3 (n = 8), 47

[35–55]

Renal function in 12 patients (10 females and 2 males; mean age: 40 years; range: 19, 71 years) with baseline CKD stage 2 declined significantly

(p < 0.05) in the year before treatment began

Renal function in 8 patients (4 females and 4 males; mean age: 49 years; range: 29, 69 years) with CKD Stage 3 also declined in the year before the start of treatment, but this change was not significant

After 1 year of treatment, however, the progressive loss of GFR had been stabilized in both groups of patients

Renal function remained stable in 8 patients with CKD stage 2 and in 5 patients with CKD stage 3 studied for 2 years after the start of ERT
Schwarting 2006b [59]FOS 401 >2 years (n = 219) >3 years(n = 133)

Observational study using data from FOS

Mean, median [range] eGFR (mL/min/1.73 m2)

◦. Patients given 1 year of therapy with agalsidase alfa

-. Female (n = 52): baseline: 66.8, 66.7 [32.0, 89.5]; year 1: 65.2, 64.5 [29.3, 87.4]

-. Male (n = 47): baseline: 66.0, 68.3 [38.4, 89.5]; year 1: 63.2, 61.7 [26.1, 113.0]

◦. Patients given 2 years of therapy with agalsidase alfa

-. Female (n = 34): baseline: 65.6, 64.3 [32.0, 89.5]; year 2: 63.1, 63.5 [30.0, 97.7]

-. Male (n = 28): baseline: 69.4, 73.1 [39.4, 89.5]; year 2: 63.3, 63.0 [12.8, 92.4]

◦. Patients given 3 years of therapy with agalsidase alfa

-. Female (n = 13): baseline: 68.4, 64.2 [47.6, 89.5]; year 3: 66.3, 65.6 [48.9, 88.2]

-. Male (n = 12): baseline: 65.6, 69.3 [38.4, 84.5]; year 3: 60.6, 62.4 [23.9, 91.2]
Thofehrn 2009 [60] 9 36 months (n = 6)18 months (n = 2)12 months (n = 1)

Single-center observational study in Brazil

Mean (SD) [range] GFR (mL/min/1.73 m2)

◦. Baseline (n = 8): 110.30 (28.68) (1 patient progressed to ESRD and underwent transplant, excluded from analysis of renal function)

◦. 12 months (n = 8): 114.78 (33.92)

◦. 24 months (n = 5): 104.38 (35.66)

◦. 36 months (n = 5): 122.61 (46.85)

No significant (p > 0.05) differences were found
Tsuboi 2017 [61]Japan Fabry Research—002 36 Median [range]: 62.5 [8, 84] months

Prospective observational study in Japan

Cohort included ERT treatment-naive patients and those who were receiving agalsidase alfa 0.2 mg/kg EOW

Mean (SD) baseline eGFR: 83.5 (28.6); after follow-up: 82.6 (29.4) mL/min/1.73 m2
West 2009 [62] 108 Mean, median (SD):2.0, 1.6 (1.0) yearsMean (SD) treatment years by baseline GFR range (mL/min/1.73 m2)≥135 (n = 8): 1.2 (0.2);90 to <135(n = 33): 2.0 (1.0);60 to <90(n = 36): 2.2 (1.2);30 to <60(n = 14): 2.1 (0.9)15 to <30(n = 2): 1.0

Summary of 3 prospective, randomized, placebo-controlled trials and their open-label extension studies

Mean (SD) [median; range] GFR (mL/min/1.73 m2):

◦. Baseline before placebo: 88.9 (32.5) [92.3; 12.7, 160]

◦. After 6 months of placebo: 85.0 (37.6) [83.3; 12.5, 184]

◦. Mean (SD) annualized rate of change in GFR: −7.7 (38.0) mL/min/1.73 m2/year; p = 0.14

3 patients had renal hyperfiltration (i.e., baseline GFR > 135 mL/min/1.73m2)

When these 3 patients were removed from the analysis of the placebo period:

◦. Mean (SD) GFR at baseline before placebo (mL/min/1.73 m2): 85.4 (29.6)

◦. Mean (SD) GFR after 6 months of placebo (mL/min/1.73 m2): 81.9 (34.8)

◦. Mean (SD) annualized rate of change in GFR −7.0 (32.9) mL/min/1.73 m2/year; p = 0.12

Mean (SD) [median; range] GFR at baseline before agalsidase alfa (mL/min/1.73 m2): 90.3 (31.2) [87.4; 25–184]

Mean (SD) baseline GFR by baseline GFR range (mL/min/1.73 m2): ≥135 (n = 8), 151.9 (16.4); 90 to <135 (n = 33), 109.6 (13.4); 60 to <90 (n = 36), 78.1 (8.4); 30 to <60 (n = 14), 50.1 (8.2); 15 to <30 (n = 2), 26.7

Mean (SD) annualized rate of change in GFR for the entire study population: −4.8 (10.6) mL/min/1.73 m2/year (p = 0.0003 compared with no change); median, −4.1 mL/min/1.73 m2/year

After removing 8 patients with hyperfiltration during agalsidase alfa therapy: rate of change in GFR, −2.9 (8.7) mL/min/1.73 m2/year (p = 0.0002 compared with no change)
Whybra 2009 [63] 36 4 years

Prospective single-center, open-label study of female patients in Germany

A cohort of female patients with FD who were experiencing manifestations of FD and had not been previously treated with ERT

Mean (SD) eGFR after 4 years of treatment: 91.0 (25.6) mL/min/1.73 m2

◦. 4 patients with eGFR > 135 mL/min/1.73 m2 at baseline (defined as hyperfiltration): eGFR at after 4 years of treatment, 128.3 (4.6) mL/min/1.73 m2

Mean (SD) eGFR by baseline eGFR range (mL/min/1.73 m2; * p < 0.05 vs. baseline; ** p < 0.001 vs. baseline):

◦. eGFR > 135 (n = 4): month 12, 140.3 (26.8); month 24, 135.3 (18.3) *; month 36, 133.0 (17.0) *; month 48, 128.3 (4.6)

◦. eGFR 90–135 (n = 9): month 12, 98.7 (15.6); month 24, 98.5 (10.9); month 36, 106.7 (15.5); month 48, 100.4 (16.4)

◦. eGFR 60–89 (n = 20): month 12, 85.5 (13.2); month 24, 88.8 (14.5); month 36, 83.0 (17.9); month 48, 85.9 (20.2)

◦. eGFR 30–59 (n = 3): month 12, 50.4 (10.8); month 24, 55.8 (8.1); month 36, 49.7 (11.5); month 48, 47.3 (14.0)

Responder definitions: I, less than 20% decrease in GFR from baseline; II, no shift to more severe CKD stage eGFR 90–135 mL/min/1.73 m2 at baseline (n = 9): responder definition I (%), 89; responder definition II (%), 89

◦. eGFR 60–89 mL/min/1.73 m2 at baseline (n = 20): responder definition I (%), 95; responder definition II (%), 95

◦. eGFR 30–59 mL/min/1.73 m2 at baseline (n = 3): responder definition I (%), 67; responder definition II (%), 100

Patients treated with ACEIs or ARBs during entire study (n = 7)

◦. Mean (SD): eGFR after 4 years of treatment, 65.0 (13.5) mL/min/1.73 m2; proteinuria after 4 years of treatment, 425 (531) mg/24 h

Patients who began treatment with ACEIs or ARBs after starting treatment with agalsidase alfa (n = 6)

◦. Mean (SD): eGFR at last measurement before starting anti-angiotensin therapy, 87.7 (29.6) mL/min/1.73 m2; eGFR at study end, 83.0 (33.4) mL/min/1.73 m2
Agalsidase beta single-arm studies
Benichou 2009 [67] 76 Median [range]: Phase 3: 55.9 [3.3, 60.7] months;Phase 4: 33.5 [1.9, 51.2] months

Retrospective analysis of efficacy data obtained from adult patients with FD who received agalsidase beta for up to 5 years during a phase 3 or phase 4 placebo-controlled trial and the associated open-label extension study

No statistically significant correlation was found between eGFR slope and peak titer (the highest anti-aGAL IgG titer observed for a given patient during treatment) among male patients from either the phase 3 (r2 = −0.22, n = 56, p = 0.10) or phase 4 studies (r2 = −0.09, n = 66, p = 0.46)

Similar correlation coefficients were found when both males and females were combined and when eGFR was examined as a function of titer/day
Breunig 2006 [68] 25 Mean (SD) [range]:23 (8) [12, 37] months

A single-center observational study of German patients with different stages of FD

Mean (SD) GFR (mL/min/1.73 m2)

◦. Patients with GFR > 90 (n = 16): baseline, 115 (18); follow-up, 102 (14); p = 0.15

◦. Patients with GFR < 90 (n = 16): baseline, 71 (17) [n = 8]; follow-up, 60 (23); p = 0.039
Burlina 2019 * [70]The Fabry Registry 49 ≥2.5 years

Observational study using data from the Fabry Registry

Included patients started on agalsidase beta (1 mg/kg EOW) when aged 5–30 years

eGFR outcomes were stratified by renal involvement (high and low) based on albuminuria/proteinuria levels

eGFR decline was higher among 16 high renal involvement males than 66 LRI males (slopes, −2.56 vs. −1.29 mL/min/1.73 m2/year; p value of interaction <0.05; median age at first treatment 25.3 vs. 20.6 years)

Slope estimates were unreliable among females
Cabrera 2017 [30] 39 Mean (SD): 68.2 (36.9) months

Long-term prospective and historical analysis of cohort of patients with FD from Argentina

At baseline, 5 patients had eGFR < 60 mL/min/1.73 m2, 2 males; 3 females

Mean (SD), eGFR (mL/min/1.73 m2):

◦. Males (n = 17): baseline: 96.9 (28); follow-up: 102 (29)

◦. Females (n = 13): baseline: 86 (23); follow-up: 84 (23)
Chen 2024 * [83] 22 48 weeks

Phase 4 open-label study of Chinese patients

Baseline mean (SD) eGFR: 115.6 (37.3) mL/min/1.73 m2

Week 48 mean (SD) eGFR: 118.4 (42.9) mL/min/1.73 m2

Change: 0.0 (12.4) mL/min/1.73 m2
Dutra-Clarke 2021 [71] 20 2–20 years

Observational study in the US

Annual decrease in eGFR of −1.88 mL/min/1.73 m2 (95% CI: −3.36, −0.40; p = 0.013) on ERT in males and females and −3.16 mL/min/1.73 m2 (95% CI: −4.97, −1.35; p = 0.001) for males alone
Germain 2015 [82] 52 Median [IQR]: 10 [7.3, 10.3] years

Analysis of phase 3 clinical trial data and Fabry Registry observational analysis

LRI subgroup (n= 32): mean eGFR slope: −1.89 mL/min/1.73 m2/year

p = 0.001

HRI subgroup (n = 20): mean eGFR slope: −6.82 mL/min/1.73 m2/year

p < 0.001

Patients with LRI whose UPCR was ≤0.5 g/g throughout the treatment period: mean slope: −1.48 mL/min/1.73 m2/year p < 0.001

Patients with LRI whose UPCR rose above 0.5 g/g during the treatment period: mean slope: −2.6 mL/min/1.73 m2/year p < 0.001
Goicoechea 2020 * [72] 69 Median [range] follow-up:60 [24, 120] months

An observational study of Spanish patients

At the end of follow-up, eGFR remained stable in 42 males and 27 females

Renal, neurological, or cardiac events were more frequent in patients with baseline eGFR ≤ 60 mL/min/1.73 m2 (log-rank, 12.423;

p = 0.001), and this remained significant even after excluding incident renal events (log-rank, 4.086; p = 0.043)

Lower baseline eGFR was associated with a 3- to 7-fold increase in the risk of clinical events in different Cox models
Hopkin 2023 [23]The Fabry Registry 785 Median: 6.3 years in males; 5.0 years in females

Observational study using data from the Fabry Registry

Baseline eGFR: males: median 91.7 mL/min/1.73 m2; females: median 102.3 mL/min/1.73 m2; p < 0.001

Male patients (n = 524): subgroup with eGFR assessments for slope analysis and renal involvement classification (n = 140); LRI, 117 (83.6%); HRI, 23 (16.4%)

eGFR slopes in males

◦. LRI subgroup: slope, −1.18 mL/min/1.73 m2/year; 95% CI: −1.66, −0.71; p < 0.001

◦. HRI subgroup: slope, −2.39 mL/min/1.73 m2/year; 95% CI: −3.53, −1.25; p < 0.001

◦. p difference: 0.055

◦. Median follow-up: 6.3 years (LRI) vs. 5.6 years (HRI)

Female patients (n = 261)

◦. Subgroup with LRI and eGFR assessments for slope analysis (n = 59); HRI subgroup analysis not possible

◦. eGFR slope: −0.92 mL/min/1.73 m2/year; 95% CI: −1.81, −0.04; p = 0.040

◦. Median follow-up: 5.0 years

Patients with baseline eGFR > 135 mL/min/1.73 m2

◦. Male LRI (n = 7): eGFR slope, −2.95 mL/min/1.73 m2/year; 95% CI: −6.01, 0.12; p = 0.057

◦. Female LRI (n = 6): eGFR slope, −3.20 mL/min/1.73 m2/year; 95% CI: −9.71, 3.32; p = 0.140

◦. p difference: 0.893

◦. Median follow-up: 4.9 years (males) vs. 5.8 years (females)

◦. Median baseline eGFR: 148.4 mL/min/1.73 m2 (males) vs. 138.0 mL/min/1.73 m2 (females)

◦. Median age at first treatment: 15.5 years (males) vs. 12.9 years (females)

◦. Median age at last eGFR assessment: 23.6 years (males) vs. 28.4 years (females)
Hwang 2022 [73] 10 22-week follow-upMean (SD) [range]: 4.6 (3.2) [1, 9] years

A phase 2 open-label study in Korea

8 patients had received previous ERT with agalsidase beta, 2 patients were treatment naive

Mean (SD) [range] eGFR: baseline: 107.00 (28.42) [68.00, 159.00] mL/min/1.73 m2; follow-up: 116.33 (29.77) [77.00–163.00] mL/min/m2
Lubanda 2009 [74] 21 96 weeks

Evaluation of a low dose, after a standard therapeutic dose, of agalsidase beta

Patients received 12 infusions of agalsidase beta at 1.0 mg/kg EOW for 6 months (weeks 0–23), followed by up to 37 infusions at 0.3 mg/kg EOW for 18 months (weeks 24–96)

◦. Mean, median (SD) [range] eGFR (mL/min/1.73 m2): baseline:

(n = 21), 93, 92.5 (21.0) [55–134]

◦. Median eGFR (mL/min/1.73 m2): 24 weeks, 93.1; 96 weeks, 92.8

Ortiz 2021 * [75] 254 Median post-treatment period: 4.1 years

Self-controlled comparison of renal function before and after ERT in male patients with LRI versus HRI

LRI (UPCR ≤ 0.5 g/g or UACR ≤ 0.3 g/g) and HRI (ratios > 0.5 g/g or >0.3 g/g, respectively)

◦. Pre-treatment eGFR slope (mL/min/1.73 m2/year): whole cohort (N = 254): −2.22 (median pre-treatment period 1.1 years); LRI (n = 251): −1.73; HRI (N = 68): −2.93

◦. eGFR slope, pre- vs. post-treatment (mL/min/1.73 m2/year): whole cohort (n = 254), −2.22 vs. −2.66 (p pre-post difference = 0.24; median pre-treatment period, 1.1 years; median post-treatment period, 4.1 years); LRI (n = 165), −1.73 vs. −1.92 (p pre-post difference = 0.66); HRI (n = 68), −2.93 vs. −4.31 (p pre-post difference = 0.04); statistically significant between LRI and HRI, p interaction <0.01
Ramaswami 2019 [76] 31 5 years

Pediatric male patients treated with 2 low-dose regimens (0.5 mg/kg q2w, n = 16; or 1.0 mg/kg q4w, n = 15)

Mean, median (SD) [range] iGFR (mL/min/1.73 m2)

◦. Year 5 overall (n = 23), 115.7, 112.4 (15.4) [90.6, 149.1]; change from baseline to year 5, −3.4, 0.5 (12.7) [−35.9, 19.2], p = 0.4065; annualized rate of iGFR decline, −0.7, 0.1 (2.5) [−7.2, 3.9]; % change from baseline, −2.0, 0.3 (10.5) [−27.4, 18.7]

Mean, median (SD) [range] eGFR (mL/min/1.73 m2)

◦. Year 5 overall (n = 27), 118.6, 121.0 (21.6) [81.1, 168.7]; change from baseline to year 5, −0.7, −4.6 (17.1) [−25.4, 58.3], p = 0.2667; annualized rate of eGFR decline, −0.1, −0.9 (3.4) [−5.1, 1.7]; % change from baseline, 0.8, −3.5 (16.4) [−20.1, 56.7]
Veloso 2023 * [69] 9 Mean (SD): 70.2 (12.9) months

Follow-up study of a family with a classic pathogenic variant (p.G35V) in Brazil

eGFR and proteinuria/albuminuria remained stable during the follow-up in both sexes (further details not reported in abstract)
Wanner 2020 [77]Fabry Registry 86 Mean (SD) [range]: 3.9 (0.9)[2.0, 5.0] years

Self-controlled pretreatment and post-treatment comparison in adult female patients in the Fabry Registry

Pretreatment vs. post-treatment eGFR slopes (95% CI) mL/min/1.73 m2/year overall and stratified by renal involvement or use of ACEI/ARBs

◦. Overall (n = 86): −0.83 (−1.52, −0.13) during pre-treatment and −0.95 (−1.59, −0.32) during post-treatment

◦. HRI (n = 22): eGFR slope pretreatment (95% CI), −1.95 (−3.23, −0.67), p < 0.01, p (pre-difference) = 0.10; eGFR slope post-treatment (95% CI), 2.08 (−3.21, −0.95), p < 0.01, p (post-difference) < 0.01; pretreatment vs. post-treatment eGFR slope difference (95% CI), −0.13 (−1.99, 1.72), p (pre-post difference) = 0.89, p (interaction) = 0.58

◦. LRI (n = 53): eGFR slope pretreatment (95% CI), −0.68 (−1.56, 0.20), p = 0.13; eGFR slope post-treatment (95% CI), −0.14 (−0.92, 0.63), p (post-difference) = 0.72; pretreatment vs. post-treatment slope difference (95% CI), 0.54 (−0.81, 1.88), p (pre-post difference) = 0.43)

◦. ‘Ever’ ACEI/ARBs (n = 52): eGFR slope pretreatment (95% CI), −1.30 (−2.17, −0.43), p (pre-difference) = 0.08; eGFR slope post-treatment (95% CI), −1.19 (−1.96, −0.43), p = < 0.01, p (post-difference) 0.38; pretreatment vs. post-treatment eGFR slope difference (95% CI), 0.10 (−1.13, 1.34), p (pre-post difference) 0.87, p (interaction) = 0.55

◦. ‘Never’ ACEI/ARBs (n = 34): eGFR slope pretreatment (95% CI), 0.01 (−1.15, 1.18), p = 0.98; slope post-treatment (95% CI), −0.57 (−1.69, 0.56), p = 0.32; pretreatment vs. post-treatment slope difference (95% CI), −0.58 (−2.43, 1.27), p (pre-post difference) = 0.54
Warnock 2012 [78]Fabry Registry 213 ≥2 years

Observational study using data from the Fabry Registry

Multivariate logistic regression analyses to identify factors associated with renal disease progression

Patients were categorized into quartiles based on eGFR slopes during treatment.

◦. Men’s eGFR slope (mL/min/1.73 m2/year) categories: quartile 1, −1.2 to 15.3; quartile 2, −2.8 to 1.3; quartile 3, −4.8 to 2.9; and quartile 4, −15.5 to −14.9.

◦. Women’s eGFR slope (mL/min/1.73 m2/year) categories: quartile 1, 1.1 to 7.5; quartile 2, −0.4 to 1.0; quartile 3, −2.3 to −0.4; and quartile 4, −7.6 to −2.4

Mean, median (SD) [IQR] pre-treatment (baseline) eGFR (mL/min/1.73 m2)

◦. Men: eGFR slope quartile 1 (n = 37), 99, 104 (22.6) [89, 115]; eGFR slope quartile 2 (n = 37), 77, 73 (32.9) [46, 108]; eGFR slope quartile 3 (n = 38), 88, 88 (38.7) [51, 123]; eGFR slope quartile 4 (n = 36), 72, 61 (34.3) [47, 95]

◦. Women: eGFR slope quartile 1 (n = 14): 88, 87 (16.0) [75, 100]; eGFR slope quartile 2 (n = 14): 90, 93 (23.9) [72, 111]; eGFR slope quartile 3 (n = 16): 95, 98 (27.6) [76, 118]; eGFR slope quartile 4 (n = 14): 78, 85 (35.6) [36, 105]

Mean, median (SD) [IQR] eGFR slope (mL/min/1.73 m2/year)

◦. Men: eGFR slope quartile 1 (n = 38): −0.1, −0.5 (1.20) [−0.9, 0.6]; eGFR slope quartile 2 (n = 38), −2.1, −2.1 (0.52) [−2.6, −1.5]; eGFR slope quartile 3 (n = 38), −3.8, −3.6 (0.61) [−4.3, −3.3]; eGFR slope quartile 4 (n = 37), −6.7, −6.2 (2.26) [−6.9, −5.5]

◦. Women: eGFR slope quartile 1 (n = 15), 2.7, 2.6 (1.65) [1.3– 3.4]; eGFR slope quartile 2 (n = 16), 0.1, 0.1 (0.41) [−0.2, 0.4]; eGFR slope quartile 3 (n = 16), −1.3,−1.4 (0.66) [−1.7, −0.6]; eGFR slope quartile 4 (n = 15), −4.4, −4.2 (1.58) [−5.5, −3.0]

The risk factor most strongly associated with renal disease progression was UPCR ≥ 1 g/g (OR: 112; 95% CI: 4, 3109; p = 0.0054)

Longer time from symptom onset to treatment was also associated with renal disease progression (OR: 19; 95% CI: 2, 184; p = 0.0098)
Warnock 2015 [79]FAACET 24 Median [IQR] duration of therapy before first visit: 3.1 [0.3, 4.4] yearsPatients were followed up during a 21-month treatment phase

The FAACET study evaluated the safety and efficacy of proteinuria control with ACEI and/or ARB therapy in patients with FD receiving ERT with agalsidase beta

Assessment of renal function in patients with classic FD stratified by achieved UPCR goal (defined as UPCR for first visit ≤ 0.5 g/g or averaged treatment UPCR ≤ 50% of baseline or averaged treatment UPCR ≤ 0.5 g/g)

eGFR slope (mL/min/1.73 m2/year)

◦. Patients who met UPCR goal (n = 18), eGFR slope (95% CI) −3.6 (−4.8, −1.1)

◦. Patients who did not meet UPCR goal (n = 6), eGFR slope (95% CI) −7.0 (−5.6, −2.0)

Median [IQR] eGFR at initial follow-up visit (mL/min/1.73 m2):

◦. Patients who met UPCR goal and eGFR slope ≥ −2 mL/min/1.73 m2/year (n = 6): 88 [56, 11]

◦. Patients who met UPCR goal and eGFR slope < −2 mL/min/1.73 m2/year (n = 12): 62 [48, 78]

◦. Patients who were above UPCR goal and eGFR slope < −2 mL/min/1.73 m2/year; (n = 6), 61 [45, 81]

Median (IQR) eGFR—average of follow-up visits (mL/min/1.73 m2):

◦. Patients who met UPCR goal and eGFR slope ≥ −2 mL/min/1.73 m2/year (n = 6): 80 [75, 126]

◦. Patients who met UPCR goal and eGFR slope < −2 mL/min/1.73 m2/year (n = 12): 56 [45, 75]

◦. Patients who were above UPCR goal and eGFR slope < −2 mL/min/1.73 m2/year (n = 6): 68 [45, 73]

Median (IQR) eGFR at last follow-up visit (mL/min/1.73 m2):

◦. Patients who met UPCR goal and eGFR slope ≥ −2 mL/min/1.73 m2/year (n = 6): 97 [75, 121]

◦. Patients who met the UPCR goal (and eGFR slope < −2 mL/min/1.73 m2/year (n = 12): 62 [51, 85]

◦. Patients who were above UPCR goal and eGFR slope < −2 mL/min/1.73 m2/year (n = 6): 47 [35, 90]
Weidemann 2013 [80] 40 Median [IQR]: 6.0 [5.1, 7.2] years

Assessment of long-term effects of agalsidase beta in patients with advanced FD at a single center in Germany

Mean (SD) GFR (mL/min): baseline, 85 (28); at follow-up, 73 (39) (p = 0.003)

Mean (SD) annual change in GFR −2.3 (4.6) mL/min/year (men: −2.4 (5.0) mL/min/1.73 m2/year and women: −1.9 (3.3) mL/min/year)
Wraith 2008 [81] 16 48 weeks

Open-label study of pediatric patients with FD from France, Poland UK, and USA

Mean (SD) eGFR (mL/min/1.73 m2): baseline (n = 16), 126 (29); week 24 (n = 16), 128 (29); week 48 (n = 15), 125 (26)
(B)
Author Year Study Identifier Treatment Groups, n Treatment Duration Key Results
Comparator studies
Arends 2018 [29] Agalsidase alfa: 248Agalsidase beta: 139Median [range]:All patients 4.9 [0.8, 14.4] years;Agalsidase alfa5.2 [0.8. 14.4] years;Agalsidase beta3.8 [0.8, 12.1] years

Retrospective cohort study involving three European centers combined with data from the Canadian FD Initiative

Median eGFR [range], mL/min/1.73 m2 at baseline: agalsidase alfa, 89 [10, 159]; agalsidase beta, 86 [10, 140]

Adjusted for sex and phenotype, there was no difference in eGFR slope between agalsidase alfa and beta in patients with a baseline eGFR ≥ 60 mL/min/1.73 m2 (beta slope alfa-beta: −0.12 mL/min/1.73 m2/year; 95% CI: −0.76, 0.51; p = 0.70)

In patients with an eGFR < 60 mL/min/1.73 m2, there was no difference in the rate of decline (beta slope alfa-beta: −0.85 mL/min/1.73 m2/year, 95% CI: −2.31, 0.62; p = 0.26), and adding the use of ACEI/ARBs and/or presence of proteinuria at baseline as covariates to the model did not result in a better fit or different results
Beck 2015 [112]FOS Agalsidase alfa: 740Published findings for untreated patients Median [range]: 5.4 [1.5, 13.7] years

Mean annualized eGFR slope (SEM) [95% CI], mL/min/1.73 m2/year

FOS evaluable treated renal cohort by baseline eGFR category (mL/min/1.73 m2):

◦. Males, ≥ 60 (n = 117): −1.68 (0.19) [−2.05, −1.31]; <60 (n = 18): −2.86 (0.53) [−3.90, −1.83]

◦. Females, ≥ 60 (n = 111): −0.43 (0.21) [−0.83, −0.02]; <60 (n = 22): 0.36 (0.42) [−0.47, 1.19]

Previously published external untreated cohort by baseline eGFR category (mL/min/1.73 m2):

◦. Males, ≥60 (n = 117): −3.0 (0.1); <60 (n = 28): −6.8 (1.5)

◦. Females, ≥60 (n = 42): −0.9 (0.9); females, <60: (n = 13); −2.1 (1.6)

In a sensitivity analysis, eGFR results were evaluated only for FOS ERT patients who had 5-year data (79 males, 71 females; median [range] treatment duration, 8.25 [2.7, 13.8] years)

◦. The annualized eGFR slopes for these patients, overall and grouped by baseline eGFR, were not significantly different from corresponding values for the full FOS ERT renal cohort
Cybulla 2009 [113]FOS Kidney transplant recipients: 27(20 received agalsidase alfa, 7 untreated)Median ERT treatment duration: 3.5 years

Baseline renal function data available for 27 kidney transplant recipients (n = 27): median [IQR] eGFR (mL/min/1.73 m2) 44.4 [33.6, 64.0]

Renal function in kidney transplant recipients receiving ERT or without ERT, medians [IQR] eGFR (mL/min/1.73 m2):

◦. Kidney recipients receiving ERT (n = 20), 59.2 [36.5, 65.2]

◦. Kidney recipients without ERT (n = 7), 35.1 [19.9, 51.7]
Cybulla 2013 * [115]FOS Kidney transplantrecipients: 93 (78 treated with ERT before or after transplant surgery, 15 untreated)Mean (SD):3.7 (3.1) years

Mean (SD) baseline eGFR (mL/min/1.73 m2)

◦. Kidney recipients receiving ERT (n = 53): 44.8 (25.9)

◦. Kidney recipients without ERT (n = 10): 61.7 (12.0)

Mean (95% CI) eGFR slope (mL/min/1.73 m2/year)

◦. Male recipients receiving ERT: −0.0 (−2.7, 2.6)

◦. Male recipients without ERT: −4.5 (−14.1, 5.0)

◦. Female recipients receiving ERT: −1.0 (−10.4, 8.4)

◦. Female recipients without ERT: −2.8 (−24.5, 18.8)
Cybulla 2014 * [114]FOS Kidney transplant recipients: 51 (47 treated with ERT before or after transplant surgery, 4 untreated)Median [range]: 2.9 [0.0, 13.4] years

Mean [range] baseline eGFR (mL/min/1.73m2)

◦. Kidney recipients receiving ERT (n = 24): 45.7 [4.1, 110.8]

◦. Kidney recipients without ERT (n = 3): 54.2 [45.9, 59.7]
Dehout 2003 [116]FOS Agalsidase alfa: 234, Untreated: 10312 months

Observational study using preliminary data from FOS

Patients with baseline GFR 60–89 mL/min (n = 39): a significant improvement in GFR from baseline, p = 0.027 following 12 months of treatment with agalsidase alfa

Patients with baseline GFR 30–59 mL/min (n = NR): GFR was maintained after 12 months of treatment with agalsidase alfa, whereas in those without treatment, GFR declined significantly (p < 0.021)

Patients with a baseline GFR > 90 mL/min (n = 51): no difference between treated and untreated patients after 1 year
Golan 2015 [118] Agalsidase alfa 0.2 mg/kg EOW: 20Agalsidase alfa 0.2 mg/kg weekly: 19Agalsidase alfa 0.4 mg/kg weekly: 51 year

Phase 3/4 multi-center open-label study

Mean baseline eGFR (mL/min/1.73 m2)

◦. 0.2 mg/kg EOW (n = 20): 82.0

◦. 0.2 mg/kg weekly (n = 19): 78.1

◦. 0.4 mg/kg weekly (n = 5): 72.1

Median baseline UACR

◦. 0.2 mg/kg EOW (n = 20): 41.5

◦. 0.2 mg/kg weekly (n = 19): 40.0

◦. 0.4 mg/kg weekly (n = 5): 250.0

Week 53 mean eGFR (mL/min/1.73 m2)

◦. 0.2 mg/kg EOW (n = 17): 78.3

◦. 0.2 mg/kg weekly (n = 18): 77.5

◦. 0.4 mg/kg weekly (n = 5): 70.4

Change in eGFR (95% CI) at week 53 (mL/min/1.73 m2)

◦. 0.2 mg/kg EOW: −1.21 (−7.46, 5.05)

◦. 0.2 mg/kg weekly: −3.32 (−9.63, 2.99)

◦. 0.4 mg/kg weekly: −1.68 (−14.00, 10.64)

0.2 mg/kg weekly minus EOW mean eGFR (mL/min/1.73 m2)

◦. LSM difference: −1.56 (95% CI: −9.23, 6.12); unadjusted p = 0.6830

Mean (95% CI) change from baseline in eGFR by CKD stage, 1A, 1B, 2, 3, 4/5 (mL/min/1.73 m2)

◦. 0.2 mg/kg EOW: CKD-1A, −24.2 (−82.6, 34.2; n = 3); CKD-1B, 1.6 (−35.4, 38.7; n = 3); CKD-2, 4.5 (−1.2, 10.1; n = 10); CKD-3, −5.0 (−27.3, 17.2; n = 3); CKD-4/5, −1.2 (−7.5, 5.0; n = 1)

◦. 0.2 mg/kg weekly: CKD-1A, −24.4 (−71.4, 22.6; n = 2); CKD-1B, −4.3 (−21.4, 12.8; n = 5); CKD-2, −1.2 (−8.4, 5.9; n = 7); CKD-3, 7.3 (−24.6, 39.2; n = 3); CKD-4/5, −2.9 (n = 2)

◦. 0.4 mg/kg weekly: CKD-1A, NA (n = 0); CKD-1B, −0.4 (n = 1); CKD-2, −2.3 (−37.0, 32.4; n = 3); CKD-3, NA (n = 0); CKD-4/5, −1.0 (n = 1)
Guerard 2018 [119] Lucerastat + ERT: 10 ERT only: 412 weeksMean (SD) previous ERT at baseline:Lucerastat:4.5 (2.6) years;ERT only:6.3 (4.2) years

Single-center, open-label, randomized study in Germany

Mean (SD) baseline eGFR (mL/min/1.73 m2)

◦. Lucerastat + ERT (n = 10): 88.7 (26.2)

◦. ERT only (n = 4): 94.9 (26.7)

Week 4 mean (SD) eGFR

◦. Lucerastat + ERT (n = 10): 97.4 (26.0)

◦. ERT only (n = 4): 91.8 (20.5)

Week 8 mean (SD) eGFR

◦. Lucerastat + ERT (n = 10): 90.3 (21.6)

◦. ERT only (n = 4): 88.8 (23.8)

Week 12 mean (SD) eGFR

◦. Lucerastat + ERT (n = 10): 92.9 (23.1)

◦. ERT only (n = 4): 95.0 (24.1)
Hughes 2008 [121] Agalsidase alfa: 7Placebo: 8Randomized phase: 6 months OLE: 2 years

Placebo-controlled study followed by open-label extension for 2 years

Mean baseline GFR showed a statistically significant increase within the normal range (106–131 mL/min; p = 0.007) in the drug group, whereas the placebo groups did not show any statistically significant change throughout the 6-month study
Hughes 2019 * [120] Agalsidase alfa: 21Untreated: 52NR

Mean (SD) eGFR changes in women with FD from before to after pregnancy (mL/min/1.73 m2)

◦. ERT: −1.5 (11.7)

◦. Untreated: −3.1 (13.6)
Jovanovic 2017 * [122]FACETSATTRACT FACETS:Migalastat or placebo: 67;OLE, migalastat: 54,24 monthsATTRACT:Migalastat or ERT: 52, 18 monthsEfficacy analyses focused on patients with amenable mutations, FACETS:(n = 41); ATTRACT:(n = 34)

Over 24 months in FACETS, the annualized rate of change in eGFR CKD-EPI (SEM) with migalastat was −0.3 (0.664) mL/min/1.73 m2

The annualized rate of change (SEM) for eGFR in the range of 60 to <90 mL/min/1.73 m2 was −0.8 (1.01), which was comparable to the rate in the range of ≥90 mL/min/1.73 m2, 0.2 (0.90)

During the 18-month controlled period of ATTRACT, the annualized means (SD) for eGFR for migalastat and ERT were comparable, −0.40 (4.3) and −1.03 (7.4), respectively

The annualized rates of change in eGFR (SEM) in the range of 60 to <90 mL/min/1.73 m2 for migalastat and ERT were −0.2 (1.25) and −7.3 (6.01), respectively; the annualized rates in the range of ≥90 mL/min/1.73 m2 were −2.0 (0.57) and −2.1 (1.60)

During the 12-month OLE, eGFR remained stable
Prabakaran 2014 [123] Agalsidase beta/agalsidase alfa: 13Untreated: 4≤6 years

Median [range] baseline eGFR (mL/min/1.73 m2)

◦. ERT-treated: 100 [64, 159]

◦. Untreated: 99 [88, 124]

Mean annualized (95% CI) change in eGFR, (mL/min/1.73 m2)

◦. ERT-treated: −1.45 (95% CI: −0.31, −2.58; p = 0.012)

◦. Untreated: −0.89 (95% CI: −1.51, 3.30; p = 0.47)

◦. Decline in the two groups was not significantly different, p = 0.68
Schiffmann 2018 * [124] Migalastat cohort: 52Natural history cohort: 90 (untreated patients)3–5 years

Mean annualized (SE) eGFR rate of change (mL/min/1.73 m2) by baseline 24-h urine protein (mg/24 h)

◦. Migalastat males

-. <100 (n = 3): 1.2 (1.2)

-. 100–1000 (n = 16): 0.9 (1.0)

-. 1000 (n = 2): −4.3 (0.1)

◦. Migalastat females

-. <100 (n = 9): −0.9 (0.5)

-. 100–1000 (n = 19): 1.3 (1.5)

-. 1000 (n = 3): −1.7 (1.1)

◦. Natural history cohort males

-. <100 (n = 18): −1.6 (1.5)

-. 100–1000 (n = 21): −3.3 (1.8)

-. 1000 (n = 22): −6.9 (1.5)

◦. Natural history cohort females

-. <100 (n = 7): −0.6 (2.6)

-. 100–1000 (n = 17): −2.2 (2.2)

-. >1 000 (n = 5): −4.6 (2.3)
Sirrs 2018 * [27] Agalsidase alfa 0.2 mg/kg: 76Agalsidase beta 1 mg/kg: 56Median [range]: 99 [5, 123] months

A prospective multi-center study of ERT in Canada

Males: rate of decline of eGFR (mL/min/1.73 m2/year) tended to be lower in patients on agalsidase beta than those on agalsidase alfa: −1.98 vs. −4.15, respectively; p = 0.09

Females: no difference in the rate of decline in eGFR was seen between the two treatment groups in females
Skuban 2017 * [108]FACETSATTRACT FACETS:Migalastat or placebo: 67OLE, migalastat: 60FACETS: 6-month double-blind followed by open-label migalastat from 6 to 12 months (stage 2) plus an additional yearATTRACT:Migalastat or ERT: 53.18 months

Analysis of 2 randomized phase 3 clinical studies

FACETS: mean annualized rate of change (SEM) over 24 months in eGFR CKD-EPI with migalastat was −0.3 (0.7) mL/min/1.73 m2

ATTRACT: migalastat and ERT had comparable effects on renal function during the 18-month controlled period

Compared with natural history, the rate of GFR decline in FACETS was slower than that of untreated patients when matched for sex and baseline proteinuria
van der Veen 2022 [33] Agalsidase beta 0.5 mg/kg: 3Agalsidase beta 1 mg/kg: 4Untreated: 2310 years

Cross-sectional retrospective study comparing outcomes in patients with classic FD after 10 years of ERT to a group of untreated patients with the same phenotype of comparable age

Median [range] eGFR (mL/min/1.73 m2)

◦. Treated: 116 [92, 132]

◦. Untreated: 116 [46, 165]; p = 0.96

Reduced renal function (eGFR < 90 mL/min/1.73 m2)

◦. Treated: n = 0

◦. Untreated: n = 4

Hyperfiltration (eGFR > 140 mL/min/1.73 m2)

◦. Treated: n = 0

◦. Untreated: n = 3
Vedder 2007 [28] Agalsidase alfa: 18Agalsidase beta: 1624 months

Median (SD) [range] GFR (mL/min)

◦. 12 months: agalsidase beta, 111 (30) [56, 159]; agalsidase alfa, 102 (42) [16, 150]

◦. 24 months: agalsidase beta, 107 (31) [49, 144]; agalsidase alfa, 100 (40) [14, 158]

◦. No significant differences between groups or from baseline in either group
Wallace 2022 * [125], Wallace 2024 [127]NCT02795676 Pegunigalsidase alfa: 52Agalsidase beta: 2524 months

Median [range] eGFR at baseline (mL/min/1.73 m2)

◦. Pegunigalsidase alfa: 73.5 [30.2, 125.9]

◦. Agalsidase beta: 74.9 [34.1, 107.6]

◦. Overall: 74.5 [30.2, 125.9] (p = 0.82)

Median eGFR change from baseline at 24 months (mL/min/1.73 m2)

◦. Pegunigalsidase alfa: −2.39

◦. Agalsidase alfa: −3.20

Median (95% CI) annual eGFR slope at 24 months (mL/min/1.73 m2/year)

◦. Pegunigalsidase alfa (n = 52): −2.51 (−3.79, −1.24)

◦. Agalsidase beta: (n = 25): −2.16 (−3.81, −0)

◦. Difference: −0.36 (−2.44, 1.73)

◦. Males

-. Pegunigalsidase alfa (n = 28): −3.44 (−5.38, −1.73)

-. Agalsidase beta (n = 18): −2. 01 (−3.98, −0.04)

-. Difference: −1.43 (−3.96, 1.10)

◦. Females

-. Pegunigalsidase alfa (n = 23): −1.15 (−3.11, 0.81)

-. Agalsidase beta (n = 7): −2.79 (−6.28, 0.70)

-. Difference: 1.64 (−2.56, 5.84)
Eng 2001 [117], Wilcox 2004 [126] Agalsidase beta: 29Placebo: 29Initial trial: 20 weeksFollow-up: 30–36 months

Mean baseline (SD) eGFR (mL/min)

◦. Agalsidase beta: 83.0 (22.0)

◦. Placebo: 96.6 (35.5)

Mean eGFR at start of extension study (mL/min/1.73 m2)

◦. Agalsidase beta/agalsidase beta: 109.6

◦. Placebo/agalsidase beta: 138.3

Mean eGFR at 30 months of extension study (mL/min/1.73 m2)

◦. Agalsidase beta/agalsidase beta: 107.1

◦. Placebo/agalsidase beta: 129.5

Patients with (<90 mL/min/1.73 m2) at baseline (n = 10):

◦. Mean (SD) eGFR (mL/min/1.73 m2)

◦. Agalsidase beta: 68.6 (19.7) at baseline; and 79.6 (6.3) at 30–36 months after treatment

◦. After 30–36 months of agalsidase beta treatment, 7 (70%) of the 10 patients had either stabilized their eGFR values (GFR: ± 20%) or improved

* Congress abstract. ACEI, angiotensin-converting enzyme inhibitor. aGAL, α-galactosidase A. ARB, angiotensin receptor blocker. CI, confidence interval. CKD, chronic kidney disease. CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration. eGFR, estimated glomerular filtration rate. EOW, every other week. ERT, enzyme replacement therapy. ESRD, end-stage renal disease. FD, Fabry disease. FOS, Fabry Outcome Survey. GFR, glomerular filtration rate. HRI, high renal involvement. iGFR, iohexol glomerular filtration rate. IgG, immunoglobulin G. IQR, interquartile range. LRI, low renal involvement. LSM, least-squares mean. MDRD, Modification of Diet in Renal Disease. NA, not applicable. NR, not reported. NS, not significant. OLE, open-label extension. q2w, every 2 weeks. q4w, every 4 weeks. SD, standard deviation. SE, standard error. SEM, standard error of the mean. UACR, urine albumin-to-creatinine ratio. UPCR, urine protein-to-creatinine ratio.

3.2. Cardiac Outcomes

Cardiovascular disease is a leading cause of death in patients with FD. Cardiac manifestations of FD include left ventricular hypertrophy (LVH), diastolic dysfunction, valvular irregularities, and conduction disturbances [1]. Publications reporting LVMI data comprised: single-arm studies of agalsidase alfa (n = 19) [39,40,41,42,46,47,48,50,51,52,55,61,63,65,66,128,141,142,143], agalsidase beta (n = 11) [30,69,73,76,80,144,145,146,147,148,149], mixed or non-specified ERT (n = 19) [31,35,36,85,86,88,89,90,91,93,150,151,152,153,154,155,156,157,158], and other treatments (n = 13) [95,98,99,100,101,103,104,105,106,107,108,111,159], comparator studies (n = 15) [29,33,37,112,118,119,121,160,161,162,163,164,165,166], and switch studies (n = 7) [14,128,129,130,134,135,139,140]. Most of the studies (63 studies in 69 publications) assessed LVMI using echocardiography. An overview of the LVMI data from agalsidase alfa and agalsidase beta single-arm studies and the comparator studies is presented in Table 2. Key results from the other types of studies are provided in Supplementary Table S6.

For the 19 publications reporting LVMI data from agalsidase alfa single-arm studies, treatment/follow-up duration varied widely, from 26 weeks to 13 years (Table 2A). Agalsidase alfa stabilized LVMI (i.e., a non-statistically significant change in LVMI or LVM over the follow-up period) in nine studies [42,46,50,52,55,61,66,128,143] and reduced LVMI in three others [39,63,141]. In addition, five studies showed improvement in or stabilization of LVMI for different subgroups [41,47,48,65,142]. A large post-marketing surveillance study of 495 patients in Japan found that treatment with agalsidase alfa for up to 8 years helped to stabilize LVMI in both females and males [52]. Early initiation of treatment with agalsidase alfa in children and adolescents maintained LVMI at pretreatment levels over several years of ERT [50,51,55,76]. In an analysis of FOS registry data (mean treatment duration: ~11 years), male patients with classic FD who started agalsidase alfa treatment before 25 years of age (n = 32) had a nonsignificant mean (standard error [SE]) annual increase in LVMI of 0.28 (0.30) g/m2.7, whereas those who started treatment at or after 25 years of age (n = 58) had a significant mean (SE) annual LVMI increase of 1.03 (0.21) g/m2.7 (p < 0.0001) [41]. Females with FD responded well to agalsidase alfa, with stable or improved LVMI observed over 4–10 years of treatment [47,48,63,142].

All 11 articles that reported the effects of agalsidase beta on LVMI in single-arm studies described a decrease or stabilization of LVMI over treatment periods ranging from 22 weeks to 5 years [30,69,73,76,80,144,145,146,147,148,149] (Table 2A). Three studies that were designed specifically to evaluate the effects of ERT with agalsidase beta on cardiac manifestations demonstrated statistically significant decreases in LVMI over treatment periods of 3–5 years [69,146,147]. Moreover, significant improvements in left ventricular morphology were seen in both males and females, and regardless of FD severity [147]. Analyses by baseline LVH (LVMI > 134 g/m2 in men and >110 g/m2 in women) showed that LVMI reduced significantly in those with baseline LVH (n = 42) and was stable in those without LVH (n = 24) over a median follow-up period of 3 years [147].

The majority of the single-arm studies (10/17) evaluating the effects of mixed or non-specified ERT showed stabilization of LVMI (Supplementary Table S6), with only three studies (two in Taiwanese patients) and one sub-analysis (adults with LVH) reporting a reduction in LVMI during ERT [31,86,151,155]. Most (10/12) of the single-arm studies for other treatments evaluated migalastat. Migalastat led to regression of LVMI in six studies [98,99,100,103,104,105,111] and stabilization in four studies [101,106,108,159] over treatment periods of 48 weeks to 5 years.

Multiple ERT studies assessing LVMI outcomes included a placebo or untreated control arm [33,37,121,156,161,162,165,166], two of which were meta-analyses of previously published data [162,164] (Table 2B). Reductions in LVMI with ERT were demonstrated in both adults [121,161] and adolescents [33], as well as among treatment-naive and treatment-experienced patients [162]. Only one study did not show a difference in LVMI between patients who received ERT (n = 47; median follow-up: 8 years) or no ERT (n = 19; median follow-up: 6 years) [37]. Early initiation of ERT before cardiac disease progression appeared to result in the best LVMI outcomes [156,166]. A randomized, controlled, open-label study found no differences between the efficacy of agalsidase alfa (n = 18) and agalsidase beta (n = 16) on LVM after 12 or 24 months of treatment [28]. In a retrospective cohort study, both agalsidase alfa and agalsidase beta reduced LVMI after 1 year in patients with LVH at baseline (n = 168), with no significant difference between the treatment groups [29]. A greater proportion of patients treated with agalsidase beta than agalsidase alfa had a decrease in LVMI over that period (79% vs. 62%) [29]. In the placebo-controlled FACETS study (n = 67), reductions in LVMI with migalastat were sustained over 30 months in the open-label extension (mean [95% CI] change from baseline: −17.0 [−26.2, −7.9] g/m2; n = 15), including in patients with baseline LVH [160].

The effect of treatment switching on LVMI was assessed in three clinical trials and two observational studies (Supplementary Table S6). In a prospective clinical trial, LVMI was maintained after 24 months in patients who switched from agalsidase beta to agalsidase alfa (n = 71) [128]. No change in LVMI was observed over 12 months in men (n = 15) who switched from agalsidase alfa to pegunigalsidase alfa in the phase 3 BRIDGE trial [139]. In the phase 3 ATTRACT study (n = 36), switching from ERT to migalastat was associated with a mean (95% CI) change in LVMI of −6.6 (−11.0, −2.2) g/m2 after 18 months of treatment [129,130]. However, the inclusion of a broad patient age range (18–72 years) with mild GLA variants associated with residual enzyme activity, may have influenced these results because some patients in this population would not have developed early-onset or severe disease symptoms [167].

Identified studies that assessed other cardiac structure outcomes (e.g., left ventricular posterior wall thickness, interventricular septal thickness, and left ventricular wall thickness) in patients receiving FD treatments are shown in Supplementary Table S7. These included single-arm studies of agalsidase alfa (n = 6) [39,42,46,47,48,61], agalsidase beta (n = 13) [70,73,75,76,77,80,82,144,145,146,147,149,168], mixed or non-specified ERT (n = 9) [85,86,88,89,93,132,152,153,157,163], and other treatments (n = 3, all on migalastat) [98,135,159]. There were seven publications of comparator studies [37,156,158,161,165,169,170] and three publications describing switch studies [129,131,140]. Overall, ERT stabilized cardiac structural changes associated with FD and improved outcomes in patients with LVH. As observed for LVMI, early treatment initiation was more effective at preventing progression than interventions during established disease.

Table 2

Overview of LVMI data from (A) single-arm agalsidase alfa or agalsidase beta studies and (B) comparator studies.

(A)
Author Year N Treatment Duration Assessment Method Key Results
Agalsidase alfa single-arm studies
Baehner 2003 [141] 15 Up to 55 weeksEchocardiography

In heterozygous female patients with FD, mean (SEM) change from baseline in LVMI (g/m2)

◦. Week 13 (n = 15): −5.5 (5.94); p = 0.372

◦. Week 27 (n = 11): −23.0 (5.78); p = 0.003

◦. Week 41 (n = 7): −25.2 (8.12); p = 0.021
Beck 2004 [39] 188 Mean [max]: 17 [56] monthsEchocardiography

In a population of patients with FD who were 52% male, echocardiographic data were available for 52/188 (28%) patients treated for 1 year and for 17/92 (18%) patients treated for 2 years

Individual data on mean LVM from serial echocardiographic examinations of patients with LVH (LVM > 50 g/m2.7) indicate a decrease in height-adjusted LVM, particularly in those patients with the greatest degree of hypertrophy

Overall, there was a significant (p < 0.05) decrease in LVM at 1 and 2 years of treatment with agalsidase alfa
Giugliani 2023 * [40] 66 Median [IQR]: 20.0 [19.6, 20.6]NR

Observational study using data from FOS

Mean (SD) baseline LVMI: 49.79 (14.23) g/m2.7

Mean (SE) annual rate of change (n = 31): 0.83 (0.32) g/m2.7

Annual increase

◦. Males: 0.65 g/m2.7

◦. Females: 1.34 g/m2.7
Goker-Alpan 2015 [128] 100 24 monthsEchocardiography

A large cohort study of patients who were started on or switched to agalsidase alfa during a worldwide shortage of agalsidase beta

Number of patients with or without baseline LVH

◦. Naive to ERT (n = 29): with LVH, 10 (34.5%); without LVH, 15 (51.7%); not determined, 4 (13.8%)

◦. Switch from agalsidase beta to agalsidase alfa (n = 71): with LVH, 27 (38.0%); without LVH, 25 (35.2%); not determined, 19 (26.8%)

Mean LVMI did not change significantly in any patient subgroup, including those with or without LVH at baseline

Cardiac data presented in figures
Goker-Alpan 2016 [46] 14 Median [range]:54.5 [54.0, 59.0] weeksEchocardiography

An open-label safety study of agalsidase alfa in children naive to ERT

LVMI values remained within the normal range throughout the study

Mean [95% CI] change from baseline at week 55

◦. Males (n = 5): −0.74 [−6.01, 4.53] g/m2.7

◦. Females (n = 9): 0.66 [−4.77, 6.08] g/m2.7
Hughes 2009 * [142]FOS 250 4 yearsEchocardiography

Observational study using data from FOS

Cohort of females (n = 78) and males (n = 172) followed for 4 years of ERT

After 4 years of agalsidase alfa, there was a significant decrease (p = 0.0312) in mean LVM in females (n = 24), which was not apparent in males (n = 45)
Hughes 2011 [48]FOS 250 ≥4 yearsEchocardiography

Observational study using data from FOS

Mean (SD) LVMI (g/m2.7) at 4 years

◦. Females (n = 24): 43.7 (14.3); p = 0.031 vs. baseline

◦. Males (n = 45): 52.2 (19.2); p = 0.247 vs. baseline

Males with LVH at baseline (n = 22): mean difference after 4 years, −9.11 g/m2.7; p = 0.0115

Males with normal LVMI at baseline (n = 23): mean difference after 4 years, −3.82 g/m2.7; p = 0.0741
Kampmann, 2009 [143] 45 30–42 months (defined as 36 months)Echocardiography

Retrospective, blinded, pooled analysis of 4 industry-sponsored clinical studies including patients with FD who had received≥ 36 months of ERT

LVH was present in 14/45 patients at baseline

LVMI (g/m2.7) at 12 months in patients with LVH at baseline (n = 9):

◦. Mean (SD) change from baseline: −9.2 (7.9)

◦. Median change from baseline: −8.9, p vs. baseline: 0.008

LVMI (g/m2.7) at 36 months in patients with LVH at baseline (n = 10):

◦. Mean (SD) change from baseline: −5.1 (7.5)

◦. Median change from baseline: −9.0, p vs. baseline: 0.037

LVMI (g/m2.7) at 12 months in patients without LVH at baseline (n = 28):

◦. Mean (SD) change from baseline: 3.6 (5.7)

◦. Median change from baseline: 3.2, p vs. baseline: 0.002

LVMI (g/m2.7) at 36 months in patients without LVH at baseline (n = 26):

◦. Mean (SD) change from baseline: 2.1 (7.9)

◦. Median change from baseline: 1.5, p vs. baseline: 0.27
Kampmann 2015 [47] 45 Median [range]: 10.8 [9.6, 12.5] yearsEchocardiography

A single-center observational study in Germany

At start of treatment, LVMI values suggested a varying degree of LVH (LVMI ≥ 50 g/m2.7)

◦. Men: 71% (n = 15/21)

◦. Women: 67% (n = 16/24)

After 1 year of treatment

◦. Males with LVH: marked improvement in LVMI; LS mean [95% CI] change, −16.46 [−23.81, −9.11] g/m2.7; p < 0.0001

◦. Females with LVH: LS mean [95% CI] change, −16.69 [−23.62, −9.75] g/m2.7; p < 0.0001; sustained for 3 years and no longer significantly different from baseline after 10 years

After 10 years of treatment

◦. Patients without baseline LVH: no change from baseline

◦. Males with LVH: LVMI was significantly reduced; LS mean [95% CI] change from baseline, −13.55 [−23.05, −4.06] g/m2.7; p = 0.0061

◦. Females with LVH: LVMI was not significantly changed

Mehta 2009 [65]FOS 181 Mean (SD): 3.1 (2.1) yearsEchocardiography

Observational study using data from FOS

Patients with baseline LVH

Year 1 (n = 23):

◦. Mean baseline LVMI: 68.5 (20.0) g/m2.7

◦. Mean LVMI at year end: 58.4 (19.6) g/m2.7

◦. Mean change from baseline: − 10.1 (12.0) g/m2.7, p = 0.0006

Year 2 (n = 24)

◦. Mean baseline LVMI: 70.1 (19.7) g/m2.7

◦. Mean LVMI at year end: 56.9 (16.7) g/m2.7

◦. Mean change from baseline: −13.3 (17.2) g/m2.7, p = 0.001

Year 3 (n = 29):

◦. Mean baseline LVMI: 70.1 (21.2) g/m2.7

◦. Mean LVMI at year end: 59.8 (18.0) g/m2.7

◦. Mean change from baseline: −10.3 (20.8) g/m2.7, p = 0.0121

Year 5 (n = 32):

◦. Mean baseline LVMI: 71.4 (22.5) g/m2.7

◦. Mean LVMI at year end: 64.1 (18.7) g/m2.7

◦. Mean change from baseline: −7.3 (15.3) g/m2.7, p = 0.0111

Patients without baseline LVH

Year 1 (n = 17):

◦. Mean baseline LVMI: 38.5 (6.5) g/m2.7

◦. Mean LVMI at year end: 35.0 (5.7) g/m2.7

Mean change from baseline: −3.5 (6.8) g/m2.7, p = NS Year 2 (n = 18):

◦. Mean baseline LVMI: 38.9 (6.5) g/m2.7

◦. Mean LVMI at year end: 35.6 (7.4) g/m2.7

◦. Mean change from baseline: −3.4 (9.2) g/m2.7, p = NS

Year 3 (n = 24):

◦. Mean baseline LVMI: 38.4 (6.2) g/m2.7

◦. Mean LVMI at year end: 36.9 (6.9) g/m2.7

◦. Mean change from baseline: −1.5 (8.5) g/m2.7, p = NS

Year 5 (n = 25):

◦. Mean baseline LVMI: 38.7 (6.3) g/m2.7

◦. Mean LVMI at year end: 40.5 (10.0) g/m2.7

◦. Mean change from baseline: +1.8 (10.1) g/m2.7, p = NS

Pintos-Morell 2023 [41]FOS 285 Mean (SD):Early initiators group: 11.2 (5.7);Late initiators group: 11.8 (5.8)NR

Observational study using data from FOS

Annual LVMI increase

◦. Early-initiators group (n = 32):

-. Mean (SE) increase: 0.28 (0.30) g/m2.7/year,

p = 0.3457

◦. Late-initiators group (n = 58):

-. Mean (SE) increase: 1.03 (0.21) g/m2.7/year,

p < 0.0001

The rate of LVMI change was significantly different between the groups (p = 0.0419)
Ramaswami 2011 [50]FOS 8 Mean (SD): 4.2 (1.9) yearsEchocardiography

Observational study in pediatric patients using data from FOS

Patients received their first dose of agalsidase alfa before reaching the age of 7 years

Mean (SD) [range] LVMI (g/m2.7)

◦. Baseline (n = 6): 40.6 (6.51) [33.3, 52.3]

◦. At follow-up (n = 6): 31.8 (7.89) [22.4, 45.1]

Ramaswami 2012 [66]FOS 98 ≥6 monthsEchocardiography

Observational study in pediatric patients (<18 years old) using data from FOS

12 months (n = 26): no change in LVMI observed in 26 children

24 months (n = 17): mean (SD) LVMI declined from 35.7 (5.7) at baseline g/m2.7 to 31.7 (5.6) g/m2.7
Ramaswami 2019 [42]FOS 69 Median [range] time from start of ERT to FOS data extraction (years):Evaluable treated cardiac cohort (n = 69): 13.6 [10.1–17.1];Females (n = 34): 12.8 [10.1–16.5]; Males (n = 35): 14.3 [10.2–17.1] Echocardiography

Observational study using data from FOS

Number of patients (%) with LVH (defined as LVMI > 48 g/m2.7 in females and LVMI > 50 g/m2.7 in males)

◦. Evaluable treated cardiac cohort: 32/69 (46.4%)

◦. Females: 18/34 (52.9%)

◦. Males: 14/35 (40.0%)

Mean (SD) [95% CI] LVMI (g/m2.7)

◦. At baseline

-. Evaluable treated cardiac cohort (n = 69): 50.65 (16.90)

-. Females (n = 34): 52.21 (16.99) [46.3–58.1]

-. Males (n = 35): 49.13 (16.92) [43.3–54.9]

◦. At year 10

-. Females (n = 34): 58.8 [48.7–68.9]

-. Males (n = 35): 52.0 [43.2–60.8]

Mean [95% CI] LVMI slope (g/m2.7/year)

◦. Patients without LVH at baseline

-. Females (n = 16): 0.52 [−0.13, 1.17]

-. Males (n = 21): 0.57 [0.02, 1.13]

◦. Patients with LVH at baseline

-. Females (n = 18): 1.51 [0.91, 2.12]

-. Males (n = 14): 0.87 [0.19, 1.55]

Mean [95% CI] LVMI (g/m2.7) among cardiac cohort patients without renal involvement (eGFR > 90 mL/min/1.73 m2 and urinary protein <0.5 g/day) at baseline

◦. At baseline

-. Females (n = 6): 43.3 [27.1, 59.5]

-. Males (n = 10): 39.3 [34.1, 44.5]

◦. At year 10

-. Females (n = 6): 45.9 [22.9, 69.0]

-. Males (n = 10): 43.2 [36.3, 50.1]
Ries 2006 [51] 24 26 weeksEchocardiography

Open-label multi-center study in pediatric patients

Pediatric patients naive to ERT

Mean (SEM) LVMI (g/m2.7) at baseline

◦. Boys (n = 19): 32.4 (1.3)

◦. Girls (n = 5): 36.0 (4.0)

Mean (SEM) LVMI (g/m2.7) after 25 weeks of treatment

◦. Boys: 31.4 (1.4)

◦. Girls: 32.8 (2.3), p vs. baseline NS

Children (n = 3) with high–normal LVMI at baseline (>40 g/m2.7) had a mean decrease of 15% in LVM/h after 25 weeks of treatment
Sasa 2019 [52] 493 Mean [range]: 3.5 [0.0, 7.9] yearsEchocardiography

A post-marketing surveillance study involving patients with FD in Japan

Mean (SD) LVMI at each year, mean (SD) change in LVMI (g/m2.7) from baseline p versus baseline

◦. Males (classic phenotype)

-. Year 0.5 (n = 43): 69.1 (45.7), 1.6 (13.6), p = 0.459

-. Year 1 (n = 40): 64.9 (40.0), 0.6 (14.3), p = 0.777

-. Year 2 (n = 35): 66.8 (42.2), 3.4 (20.0), p = 0.320

-. Year 3 (n = 31): 69.8 (42.1), 3.3 (18.5), p = 0.328

-. Year 4 (n = 23): 61.8 (38.2), 7.4 (15.7), p = 0.035

-. Year 5 (n = 8): 68.9 (50.9), 15.0 (23.4), p = 0.112

-. Year 6 (n = 4): 81.3 (73.2), 23.5 (34.7), p = 0.268

-. Year 7 (n = 2): 122.8 (121.8), 51.7 (58.7), p = 0.430

-. Year 8 (n = 1): 192.1 (NA), 76.4 (NA)

◦. Males (non-typical variant)

-. Year 0.5 (n = 23): 79.4 (39.6), −1.4 (13.9), p = 0.638

-. Year 1 (n = 19): 79.9 (35.7), −5.3 (9.9), p = 0.031

-. Year 2 (n = 15): 70.3 (26.7), −8.5 (16.1), p = 0.060

-. Year 3 (n = 14): 68.8 (37.3), −4.2 (13.8), p = 0.271

-. Year 4 (n = 14): 67.2 (33.2), −3.4 (10.3), p = 0.240

-. Year 5 (n = 5): 75.4 (23.3), −0.2 (14.4), p = 0.973

-. Year 6 (n = 2): 91.0 (63.5), 15.5 (16.5), p = 0.412

◦. Females

-. Year 0.5 (n = 50): 65.9 (22.8), 1.8 (14.5), p = 0.384

-. Year 1 (n = 45): 64.2 (25.1), 2.8 (12.7), p = 0.147

-. Year 2 (n = 39): 66.9 (25.5), 2.7 (14.0), p = 0.240

-. Year 3 (n = 27): 74.3 (27.1), 4.3 (16.4), p = 0.187

-. Year 4 (n = 19): 71.3 (30.0), 2.6 (22.7), p = 0.626

-. Year 5 (n = 7): 79.8 (34.0), 4.3 (30.8), p = 0.727
Schiffmann 2014 [55] 17 Mean (SD): 6.5 (0.6) yearsEchocardiography

Open-label multi-center extension study for pediatric patients who had completed a 26-week study

This study represented the longest assessment of ERT in children with FD in a clinical trial setting

Pediatric patients with FD (7–17 years of age at study enrollment) received 6 months of 0.2 mg/kg agalsidase alfa

This study was divided into two phases, before (phase 1) and after (phase 2) a change in the agalsidase alfa manufacturing process

For all 17 patients, baseline mean (SD) [range] LVMI (g/m2.7) measurements were within the normal range (upper limit of normal range: males = 51 g/m2.7; females = 48 g/m2.7): 30.66 (5.96) [22.7, 42.3]

Through phase 1, LVMI decreased from baseline (mean change: −3.25 at week 185)

LVMI continued to decrease through phase 2 (except week 104)

Despite LVMI fluctuations observed in individual patients, levels remained below LVH criteria throughout the study
Tsuboi 2017 [61]Japan Fabry Research—002 36 Median [range]: 62.5 [8, 84] monthsEchocardiography

Prospective observational study in Japan

Cohort included ERT treatment-naive patients and those who were receiving agalsidase alfa 0.2 mg/kg every 2 weeks

At 60 months, LVMI had decreased from 50.3 at baseline to 46.6 g/m2.7
Whybra 2009 [63] 36 4 yearsEchocardiography

Prospective single-center open-label study of adult women in

Germany

A cohort of female patients with FD who were experiencing manifestations of FD and had not been previously treated with ERT

◦. LVH (defined as LVM ≥ 48 g/m2.7) at baseline (n/N [%]): 25/36 (69.4%)

◦. For patients with LVH, mean (SD) [range] LVM (g/m2.7) at baseline: 89.4 (42.1) [52.8, 201.1]

Number of patients with LVH at baseline (n = 25) with decreases in LVM

◦. LVM decrease of >20%: 13/25 (52%)

◦. LVM decreases of 10–20%: 7/25 (28%)

◦. LVM decreases of <10%: 5/25 (20%)

Mean (SD) LVMI (g/m2.7) over time by number of months of treatment and LVM classification (* p < 0.05 vs. baseline; ** p < 0.01 vs. baseline; *** p < 0.001 vs. baseline)

◦. LVM classification, > 85 (n = 9)

-. Month 12: 98.1 (31.1) ***

-. Month 24: 98.1 (31.7) ***

-. Month 36: 96.3 (34.0) ***

-. Month 48: 91.9 (29.7) ***

◦. LVM classification, > 60–85 (n = 9)

-. Month 12: 57.4 (13.3) ***

-. Month 24: 56.5 (14.6) ***

-. Month 36: 58.2 (13.2) ***

-. Month 48: 62.0 (17.7) ***

◦. LVM classification, > 48–60 (n = 8)

-. Month 12: 46.3 (4.7) ***

-. Month 24: 44.0 (5.2) ***

-. Month 36: 47.0 (2.8) ***

-. Month 48: 48.7 (4.1) ***

◦. LVM classification, <48 (n = 11)

-. Month 12: 36.2 (5.8) **

-. Month 24: 35.3 (7.8) **

-. Month 36: 37.0 (10.1) *

-. Month 48: 36.2 (7.1) **
Agalsidase beta single-arm studies
Cabrera 2017 [30] 39 Mean (SD): 68.2 (36.9) monthsEchocardiography

Long-term prospective and historical analysis of a cohort from Argentina

Mean (SD) LVMI in males slightly increased from 113.2 (45) to 127.4 (64) g/m2

11 male patients had LVH at baseline

In 4/11 males, baseline LVMI was reduced from 163.1 (64.7) to 123.4 (49.8) g/m2, 2 patients had a stabilized LVMI and 4 patients had an increased LVMI from 157.9 (32.3) to 261.6 (48.6) g/m2

9 female patients had LVH at baseline, only 1 patient increased their LVMI from 158 to 204 g/m2; all remaining patients reduced or stabilized their LVMI

All patients without LVH at baseline remained with a normal LVMI at the end of the study
Elliot 2006 [144] 5 Mean (SD): 10.1 (2.3) monthsEchocardiography

Males receiving 1 or 2 mg/kg agalsidase beta EOW

LVMI did not change from baseline to follow-up: mean (SD) [range] change, 0.4 (37.8) [−66.3, 26.4] g/m2; p = NS
Hwang 2022 [73] 10 22-week follow-upMean (SD) [range]: 4.6 (3.2) [1, 9] yearsEchocardiography

A phase 2 open-label study in Korea

8 patients had received previous ERT with agalsidase beta,

2 patients were treatment naive

Mean (SD) LVMI at week 22: 111.66 (61.74) g/m2; change from baseline, 4.00 (13.44); p = 0.625
Kalliokoski 2006 [145] 10 12 monthsEchocardiography

Observational study in Finland

Mean (SD) LVM (g)

◦. Before ERT: 275 (28)

◦. After 12 months of treatment: 292 (35); p = 0.27

Mean (SD) LVMI (g/m2)

◦. Before ERT: 151 (12)

◦. After 12 months of treatment: 156 (14); p = 0.37
Messalli 2012 [146] 16 48 monthsMRI

Observational study in Italy

Study specifically on cardiac structures (MRI study)

Baseline: mean (SD) LVM baseline (g), 187 (59)

LVM: mean (SD), 149 (44) g; p < 0.001 vs. baseline
Motwani, 2012 [147] 66 Median [range]: 3 [2, 5] yearsEchocardiography

Observational study in the United Kingdom

The overall mean (SD) LVMI was significantly reduced by ERT at follow-up (n = 66): 116 (28) vs. 113 (26) g/m2; p < 0.001

On sub-group analysis, this improvement was seen in both sexes and in both mild (FOS-MSSI ≤18) and moderate/severe (FOS-MSSI > 18) disease groups (all p < 0.05)

In patients with LVH at baseline (n = 42), mean (SD) LVMI was significantly reduced by ERT 135 (13) vs. 133 (3) g/m2; p < 0.05

There was no significant change in mean (SD) LVMI in those patients without baseline LVH (n = 24): 82 (6) vs. 82 (5) g/m2; p > 0.05
Pisani 2005 [148] 9 24-monthsEchocardiography

Non-randomized, open-label, prospective study in male patients undergoing maintenance dialysis in the context of renal replacement therapy

After 24 months of ERT (n = 9), LVMI did not change compared with basal values

Pre- vs. post-changes in LVMI

◦. In the 24 months before ERT, LVMI increased in all patients, and during the 24 months of therapy, progression of LVMI decreased in all except 2 patients

Average percentage of increase per year in LVMI was 6% during the 24 months preceding ERT and 3% during the 2 years of treatment

This also was shown by the comparison (p = 0.06) of mean (SD) LVMI curve slopes for the pretreatment period 0.98 (0.017) g/height2.7 with those obtained during the treatment period 0.46 (0.960) g/height2.7
Ramaswami 2019 [76] 31 5 yearsEchocardiography

Open-label parallel-group phase 3b study in male pediatric patients treated with 2 low-dose regimens (0.5 mg/kg q2w, n = 16 or 1.0 mg/kg q4w, n = 15)

Mean, median (SD) [range] LVMI, g/m2.7

◦. Baseline (n = 23): 33.2, 32.0 (5.1) [20.5, 44.1]

◦. Year 5 (n = 24): 31.4, 31.9 (7.2) [22.1, 53.4]
Veloso 2023 * [69] 9 Mean (SD):70.2 (12.9) monthsMRI and Echocardiography

Follow-up study of a family with FD with a classic pathogenic variant (p.G35V) in Brazil

Female patients presented a mean reduction of LVMI of

9.73 g/m2 (95% CI: −26.9, 6.8); p = NR
Weidemann 2013 [80] 40 ≥5 yearsMedian [IQR]: 6.0 [5.1, 7.2]MRI and Echocardiography

Assessment of long-term effects of agalsidase beta in Germany

Patients treated for at least 5 years with agalsidase beta

Mean (SD) LVM (g)

◦. Baseline: 270 (87)

◦. At follow-up: 224 (71); p < 0.0001 vs. baseline
Wuest 2011 [149] 14 13 ± 1 monthsEchocardiography

Assessment of the effect of ERT on right ventricular cardiac morphology and function

◦. Baseline: mean (SD) normalized LVM, 102 (26) g/m2

◦. At follow-up: mean (SD) normalized LVM, 94 (27) g/m2;

p < 0.05 between baseline and follow-up
(B)
Author Year Comparator Arms, n/N Treatment Duration Assessment Method Key Results
Comparator studies
Arends 2018 [29] Agalsidase alfa: 248 Agalsidase beta: 139 Median [range]: All patients: 4.9 [0.8, 14.4] years; Agalsidase alfa: 5.2 [0.8, 14.4] years; Agalsidase beta: 3.8 [0.8, 12.1] years Echocardiography

Retrospective cohort study involving three European centers and the Canadian FD Initiative

◦. In patients without LVH at baseline (n = 110), there was no change in LVMI after 1 year of ERT

◦. In patients with LVH (n = 168), there was a decrease after 1 year of treatment

The magnitude of the decrease depended on the LVMI at baseline (p < 0.001) and was independent of sex and phenotype

◦. Patients with an LVMI above the reference value but <75 g/m2.7 treated with agalsidase beta showed a larger but non-significant decrease of LVMI over the first year compared with alfa (beta alfa-beta: −3.31 g/m2.7; 95% CI: −6.84, 0.23; p = 0.07), but no difference for the entire group was found (beta alfa-beta: −2.26 g/m2.7; 95% CI: −5.39, 0.87; p = 0.15)

The decrease over the first year was followed by stabilization of LVMI in the following years (beta time on ERT: 0.22; p = 0.33)

The analysis of the number of patients who showed a decrease in LVMI after 1 year of treatment revealed that treatment with agalsidase beta resulted in a higher proportion of patients with a decrease in LVMI compared with agalsidase alfa (79% vs. 62%) (OR: 2.27; 95% CI: 1.11, 4.86; p = 0.03), adjusted for the LVMI at baseline
Beck 2015 [112] Agalsidase alfa: 164 Previously published untreated cohort: 78 Median [range]: 5.4 [1.5, 13.7] years Echocardiography

Retrospective comparisons with previously published data (agalsidase alfa-treated patients from the FOS registry with well-described cohorts of untreated individuals from previously published studies)

Mean annualized LVMI slope (SEM) [95% CI], g/m2.7/year by baseline LVH status

◦. Evaluable treated cardiac cohort from FOS

-. Males

▪. Total (n = 71): 0.33 (0.10) [0.13, 0.53]

▪. LVH (n = 29): 0.19 (0.16) [−0.13, 0.50]

▪. No LVH (n = 42): 0.47 (0.13) [0.22, 0.72]

Females

▪. Total (n = 93): 0.48 (0.09) [0.30, 0.66]

▪. LVH (n = 45): 0.77 (0.14) [0.49, 1.05]

▪. No LVH (n = 48): 0.19 (0.11) [−0.03, 0.41]

Previously published external untreated comparator cohort

-. Males

▪. Total (n = 39): 4.07 (1.03)

▪. LVH (n = 18): 6.59 (8.5)

▪. No LVH: not available

Females

▪. Total (n = 39): 2.31 (0.81)

▪. LVH (n = 15): 3.77 (7.7)

▪. No LVH: not available

A sensitivity analysis evaluating available 5-year follow-up LVMI FOS data was conducted in 38 males and 40 females (median [range] treatment duration, 8.45 [0.9, 11.7] years)

◦. The rates of change in LVMI overall and in patients with baseline LVH were not significantly different from the corresponding values for the full FOS ERT cardiac cohort
Figliozzi 2024 [164] 445 Median [IQR]: 45 [24–58] months MRI

Systematic review and meta-analysis of patients with baseline and follow-up cardiac MRI after ERT

Baseline LVM range: 95–270 g

LVMI range: 53–176 g/m2

Meta-analysis (random-effects model) of LVMI following ERT showed no changes; mean difference: −1 g/m2 (95% CI: −6, 3; 6 studies; 290 patients; I2 = 81%); p < 0.01

Meta-analysis of LVM following ERT: minimal decrease (mean difference: −18 g; 95% CI: −33, −3; 7 studies; 107 patients,

I2 = 96%); p < 0.01
Germain 2013 [166] Untreated group: 48 Agalsidase beta: 115 (11 included in both panels, because they had at least 2 years of LVM data during each observation period) Mean [range]: Untreated group, 4.1 [2.1, 12.7] years; Agalsidase beta, 4.8 [1.8, 9.5] years Echocardiography

Fabry Registry study to document the progression of LVH in male patients

Patients with LVH (LVM ≥ 225 g) at baseline, n/N (%)

◦. Untreated group: 29/48 (60%)

◦. Agalsidase beta: 66/115 (57%)

At follow-up, LVM slope (g/year) (SEM) by age category

◦. Age 18–29 years

-. During untreated period (n = 15): 9.5 (2.36)

-. During treatment (n = 31): −3.6 (1.62)

-. Difference in LVM slope: −13.0 (2.72); p < 0.0001

Age 30–39 years

-. During untreated period (n = 17): 8.4 (3.55)

-. During treatment (n = 44): 2.8 (2.20)

-. Difference in LVM slope: −5.6 (4.12); p = 0.1760

Age 40–49 years

-. During untreated period (n = 7): 13.4 (6.63)

-. During treatment (n = 23): 3.4 (2.87)

-. Difference in LVM slope: −10.0 (7.21); p = 0.1691

Age ≥ 50 years

-. During untreated period (n = 9): 0.4 (9.41)

-. During treatment (n = 17): 7.7 (4.48)

-. Difference in LVM slope: 7.3 (10.33); p = 0.4843
Golan 2015 [118] Agalsidase alfa 0.2 mg/kg EOW: 20 Agalsidase alfa 0.2 mg/kg weekly: 19 Agalsidase alfa 0.4 mg/kg weekly: 5 1 year Echocardiography

Phase 3/4 multi-center open-label study in treatment-naive adults

Evaluated the efficacy and safety of two agalsidase alfa dosing regimens (0.2 mg/kg EOW and 0.2 mg/kg weekly) in a specific population of adults with FD and LVH (defined as > 50 g/m2.7 for males and > 47 g/m2.7 for females)

Change from baseline in mean LVMI, g/m2.7

◦. 0.2 mg/kg EOW (n = 15): 3.2

◦. 0.2 mg/kg weekly (n = 18): 0.5

◦. 0.4 mg/kg weekly (n = 5): −10.3

% change (95% CI)

◦. 0.2 mg/kg EOW (n = 15): 3.9 (−3.71, 10.14)

◦. 0.2 mg/kg weekly (n = 18): 3.4 (−7.35, 8.32)

◦. 0.4 mg/kg weekly (n = 5): −9.3 (−24.9, 4.3)

0.2 mg/kg weekly minus EOW: LSM, −2.20 (95% CI: −12.26, 7.85); unadjusted p = 0.6585
Guerard 2018 [119] Lucerastat + ERT: 10 ERT only: 4 Lucerastat 1000 mg b.i.d. for 12 weeks Echocardiography

Single-center, open-label randomized study of lucerastat in adult patients in Germany

Investigated the safety and pharmacodynamics of lucerastat as oral substrate reduction therapy in patients with FD receiving ERT

All patients were on ERT for at least 24 months with no change in dose in the last 6 months

Mean (SD) baseline LVMI (g/m2)

◦. Lucerastat + ERT (n = 10): 111.7 (38.4)

◦. ERT only (n = 4): 88.6 (17.9)

Mean (SD) LVMI (g/m2) at week 4

◦. Lucerastat + ERT (n = 10): 104.1 (21.5)

◦. ERT only (n = 4): 95.3 (35.7)

Mean (SD) LVMI (g/m2) at week 8

◦. Lucerastat + ERT (n = 10): 105.9 (24.7)

◦. ERT only (n = 4): 90.2 (25.1)

Mean (SD) LVMI (g/m2) at week 12

◦. Lucerastat + ERT (n = 10): 104.4 (24.3)

◦. ERT only (n = 4): 94.3 (24.3)

No effect of treatment with lucerastat on LVMI was observed when comparing values obtained at each visit up to 12 weeks with those at baseline
Hughes 2008 [121] Agalsidase alfa: 7 Placebo: 8 Up to 4 years MRI and Echocardiography

Placebo-controlled study followed by open-label extension for 2 years

Mean (SEM) LVMI (g/m2) similar at baseline between groups

◦. Agalsidase alfa: 176 (10)

◦. Placebo: 186 (18); p = 0.7

Randomized phase

◦. MRI

-. Agalsidase alfa: mean decrease in LVM of 11.5 g

-. Placebo: mean increase of 21.8 g (p = 0.041 between groups)

-. Equated to mean increase in LVMI for the placebo group of 12 g/m2 compared with a decrease in the treated group of 6.4 g/m2 (p = 0.02 vs. placebo)

◦. Echocardiography

-. Placebo: 6.3% increase in LVM 21.5 (20.4) g

-. Agalsidase alfa: 6.2% decrease −20.4 (27.2) g; p > 0.05

◦. Open-label extension

-. MRI measurements in the 10 patients who continued to receive agalsidase alfa in the open-label extension phase of the trial demonstrated individual heterogeneity in response

-. After 2 years of active treatment mean LVM was not significantly changed (p = 0.18)

Subsequent to the trial, 11 patients continued to receive uninterrupted therapy with agalsidase alfa and have been monitored by annual echocardiography

After 4 years, 7 patients demonstrated a reduction in LVM while 4 showed increases compared with their pre-treatment baseline
Jovanovic 2017 * [160]FACETSATTRACT FACETS Migalastat or placebo: 67ATTRACT Migalastat or ERT: 60 FACETS: up to 24 months (plus OLE) ATTRACT: up to 30 months (including OLE) Echocardiography

To assess changes in cardiac parameters with long-term migalastat treatment (150 mg once daily; data from 2 phase 3 RCTs) versus placebo (FACETS) or ERT (ATTRACT)

FACETS (migalastat vs. placebo)

◦. After 18 or 24 months of migalastat treatment in FACETS (18 months for patients initially randomized to placebo, 24 months for patients randomized to migalastat), there was a statistically significant mean change from baseline in LVMI −7.7 g/m2; 95% CI: −15.4, −0.01; n = 27

◦. Among patients who entered the OLE, further reductions were seen month 30/36: −17.0 g/m2; 95% CI: −26.2, −7.9;

n = 15, including statistically significant changes in patients with LVH at baseline −20.8 g/m2; 95% CI: −37.4, −4.1; n = 11; 82% (9/11) had reductions and 45% (5/11) had normalizations of LVMI

ATTRACT vs. ERT

◦. LVMI was reduced in patients treated with migalastat in the ATTRACT trial

◦. Mean changes from baseline at 18 months

-. Migalastat (n = 31): −6.6 g/m2 (95% CI: −11.0, −2.1)

-. ERT (n = 13): −2.0 g/m2 (95% CI: −11.0, 7.0);

Mean changes from baseline at 30 months

-. Migalastat (n = 30): −3.8 g/m2 (95% CI: −8.9, 1.3)

Among those with baseline LVH (n = 13), LVMI was reduced by −9.0 g/m2; 85% (11/13) had reductions and 31% (4/13) had normalizations of LVMI and regression of LVH
Kramer 2014 [161] ERT: 57 No ERT: 16 Mean (SD): 4.8 (2.4) years MRI

Observational study of adults in a single center in Germany

Investigated the impact of myocardial fibrosis in FD; ERT vs. no ERT (type of ERT not defined)

Mean (SD) LVM (g/m2)

◦. Baseline

-. ERT (n = 57): 92 (33)

-. p < 0.05 vs. no ERT at baseline

-. No ERT (n = 16): 59 (11)

At follow-up

-. ERT (n = 56): 90 (30)

-. p < 0.05 vs. no ERT at follow-up

-. No ERT (n = 16): 61 (14)
Lee 2022 [162] ERT: 267 No ERT: 285 4.1 years NR

Meta-analysis to characterize patients with FD with LVH, with or without ERT, and to assess the effectiveness of ERT in LVH improvement

Patients (either ERT-experienced [agalsidase alfa or agalsidase beta]) or ERT-naive) included from 5 clinical cohort studies and 2 RCTs

Additional subgroup analysis for 4 years after ERT (n = 214) and before ERT (n = 228; patients from 3 cohort studies and 1 RCT)

LVMI at follow-up

◦. Difference in means of LVMI between the ERT treatment group and the ERT treatment-naive group: −0.149 [95% CI: −0.431, 0.132]; p = 0.034

◦. Difference in means of LVMI between the before ERT group and the 4 years after ERT group: −0.448 [95% CI: −0.787, −0.108]; p = 0.037
Madsen 2017 [37] ERT: 47 No ERT: 19 Median [range]: Patients in ERT 8 [0, 12] years; Patients without ERT 6 [0, 13] years Echocardiography

Progression of cardiac involvement was assessed in a Danish cohort

Baseline LVMI (g/m2), median [range]

◦. ERT (n = 45): 102 [54, 231]

◦. Non-ERT (n = 17): 89 [50, 271]

LVMI (g/m2) at follow-up, median [range]

◦. ERT (n = 39): 97 [47, 306]

◦. No ERT (n = 14): 104 [55, 328]

◦. ERT with cardiac disease (n = 30): 100 [66, 306]

◦. ERT without cardiac disease (n = 9): 73 [54, 113]

Progression in LVMI (g/m2) per year, estimate (SEM)

◦. ERT: −0.8 (0.6)

◦. No ERT: 0.2 (0.7)

◦. ERT with cardiac disease: −1.0 (0.6)

◦. ERT without cardiac disease: −0.5 (1.2)
Mignani 2008 [163] Dialysis: 17 Transplant: 17 Mean (SD):Dialysis patients: 45.1 (19.8) months; Transplant patients: 48.4 (13.2) months Echocardiography

Cross-sectional survey study of patients in Italy with FD and ESRD receiving RRT (dialysis or renal transplant) and ERT

ERT comprised agalsidase beta (n = 30) 1 mg/kg or agalsidase alfa

(n = 3) 0.2 mg/kg

Mean baseline LVMI (g/m2)

◦. Dialysis patients (n = 7): 210.9

◦. Transplant patients (n = 11): 234.6

LVMI percentage change from baseline at year 3

◦. Dialysis patients (n = 7): 19%

◦. Transplant patients (n = 11): −6%
Nordin 2019 [156] Pre-ERT group, 20 Established ERT, 18 No ERT, 18 Mean (SD): 1.1 (0.2) years Median [range]: Pre-ERT group: 1 year; Established ERT: 4.2 [1.4, 12.2] years; No ERT: 1 year MRI

Pre-ERT (initiated ERT, n = 20)

◦. Overall, there was no change in mean (SD) LVMI: 93 (42) g/m2 at baseline to 92 (40) g/m2 (p = 0.186) over 1 year after ERT initiation

◦. Among LVH-positive patients, change in mean (SD) LVMI: −2 (3) g/m2; p = 0.048

◦. Among LVH-negative patients, no change in mean (SD) LVMI: 0 (4) g/m2; p = 0.766

Established ERT (advanced stable disease, n = 18)

◦. Over 1 year, there was no significant difference in LVMI:

124 (45) g/m2 at baseline to 125 (45) g/m2 (p = 0.070)

◦. LVH-positive vs. LVH-negative: NA (sample size too small)

No ERT (early disease, mostly females, n = 18)

◦. Over 1 year, there was a small increase in LVMI: 65 (15) g/m2 at baseline to 67 (16) g/m2 (p = 0.005)

◦. LVH-positive vs. LVH-negative: NA (sample size too small)

Interactions between all three groups revealed statistically significant difference in LVMI (p = 0.009; difference for pre-ERT vs. both established ERT and no ERT)
Pogoda 2023 [165] Untreated controls: 30 Migalastat-treated: 20 ERT-treated: 48 Up to 81 months Echocardiography

A prospective observational single-center study in Germany

The control group was untreated females with FD who were younger than the treated group

LVMI at baseline, median [range] g/m2

◦. Untreated females: 82.9 [46.6–155.2]

◦. Migalastat-treated females: 88.2 [48.6–151.3]

◦. ERT-treated females: 114.4 [64.9–297.8]

◦. Migalastat-treated males: 138 [76–220]

◦. ERT-treated males: 130.2 [80.1–396.0]

Change per year in LVMI from baseline, median [range] g/m2

◦. Untreated females: 1.44 [−44.6, 45.6]

◦. Migalastat-treated females: 2.57 [−36.8, 10.0]

◦. ERT-treated females: 0.86 [−10.9, 13.9]

◦. Migalastat-treated males: −7.2 [−14.2, 27.9]

◦. ERT-treated males: −1.17 [−15.6, 15.7]

Independent of treatment, yearly changes in cardiac parameters including LVMI in females and males were stable, pointing at disease stabilization
Van der Veen 2022 [33] 0.5 mg/kg agalsidase beta: 3 1.0 mg/kg agalsidase beta: 4 Untreated: 23 Median [range]: 10.4 [9.5, 10.7] years MRI and Echocardiography

Compared outcomes in young male patients (median [range]: treated, 24 [14, 26] years; untreated, 22 [13, 27] years) after 10 years of treatment with ERT with those of a group of untreated patients with FD with the same phenotype (classic) and of comparable age

6/7 patients switched to full dose (1 mg/kg EOW) after a median treatment duration of 9 years (range: 8.3, 10)

LVM median [range] g/m2 at follow-up (baseline values NR)

◦. Based on echocardiography

-. Treated: 80 [67, 84]

-. Untreated: 94 [59, 149]

-. p = 0.02

Based on MRI (including papillary muscles)

-. Treated: 53 [46, 59]

-. Untreated: 68 [53, 99]

-. p = 0.02

Analyses were repeated after excluding patients with renal involvement; this did not change the outcome

Mass measured by echocardiography and MRI correlated well (ϱ = 0.72, p = 0.002)
Vedder 2007 [28] Agalsidase alfa: 18 Agalsidase beta: 16 24 months Echocardiography

Median LVM (SD) [range], g

◦. 12 months: agalsidase beta, 296 (76) [169, 401]; agalsidase alfa, 244 (89) [157, 424]

◦. 24 months: agalsidase beta, 308 (90) [196, 471]; agalsidase alfa, 294 (87) [196, 502]

No significant differences between groups

* Congress abstract. B.i.d., twice a day. CI, confidence interval. EOW, every other week. ERT, enzyme replacement therapy. ESRD, end-stage renal disease. FD, Fabry disease. FOS, Fabry Outcome Survey. IQR, interquartile range. LS, least-squares. LSM, least-squares mean. LVH, left ventricular hypertrophy. LVM, left ventricular mass. LVMI, left ventricular mass index. max, maximum. MRI, magnetic resonance imaging. NA, not applicable. NR, not reported. NS, non-significant. OLE, open-label extension. OR, odds ratio. q2w, every 2 weeks. q4w, every 4 weeks. RCT, randomized controlled trial. RRT, renal replacement therapy. SD, standard deviation. SE, standard error. SEM, standard error of the mean.

3.3. Cerebrovascular Outcomes

Cerebrovascular disease is a common manifestation of FD [1]. Overall, 24 studies assessing cerebrovascular outcomes were identified, with publications describing single-arm studies of agalsidase alfa (n = 6) [21,48,51,60,171,172], agalsidase beta (n = 4) [30,71,80,148], mixed or non-specified ERT (n = 12) [31,32,34,35,36,76,88,89,90,173,174,175], and other treatments (n = 2, both on migalastat) [101,176]. In total, eight publications reported the results of comparator studies [33,37,108,126,163,177,178,179] and one publication described a switch study [131]. An overview of cerebrovascular data from agalsidase alfa and agalsidase beta single-arm studies and the comparator studies is presented in Table 3. Key results from the other types of studies are provided in Supplementary Table S8.

The six agalsidase alfa single-arm studies of cerebrovascular outcomes had follow-up periods ranging from 6 months to 4 years (Table 3A). The largest of these was a long-term study in 677 patients from the FOS registry, of whom 85.4% had no cerebrovascular events over 3 years of treatment with agalsidase alfa [21]. Differences were noted in the frequency of cerebrovascular events between males and females, although these were inconsistent between studies [21,48]. Some smaller studies reported the development of WMLs in patients during treatment, possibly related to aging [51,60,171]. In the four agalsidase beta single-arm studies reporting on cerebrovascular outcomes, follow-up periods ranged from 1 to 20 years (Table 3A). Two studies reported no cerebrovascular events after at least 12 or 24 months of follow-up (n = 39 and 9, respectively) [30,148], although the development of new lesions in two asymptomatic male patients was noted in one of these studies [30]. In another study of Fabry Registry data, 10% of patients had a stroke or TIA over a median treatment duration of 6 years (n = 40) [80].

Single-arm studies of the effects of mixed or non-specified ERT on cerebrovascular outcomes in adults had median follow-up periods of 3.5 to 9 years, and all found that some patients receiving ERT developed cerebrovascular events (such as stroke or TIA) and/or WMLs (Supplementary Table S8). Two congress publications reported cerebrovascular outcomes in patients receiving migalastat in single-arm studies (one meta-analysis and one observational study) [101,176]. The meta-analysis of data from phase 2 and 3 clinical trials (n = 114) found that 7% of patients had cerebrovascular events over a median treatment duration of 4.4 years, with 2% having a first cerebrovascular event during treatment [176]. The observational study (n = 97) reported an incidence of 13.2 cerebrovascular events per 1000 patient-years over a median follow-up of 5.1 years [101].

Overall, studies reporting the efficacy of ERT versus placebo or other comparators in relation to cerebrovascular outcomes did not show a significant effect of treatment (Table 3B). One observational study (n = 112) investigated cerebrovascular outcomes in patients who either remained on agalsidase beta throughout the whole study, switched from agalsidase beta to alfa or switched from agalsidase beta to alfa and switched back to beta [131] (Supplementary Table S8). Over 24 months, the relative risk for stroke/TIA was lower in the agalsidase beta and switch groups than in the re-switch group [131]. Table 3

Overview of cerebrovascular data from (A) single-arm agalsidase alfa or agalsidase beta studies and (B) comparator studies.

(A)
Author, YearNTreatment DurationKey Results
Agalsidase alfa single-arm studies
Beck 2018 [21]FOSTotal: 677Female: 317 (47%)Male: 360 (53%)Median [IQR]:Overall: 3.0 (1.1, 6.7) years;Female: 2.9 (1.2, 6.3) yearsMale: 3.2 (1.0, 7.0) years

Observational study from FOS

578 patients (85.4%) (258 female [81.4%] and 320 male [88.9%]) did not experience a CBV event (stroke/TIA/PRIND) during follow-up

The Kaplan–Meier point estimate (95% CI) for median age in years at first CBV event was 70.9 (68.1, NE; due to the small number of events) in female patients and NE (64.9, NE) in male patients

Hughes 2011 [48]FOSTotal: 250Female: 78 (31.2%)Male: 172 (68.8%)4 years

Observational study using data from FOS

Retrospective chart review to determine whether women respond to ERT in a similar way to men

Data on CBV events (stroke/TIA/PRIND) were available for 21 women (27%)

4 women (19%) experienced a CBV event at baseline

1 (25%) of these 4 patients was reported to have also had an event between 42 and 54 months after the start of ERT

Of the 17 women (81%) who did not experience a CBV event at baseline,

1 (6%) experienced an event between 42 and 54 months after the start of ERT

Data on CBV events were available for 23 men (13%)

Of the 7 men (30%) in whom a CBV event was reported at baseline, 4 (57%) were noted to have had a subsequent event at the 4-year time point

Among the 16 male patients (70%) who were not reported to have had an event at baseline, there were 2 (13%) new reports of a CBV event

Jardim 2006 [171]824 months

Prospective observational open-label study observing central nervous system manifestations during ERT

At baseline, 4 patients (50%) showed a widespread pattern of deep WML

In this group, WML showed a trend related to age and to the presence of hypoacusia

After 12 months of ERT, MRI remained normal in 4 patients (50%), showed the same WML in 2 other patients (25%) and showed worsening in

2 patients (25%) who were the eldest

Of the 6 (75%) who completed 24 months on ERT, MRI was stable in 3 (50%); it was normal in 2 patients and showed the same lesions in the other patient. WML worsened in 1 patient (16.7%), fluctuated in 1 patient (16.7%) and disappeared in 1 patient (16.7%), who was the youngest

These variations in WML numbers did not correlate with residual enzymatic activity

In 2 years, 4 lesions disappeared and 8 appeared

Number of WML by patient (age in years at baseline), at baseline/12 months/24 months

◦. Patient 1 (46): 6/9/10

◦. Patient 2 (36): 6/8/8

◦. Patient 3 (31): 1/1/1

◦. Patient 4 (27): 0/0/0

◦. Patient 5 (27): 0/0

◦. Patient 6 (24): 2/2/0

◦. Patient 7 (24): 0/0

◦. Patient 8 (NR): 0/0/0

Lee 2017 [172]FOSTotal: 37IVS4: 25Classic FD: 12NR

Retrospective analysis comparing central nervous system manifestations in Taiwanese patients with the IVS4 mutation or classic FD mutations

Infarcts were observed in similar proportions of patients with IVS4 and classic FD (32.0% and 33.3%, respectively), although there were differences in the site of occurrence

Anterior circulation stroke and posterior circulation stroke alone each occurred in 8.0% of patients with IVS4

Anterior and posterior circulation stroke occurred in combination in 16.0% of patients with IVS4

Posterior circulation stroke alone was not observed in patients with classic FD

Anterior circulation stroke alone and anterior and posterior circulation stroke combined each occurred in 16.7% of classic patients with FD

There was a high prevalence of non-specific signs and symptoms or silent infarcts in both groups (62.5% in IVS4 and 50.0% in classic FD)

The pulvinar sign was observed in a greater proportion of patients with classic FD (50.0%) than IVS4 (32.0%)

Hemorrhage was noted in MRIs from 16.7% of patients with classic FD but not in patients with IVS4 (p = 0.0991)

Median (range) basilary artery diameter (mm) was 2.7 (1.4, 4.0) in patients with IVS4 and 3.2 (2.3, 4.7) in patients with classic FD (p = 0.0293)

Ries 2006 [51]24 pediatric patients24 weeks

Open-label study at 3 tertiary care centers in pediatric patients

One CBV accident occurred and was classed as a serious adverse event, considered unrelated to treatment

One 16-year-old patient had repeated small-vessel strokes, commencing at 14 years of age, which continued after >18 months on ERT

The patient had an intensive work-up that did not uncover a prothrombotic disorder other than FD. However, an unrecognized susceptibility factor for strokes (in addition to FD) was not excluded owing to the uncommonness of recurrent small-vessel strokes at that age

Thofehrn 2009 [60]936 months

Single-center, open-label study in Brazil

One patient had a transient CBV ischemic episode at 8 months of ERT and received aspirin and ticlopidine

Agalsidase beta single-arm studies
Cabrera 2017 [30]39 (switching owing to treatment shortage was allowed)≥12 months

Long-term prospective and historical analysis of cohort of patients from

Argentina

Observational cohort study analyzing the effectiveness of long-term follow-up of ERT on renal, cardiac and CBV parameters

No patient had a stroke at baseline or during the follow-up

Two male patients presented progression in the number of new MRI lesions, all were asymptomatic

Dutra-Clarke 2021 [71]Total: 26AdultsFemale: 13 (50%)Male: 11 (42%)ChildrenMale: 2 (8%)2–20 years

Retrospective cohort study in the US

WMLs were present in 4 adult participants (25%) who had brain imaging (3/10 female patients [30%], 1/6 male patients [17%])

One male patient in this cohort had a history of two CBV accidents, one TIA at 52 years of age and one stroke at 60 years of age

Another male patient and one female patient in this cohort had a history of TIAs while on ERT; they were not taking low dose aspirin at the time

Adult male patients had higher frequencies of clinical manifestations than adult female patients in all categories, with the exception of neuropathic pain, WMLs and corneal verticillate

Pisani 2005 [148]924 months

Non-randomized, open-label, prospective study evaluating the impact of 2 years of ERT on the clinical expression of FD in patients undergoing maintenance dialysis, and to investigate changes in symptoms and the echocardiographic evolution of FD cardiomyopathy in the context of RRT

2 patients (22%) had CBV symptoms (TIA and stroke) at baseline (before starting ERT)

During the entire follow-up period, no patient experienced CBV events, and antihypertensive therapy had to be intensified in only 2 patients

Weidemann 2013 [80]40Median [IQR]: 6 (5.1, 7.2) years

Prospective observational study in patients with advanced FD at a single center in Germany

4 patients (10%) developed a stroke during follow-up at ages 41, 46, 54, and 60 years

Only 1 of these patients experienced a TIA before the onset of stroke

3 patients (8%) developed new TIA

(B)
Author, YearNTreatment DurationKey Results
Comparator studies
Banikazemi 2007 [177]Agalsidase beta: 51Placebo: 31Mean (SD): 18.4 (8.8) months

Randomized, double-blind, multi-center placebo-controlled trial

There were no stroke or TIA events in the agalsidase beta group compared with 2 strokes in the placebo group (OR: 0 [95% CI: 0, 3.2]; p = 0.14)

Fellgiebel 2014 [178]Agalsidase beta: 25Placebo: 16Mean [range]: 27 [12, 33] months

Post hoc analysis of data from a phase 4 placebo-controlled study

The effect of agalsidase beta on WML progression and CBV events were assessed longitudinally

At baseline, MRIs showed signs of brain infarction in 20% (5 of 25) of patients in the ERT group and 19% (3/16) of patients in the placebo group

At follow-up, MRIs showed that 13% (2/16) of patients in the placebo group and 4% (1 of 25) of patients in the ERT group had

developed new infarcts

WML burden was present in 63% of patients at baseline and correlated with LVH and previous or recent strokes

Mean normalized WML diameter (SD) at baseline, follow-up, follow-up minus baseline:

◦. Agalsidase beta (n = 25): 3.5 (5.2), 4.2 (5.6), 0.7 (1.9)

◦. Placebo (n = 16): 2.8 (3.0), 3.9 (4.3), 1.0 (2.1)

Overall, there were no significant differences in WML burden between the ERT and placebo groups at baseline or at follow-up

Patients > 50 years had a significantly higher WML burden at follow-up and significantly higher increases in WML burden over time compared with patients aged ≤ 50 years

In a subgroup analysis of patients ≤ 50 years of age, the proportion of patients with a stable or decreased WML load was significantly higher in the agalsidase beta group, (8/18 [44%]) than in the placebo group (4/13 [31%]; p = 0.014)

Lenders 2015 [179]ERT: 187No ERT: 117Mean [range]: 6.1 [1, 12]

Observational, retrospective study investigating the risk of thromboembolic events in Germany

The additional risk of thromboembolic events with the concurrence of FVL was assessed

Among all patients, 14.1% had experienced ≥ 1 stroke or TIA, while 3.3% experienced a deep vein thrombosis or pulmonary embolism

◦. Overall (n = 304): 89 thromboembolic events reported, 1.68 events per 100 person-years

◦. ERT (n = 8): 15 thromboembolic events, 1.94 events per 100 person-years

◦. No ERT (n = 15): 8 thromboembolic events, 3.73 events per 100 person-years

Patients with FD not receiving ERT have an ~2.8-fold increased risk of thromboembolic events compared with those receiving ERT

The occurrence of thromboembolic events was significantly increased for patients with FVL compared with those without FVL; HR: 5.45; 95% CI: 2.29, 12.99; p < 0.0001

Madsen 2017 [37]Agalsidase alfa or beta (switching allowed): 47No ERT: 19Median [range]:ERT: 8 [0, 12] years;No ERT: 6 [0, 13] years

Retrospective cohort study in a Danish cohort

At baseline, CBV events (stroke/TIA) occurred in 6 patients (13%) in the ERT group and 1 patient (5%) in the no ERT group

At follow-up, CBV events occurred in 7 patients (16%) in the ERT group and 0 patients (0%) in the no ERT group (p = 0.37)

Mignani 2008 [163]Dialysis: 17Kidney transplant: 17Mean (SD): Dialysis: 45.1 (19.8) months;Transplant: 48.4 (13.2) months

Cross-sectional survey study in Italian patients with FD and ESRD

During ERT, 9 acute cardiac and CBV events occurred in the dialysis group and 3 in the group of allograft recipients (p < 0.05); all were considered to unrelated to ERT

Skuban 2017 * [108]FACETSATTRACTFACETSMigalastat or placebo: 67OLE, migalastat: 60FACETS: 6-month double-blind followed by open-label migalastat from 6 to 12 months (stage 2) plus an additional yearATTRACT:Migalastat or ERT: 5318 months

Analysis of 2 randomized phase 3 clinical studies

ATTRACT: 1 CBV event (6%), a TIA, was reported in the ERT group

Van der Veen 2022 [33]TreatedAgalsidase beta: 3Agalsidase alfa: 4Untreated: 23Median [range]: 10.4 [9.5, 10.7] years

Cross-sectional retrospective study comparing outcomes in patients with classic FD after 10 years of treatment with ERT to a group of untreated patients with the same phenotype of comparable age

WMLs were present in 1 treated patient (14%) and 6 untreated patients (26%) (p = 0.6)

In the untreated group, a lacunar infarction was described in one patient and microbleeds were found in another

Wilcox 2004 [126]Agalsidase beta: 29Placebo: 2930–36 months

Phase 3 randomized, placebo-controlled, double-blind trial

5/58 (8.6%) patients reported CBV events (stroke or TIA) at the time of the report

1 of these patients had an extensive past history of stroke; the other 4 patients, presumably, did not have a prior history of stroke

The lack of a placebo group makes interpretation of these data difficult

To note, the phase 3 extension study was not designed to assess the effect of ERT on clinical outcomes

Data on stroke and CV events were not collected as part of the study but rather as AEs

* Congress abstract. AE, adverse event. CBV, cerebrovascular. CI, confidence interval. CV, cardiovascular. ERT, enzyme replacement therapy. FD, Fabry disease. FOS, Fabry Outcome Survey. FVL, factor V Leiden. HR, hazard ratio. IQR, interquartile range. MRI, magnetic resonance imaging. NE, not estimable. NR, not reported. OLE, open-label extension. OR, odds ratio. PRIND, prolonged reversible ischemic neurologic deficit. RRT, renal replacement therapy. SD, standard deviation. TIA, transient ischemic attack. WML, white matter lesion.

3.4. Disease Severity

The MSSI was developed to measure the severity of general, renal, cardiovascular, and neurological signs and symptoms of FD and to monitor the clinical course of disease response to treatment [180]. The MSSI ranges from 0 to 76, with higher scores indicating greater disease severity. Scores are categorized as mild (<20 points), moderate (20–40 points), and severe (>40 points) [180]. Overall, 15 studies were identified that explored the impact of FD treatment on MSSI scores: four single-arm studies of agalsidase alfa [63,180,181,182], one with mixed ERT [28], two with other treatments (migalastat and pegunigalsidase alfa) [107,159], four comparator studies [113,183,184,185,186], and four switch studies [131,133,136,137,187]. No single-arm studies with MSSI data were identified for agalsidase beta. An overview of MSSI data is presented in Table 4.

Three of the four single-arm studies on agalsidase alfa demonstrated significant improvements in MSSI scores after 1–4 years of treatment [63,180,181] (Table 4A). In the fourth study (n = 85), 77% of patients had no improvement in MSSI score, and 14% progressed to more severe disease after 1 year of home therapy [182]. A mixed ERT study including agalsidase alfa and agalsidase beta (n = 20) found that a severe MSSI score at baseline was associated with treatment failure in male patients after 2 years of follow-up [28]. In an observational study of migalastat (n = 16), no significant changes in MSSI scores were observed over 18 months of treatment [159]. An observational study of pegunigalsidase alfa (n = 19) showed improvements in each MSSI subscale after 12 months of treatment [107].

Four comparator studies reporting MSSI scores were identified, all of which compared patients receiving unspecified ERT with those not receiving ERT (Table 4B). Two studies found no significant differences in MSSI scores between males in either group, while females on ERT had significantly higher scores [183,185]. One study found a significant improvement in cardiovascular MSSI scores with ERT after 12 months of treatment, although the number of patients was not reported [184,186]. The final study, which used the adapted FOS-MSSI in patients who underwent a kidney transplantation, did not find any differences between the treatment groups [113]. Of the four switch studies, two showed stable MSSI scores after switching from agalsidase beta to agalsidase alfa for 12 or 24 months [137,187], one found similar stable scores after re-switching to agalsidase beta [131], and one showed similar increases in MSSI scores in patients regardless of switching [133].

Table 4

Overview of MSSI data in (A) single-arm studies and (B) comparator and switch studies.

(A)
Author, Year Study Identifier N Treatment Duration Key Results
Agalsidase alfa single-arm studies
Concolino 2017 [182] 85 Mean [range]:1.9 years [3 months, 4.5 years]

Multi-center observational study of Italian patients receiving home infusions

MSSI total score, mean [range]

◦. Diagnosis (n = 73): 16.1 [1, 55]

◦. Starting home therapy (n = 75): 18.6 [2, 56]

◦. Last follow-up (n = 74): 19.3 [2, 54]
Parini 2008 [181] 30 Median [range]:2.9 [1.0, 6.2] years

Multi-center observational study in Italy

Change from baseline to follow-up in MSSI score, median [range]

◦. Total: −4 [−21, 6]; p < 0.0001

◦. General: −1 [−5, 3]; p = 0.0005

◦. Neurological: −1 [−13, 5]; p = 0.0056

◦. CV and renal MSSI scores did not change from baseline
Whybra 2004 [180] 39 1 year

Single-center study of adults with FD in Germany

Decrease in MSSI score from baseline, median [range]

◦. Total: 9 [6, 12]; p < 0.001

◦. General: 2 [1, 3]; p < 0.001

◦. Neurological: 3 [2, 5]; p < 0.001

◦. CV: 2 [0, 4]; p < 0.001

◦. Renal: 0 [0, 2]
Whybra 2009 [63] 40 4 years

Prospective single-center open-label study of female patients in Germany

MSSI total score decreased significantly after the first year of treatment and remained significantly reduced through 4 years

◦. Changes in the neurologic and CV subscores were responsible for most of the change in MSSI
Mixed ERT single-arm studies
Vedder 2007 [28] 34 2 years

Randomized open-label study of Dutch and Norwegian patients

MSSI score, mean [range]

◦. Males with treatment failure (progression of cardiac, renal or cerebrovascular disease): 44 [17, 59]

◦. Males without treatment failure: 21 [12, 37]; p = 0.02 vs. with treatment failure
Migalastat single-arm studies
Camporeale 2023 [159]MAIORA 16 18 months

Prospective, observational single-center study to evaluate cardiac outcomes in Italian patients

MSSI (Median [range])

◦. Total score:

baseline: 19.0 [16.0, 23.0]; follow-up: 18.5 [13.5, 24.5]; p = 0.31

◦. General score:

baseline: 5.0 [3.0, 6.0]; follow-up: 5.0 [2.0, 6.0]; p = 0.31

◦. Neurological score:

baseline: 5.0 [3.0, 7.0]; follow-up: 6.5 [3.5, 8.0]; p = 0.85

◦. CV score:

baseline: 9.0 [0.0, 13.0]; follow-up: 9.5 [3.0, 13.0]; p = 1.00

◦. Renal score:

baseline: 0.0 [0.0, 2.0]; follow-up: 0.0 [0.0, 0.0]; p = 1.00
Pegunigalsidase alfa single-arm studies
Schiffmann 2019 [107] NCT01678898, NCT01769001 19 12 months

Improvements in each subscale of the MSSI were observed during the study

◦. Total MSSI score:

baseline: 6.6, follow-up change from baseline: −1.9

◦. Neurological score:

baseline: 7.8, follow-up change from baseline: −2.6

◦. CV score:

baseline: 3.7, follow-up change from baseline: −0.8

◦. Renal score:

baseline: 2.5, follow-up change from baseline: −1.0
(B)
Author, year Study Identifier Treatment Groups, n Key Results
Comparator studies
Biegstraaten 2010 [183] ERT: 30No ERT: 18

Cohort from the Netherlands

MSSI total/general/neurological/CV/renal, median [range]

◦. ERT male (n = 13)

-. 27 [10, 47]/5 [2, 11]/6 [3, 13]/9 [1, 15]/0 [0, 12]

◦. Non-ERT male (n = 2)

-. 11 [5, 17]; p = 0.23 vs. ERT male/3.5 [2, 5]; p = 0.31 vs. ERT male/0.5 [0, 1]; p = 0.02 vs. ERT male/7 [3, 11]; p = 0.69 vs. ERT male/0; p = 0.38 vs. ERT male

◦. ERT female (n = 17)

-. 23 [3, 35]/5 [1, 8]/4 [1, 12]/9 [0, 15]/4 [0, 12]

◦. Non-ERT female (n = 16)

-. 7 [1, 18]; p = 0.00 vs. ERT female/2 [0, 5]; p = 0.00 vs. ERT female/1.5 [0, 7]; p = 0.04 vs. ERT female/1.5 [0, 11]; p = 0.07 vs. ERT female/0; p = 0.00 vs. ERT female
Chen 2016 [184], Chen 2017 [186] ERT: 25

MSSI CV score from baseline to 12 months, mean (SD)

◦. ERT baseline: 13.8 (2.8)

◦. ERT follow-up: 12.4 (2.3); p < 0.05 vs. baseline
Cybulla 2008 [113]FOS Kidney transplant + ERT: 20Kidney transplant + no ERT: 7

FOS-MSSI score, mean (SD) at baseline

◦. ERT: 34.7 (9.2)

◦. No ERT: 31.6 (6.3)
Rosa 2021 [185] ERT: 22No ERT: NR

MSSI score, mean (SD) at baseline

◦. ERT men: 29.0 (11.1)

◦. No ERT men: 26.7 (14.9); p = 0.78 vs. ERT men

◦. ERT women: 25.8 (8.2)

◦. No ERT women: 10.3 (7.1); p = 0.0003 vs. ERT women
Switch studies
Kramer 2018 [131] Regular dose agalsidase beta: 37Switch group to agalsidase alfa: 38Re-switch group to agalsidase beta after 12 months agalsidase alfa: 37

MSSI score, after 12 months of treatment/24 months of treatment, mean (SD)

◦. Regular dose: 25 (13)/27 (12)

◦. Switch: 23 (12)/25 (12)

◦. Re-switch: 21 (10)/22 (11)

◦. p < 0.05 switch v re-switch after 12 months
Lenders 2021 [133] Agalsidase beta regular dose: 17 Switch: 22 (patients treated with agalsidase beta for ≥12 months, then dose-reduced and subsequently switched to agalsidase alfa)Re-switch: 39 (patients treated with agalsidase beta for≥12 months, then dose-reduced or switched to agalsidase alfa for≥24 months and then re-switched to agalsidase beta)

All groups showed a significant increase in MSSI scores over the follow-up period of ~80 months

◦. Re-switch group: MSSI increase: 1.0 (95% CI: 0.7, 1.4) per year (p < 0.001)

◦. Switch group: MSSI increase: 0.8 (95% CI: 0.2, 1.5) per year(p = 0.0189)

◦. Regular agalsidase-beta group: MSSI increase: 1.1 (95% CI: 0.7, 1.4) per year (p < 0.001)

Comparison between groups: no significant differences in yearly MSSI increase between the three groups (p = 0.7483)
Ripeau 2017 [187] Agalsidase beta switch to agalsidase alfa: 33

MSSI score, mean (SD)

◦. Baseline: 22.1 (1.4)

◦. 24 months: 22.5 (1.4); p = NS vs. baseline
Tsuboi 2012 [136], Tsuboi 2014 [137] Agalsidase beta switch to agalsidase alfa: 11

MSSI score general/neurological/CV/renal/total, mean

◦. Baseline of switch: 4.09/5.18/8.73/4.73/22.73

◦. After 12 months: 3.91/5.00/8.73/4.73/22.36

CV, cardiovascular. ERT, enzyme replacement therapy. FD, Fabry disease. FOS, Fabry Outcome Survey. IQR, interquartile range. MSSI, Mainz Severity Score Index. NR, not reported. NS, non-significant. SD, standard deviation.

4. Discussion

This SLR identified a total of 247 publications reporting findings from 231 studies that reported data on renal, cardiovascular, cerebrovascular, and disease severity (MSSI) outcomes with FD treatments. The majority of these were real-world studies involving adults. As expected, the approved treatments for FD were well represented in the literature, with 187 studies evaluating ERT with agalsidase alfa and/or agalsidase beta, 30 studies examining migalastat, and 11 studies investigating pegunigalsidase alfa. The treatments for which the longest follow-up data were available were agalsidase alfa (up to 20 years [40,43]) and agalsidase beta (up to 10 years [82]). In general, FD treatments stabilized or slowed kidney function decline and cardiac structural changes. However, in the absence of a randomized control group, as was the case for many of the studies, and owing to the variable presentation and slow progression of FD, such findings should be interpreted with caution. There was substantial heterogeneity in the disease severity and clinical characteristics of patients at baseline, both within and between studies, as well as differences in study designs with regard to the length of follow-up, sex balance, age groups, treatment duration, and treatment doses. As a result, cross-study conclusions about the effectiveness of different therapies cannot be accurately made. This is aligned with SLRs by Orsborne et al. (2023) [188], Besekar et al. (2023) [189], and Riccio et al. (2023) [190,191].

FD can significantly impair kidney function, leading to reduced GFR and increased proteinuria [1]. The results of this SLR suggest that ERT with agalsidase alfa or agalsidase beta has renoprotective effects and stabilizes GFR over time. Migalastat also demonstrated stability in renal function in many studies. Cardiac manifestations of FD, including LVH, also contribute significantly to morbidity and mortality [1]. ERT with agalsidase alfa or agalsidase beta or oral chaperone therapy with migalastat stabilized or reduced LVMI, indicating beneficial effects on cardiac structure. A study of 2171 patients from FOS treated with agalsidase alfa for up to 20.8 years (published in April 2025) also demonstrated improved renal and cardiac outcomes compared with external untreated cohorts [192]. Renal outcomes improved regardless of sex or baseline proteinuria, and LVMI stabilized regardless of sex or baseline LVH status. Agalsidase alfa also delayed composite morbidity events and mortality compared with untreated external cohorts [192].

Evidence from studies directly comparing agalsidase alfa and agalsidase beta (limited to two cohort studies and one randomized, controlled, open-label trial) suggests they have similar efficacy with respect to renal and cardiac outcomes. The importance of early treatment initiation was demonstrated, with early initiation of ERT in childhood or young adulthood, before established organ involvement, associated with improved preservation of GFR outcomes and LVMI. In subgroup analyses of ERT studies, patients with impaired kidney function/high renal involvement at baseline experienced a greater decline in eGFR than those with preserved kidney function/low renal involvement at baseline.

Patients with FD are also at increased risk of cerebrovascular events, such as strokes [1]. Studies so far have provided little evidence of a benefit with ERT or migalastat treatment on cerebrovascular outcomes. Comparisons between different ERTs, which do not cross the blood–brain barrier, and migalastat, which may be able to cross the blood–brain barrier [193], require further investigation to establish the optimal treatment strategy for cerebrovascular risk reduction. However, the improvements in cardiovascular function observed with ERT and migalastat treatment may contribute to better cerebrovascular outcomes. After the completion of the literature search for this SLR (17 June 2024), the incidence of stroke was reported in a publication from the Fabry Registry [194]. In agalsidase beta-treated patients, the stroke incidence was 5.55 per 1000 person-years compared with 11.18 per 1000 person-years in matched untreated patients and agalsidase beta-treated patients had a significantly lower risk of stroke compared with untreated patients (HR: 0.36; 95% CI: 0.23, 0.56) [194].

Compared with other outcomes of interest, there was a paucity of research into the effects of FD treatments on MSSI, which incorporates multiple clinical parameters to assess and monitor FD severity as a multisystem disease and helps to stratify patients by clinical phenotype [180]. Agalsidase alfa showed improvements in MSSI scores in several studies (particularly in the general, neurological, and cardiovascular subscores), whereas the effects of agalsidase beta on MSSI scores remain less explored. Studies on the impact of switching treatments showed stability in MSSI scores, suggesting comparable efficacy between agalsidase alfa and beta. Although not evaluated in this SLR, ERT has been shown to improve neuropathic pain and quality of life in patients with FD [195].

Following the completion of the literature search for this SLR (17 June 2024), nine further clinical studies reporting renal and cardiac outcomes in FD have been published. This comprised two studies of agalsidase alfa, two studies of agalsidase beta, four studies of migalastat, and one study of pegunigalsidase alfa [196,197,198,199,200,201,202,203,204]. Overall, these publications support the efficacy of ERT and migalastat (in patients with amenable GLA variants) on improving renal and cardiac function and reducing the risk of severe clinical events.

The slow and variable progression of FD mean that careful baseline phenotyping and long-term follow-up is required to demonstrate the clinical benefit–risk profile of treatments and patient adherence with them. Results from long-term studies are awaited for the more recent pegunigalsidase alfa, gene therapy, and substrate reduction therapies. Regarding cardiac outcomes, the major limitation of most of the clinical trials is the limited follow-up time and the inadequacy of surrogate biomarkers for cardiomyopathy [167]. While LVM and LVMI measure the hypertrophic aspect of cardiac deterioration, they do not reflect the risk of arrhythmias and diastolic heart failure, which are the prevalent complications in patients with FD [167]. There were also limited data on the use of additional supportive medications in patients with FD, such as renin–angiotensin blockade, anti-platelet therapies etc. Patients with FD often receive multiple treatments, such as those to manage primary and secondary cardiovascular risks. Use of concomitant medicines are also likely to affect treatment outcomes [15]. Therefore, future studies should address the potential effect of concomitant medications on the efficacy of FD treatments.

Published congress abstracts were included in this SLR to capture all available published data on the outcomes of interest. Unlike journal articles, however, congress publications are typically not peer reviewed and often contain limited study details. Therefore, the results of such studies should be considered with caution. Different studies were identified in this SLR compared with previous SLR reports [188,189,190], owing to differences in methodology and focus. Laboratory measurements, such as serum levels of globotriaosylsphingosine (lyso-Gb3) or the presence of antidrug antibodies, have been suggested to relate to the effectiveness of FD treatments; however, they do not translate directly to clinical outcomes and were therefore not evaluated in this SLR. Although safety outcomes were reported in various identified publications, these outcomes have not been covered here owing to the heterogenous nature of safety reporting in the clinical studies.

A major limitation of this SLR is the small number and heterogeneous phenotypes of patients enrolled in many of the identified clinical trials and observational studies. Although this issue is common in studies of rare diseases, such limited sample sizes may lead to difficulty in generalizing results for larger populations. In addition, follow-up times varied substantially between studies. Long-term follow-up studies with larger patient cohorts, stratified according to clinical phenotype, will be essential for the accurate assessment of the sustained benefits and potential side effects of FD treatments over extended periods. The variability of study designs and the small treatment effects also meant that it was not possible to directly compare different subgroups and studies, so the differential effects for certain patient groups could not be ascertained. Furthermore, studies comparing agalsidase alfa and agalsidase beta had significant limitations. Specifically, studies with a retrospective design can introduce significant biases related to patient selection and data collection, while open-label studies may suffer from biases in data analysis and interpretation. Future studies should address the effects of different FD treatments in different age groups on specific outcomes, with methodology that is reproducible enough to produce robust data for meta-analysis.

In conclusion, after more than 20 years of experience with ERT, data indicate that agalsidase alfa and agalsidase beta demonstrate similar efficacy in stabilizing renal and cardiac outcomes in patients with FD. Early initiation of ERT in childhood or young adulthood before established organ involvement is critical for optimizing treatment outcomes. Treatment with migalastat has also been associated with the stabilization of renal and cardiac outcomes in patients with amenable GLA variants. Large cohort studies of current and emerging treatments will require long-term follow-up periods. In addition, better stratification according to clinical phenotype and prognosis will be crucial for addressing evidence gaps and providing clinicians and policymakers with comprehensive and reliable data to offer informed treatment options and share treatment decisions with their patients.

Author Contributions

Conception of the analysis: F.C.; Development of the protocol: F.C., O.E. and C.S.; Performing the systematic literature review: F.C., O.E. and C.S.; Interpretation of the results: A.J., E.M.-H., F.C., O.E., O.A., D.H., G.P.-M., R.G. and S.F.; Contribution to drafting the manuscript or to revising it critically for important intellectual content: C.S., A.J., E.M.-H., F.C., O.E., O.A., D.H., G.P.-M., R.G. and S.F. All authors have read and agreed to the published version of the manuscript.

 Data Availability Statement

The data included in this report are from the published literature.

 Acknowledgments

Under the direction of the authors, medical writing support was provided by Sarah Graham of PharmaGenesis, London, UK, and funded by Takeda Development Center Americas, Inc. in accordance with Good Publication Practice (GPP 2022) guidelines (www.ismpp.org/gpp-2022 [accessed on 14 October 2024]).

 Conflicts of Interest

Ana Jovanovic has received honoraria for speaking and advisory boards from Amicus, Chiesi, Sanofi, and Takeda and research grants from Amicus and Takeda. Eve Miller-Hodges has received consultancy fees from Takeda and Amicus and speakers’ fees from Sanofi and Amicus. Felicia Castriota is an employee of Takeda Development Center Americas, Inc. and owns Takeda stock. Obaro Evuarherhe is an employee of Oxford PharmaGenesis Ltd. Olulade Ayodele is an employee of Takeda Development Center Americas, Inc. and owns Takeda stock. Derralynn Hughes has received honoraria for speaking and advisory boards from Amicus, Chiesi, Freeline, Idorsia, Sanofi, and Takeda. Guillem Pintos-Morell has received honoraria from Alexion, Amicus, Chiesi, Immedica, Lucane, Sanofi, Takeda, and Vitaflo and unrestricted grants from Sanofi and Takeda to the Vall d’Hebron Research Foundation for funding research on rare diseases. Roberto Giugliani has received consulting fees, honoraria for speaking and advisory boards, and/or research funding from Alexion, Alnylam Pharmaceuticals, Amicus Therapeutics, Astellas Pharma, Azafaros, BioMarin Pharmaceutical, Chiesi, JCR Pharmaceutical, Novartis, Paradigm BioPharmaceuticals, Passage Bio, Praxis Precision Medicines, PTC Therapeutics, Regenxbio, Sanofi, Takeda, and Ultragenyx. He is a member and the current chair of the Fabry Outcome Survey Steering Committee. Sandro Feriozzi has received honoraria for speaking and advisory boards from Amicus, Chiesi, Otsuka, Sanofi, and Takeda. Csaba Siffel is an employee of Takeda Development Center Americas, Inc. and owns Takeda stock.

Footnotes

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Figure and Tables

Figure 1 PRISMA flow diagram for identified publications (initial and updated searches). PRISMA, Preferred Reporting Items for Systematic reviews and Meta-Analyses.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jcm14145131/s1, Figure S1: Study locations; Table S1: EMBASE, MEDLINE and Cochrane search strategies; Table S2: Eligibility search criteria; Table S3: Risk of bias assessment for included studies; Table S4: Overview of GFR data from (A) mixed or non-specified ERT single-arm studies and single-arm studies for other treatments and (B) switch studies; Table S5: Overview of proteinuria data from (A) single-arm studies and (B) comparator and switch studies; Table S6: Overview of LVMI data from (A) mixed or non-specified ERT single-arm studies and single-arm studies for other treatments and (B) switch studies; Table S7: Overview of data for other structural cardiovascular parameters from (A) single-arm studies, (B) comparator and (C) switch studies; Table S8: Overview of cerebrovascular data from (A) mixed or non-specified ERT single-arm studies and single-arm studies for other treatments and (B) switch studies.

References

1. Germain, D.P. Fabry disease. Orphanet J. Rare Dis.; 2010; 5, pp. 30-79. [DOI: https://dx.doi.org/10.1186/1750-1172-5-30] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21092187]

2. Biegstraaten, M.; Arngrímsson, R.; Barbey, F.; Boks, L.; Cecchi, F.; Deegan, P.B.; Feldt-Rasmussen, U.; Geberhiwot, T.; Germain, D.P.; Hendriksz, C. . Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: The European Fabry Working Group consensus document. Orphanet J. Rare Dis.; 2015; 10, 36. [DOI: https://dx.doi.org/10.1186/s13023-015-0253-6] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25885911]

3. MacDermot, K.D.; Holmes, A.; Miners, A.H. Anderson-Fabry disease: Clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J. Med. Genet.; 2001; 38, pp. 750-760. [DOI: https://dx.doi.org/10.1136/jmg.38.11.750] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11694547]

4. MacDermot, K.D.; Holmes, A.; Miners, A.H. Anderson-Fabry disease: Clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J. Med. Genet.; 2001; 38, pp. 769-775. [DOI: https://dx.doi.org/10.1136/jmg.38.11.769] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11732485]

5. Germain, D.P.; Altarescu, G.; Barriales-Villa, R.; Mignani, R.; Pawlaczyk, K.; Pieruzzi, F.; Terryn, W.; Vujkovac, B.; Ortiz, A. An expert consensus on practical clinical recommendations and guidance for patients with classic Fabry disease. Mol. Genet. Metab.; 2022; 137, pp. 49-61. [DOI: https://dx.doi.org/10.1016/j.ymgme.2022.07.010] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35926321]

6. Mehta, A.; Hughes, D.A. Fabry disease. GeneReviews® [Internet]; Adam, M.P.; Feldman, J.; Mirzaa, G.M.; Pagon, R.A.; Wallace, S.E.; Amemiya, A. Updated 11 April 2024; University of Washington: Seattle, WA, USA, 2002; Available online: https://www.ncbi.nlm.nih.gov/books/NBK1292/pdf/Bookshelf_NBK1292.pdf (accessed on 14 October 2024).

7. Arends, M.; Wanner, C.; Hughes, D.; Mehta, A.; Oder, D.; Watkinson, O.T.; Elliott, P.M.; Linthorst, G.E.; Wijburg, F.A.; Biegstraaten, M. . Characterization of classical and nonclassical Fabry disease: A multicenter study. J. Am. Soc. Nephrol.; 2017; 28, pp. 1631-1641. [DOI: https://dx.doi.org/10.1681/ASN.2016090964] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27979989]

8. European Medicines Agency. Replagal. Summary of Product Characteristics 2022. Available online: https://www.ema.europa.eu/en/documents/product-information/replagal-epar-product-information_en.pdf (accessed on 14 October 2024).

9. European Medicines Agency. Fabrazyme. Summary of Product Characteristics 2024. Available online: https://www.ema.europa.eu/en/documents/product-information/fabrazyme-epar-product-information_en.pdf (accessed on 14 October 2024).

10. Food and Drug Administration. Fabrazyme. Prescribing Information 2024. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/103979s5313lbl.pdf (accessed on 14 October 2024).

11. European Medicines Agency. Elfabrio. Summary of Product Characteristics 2023. Available online: https://www.ema.europa.eu/en/documents/product-information/elfabrio-epar-product-information_en.pdf (accessed on 14 October 2024).

12. Food and Drug Administration. Elfabrio. Prescribing Information 2023. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761161s000lbl.pdf (accessed on 14 October 2024).

13. European Medicines Agency. Galafold. Summary of Product Characteristics 2023. Available online: https://www.ema.europa.eu/en/documents/product-information/galafold-epar-product-information_en.pdf (accessed on 14 October 2024).

14. Food and Drug Administration. Galafold. Prescribing Information 2024. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/208623s008lbl.pdf (accessed on 14 October 2024).

15. Lenders, M.; Brand, E. Fabry disease: The current treatment landscape. Drugs; 2021; 81, pp. 635-645. [DOI: https://dx.doi.org/10.1007/s40265-021-01486-1] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33721270]

16. Van der Veen, S.J.; Hollak, C.E.M.; van Kuilenburg, A.B.P.; Langeveld, M. Developments in the treatment of Fabry disease. J. Inherit. Metab. Dis.; 2020; 43, pp. 908-921. [DOI: https://dx.doi.org/10.1002/jimd.12228] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32083331]

17. Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.; Brennan, S.E. . The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ; 2021; 372, n71. [DOI: https://dx.doi.org/10.1136/bmj.n71] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33782057]

18. Bierer, G.; Balfe, D.; Wilcox, W.R.; Mosenifar, Z. Improvement in serial cardiopulmonary exercise testing following enzyme replacement therapy in Fabry disease. J. Inherit. Metab. Dis.; 2006; 29, pp. 572-579. [DOI: https://dx.doi.org/10.1007/s10545-006-0361-5] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16817011]

19. Bodensteiner, D.; Scott, C.R.; Sims, K.B.; Shepherd, G.M.; Cintron, R.D.; Germain, D.P. Successful reinstitution of agalsidase beta therapy in Fabry disease patients with previous IgE-antibody or skin-test reactivity to the recombinant enzyme. Genet. Med.; 2008; 10, pp. 353-358. [DOI: https://dx.doi.org/10.1097/GIM.0b013e318170f868] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18496035]

20. Hughes, D.; Linhart, A.; Gurevich, A.; Kalampoki, V.; Jazukeviciene, D.; Feriozzi, S. Prompt initiation of agalsidase alfa therapy is associated with improved cardiovascular and renal outcomes in the Fabry Outcome Survey (FOS). Mol. Genet. Metab.; 2020; 129, (Suppl. S2), S77. [DOI: https://dx.doi.org/10.1016/j.ymgme.2019.11.187]

21. Beck, M.; Hughes, D.; Kampmann, C.; Pintos-Morell, G.; Ramaswami, U.; West, M.L.; Giugliani, R. Long-term outcomes with agalsidase alfa enzyme replacement therapy: Analysis using deconstructed composite events. Mol. Genet. Metab. Rep.; 2018; 14, pp. 31-35. [DOI: https://dx.doi.org/10.1016/j.ymgmr.2017.10.008] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29159077]

22. Feriozzi, S.; Linhart, A.; Ramaswami, U.; Kalampoki, V.; Gurevich, A.; Hughes, D. Effects of baseline left ventricular hypertrophy and decreased renal function on cardiovascular and renal outcomes in patients with Fabry disease treated with agalsidase alfa: A Fabry Outcome Survey study. Clin. Ther.; 2020; 42, pp. 2321-2330.e0. [DOI: https://dx.doi.org/10.1016/j.clinthera.2020.10.007] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33218740]

23. Hopkin, R.J.; Cabrera, G.H.; Jefferies, J.L.; Yang, M.; Ponce, E.; Brand, E.; Feldt-Rasmussen, U.; Germain, D.P.; Guffon, N.; Jovanovic, A. . Clinical outcomes among young patients with Fabry disease who initiated agalsidase beta treatment before 30 years of age: An analysis from the Fabry Registry. Mol. Genet. Metab.; 2023; 138, 106967. [DOI: https://dx.doi.org/10.1016/j.ymgme.2022.106967] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36709533]

24. Hughes, D.; Linhart, A.; Gurevich, A.; Kalampoki, V.; Jazukeviciene, D.; Feriozzi, S. Prompt agalsidase alfa therapy initiation is associated with improved renal and cardiovascular outcomes in a Fabry Outcome Survey analysis. Drug Des. Dev. Ther.; 2021; 15, pp. 3561-3572. [DOI: https://dx.doi.org/10.2147/DDDT.S313789] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34429585]

25. Ortiz, A.; Abiose, A.; Bichet, D.G.; Cabrera, G.; Charrow, J.; Germain, D.P.; Hopkin, R.J.; Jovanovic, A.; Linhart, A.; Maruti, S.S. . Time to treatment benefit for adult patients with Fabry disease receiving agalsidase beta: Data from the Fabry Registry. J. Med. Genet.; 2016; 53, pp. 495-502. [DOI: https://dx.doi.org/10.1136/jmedgenet-2015-103486] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26993266]

26. Parini, R.; Pintos-Morell, G.; Hennermann, J.B.; Hsu, T.-R.; Karabul, N.; Kalampoki, V.; Gurevich, A.; Ramaswami, U. 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. Drug Des. Dev. Ther.; 2020; 14, pp. 2149-2158. [DOI: https://dx.doi.org/10.2147/DDDT.S249433] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32581513]

27. Sirrs, S.M.; Bichet, D.G.; Iwanochko, R.M.; Khan, A.; Doucette, S.; Lemoine, K. Differential effects of agalsidase alfa and agalsidase beta in Fabry out-comes: 10 year outcomes from the Canadian Fabry Disease Initiative. J. Inherit. Metab. Dis.; 2018; 41, (Suppl. S1), S188.

28. Vedder, A.C.; Linthorst, G.E.; Houge, G.; Groener, J.E.; Ormel, E.E.; Bouma, B.J.; Aerts, J.M.; Hirth, A.; Hollak, C.E.; Schiffmann, R. Treatment of Fabry disease: Outcome of a comparative trial with agalsidase alfa or beta at a dose of 0.2 mg/kg. PLoS ONE; 2007; 2, e598. [DOI: https://dx.doi.org/10.1371/journal.pone.0000598] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17622343]

29. Arends, M.; Biegstraaten, M.; Wanner, C.; Sirrs, S.; Mehta, A.; Elliott, P.M.; Oder, D.; Watkinson, O.T.; Bichet, D.G.; Khan, A. . Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: An international cohort study. J. Med. Genet.; 2018; 55, pp. 351-358. [DOI: https://dx.doi.org/10.1136/jmedgenet-2017-104863] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29437868]

30. Cabrera, G.; Politei, J.; Antongiovani, N.; Amartino, H. Effectiveness of enzyme replacement therapy in Fabry disease: Long term experience in Argentina. Mol. Genet. Metab. Rep.; 2017; 11, pp. 65-68. [DOI: https://dx.doi.org/10.1016/j.ymgmr.2017.02.005] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28507907]

31. Arends, M.; Biegstraaten, M.; Hughes, D.A.; Mehta, A.; Elliott, P.M.; Oder, D.; Watkinson, O.T.; Vaz, F.M.; van Kuilenburg, A.B.P.; Wanner, C. . Retrospective study of long-term outcomes of enzyme replacement therapy in Fabry disease: Analysis of prognostic factors. PLoS ONE; 2017; 12, e0182379. [DOI: https://dx.doi.org/10.1371/journal.pone.0182379] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28763515]

32. Arends, M.; Wijburg, F.A.; Wanner, C.; Vaz, F.M.; van Kuilenburg, A.B.; Hughes, D.A.; Biegstraaten, M.; Mehta, A.; Hollak, C.E.; Langeveld, M. Favourable effect of early versus late start of enzyme replacement therapy on plasma globotriaosylsphingosine levels in men with classical Fabry disease. Mol. Genet. Metab.; 2017; 121, pp. 157-161. [DOI: https://dx.doi.org/10.1016/j.ymgme.2017.05.001] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28495078]

33. Van der Veen, S.; Körver, S.; Hirsch, A.; Hollak, C.; Wijburg, F.; Brands, M.; Tøndel, C.; van Kuilenburg, A.; Langeveld, M. Early start of enzyme replacement therapy in pediatric male patients with classical Fabry disease is associated with attenuated disease progression. Mol. Genet. Metab.; 2022; 135, pp. 163-169. [DOI: https://dx.doi.org/10.1016/j.ymgme.2021.12.004] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35033446]

34. Nowak, A.; Koch, G.; Huynh-Do, U.; Siegenthaler, M.; Marti, H.P.; Pfister, M. Disease progression modeling to evaluate the effects of enzyme replacement therapy on kidney function in adult patients with the classic phenotype of Fabry disease. Kidney Blood Press. Res.; 2017; 42, pp. 1-15. [DOI: https://dx.doi.org/10.1159/000464312] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28253518]

35. Wyatt, K.; Henley, W.; Anderson, L.; Anderson, R.; Nikolaou, V.; Stein, K.; Klinger, L.; Hughes, D.; Waldek, S.; Lachmann, R. . The effectiveness and cost-effectiveness of enzyme and substrate replacement therapies: A longitudinal cohort study of people with lysosomal storage disorders. Health Technol. Assess.; 2012; 16, pp. 1-543. [DOI: https://dx.doi.org/10.3310/hta16390] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23089251]

36. Anderson, L.J.; Wyatt, K.M.; Henley, W.; Nikolaou, V.; Waldek, S.; Hughes, D.A.; Pastores, G.M.; Logan, S. Long-term effectiveness of enzyme replacement therapy in Fabry disease: Results from the NCS-LSD cohort study. J. Inherit. Metab. Dis.; 2014; 37, pp. 969-978. [DOI: https://dx.doi.org/10.1007/s10545-014-9717-4] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24831586]

37. Madsen, C.V.; Bundgaard, H.; Rasmussen, Å.K.; Sørensen, S.S.; Petersen, J.H.; Køber, L.; Feldt-Rasmussen, U.; Petri, H. Echocardiographic and clinical findings in patients with Fabry disease during long-term enzyme replacement therapy: A nationwide Danish cohort study. Scand. Cardiovasc. J.; 2017; 51, pp. 207-216. [DOI: https://dx.doi.org/10.1080/14017431.2017.1332383] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28545342]

38. Silva, C.A.B.; Moura-Neto, J.A.; Reis, M.A.D.; Neto, O.M.V.; Barreto, F.C. Renal manifestations of Fabry disease: A narrative review. Can. J. Kidney Health Dis.; 2021; 8, 2054358120985627. [DOI: https://dx.doi.org/10.1177/2054358120985627] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33786192]

39. Beck, M.; Ricci, R.; Widmer, U.; Dehout, F.; De Lorenzo, A.G.; Kampmann, C.; Linhart, A.; Sunder-Plassmann, G.; Houge, G.; Ramaswami, U. . Fabry disease: Overall effects of agalsidase alfa treatment. Eur. J. Clin. Investig.; 2004; 34, pp. 838-844. [DOI: https://dx.doi.org/10.1111/j.1365-2362.2004.01424.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15606727]

40. Giugliani, R.; Hughes, D.; Nicholls, K.; Niu, D.-M.; Reisin, R.C.; Botha, J.; Anagnostopoulou, C.; West, M.L. Long-term outcomes in patients with Fabry disease who were treated with agalsidase alfa for more than nineteen years: The Fabry Outcome Survey. Mol. Genet. Metab.; 2023; 138, 107118. [DOI: https://dx.doi.org/10.1016/j.ymgme.2022.107118]

41. Pintos-Morell, G.; Kampmann, C.; Botha, J.; Anagnostopoulou, C.; West, M.L.; Ramaswami, U. Early initiation of agalsidase alfa treatment improves clinical outcomes in male patients with classical Fabry disease: A Fabry Outcome Survey (FOS) analysis. Mol. Genet. Metab.; 2023; 138, 107273. [DOI: https://dx.doi.org/10.1016/j.ymgme.2022.107273]

42. Ramaswami, U.; Beck, M.; Hughes, D.; Kampmann, C.; Botha, J.; Pintos-Morell, G.; West, M.L.; Niu, D.M.; Nicholls, K.; Giugliani, R. . Cardio-renal outcomes with long-term agalsidase alfa enzyme replacement therapy: A 10-year Fabry Outcome Survey (FOS) analysis. Drug Des. Dev. Ther.; 2019; 13, pp. 3705-3715. [DOI: https://dx.doi.org/10.2147/DDDT.S207856] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31749608]

43. Cybulla, M.; Nicholls, K.; Feriozzi, S.; Linhart, A.; Torras, J.; Vujkovac, B.; Botha, J.; Anagnostopoulou, C.; West, M.L. Renoprotective effect of agalsidase alfa: A long-term follow-up of patients with Fabry disease. J. Clin. Med.; 2022; 11, 4810. [DOI: https://dx.doi.org/10.3390/jcm11164810] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36013057]

44. Feriozzi, S.; Schwarting, A.; Sunder-Plassmann, G.; West, M.; Cybulla, M.I. International Fabry Outcome Survey Investigators. Agalsidase alfa slows the decline in renal function in patients with Fabry disease. Am. J. Nephrol.; 2008; 29, pp. 353-361. [DOI: https://dx.doi.org/10.1159/000168482] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18974635]

45. Feriozzi, S.; Torras, J.; Cybulla, M.; Nicholls, K.; Sunder-Plassmann, G.; West, M. FOS Investigators. The effectiveness of long-term agalsidase alfa therapy in the treatment of Fabry nephropathy. Clin. J. Am. Soc. Nephrol.; 2012; 7, pp. 60-69. [DOI: https://dx.doi.org/10.2215/CJN.03130411] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22246281]

46. Goker-Alpan, O.; Longo, N.; McDonald, M.; Shankar, S.P.; Schiffmann, R.; Chang, P.; Shen, Y.; Pano, A. An open-label clinical trial of agalsidase alfa enzyme replacement therapy in children with Fabry disease who are naive to enzyme replacement therapy. Drug Des. Dev. Ther.; 2016; 10, pp. 1771-1781. [DOI: https://dx.doi.org/10.2147/DDDT.S102761] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27307708]

47. Kampmann, C.; Perrin, A.; Beck, M. Effectiveness of agalsidase alfa enzyme replacement in Fabry disease: Cardiac outcomes after 10 years’ treatment. Orphanet J. Rare Dis.; 2015; 10, 125. [DOI: https://dx.doi.org/10.1186/s13023-015-0338-2] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26416388]

48. Hughes, D.A.; Romero, M.A.B.; Hollak, C.E.M.; Giugliani, R.; Deegan, P.B. Response of women with Fabry disease to enzyme replacement therapy: Comparison with men, using data from FOS—the Fabry Outcome Survey. Mol. Genet. Metab.; 2011; 103, pp. 207-214. [DOI: https://dx.doi.org/10.1016/j.ymgme.2011.03.022] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21543245]

49. Pastores, G.M.; Boyd, E.; Crandall, K.; Whelan, A.; Piersall, L.; Barnett, N. Safety and pharmacokinetics of agalsidase alfa in patients with Fabry disease and end-stage renal disease. Nephrol. Dial. Transplant.; 2007; 22, pp. 1920-1925. [DOI: https://dx.doi.org/10.1093/ndt/gfm096] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17395657]

50. Ramaswami, U.; Parini, R.; Kampmann, C.; Beck, M. Safety of agalsidase alfa in patients with Fabry disease under 7 years. Acta Paediatr.; 2010; 100, pp. 605-611. [DOI: https://dx.doi.org/10.1111/j.1651-2227.2010.02101.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21114524]

51. Ries, M.; Clarke, J.T.; Whybra, C.; Timmons, M.; Robinson, C.; Schlaggar, B.L.; Pastores, G.; Lien, Y.H.; Kampmann, C.; Brady, R.O. . Enzyme-replacement therapy with agalsidase alfa in children with Fabry disease. Pediatrics; 2006; 118, pp. 924-932. [DOI: https://dx.doi.org/10.1542/peds.2005-2895] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16950982]

52. Sasa, H.; Nagao, M.; Kino, K. Safety and effectiveness of enzyme replacement therapy with agalsidase alfa in patients with Fabry disease: Post-marketing surveillance in Japan. Mol. Genet. Metab.; 2019; 126, pp. 448-459. [DOI: https://dx.doi.org/10.1016/j.ymgme.2019.02.005] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30803893]

53. Schiffmann, R.; Askari, H.; Timmons, M.; Robinson, C.; Benko, W.; Brady, R.O.; Ries, M. Weekly enzyme replacement therapy may slow decline of renal function in patients with Fabry disease who are on long-term biweekly dosing. J. Am. Soc. Nephrol.; 2007; 18, pp. 1576-1583. [DOI: https://dx.doi.org/10.1681/ASN.2006111263] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17409308]

54. Schiffmann, R.; Ries, M.; Timmons, M.; Flaherty, J.T.; Brady, R.O. Long-term therapy with agalsidase alfa for Fabry disease: Safety and effects on renal function in a home infusion setting. Nephrol. Dial. Transplant.; 2006; 21, pp. 345-354. [DOI: https://dx.doi.org/10.1093/ndt/gfi152] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16204287]

55. Schiffmann, R.; Pastores, G.M.; Lien, Y.-H.H.; Castaneda, V.; Chang, P.; Martin, R.; Wijatyk, A. Agalsidase alfa in pediatric patients with Fabry disease: A 6.5-year open-label follow-up study. Orphanet J. Rare Dis.; 2014; 9, 169. [DOI: https://dx.doi.org/10.1186/s13023-014-0169-6] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25425121]

56. Schiffmann, R.; Ries, M.; Blankenship, D.; Nicholls, K.; Mehta, A.; Clarke, J.T.R.; Steiner, R.D.; Beck, M.; Barshop, B.A.; Rhead, W. . Changes in plasma and urine globotriaosylceramide levels do not predict Fabry disease progression over 1 year of agalsidase alfa. Genet. Med.; 2013; 15, pp. 983-989.

57. Schiffmann, R.; Swift, C.; Wang, X.; Blankenship, D.; Ries, M. A prospective 10-year study of individualized, intensified enzyme replacement therapy in advanced Fabry disease. J. Inherit. Metab. Dis.; 2015; 38, pp. 1129-1136. [DOI: https://dx.doi.org/10.1007/s10545-015-9845-5] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25900714]

58. Schwarting, A.; Dehout, F.; Beck, M.; Mehta, A.; Sunder-Plassmann, G.; Bodamer, O. European FOS Investigators. Enzyme replacement therapy and renal function in 201 patients with Fabry disease. Clin. Nephrol.; 2006; 66, pp. 77-84. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16939062]

59. Schwarting, A.; Sunder-Plassmann, G.; Mehta, A.; Beck, M. Effect of enzyme replacement therapy with agalsidase alfa on renal function in patients with Fabry disease: Data from FOS—The Fabry Outcome Survey. Fabry Disease: Perspectives from 5 Years of FOS; Adam, M.P.; Feldman, J.; Mirzaa, G.M.; Pagon, R.A.; Wallace, S.E.; Amemiya, A. Oxford PharmaGenesis: Oxford, UK, 2006; 38.

60. Thofehrn, S.; Netto, C.; Cecchin, C.; Burin, M.; Matte, U.; Brustolin, S.; Nunes, A.C.F.; Coelho, J.; Tsao, M.; Jardim, L. . Kidney function and 24-hour proteinuria in patients with Fabry disease during 36 months of agalsidase alfa enzyme replacement therapy: A Brazilian experience. Ren. Fail.; 2009; 31, pp. 773-778. [DOI: https://dx.doi.org/10.3109/08860220903150296] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19925283]

61. Tsuboi, K.; Yamamoto, H. Efficacy and safety of enzyme-replacement-therapy with agalsidase alfa in 36 treatment-naive Fabry disease patients. BMC Pharmacol. Toxicol.; 2017; 18, 43. [DOI: https://dx.doi.org/10.1186/s40360-017-0152-7] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28592315]

62. West, M.; Nicholls, K.; Mehta, A.; Clarke, J.T.; Steiner, R.; Beck, M.; Barshop, B.A.; Rhead, W.; Mensah, R.; Ries, M. . Agalsidase alfa and kidney dysfunction in Fabry disease. J. Am. Soc. Nephrol.; 2009; 20, pp. 1132-1139. [DOI: https://dx.doi.org/10.1681/ASN.2008080870] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19357250]

63. Whybra, C.; Miebach, E.; Mengel, E.; Gal, A.; Baron, K.; Beck, M.; Kampmann, C. A 4-year study of the efficacy and tolerability of enzyme replacement therapy with agalsidase alfa in 36 women with Fabry disease. Genet. Med.; 2009; 11, pp. 441-449. [DOI: https://dx.doi.org/10.1097/GIM.0b013e3181a23bec] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19346951]

64. Kleinert, J.; Dehout, F.; Schwarting, A.; de Lorenzo, A.; Ricci, R.; Kampmann, C.; Beck, M.; Ramaswami, U.; Linhart, A.; Gal, A. . Prevalence of uncontrolled hypertension in patients with Fabry disease. Am. J. Hypertens.; 2006; 19, pp. 782-787. [DOI: https://dx.doi.org/10.1016/j.amjhyper.2006.01.011] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16876675]

65. Mehta, A.; Beck, M.; Elliott, P.; Giugliani, R.; Linhart, A.; Sunder-Plassmann, G.; Schiffmann, R.; Barbey, F.; Ries, M.; Clarke, J. Enzyme replacement therapy with agalsidase alfa in patients with Fabry’s disease: An analysis of registry data. Lancet; 2009; 374, pp. 1986-1996. [DOI: https://dx.doi.org/10.1016/S0140-6736(09)61493-8] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19959221]

66. Ramaswami, U.; Parini, R.; Pintos-Morell, G.; Kalkum, G.; Kampmann, C.; Beck, M. Fabry disease in children and response to enzyme replacement therapy: Results from the Fabry Outcome Survey. Clin. Genet.; 2011; 81, pp. 485-490. [DOI: https://dx.doi.org/10.1111/j.1399-0004.2011.01671.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21457233]

67. Benichou, B.; Goyal, S.; Sung, C.; Norfleet, A.M.; O’Brien, F. A retrospective analysis of the potential impact of IgG antibodies to agalsidase beta on efficacy during enzyme replacement therapy for Fabry disease. Mol. Genet. Metab.; 2009; 96, pp. 4-12. [DOI: https://dx.doi.org/10.1016/j.ymgme.2008.10.004] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19022694]

68. Breunig, F.; Weidemann, F.; Strotmann, J.; Knoll, A.; Wanner, C. Clinical benefit of enzyme replacement therapy in Fabry disease. Kidney Int.; 2006; 69, pp. 1216-1221. [DOI: https://dx.doi.org/10.1038/sj.ki.5000208] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16609685]

69. Veloso, V.S.P.; Veloso, M.; Pereira, E.; Barreto, F.; Hagemann, R. Algalsidase-beta stabilizes renal and cardiac involvement: A follow-up study of a Brazilian Fabry disease family. Nephrol. Dial. Transplant.; 2023; 38, (Suppl. S1), 5209. [DOI: https://dx.doi.org/10.1093/ndt/gfad063d_5209]

70. Burlina, A.P.; Mauer, M.; Cabrera, G.H.; Jefferies, J.L.; Yang, M.; Ponce, E.; Brand, E.; Feldt-Rasmussen, U.; Germain, P. Clinical outcomes in young patients with Fabry disease who initiated agalsidase beta treatment before 30 years of age. J. Inherit. Metab. Dis.; 2019; 42, (Suppl. S1), pp. 233-234.

71. Dutra-Clarke, M.; Tapia, D.; Curtin, E.; Ruenger, D.; Lakatos, A.; Alandy-Dy, Z.; Freedkin, L.; Hall, K.; Ercelen, N.; Alandy-Dy, J. . Variable clinical features of patients with Fabry disease and outcome of enzyme replacement therapy. Mol. Genet. Metab.; 2021; 132, (Suppl. S2), S36. [DOI: https://dx.doi.org/10.1016/j.ymgme.2020.12.069]

72. Goicoechea, M.; Gomez-Preciado, F.; Benito, S.; Torras, J.; Torra, R.; Huerta, A.; Restrepo, A.; Ugalde, J.; Astudillo, D.; Agraz, I. . Predictors of long-term outcome in a Spanish cohort of patients with Fabry disease on enzyme replacement therapy. Nephrol. Dial. Transplant.; 2020; 35, (Suppl. S3), iii363. [DOI: https://dx.doi.org/10.1093/ndt/gfaa142.P0067]

73. Hwang, S.; Lee, B.H.; Kim, W.-S.; Kim, D.-S.; Cheon, C.K.; Lee, C.H.; Choi, Y.; Choi, J.-H.; Kim, J.H.; Yoo, H.-W. A phase II, multicenter, open-label trial to evaluate the safety and efficacy of ISU303 (Agalsidase beta) in patients with Fabry disease. Medicine; 2022; 101, e30345. [DOI: https://dx.doi.org/10.1097/MD.0000000000030345] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36123934]

74. Lubanda, J.C.; Anijalg, E.; Bzduch, V.; Thurberg, B.L.; Benichou, B.; Tylki-Szymanska, A. Evaluation of a low dose, after a standard therapeutic dose, of agalsidase beta during enzyme replacement therapy in patients with Fabry disease. Genet. Med.; 2009; 11, pp. 256-264. [DOI: https://dx.doi.org/10.1097/GIM.0b013e3181981d82] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19265719]

75. Ortiz, A.; Mauer, M.; Ponce, E.; Yang, M.; Gudigava, B.; Hong, G.R. Stabilization of kidney function decline and cardiomyopathy in male patients with classic Fabry disease: A pre-vs. post-agalsidase beta treatment Fabry Registry analysis. Nephrol. Dial. Transplant.; 2021; 36, (Suppl. S1), pp. i110-i111. [DOI: https://dx.doi.org/10.1093/ndt/gfab080.0013]

76. Ramaswami, U.; Bichet, D.G.; Clarke, L.A.; Dostalova, G.; Fainboim, A.; Fellgiebel, A.; Forcelini, C.M.; Haack, K.A.; Hopkin, R.J.; Mauer, M. . Low-dose agalsidase beta treatment in male pediatric patients with Fabry disease: A 5-year randomized controlled trial. Mol. Genet. Metab.; 2019; 127, pp. 86-94. [DOI: https://dx.doi.org/10.1016/j.ymgme.2019.03.010] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30987917]

77. Wanner, C.; Feldt-Rasmussen, U.; Jovanovic, A.; Linhart, A.; Yang, M.; Ponce, E.; Brand, E.; Germain, D.P.; Hughes, D.A.; Jefferies, J.L. . Cardiomyopathy and kidney function in agalsidase beta-treated female Fabry patients: A pre-treatment vs. post-treatment analysis. ESC Heart Fail.; 2020; 7, pp. 825-834. [DOI: https://dx.doi.org/10.1002/ehf2.12647] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32100468]

78. Warnock, D.G.; Ortiz, A.; Mauer, M.; Linthorst, G.E.; Oliveira, J.P.; Serra, A.L.; Maródi, L.; Mignani, R.; Vujkovac, B.; Beitner-Johnson, D. . Renal outcomes of agalsidase beta treatment for Fabry disease: Role of proteinuria and timing of treatment initiation. Nephrol. Dial. Transplant.; 2012; 27, pp. 1042-1049. [DOI: https://dx.doi.org/10.1093/ndt/gfr420] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21804088]

79. Warnock, D.G.; Thomas, C.P.; Vujkovac, B.; Campbell, R.C.; Charrow, J.; A Laney, D.; Jackson, L.L.; Wilcox, W.R.; Wanner, C. Antiproteinuric therapy and Fabry nephropathy: Factors associated with preserved kidney function during agalsidase-beta therapy. J. Med. Genet.; 2015; 52, pp. 860-866. [DOI: https://dx.doi.org/10.1136/jmedgenet-2015-103471] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26490103]

80. Weidemann, F.; Niemann, M.; Störk, S.; Breunig, F.; Beer, M.; Sommer, C.; Herrmann, S.; Ertl, G.; Wanner, C. Long-term outcome of enzyme-replacement therapy in advanced Fabry disease: Evidence for disease progression towards serious complications. J. Intern. Med.; 2013; 274, pp. 331-341. [DOI: https://dx.doi.org/10.1111/joim.12077] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23586858]

81. Wraith, J.E.; Tylki-Szymanska, A.; Guffon, N.; Lien, Y.H.; Tsimaratos, M.; Vellodi, A.; Germain, D.P. Safety and efficacy of enzyme replacement therapy with agalsidase beta: An international, open-label study in pediatric patients with Fabry disease. J. Pediatr.; 2008; 152, pp. 563-570.e1. [DOI: https://dx.doi.org/10.1016/j.jpeds.2007.09.007] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18346516]

82. Germain, D.P.; Charrow, J.; Desnick, R.J.; Guffon, N.; Kempf, J.; Lachmann, R.H.; Lemay, R.; E Linthorst, G.; Packman, S.; Scott, C.R. . Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease. J. Med. Genet.; 2015; 52, pp. 353-358. [DOI: https://dx.doi.org/10.1136/jmedgenet-2014-102797] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25795794]

83. Chen, N.; Ren, H.; Zhang, W.; Ouyang, Y.; Xu, H.; Li, B.; Feng, Q. A phase 4, open-label, multicenter prospective study of the safety and efficacy of agalsidase beta in Chinese patients with Fabry disease. Nephrol. Dial. Transplant.; 2024; 39, (Suppl. S1), 636. [DOI: https://dx.doi.org/10.1093/ndt/gfae069.1205]

84. Goicoechea, M.; Gomez-Preciado, F.; Benito, S.; Torras, J.; Torra, R.; Huerta, A.; Restrepo, A.; Ugalde, J.; Astudillo, D.E.; Agraz, I. . Predictors of outcome in a Spanish cohort of patients with Fabry disease on enzyme replacement therapy. Nefrologia; 2021; 41, pp. 652-660. [DOI: https://dx.doi.org/10.1016/j.nefro.2021.01.002] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36165155]

85. Lin, H.-Y.; Huang, Y.-H.; Liao, H.-C.; Liu, H.-C.; Hsu, T.-R.; Shen, C.-I.; Li, S.-T.; Li, C.-F.; Lee, L.-H.; Lee, P.-C. . Clinical observations on enzyme replacement therapy in patients with Fabry disease and the switch from agalsidase beta to agalsidase alfa. J. Chin. Med Assoc.; 2014; 77, pp. 190-197. [DOI: https://dx.doi.org/10.1016/j.jcma.2013.11.006] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24388678]

86. Lin, H.-Y.; Liu, H.-C.; Huang, Y.-H.; Liao, H.-C.; Hsu, T.-R.; Shen, C.-I.; Li, S.-T.; Li, C.-F.; Lee, L.-H.; Lee, P.-C. . Effects of enzyme replacement therapy i for cardiac-type Fabry patients with a Chinese hotspot late-onset Fabry mutation (IVS4+919G>A). BMJ Open; 2013; 3, e003146. [DOI: https://dx.doi.org/10.1136/bmjopen-2013-003146] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23864212]

87. Madsen, C.V.; Granqvist, H.; Petersen, J.H.; Rasmussen, Å.K.; Lund, A.M.; Oturai, P.; Sørensen, S.S.; Feldt-Rasmussen, U. Age-related renal function decline in Fabry disease patients on enzyme replacement therapy: A longitudinal cohort study. Nephrol. Dial. Transplant.; 2019; 34, pp. 1525-1533. [DOI: https://dx.doi.org/10.1093/ndt/gfy357] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30535327]

88. Miwa, K.; Sakai, N.; Yagita, Y.; Takeuchi, M.; Todo, K.; Sakaguchi, M.; Mochizuki, H. Basilar artery diameter is associated with cerebral small vessel disease and the duration of enzyme-replacement therapy in Fabry disease. Stroke.; 2018; 49, (Suppl. 1), WP388. [DOI: https://dx.doi.org/10.1161/str.49.suppl_1.WP388]

89. Miwa, K.; Yagita, Y.; Sakaguchi, M.; Kitagawa, K.; Sakai, N.; Mochizuki, H. Effect of enzyme replacement therapy on basilar artery diameter in male patients with Fabry disease. Stroke; 2019; 50, pp. 1010-1012. [DOI: https://dx.doi.org/10.1161/STROKEAHA.118.024426] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30852964]

90. Rombach, S.M.; Smid, B.E.; Bouwman, M.G.; Linthorst, G.E.; Dijkgraaf, M.G.; Hollak, C.E. Long term enzyme replacement therapy for Fabry disease: Effectiveness on kidney, heart and brain. Orphanet J. Rare Dis.; 2013; 8, 47. [DOI: https://dx.doi.org/10.1186/1750-1172-8-47] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23531228]

91. Sirrs, S.; Bichet, D.; Casey, R.; Clarke, J.; Lemoine, K.; Doucette, S.; West, M. Outcomes of patients treated through the Canadian Fabry disease initiative. Mol. Genet. Metab.; 2014; 111, pp. 499-506. [DOI: https://dx.doi.org/10.1016/j.ymgme.2014.01.014] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24534763]

92. Skrunes, R.; Tøndel, C.; Leh, S.; Larsen, K.K.; Houge, G.; Davidsen, E.S.; Hollak, C.; van Kuilenburg, A.B.; Vaz, F.M.; Svarstad, E. Long-term dose-dependent agalsidase effects on kidney histology in Fabry disease. Clin. J. Am. Soc. Nephrol.; 2017; 12, pp. 1470-1479. [DOI: https://dx.doi.org/10.2215/CJN.01820217] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28625968]

93. Talbot, A.S.; Lewis, N.T.; Nicholls, K.M. Cardiovascular outcomes in Fabry disease are linked to severity of chronic kidney disease. Heart; 2015; 101, pp. 287-293. [DOI: https://dx.doi.org/10.1136/heartjnl-2014-306278] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25381325]

94. Bernat, J.; Holida, M.D.; Longo, N.; Goker-Alpan, O.; Wallace, E.; Deegan, P.B.; Tøndel, C.; Eyskens, F.J.; Feldt-Rasmussen, U.; Hughes, D. . Long-term safety and efficacy of pegunigalsidase alfa administered every 4 weeks in patients with Fabry disease: Two-year interim results from the ongoing phase 3 BRIGHT51 open-label extension study. Mol. Genet. Metab.; 2023; 138, 107027. [DOI: https://dx.doi.org/10.1016/j.ymgme.2022.107027]

95. Hughes, D.; Gonzalez, D.; Maegawa, G.; Bernat, J.A.; Holida, M.; Giraldo, P.; Atta, M.G.; Chertkoff, R.; Alon, S.; Almon, E.B. . Long-term safety and efficacy of pegunigalsidase alfa: A multicenter 6-year study in adult patients with Fabry disease. Genet. Med.; 2023; 25, 100968. [DOI: https://dx.doi.org/10.1016/j.gim.2023.100968] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37634127]

96. Bernat, J.; Holida, M.; Longo, N.; Goker-Alpan, O.; Wallace, E.; Deegan, P.; Nedd, K.; Tondel, C.; Eyskens, F.; Feldt-Rasmussen, U. . eP149: Safety and efficacy of pegunigalsidase alfa, every 4 weeks, in Fabry disease: Results from the phase 3, open-label, BRIGHT study. Genet. Med.; 2022; 24, (Suppl. S3), pp. S91-S92. [DOI: https://dx.doi.org/10.1016/j.gim.2022.01.185]

97. West, M.L.; Hughes, D.; Sunder-Plassmann, G.; Jovanovic, A.; Brand, E.; Bichet, D.G.; Pisani, A.; Nowak, A.; Torra, R.; Khan, A. . FollowME Fabry Pathfinders Registry: Renal effectiveness in a cohort of patients on migalastat treatment for at least three years. J. Am. Soc. Nephrol.; 2023; 34, (Suppl. S11), 952. [DOI: https://dx.doi.org/10.1681/ASN.20233411S1952a]

98. Germain, D.P.; Hughes, D.A.; Nicholls, K.; Bichet, D.G.; Giugliani, R.; Wilcox, W.R.; Feliciani, C.; Shankar, S.P.; Ezgu, F.; Amartino, H. . Treatment of Fabry’s disease with the pharmacologic chaperone migalastat. N. Engl. J. Med.; 2016; 375, pp. 545-555. [DOI: https://dx.doi.org/10.1056/NEJMoa1510198] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27509102]

99. Germain, D.P.; Nicholls, K.; Giugliani, R.; Bichet, D.G.; Hughes, D.A.; Barisoni, L.M.; Colvin, R.B.; Jennette, J.C.; Skuban, N.; Castelli, J.P. . Efficacy of the pharmacologic chaperone migalastat in a subset of male patients with the classic phenotype of Fabry disease and migalastat-amenable variants: Data from the phase 3 randomized, multicenter, double-blind clinical trial and extension study. Genet. Med.; 2019; 21, pp. 1987-1997. [DOI: https://dx.doi.org/10.1038/s41436-019-0451-z] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30723321]

100. Giugliani, R.; Waldek, S.; Germain, D.; Nicholls, K.; Bichet, D.; Simosky, J.; Bragat, A.; Castelli, J.; Benjamin, E.; Boudes, P. A Phase 2 study of migalastat hydrochloride in females with Fabry disease: Selection of population, safety and pharmacodynamic effects. Mol. Genet. Metab.; 2013; 109, pp. 86-92. [DOI: https://dx.doi.org/10.1016/j.ymgme.2013.01.009] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23474038]

101. Hopkin, R.J.; Bichet, D.G.; Sunder-Plassmann, G.; Nicholls, K.; Olivotto, I.; Giugliani, R.; Krusinska, E.; Veleva-Rotse, B.; Hughes, D. Long-term multisystemic efficacy with migalastat in ERT-naive and ERT-experienced patients with amenable GLA variants. Mol. Genet. Metab.; 2022; 135, (Suppl. S2), S56.

102. Khan, A.; Barber, D.L.; Huang, J.; Rupar, C.A.; Rip, J.W.; Auray-Blais, C.; Boutin, M.; O’Hoski, P.; Gargulak, K.; McKillop, W.M. . Lentivirus-mediated gene therapy for Fabry disease. Nat. Commun.; 2021; 12, 1178. [DOI: https://dx.doi.org/10.1038/s41467-021-21371-5] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33633114]

103. Lenders, M.; Nordbeck, P.; Kurschat, C.; Eveslage, M.; Karabul, N.; Kaufeld, J.; Hennermann, J.B.; Patten, M.; Cybulla, M.; Müntze, J. . Treatment of Fabry disease management with migalastat—outcome from a prospective 24 months observational multicenter study (FAMOUS). Eur. Heart J. Cardiovasc. Pharmacother.; 2022; 8, pp. 272-281. [DOI: https://dx.doi.org/10.1093/ehjcvp/pvab025] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35512362]

104. Lenders, M.; Nordbeck, P.; Kurschat, C.; Karabul, N.; Kaufeld, J.; Hennermann, J.B.; Patten, M.; Cybulla, M.; Müntze, J.; Üçeyler, N. . Treatment of Fabry’s disease with migalastat: Outcome from a prospective observational multicenter study (FAMOUS). Clin. Pharmacol. Ther.; 2020; 108, pp. 326-337. [DOI: https://dx.doi.org/10.1002/cpt.1832] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32198894]

105. Orsborne, C.; Thompson, L.; Jovanovic, A. A retrospective outcome analysis of chaperone therapy in Fabry disease: Clinical outcomes after the first year of therapy—A single centre experience. Mol. Genet. Metab.; 2020; 129, (Suppl. S2), S123. [DOI: https://dx.doi.org/10.1016/j.ymgme.2019.11.321]

106. Ramaswami, U.; Wilcox, W.; Hopkin, R.J.; Yang, H.; Jiang, H.; Lengoc, V. Migalastat HCl 150mg every other day is well-tolerated and efficacious in adolescent patients with Fabry disease. Mol. Genet. Metab.; 2022; 135, (Suppl. S2), S104. [DOI: https://dx.doi.org/10.1016/j.ymgme.2021.11.273]

107. Schiffmann, R.; Goker-Alpan, O.; Holida, M.; Giraldo, P.; Barisoni, L.; Colvin, R.B.; Jennette, C.J.; Maegawa, G.; Boyadjiev, S.A.; Gonzalez, D. . Pegunigalsidase alfa, a novel PEGylated enzyme replacement therapy for Fabry disease, provides sustained plasma concentrations and favorable pharmacodynamics: A 1-year Phase 1/2 clinical trial. J. Inherit. Metab. Dis.; 2019; 42, pp. 534-544. [DOI: https://dx.doi.org/10.1002/jimd.12080] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30834538]

108. Skuban, N.; Feldt-Rasmussen, U.; Giugliani, R.; Germain, D.P.; Hughes, D.A.; Wilcox, W.R.; Schiffmann, R.; Bichet, D.G.; Jovanovic, A.; Bratkovic, D. . Efficacy and safety of migalastat, an oral pharmacologic chaperone for Fabry disease: Results from two randomized phase 3 studies, FACETS and ATTRACT. Nephron; 2017; 136, 175.

109. Hughes, D.; Sunder-Plassmann, G.; Jovanovic, A.; Brand, E.; West, M.L.; Bichet, D.G.; Pisani, A.; Nowak, A.; Torra, R.; Khan, A. . FollowME Fabry Pathfinders registry: Renal effectiveness in a multi-national, multi-center cohort of patients on migalastat treatment for at least three years. Mol. Genet. Metab.; 2023; 138, 107159. [DOI: https://dx.doi.org/10.1016/j.ymgme.2022.107159]

110. Bichet, D.G.; Torra, R.; Wallace, E.; Hughes, D.; Giugliani, R.; Skuban, N.; Krusinska, E.; Feldt-Rasmussen, U.; Schiffmann, R.; Nicholls, K. Long-term follow-up of renal function in patients treated with migalastat for Fabry disease. Mol. Genet. Metab. Rep.; 2021; 28, 100786. [DOI: https://dx.doi.org/10.1016/j.ymgmr.2021.100786] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34401344]

111. Torra, R.; Germain, D.; Bichet, D.; Schiffmann, R.; Yu, J.; Castelli, J.; Skuban, N.; Barth, J. Clinical outcomes with migalastat in patients with Fabry disease based on degree of renal impairment: Results from phase 3 trials. Nephrol. Dial. Transplant.; 2018; 33, (Suppl. S1), pp. i346-i356. [DOI: https://dx.doi.org/10.1093/ndt/gfy104.SP002]

112. Beck, M.; Hughes, D.; Kampmann, C.; Larroque, S.; Mehta, A.; Pintos-Morell, G.; Ramaswami, U.; West, M.; Wijatyk, A.; Giugliani, R. Long-term effectiveness of agalsidase alfa enzyme replacement in Fabry disease: A Fabry Outcome Survey analysis. Mol. Genet. Metab. Rep.; 2015; 3, pp. 21-27. [DOI: https://dx.doi.org/10.1016/j.ymgmr.2015.02.002] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26937390]

113. Cybulla, M.; Walter, K.N.; Schwarting, A.; Divito, R.; Feriozzi, S.; Sunder-Plassmann, G. Kidney transplantation in patients with Fabry disease. Transpl. Int.; 2009; 22, pp. 475-481. [DOI: https://dx.doi.org/10.1111/j.1432-2277.2008.00824.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19207191]

114. Cybulla, M.; West, M.; Nicholls, K.; Torras, J.; Neumann, P.; Sunder-Plassmann, G.; Feriozzi, S. on behalf of the Fabry Outcome Survey Renal Working Group. Efficacy and safety of enzyme replacement therapy (ERT) in a cohort of kidney transplant recipients with Fabry disease. Nephrol. Dial. Transplant.; 2014; 29, (Suppl. S3), iii349.

115. Cybulla, M.; West, M.; Nicholls, K.; Torras, J.; Sunder-Plassmann, G.; Feriozzi, S. Effectiveness and safety of enzyme replacement therapy (ERT) in a cohort of kidney transplant recipients with Fabry disease. Nephrol. Dial. Transplant.; 2013; 28, (Suppl. S1), i287.

116. Dehout, F.; Schwarting, A.; Beck, M.; Mehta, A.; Ricci, R.; Widmer, U. Effects of enzyme replacement therapy with agalsidase alfa on glomerular filtration rate in patients with Fabry disease: Preliminary data. Acta Paediatr.; 2003; 92, (Suppl. S443), pp. 14-15. [DOI: https://dx.doi.org/10.1111/j.1651-2227.2003.tb00214.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/14989460]

117. Eng, C.M.; Banikazemi, M.; Gordon, R.E.; Goldman, M.; Phelps, R.; Kim, L.; Gass, A.; Winston, J.; Dikman, S.; Fallon, J.T. . A phase 1/2 clinical trial of enzyme replacement in Fabry disease: Pharmacokinetic, substrate clearance, and safety studies. Am. J. Hum. Genet.; 2001; 68, pp. 711-722. [DOI: https://dx.doi.org/10.1086/318809] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11179018]

118. Goláň, L.; Goker-Alpan, O.; Holida, M.; Kantola, I.; Klopotowski, M.; Kuusisto, J.; Linhart, A.; Musial, J.; Nicholls, K.; Rodríguez, D.G. . Evaluation of the efficacy and safety of three dosing regimens of agalsidase alfa enzyme replacement therapy in adults with Fabry disease. Drug Des. Dev. Ther.; 2015; 9, pp. 3435-3444. [DOI: https://dx.doi.org/10.2147/DDDT.S80928] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26185417]

119. Guérard, N.; Oder, D.; Nordbeck, P.; Zwingelstein, C.; Morand, O.; Welford, R.W.; Dingemanse, J.; Wanner, C. Lucerastat, an iminosugar for substrate reduction therapy: Tolerability, pharmacodynamics, and pharmacokinetics in patients with Fabry disease on enzyme replacement. Clin. Pharmacol. Ther.; 2018; 103, pp. 703-711. [DOI: https://dx.doi.org/10.1002/cpt.790] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28699267]

120. Hughes, D.; Romero, M.B.; Gurevich, A.; Engrand, P.; Giugliani, R. Menarche, menopause, and pregnancy data in untreated/agalsidase alfa-treated females in the Fabry Outcome Survey. Twin Res. Hum. Genet.; 2019; 21, 439. [DOI: https://dx.doi.org/10.1016/j.ymgme.2017.12.164]

121. Hughes, D.A.; Elliott, P.M.; Shah, J.; Zuckerman, J.; Coghlan, G.; Brookes, J.; Mehta, A.B. Effects of enzyme replacement therapy on the cardiomyopathy of Anderson-Fabry disease: A randomised, double-blind, placebo-controlled clinical trial of agalsidase alfa. Heart; 2008; 94, pp. 153-158. [DOI: https://dx.doi.org/10.1136/hrt.2006.104026] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17483124]

122. Jovanovich, A.; Schiffmann, R.; Nicholls, K.; Bichet, D.; Feldt-Rasmussen, U.; Jovanovic, A.; Hughes, D.; Jain, V.; Castelli, J.; Skuban, N. . Efficacy and safety of migalastat, an oral pharmacological chaperone for Fabry disease: Renal findings from two randomized phase 3 studies (facets and attract). J. Inborn Errors Metab. Screen.; 2017; 5, 356.

123. Prabakaran, T.; Birn, H.; Bibby, B.M.; Regeniter, A.; Sørensen, S.S.; Feldt-Rasmussen, U.; Nielsen, R.; Christensen, E.I. Long-term enzyme replacement therapy is associated with reduced proteinuria and preserved proximal tubular function in women with Fabry disease. Nephrol. Dial. Transplant.; 2014; 29, pp. 619-625. [DOI: https://dx.doi.org/10.1093/ndt/gft452] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24215016]

124. Schiffmann, R.; Bichet, D.; Germain, D.; Giugliani, R.; Hughes, D.; Nicholls, K.; Wilcox, W.; Williams, H.; Yu, J.; Castelli, J. . Effects of long-term migalastat treatment on renal function by baseline proteinuria in patients (PTS) with Fabry disease. Nephrol. Dial. Transplant.; 2018; 33, (Suppl. S1), pp. i346-i347. [DOI: https://dx.doi.org/10.1093/ndt/gfy104.SP004]

125. Wallace, E.; Goker-Alpan, O.; Alon, S.; Chertkoff, R.; Almon, E.; Rocco, R.; Warnock, D.G.; Longo, N. Safety and efficacy of pegunigalsidase alfa vs agalsidase beta on renal function in Fabry disease: 24-month results from the phase III randomized, double-blind, BALANCE study. Nephron; 2022; 146, (Suppl. S1), 39.

126. Wilcox, W.R.; Banikazemi, M.; Guffon, N.; Waldek, S.; Lee, P.; Linthorst, G.E.; Desnick, R.J.; Germain, D.P. International Fabry Disease Study Group. Long-term safety and efficacy of enzyme replacement therapy for Fabry disease. Am. J. Hum. Genet.; 2004; 75, pp. 65-74. [DOI: https://dx.doi.org/10.1086/422366] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15154115]

127. Wallace, E.L.; Goker-Alpan, O.; Wilcox, W.R.; Holida, M.; Bernat, J.; Longo, N.; Linhart, A.; A Hughes, D.; Hopkin, R.J.; Tøndel, C. . Head-to-head trial of pegunigalsidase alfa versus agalsidase beta in patients with Fabry disease and deteriorating renal function: Results from the 2-year randomised phase III BALANCE study. J. Med. Genet.; 2023; 61, pp. 520-530. [DOI: https://dx.doi.org/10.1136/jmg-2023-109445] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37940383]

128. Goker-Alpan, O.; Nedd, K.; Shankar, S.P.; Lien, Y.-H.H.; Weinreb, N.; Wijatyk, A.; Chang, P.; Martin, R. Effect and tolerability of agalsidase alfa in patients with Fabry disease who were treatment naive or formerly treated with agalsidase beta or agalsidase alfa. JIMD Rep.; 2015; 23, pp. 7-15. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25822820]

129. Hughes, D.A.; Nicholls, K.; Shankar, S.P.; Sunder-Plassmann, G.; Koeller, D.; Nedd, K.; Vockley, G.; Hamazaki, T.; Lachmann, R.; Ohashi, T. . Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study. J. Med. Genet.; 2017; 54, pp. 288-296. [DOI: https://dx.doi.org/10.1136/jmedgenet-2016-104178] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27834756]

130. Narita, I.; Ohashi, T.; Sakai, N.; Hamazaki, T.; Skuban, N.; Castelli, J.P.; Lagast, H.; Barth, J.A. Efficacy and safety of migalastat in a Japanese population: A subgroup analysis of the ATTRACT study. Clin. Exp. Nephrol.; 2020; 24, pp. 157-166. [DOI: https://dx.doi.org/10.1007/s10157-019-01810-w] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31889231]

131. Krämer, J.; Lenders, M.; Canaan-Kühl, S.; Nordbeck, P.; Üçeyler, N.; Blaschke, D.; Duning, T.; Reiermann, S.; Stypmann, J.; Brand, S.-M. . Fabry disease under enzyme replacement therapy—new insights in efficacy of different dosages. Nephrol. Dial. Transplant.; 2018; 33, pp. 1362-1372. [DOI: https://dx.doi.org/10.1093/ndt/gfx319] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29186537]

132. Lenders, M.; Canaan-Kühl, S.; Krämer, J.; Duning, T.; Reiermann, S.; Sommer, C.; Stypmann, J.; Blaschke, D.; Üçeyler, N.; Hense, H.-W. . Patients with Fabry disease after enzyme replacement therapy dose reduction and switch-2-year follow-up. J. Am. Soc. Nephrol.; 2016; 27, pp. 952-962. [DOI: https://dx.doi.org/10.1681/ASN.2015030337] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26185201]

133. Lenders, M.; Nordbeck, P.; Canaan-Kühl, S.; Kreul, L.; Duning, T.; Lorenz, L.; Pogoda, C.; Brand, S.-M.; Wanner, C.; Brand, E. Treatment switch in Fabry disease—a matter of dose?. J. Med. Genet.; 2021; 58, pp. 342-350. [DOI: https://dx.doi.org/10.1136/jmedgenet-2020-106874] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32522756]

134. Muentze, J.; Gensler, D.; Salinger, T.; Oder, D.; Wanner, C.; Frantz, S.; Nordbeck, P. Treatment of cardiac manifestations in Fabry disease with the oral drug migalastat: First 12 months results from a cohort of amenable all-comers. Eur. Heart J.; 2018; 39, (Suppl. S1), 460. [DOI: https://dx.doi.org/10.1093/eurheartj/ehy565.2355]

135. Müntze, J.; Gensler, D.; Maniuc, O.; Liu, D.; Cairns, T.; Oder, D.; Hu, K.; Lorenz, K.; Frantz, S.; Wanner, C. . Oral chaperone therapy migalastat for treating Fabry disease: Enzymatic response and serum biomarker changes after 1 year. Clin. Pharmacol. Ther.; 2019; 105, pp. 1224-1233. [DOI: https://dx.doi.org/10.1002/cpt.1321] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30506669]

136. Tsuboi, K.; Yamamoto, H. Clinical observation of patients with Fabry disease after switching from agalsidase beta (Fabrazyme) to agalsidase alfa (Replagal). Genet. Med.; 2012; 14, pp. 779-786. [DOI: https://dx.doi.org/10.1038/gim.2012.39] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22878505]

137. Tsuboi, K.; Yamamoto, H. Clinical course of patients with Fabry disease who were switched from agalsidase-beta to agalsidase-alpha. Genet. Med.; 2014; 16, pp. 766-772. [DOI: https://dx.doi.org/10.1038/gim.2014.28] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24651606]

138. Weidemann, F.; Krämer, J.; Duning, T.; Lenders, M.; Canaan-Kühl, S.; Krebs, A.; González, H.G.; Sommer, C.; Üçeyler, N.; Niemann, M. . Patients with Fabry disease after enzyme replacement therapy dose reduction versus treatment switch. J. Am. Soc. Nephrol.; 2014; 25, pp. 837-849. [DOI: https://dx.doi.org/10.1681/ASN.2013060585] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24556354]

139. Linhart, A.; Dostálová, G.; Nicholls, K.; West, M.L.; Tøndel, C.; Jovanovic, A.; Giraldo, P.; Vujkovac, B.; Geberhiwot, T.; Brill-Almon, E. . Safety and efficacy of pegunigalsidase alfa in patients with Fabry disease who were previously treated with agalsidase alfa: Results from BRIDGE, a phase 3 open-label study. Orphanet J. Rare Dis.; 2023; 18, 332. [DOI: https://dx.doi.org/10.1186/s13023-023-02937-6] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37865771]

140. Riccio, E.; Zanfardino, M.; Ferreri, L.; Santoro, C.; Cocozza, S.; Capuano, I.; Imbriaco, M.; Feriozzi, S.; Pisani, A. AFFIINITY Group. Switch from enzyme replacement therapy to oral chaperone migalastat for treating Fabry disease: Real-life data. Eur. J. Hum. Genet.; 2020; 28, pp. 1662-1668. [DOI: https://dx.doi.org/10.1038/s41431-020-0677-x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32647377]

141. Baehner, F.; Kampmann, C.; Whybra, C.; Miebach, E.; Wiethoff, C.M.; Beck, M. Enzyme replacement therapy in heterozygous females with Fabry disease: Results of a phase IIIB study. J. Inherit. Metab. Dis.; 2003; 26, pp. 617-627. [DOI: https://dx.doi.org/10.1023/B:BOLI.0000005658.14563.77] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/14707510]

142. Hughes, D.A.; Deegan, P.B.; Romero, M.B.; Giugliani, R. Responses of females with Fabry disease to ERT: Comparison with males, using data from FOS—The Fabry outcome survey. Mol. Genet. Metab.; 2009; 98, 81.

143. Kampmann, C.; Linhart, A.; Devereux, R.B.; Schiffmann, R. Effect of agalsidase alfa replacement therapy on Fabry disease-related hypertrophic cardiomyopathy: A 12- to 36-month, retrospective, blinded echocardiographic pooled analysis. Clin. Ther.; 2009; 31, pp. 1966-1976. [DOI: https://dx.doi.org/10.1016/j.clinthera.2009.09.008] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19843486]

144. Elliott, P.M.; Kindler, H.; Shah, J.S.; Sachdev, B.; Rimoldi, O.E.; Thaman, R.; Tome, M.T.; McKenna, W.J.; Lee, P.; Camici, P.G. Coronary microvascular dysfunction in male patients with Anderson-Fabry disease and the effect of treatment with alpha galactosidase A. Heart; 2006; 92, pp. 357-360. [DOI: https://dx.doi.org/10.1136/hrt.2004.054015] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16085718]

145. Kalliokoski, R.J.; Kantola, I.; Kalliokoski, K.K.; Engblom, E.; Sundell, J.; Hannukainen, J.C.; Janatuinen, T.; Raitakari, O.T.; Knuuti, J.; Penttinen, M. . The effect of 12-month enzyme replacement therapy on myocardial perfusion in patients with Fabry disease. J. Inherit. Metab. Dis.; 2006; 29, pp. 112-118. [DOI: https://dx.doi.org/10.1007/s10545-006-0221-3] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16601877]

146. Messalli, G.; Imbriaco, M.; Avitabile, G.; Russo, R.; Iodice, D.; Spinelli, L.; Dellegrottaglie, S.; Cademartiri, F.; Salvatore, M.; Pisani, A. Role of cardiac MRI in evaluating patients with Anderson-Fabry disease: Assessing cardiac effects of long-term enzyme replacement therapy. Radiol. Med.; 2012; 117, pp. 19-28. [DOI: https://dx.doi.org/10.1007/s11547-011-0710-9] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21744250]

147. Motwani, M.; Banypersad, S.; Woolfson, P.; Waldek, S. Enzyme replacement therapy improves cardiac features and severity of Fabry disease. Mol. Genet. Metab.; 2012; 107, pp. 197-202. [DOI: https://dx.doi.org/10.1016/j.ymgme.2012.05.011] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22704481]

148. Pisani, A.; Spinelli, L.; Sabbatini, M.; Andreucci, M.V.; Procaccini, D.; Abbaterusso, C.; Pasquali, S.; Savoldi, S.; Comotti, C.; Cianciaruso, B. Enzyme replacement therapy in Fabry disease patients undergoing dialysis: Effects on quality of life and organ involvement. Am. J. Kidney Dis.; 2005; 46, pp. 120-127. [DOI: https://dx.doi.org/10.1053/j.ajkd.2005.03.016] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15983965]

149. Wuest, W.; Machann, W.; Breunig, F.; Weidemann, F.; Koestler, H.; Hahn, D.; Wanner, C.; Beer, M. Right ventricular involvement in patients with Fabry disease and the effect of enzyme replacement therapy. Rofo; 2011; 183, pp. 1037-1042. [DOI: https://dx.doi.org/10.1055/s-0031-1281744] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21959886]

150. Pietilä-Effati, P.; Saarinen, J.T.; Loyttyniemi, E.; Saarenhovi, M.; Autio, R.; Kantola, I. Long-term effectiveness of enzyme replacement therapy in Fabry disease with the p.Arg227Ter (R227*) mutation. Mol. Genet. Metab.; 2023; 138, 107270. [DOI: https://dx.doi.org/10.1016/j.ymgme.2022.107270]

151. Huang, S.; Wang, J.; Zhang, W.; Gao, F.; Chen, Y.; Shui, W.; Xing, X.; Chen, S.; Mu, Y. Clinical study of left ventricular structure and function in patients with Anderson-Fabry disease before and after enzyme replacement therapy. J. Clin. Ultrasound; 2024; 52, pp. 20-29. [DOI: https://dx.doi.org/10.1002/jcu.23592] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37883130]

152. Hongo, K.; Ito, K.; Date, T.; Anan, I.; Inoue, Y.; Morimoto, S.; Ogawa, K.; Kawai, M.; Kobayashi, H.; Kobayashi, M. . The beneficial effects of long-term enzyme replacement therapy on cardiac involvement in Japanese Fabry patients. Mol. Genet. Metab.; 2018; 124, pp. 143-151. [DOI: https://dx.doi.org/10.1016/j.ymgme.2018.04.008] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29747997]

153. Kovacevic-Preradovic, T.; Zuber, M.; Jost, C.A.; Widmer, U.; Seifert, B.; Schulthess, G.; Fischer, A.; Jenni, R. Anderson-Fabry disease: Long-term echocardiographic follow-up under enzyme replacement therapy. Eur. J. Echocardiogr.; 2008; 9, pp. 729-735. [DOI: https://dx.doi.org/10.1093/ejechocard/jen129] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18490303]

154. Lenders, M.; Stypmann, J.; Duning, T.; Schmitz, B.; Brand, S.M.; Brand, E. Serum-mediated inhibition of enzyme replacement therapy in Fabry disease. J. Am. Soc. Nephrol.; 2016; 27, pp. 256-264. [DOI: https://dx.doi.org/10.1681/ASN.2014121226] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25933799]

155. Liu, H.-C.; Lin, H.-Y.; Yang, C.-F.; Liao, H.-C.; Hsu, T.-R.; Lo, C.-W.; Chang, F.-P.; Huang, C.-K.; Lu, Y.-H.; Lin, S.-P. . Globotriaosylsphingosine (lyso-Gb3) might not be a reliable marker for monitoring the long-term therapeutic outcomes of enzyme replacement therapy for late-onset Fabry patients with the Chinese hotspot mutation (IVS4+919G>A). Orphanet J. Rare Dis.; 2014; 9, 111. [DOI: https://dx.doi.org/10.1186/s13023-014-0111-y] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25047006]

156. Nordin, S.; Kozor, R.; Vijapurapu, R.; Augusto, J.B.; Knott, K.D.; Captur, G.; Treibel, T.A.; Ramaswami, U.; Tchan, M.; Geberhiwot, T. . Myocardial storage, inflammation, and cardiac phenotype in Fabry disease after one year of enzyme replacement therapy. Circ. Cardiovasc. Imaging; 2019; 12, e009430. [DOI: https://dx.doi.org/10.1161/CIRCIMAGING.119.009430] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31826677]

157. Schmied, C.; Nowak, A.; Gruner, C.; Olinger, E.; Debaix, H.; Brauchlin, A.; Frank, M.; Reidt, S.; Monney, P.; Barbey, F. . The value of ECG parameters as markers of treatment response in Fabry cardiomyopathy. Heart; 2016; 102, pp. 1309-1314. [DOI: https://dx.doi.org/10.1136/heartjnl-2015-308897] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27056970]

158. Weidemann, F.; Niemann, M.; Breunig, F.; Herrmann, S.; Beer, M.; Störk, S.; Voelker, W.; Ertl, G.; Wanner, C.; Strotmann, J. Long-term effects of enzyme replacement therapy on Fabry cardiomyopathy: Evidence for a better outcome with early treatment. Circulation; 2009; 119, pp. 524-529. [DOI: https://dx.doi.org/10.1161/CIRCULATIONAHA.108.794529] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19153271]

159. Camporeale, A.; Bandera, F.; Pieroni, M.; Pieruzzi, F.; Spada, M.; Bersano, A.; Econimo, L.; Lanzillo, C.; Rubino, M.; Mignani, R. . Effect of Migalastat on cArdiac InvOlvement in FabRry DiseAse: MAIORA study. J. Med. Genet.; 2023; 60, pp. 850-858. [DOI: https://dx.doi.org/10.1136/jmg-2022-108768] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36669872]

160. Jovanovic, A.; Schiffmann, R.; Nicholls, K.; Feldt-Rasmussen, U.; Bichet, D.G.; Hughes, D.; Jain, V.; Yu, J.; Castelli, J.; Skuban, N. . Improvements in cardiac mass with long-term migalastat treatment in patients with Fabry disease: Results from phase 3 trials. J. Inborn Errors Metab. Screen.; 2017; 5, Abstract LBN 02. [DOI: https://dx.doi.org/10.1177/2326409817730396]

161. Krämer, J.; Niemann, M.; Störk, S.; Frantz, S.; Beer, M.; Ertl, G.; Wanner, C.; Weidemann, F. Relation of burden of myocardial fibrosis to malignant ventricular arrhythmias and outcomes in Fabry disease. Am. J. Cardiol.; 2014; 114, pp. 895-900. [DOI: https://dx.doi.org/10.1016/j.amjcard.2014.06.019] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25073565]

162. Lee, C.L.; Lin, S.P.; Niu, D.M.; Lin, H.Y. Fabry disease and the effectiveness of enzyme replacement therapy (ERT) in left ventricular hypertrophy (LVH) improvement: A review and meta-analysis. Int. J. Med Sci.; 2022; 19, pp. 126-131. [DOI: https://dx.doi.org/10.7150/ijms.66448] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34975306]

163. Mignani, R.; Feriozzi, S.; Pisani, A.; Cioni, A.; Comotti, C.; Cossu, M.; Foschi, A.; Giudicissi, A.; Gotti, E.; Lozupone, V.A. . Agalsidase therapy in patients with Fabry disease on renal replacement therapy: A nationwide study in Italy. Nephrol. Dial. Transplant.; 2008; 23, pp. 1628-1635. [DOI: https://dx.doi.org/10.1093/ndt/gfm813] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18057066]

164. Figliozzi, S.; Georgiopoulos, G.; Stankowski, K.M.; Camporeale, A.; Pieroni, M. Effects of enzyme replacement therapy on CMR parameters in patients with Fabry disease: A systematic review and meta-analysis. Eur. Heart. J. Suppl.; 2022; 24, (Suppl. K), pp. K219-K220. [DOI: https://dx.doi.org/10.1093/eurheartjsupp/suac121.617]

165. Pogoda, C.; Brand, S.-M.; Duning, T.; Schmidt-Pogoda, A.; Sindermann, J.; Lenders, M.; Brand, E. Impact of enzyme replacement therapy and migalastat on left atrial strain and cardiomyopathy in patients with Fabry disease. Front. Cardiovasc. Med.; 2023; 10, 1223635. [DOI: https://dx.doi.org/10.3389/fcvm.2023.1223635] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/38028489]

166. Germain, D.P.; Weidemann, F.; Abiose, A.; Patel, M.R.; Cizmarik, M.; Cole, J.A.; Beitner-Johnson, D.; Benistan, K.; Cabrera, G.; Charrow, J. . Analysis of left ventricular mass in untreated men and in men treated with agalsidase-beta: Data from the Fabry Registry. Genet. Med.; 2013; 15, pp. 958-965. [DOI: https://dx.doi.org/10.1038/gim.2013.53] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23703683]

167. Veldman, B.C.F.; Schoenmakers, D.H.; van Dussen, L.; Datema, M.R.; Langeveld, M. Establishing treatment effectiveness in Fabry disease: Observation-based recommendations for improvement. Int. J. Mol. Sci.; 2024; 25, 9752. [DOI: https://dx.doi.org/10.3390/ijms25179752] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/39273698]

168. Imbriaco, M.; Pisani, A.; Spinelli, L.; Cuocolo, A.; Messalli, G.; Capuano, E.; Marmo, M.; Liuzzi, R.; Visciano, B.; Cianciaruso, B. . Effects of enzyme-replacement therapy in patients with Anderson-Fabry disease: A prospective long-term cardiac magnetic resonance imaging study. Heart; 2009; 95, pp. 1103-1107. [DOI: https://dx.doi.org/10.1136/hrt.2008.162800] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19372091]

169. Niemann, M.; Breunig, F.; Beer, M.; Herrmann, S.; Strotmann, J.; Hu, K.; Emmert, A.; Voelker, W.; Ertl, G.; Wanner, C. . The right ventricle in Fabry disease: Natural history and impact of enzyme replacement therapy. Heart; 2010; 96, pp. 1915-1919. [DOI: https://dx.doi.org/10.1136/hrt.2010.204586] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20965976]

170. Weidemann, F.; Breunig, F.; Beer, M.; Knoll, A.; Turschner, O.; Wanner, C.; Sandstede, J.; Voelker, W.; Ertl, G.; Strotmann, J. Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease: A prospective strain rate imaging study. Circulation; 2003; 108, pp. 1299-1301. [DOI: https://dx.doi.org/10.1161/01.CIR.0000091253.71282.04] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12952834]

171. Jardim, L.B.; Aesse, F.; Vedolin, L.M.; Pitta-Pinheiro, C.; Marconato, J.; Burin, M.G.; Cecchin, C.; Netto, C.B.; Matte, U.S.; Pereira, F. . White matter lesions in Fabry disease before and after enzyme replacement therapy: A 2-year follow-up. Arq. Neuro-Psiquiatria; 2006; 64, pp. 711-717. [DOI: https://dx.doi.org/10.1590/S0004-282X2006000500002] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17057872]

172. Lee, H.-J.; Hsu, T.-R.; Hung, S.-C.; Yu, W.-C.; Chu, T.-H.; Yang, C.-F.; Bizjajeva, S.; Tiu, C.-M.; Niu, D.-M. A comparison of central nervous system involvement in patients with classical Fabry disease or the later-onset subtype with the IVS4 + 919G > A mutation. BMC Neurol.; 2017; 17, 25. [DOI: https://dx.doi.org/10.1186/s12883-017-0810-9] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28166746]

173. Korver, S.; Vergouwe, M.; Hollak, C.E.M.; van Schaik, I.N.; Langeveld, M. Development and clinical consequences of white matter lesions in Fabry disease: A systematic review. Mol. Genet. Metab.; 2018; 125, pp. 205-216. [DOI: https://dx.doi.org/10.1016/j.ymgme.2018.08.014] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30213639]

174. Korver, S.; Longo, M.G.F.; Lima, M.R.; Hollak, C.E.M.; El Sayed, M.; van Schaik, I.N.; Vedolin, L.; Dijkgraaf, M.G.W.; Langeveld, M. Determinants of cerebral radiological progression in Fabry disease. J. Neurol. Neurosurg. Psychiatry; 2020; 91, pp. 756-763. [DOI: https://dx.doi.org/10.1136/jnnp-2019-322268] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32317398]

175. Lulla, D.S.; Higuita, L.; Shukla-Parekh, S.; Lau, H. Survey assessing the prevalence and severity of neuropsychiatric manifestations in patients living with Fabry disease. Mol. Genet. Metab.; 2020; 129, (Suppl. S2), S103. [DOI: https://dx.doi.org/10.1016/j.ymgme.2019.11.263]

176. Sunder-Plassmann, G.; Shankar, S.; Wilcox, W.; Nicholls, K.; Giugliani, R.; Lagast, H.; Skuban, N.; Germain, D.P. Occurrence of cerebrovascular events during long-term treatment with migalastat in patients with Fabry disease. J. Inherit. Metab. Dis.; 2019; 42, (Suppl. S1), 233.

177. Banikazemi, M.; Bultas, J.; Waldek, S.; Wilcox, W.R.; Whitley, C.B.; McDonald, M.; Finkel, R.; Packman, S.; Bichet, D.G.; Warnock, D.G. . Agalsidase-beta therapy for advanced Fabry disease: A randomized trial. Ann. Intern. Med.; 2007; 146, pp. 77-86. [DOI: https://dx.doi.org/10.7326/0003-4819-146-2-200701160-00148] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17179052]

178. Fellgiebel, A.; Gartenschlager, M.; Wildberger, K.; Scheurich, A.; Desnick, R.J.; Sims, K. Enzyme replacement therapy stabilized white matter lesion progression in Fabry disease. Cerebrovasc. Dis.; 2014; 38, pp. 448-456. [DOI: https://dx.doi.org/10.1159/000369293] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25502511]

179. Lenders, M.; Karabul, N.; Duning, T.; Schmitz, B.; Schelleckes, M.; Mesters, R.; Hense, H.-W.; Beck, M.; Brand, S.-M.; Brand, E. Thromboembolic events in Fabry disease and the impact of factor v Leiden. Neurology; 2015; 84, pp. 1009-1016. [DOI: https://dx.doi.org/10.1212/WNL.0000000000001333] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25663229]

180. Whybra, C.; Kampmann, C.; Krummenauer, F.; Ries, M.; Mengel, E.; Miebach, E.; Baehner, F.; Kim, K.; Bajbouj, M.; Schwarting, A. . The Mainz Severity Score Index: A new instrument for quantifying the Anderson-Fabry disease phenotype, and the response of patients to enzyme replacement therapy. Clin. Genet.; 2004; 65, pp. 299-307. [DOI: https://dx.doi.org/10.1111/j.1399-0004.2004.00219.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15025723]

181. Parini, R.; Rigoldi, M.; Santus, F.; Furlan, F.; De Lorenzo, P.; Valsecchi, G.; Concolino, D.; Strisciuglio, P.; Feriozzi, S.; Di Vito, R. . Enzyme replacement therapy with agalsidase alfa in a cohort of Italian patients with Anderson-Fabry disease: Testing the effects with the Mainz Severity Score Index. Clin. Genet.; 2008; 74, pp. 260-266. [DOI: https://dx.doi.org/10.1111/j.1399-0004.2008.01012.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18445046]

182. Concolino, D.; Amico, L.; Cappellini, M.D.; Cassinerio, E.; Conti, M.; Donati, M.; Falvo, F.; Fiumara, A.; Maccarone, M.; Manna, R. . Home infusion program with enzyme replacement therapy for Fabry disease: The experience of a large Italian collaborative group. Mol. Genet. Metab. Rep.; 2017; 12, pp. 85-91. [DOI: https://dx.doi.org/10.1016/j.ymgmr.2017.06.005] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28702361]

183. Biegstraaten, M.; van Schaik, I.N.; Wieling, W.; Wijburg, F.A.; Hollak, C.E. Autonomic neuropathy in Fabry disease: A prospective study using the Autonomic Symptom Profile and cardiovascular autonomic function tests. BMC Neurol.; 2010; 10, 38. [DOI: https://dx.doi.org/10.1186/1471-2377-10-38] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20529242]

184. Chen, K.-H.; Chien, Y.; Wang, K.-L.; Leu, H.-B.; Hsiao, C.-Y.; Lai, Y.-H.; Wang, C.-Y.; Chang, Y.-L.; Lin, S.-J.; Niu, D.-M. . Evaluation of proinflammatory prognostic biomarkers for Fabry cardiomyopathy with enzyme replacement therapy. Can. J. Cardiol.; 2016; 32, pp. 1221.e1221-1221.e1229. [DOI: https://dx.doi.org/10.1016/j.cjca.2015.10.033] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26919792]

185. Neto, N.S.R.; Bento, J.C.B.; Caparbo, V.F.; Pereira, R.M.R. Increased serum interleukin-6 and tumor necrosis factor alpha levels in Fabry disease: Correlation with disease burden. Clinics; 2021; 76, e2643. [DOI: https://dx.doi.org/10.6061/clinics/2021/e2643] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34287477]

186. Chen, K.-H.; Chou, Y.-C.; Hsiao, C.-Y.; Chien, Y.; Wang, K.-L.; Lai, Y.-H.; Chang, Y.-L.; Niu, D.-M.; Yu, W.-C. Amelioration of serum 8-OHdG level by enzyme replacement therapy in patients with Fabry cardiomyopathy. Biochem. Biophys. Res. Commun.; 2017; 486, pp. 293-299. [DOI: https://dx.doi.org/10.1016/j.bbrc.2017.03.030] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28300554]

187. Ripeau, D.; Amartino, H.; Cedrolla, M.; Urtiaga, L.; Urdaneta, B.; Cano, M.; Valdez, R.; Antongiovanni, N.; Masllorens, F. Cambio de agalsidasa beta por agalsidasa alfa en la terapia de reemplazo enzimatica de pacientes con enfermedad de Fabry en Latinoamerica. Medicina; 2017; 77, pp. 173-179. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28643672]

188. Orsborne, C.; Black, N.; Naish, J.H.; Woolfson, P.; Reid, A.B.; Schmitt, M.; Jovanovic, A.; A Miller, C. Disease-specific therapy for the treatment of the cardiovascular manifestations of Fabry disease: A systematic review. Heart; 2023; 110, pp. 19-26. [DOI: https://dx.doi.org/10.1136/heartjnl-2023-322712] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37640453]

189. Besekar, S.M.; Jogdand, S.D.; Naqvi, W.M. Fabry disease and its management: A literature analysis. Cureus; 2023; 15, e37048. [DOI: https://dx.doi.org/10.7759/cureus.37048] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37153259]

190. Riccio, E.; Pisani, A. New insights in efficacy of different enzyme replacement therapy dosages in Fabry disease: Switch studies data following agalsidase beta shortage. Clin. Genet.; 2023; 103, pp. 371-376. [DOI: https://dx.doi.org/10.1111/cge.14266] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36373246]

191. Riccio, E.; de Marco, O.; Pisani, A. Medication adherence in Fabry patients treated with migalastat: Real world experience. Mol. Genet. Metab. Rep.; 2023; 35, 100976. [DOI: https://dx.doi.org/10.1016/j.ymgmr.2023.100976] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37180842]

192. Ramaswami, U.; Pintos-Morell, G.; Kampmann, C.; Nicholls, K.; Niu, D.-M.; Reisin, R.; West, M.L.; Anagnostopoulou, C.; Botha, J.; Jazukeviciene, D. . Two decades of experience of the Fabry Outcome Survey provides further confirmation of the long-term effectiveness of agalsidase alfa enzyme replacement therapy. Mol. Genet. Metab. Rep.; 2025; 43, 101215. [DOI: https://dx.doi.org/10.1016/j.ymgmr.2025.101215] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/40276560]

193. Khanna, R.; Soska, R.; Lun, Y.; Feng, J.; Frascella, M.; Young, B.; Brignol, N.; Pellegrino, L.; A Sitaraman, S.; Desnick, R.J. . The pharmacological chaperone 1-deoxygalactonojirimycin reduces tissue globotriaosylceramide levels in a mouse model of Fabry disease. Mol. Ther.; 2010; 18, pp. 23-33. [DOI: https://dx.doi.org/10.1038/mt.2009.220] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19773742]

194. Burlina, A.; Al-Shaar, L.; Germain, D.P.; Banikazemi, M.; Ponce, E.; Crespo, A.; Lawson, V.; Politei, J. Reduced incidence of stroke in patients with Fabry disease treated with agalsidase beta: A matched analysis from the Fabry Registry. Mol. Genet. Metab.; 2025; 144, 16. [DOI: https://dx.doi.org/10.1016/j.ymgme.2024.108669]

195. Feriozzi, S.; Chimenti, C.; Reisin, R.C. Updated evaluation of agalsidase alfa enzyme replacement therapy for patients with Fabry disease: Insights from real-world data. Drug Des. Dev. Ther.; 2024; 18, pp. 1083-1101. [DOI: https://dx.doi.org/10.2147/DDDT.S365885] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/38585254]

196. Batista, J.L.; Hariri, A.; Maski, M.; Richards, S.; Gudivada, B.; A Raynor, L.; Ponce, E.; Wanner, C.; Desnick, R.J. Reduction in kidney function decline and risk of severe clinical events in agalsidase beta-treated Fabry disease patients: A matched analysis from the Fabry Registry. Clin. Kidney J.; 2024; 17, sfae194. [DOI: https://dx.doi.org/10.1093/ckj/sfae194] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/39139182]

197. Pisani, A.; Wilson, K.M.; Batista, J.L.; Kantola, I.; Ortiz, A.; Politei, J.; Al-Shaar, L.; Maski, M.; Crespo, A.; Ponce, E. . Clinical outcomes in patients switching from agalsidase beta to migalastat: A Fabry Registry analysis. J. Inherit. Metab. Dis.; 2024; 47, pp. 1080-1095. [DOI: https://dx.doi.org/10.1002/jimd.12773] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/38961737]

198. Lenders, M.; Nowak, A.; Cybulla, M.; Kaufeld, J.; Köhn, A.F.; Muschol, N.M.; Kurschat, C.; Brand, E. Impact of enzyme replacement therapy and migalastat on disease progression in females with Fabry disease. Orphanet J. Rare Dis.; 2025; 20, 79. [DOI: https://dx.doi.org/10.1186/s13023-025-03600-y] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/39980015]

199. Hughes, D.A.; Sunder-Plassmann, G.; Jovanovic, A.; Brand, E.; West, M.L.; Bichet, D.G.; Pisani, A.; Nowak, A.; Torra, R.; Khan, A. . Renal and multisystem effectiveness of 3.9 years of migalastat in a global real-world cohort: Results from the followME Fabry Pathfinders registry. J. Inherit. Metab. Dis.; 2025; 48, e12771. [DOI: https://dx.doi.org/10.1002/jimd.12771] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/39031114]

200. Ramaswami, U.; Font-Montgomery, E.; Goker-Alpan, O.; Ortiz, D.; Sanchez-Valle, A.; Whitley, C.B.; Wilcox, W.R.; Jiang, H.; Lawson, L.A.; Vosk, J. . Safety and efficacy of migalastat in adolescent patients with Fabry disease: Results from ASPIRE, a phase 3b, open-label, single-arm, 12-month clinical trial, and its open-label extension. Mol. Genet. Metab.; 2025; 145, 109102. [DOI: https://dx.doi.org/10.1016/j.ymgme.2025.109102] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/40215726]

201. Nowak, A.; Botha, J.; Anagnostopoulou, C.; Hughes, D.A. Clinical outcomes in elderly patients receiving agalsidase alfa treatment in the Fabry Outcome Survey. Mol. Genet. Metab.; 2024; 143, 108561. [DOI: https://dx.doi.org/10.1016/j.ymgme.2024.108561] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/39159540]

202. Arakawa, M.; Ikeda, Y.; Otaka, H.; Iwashiro, S. Long-term safety of enzyme replacement therapy with agalsidase alfa in patients with Fabry disease: Post-marketing extension surveillance in Japan. Mol. Genet. Metab. Rep.; 2024; 40, 101122. [DOI: https://dx.doi.org/10.1016/j.ymgmr.2024.101122] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/39077747]

203. Liu, Y.; Li, Y.; Li, P.; Zhang, S.; Zhiqing, Z. Effectiveness and safety of enzyme replacement therapy in the treatment of Fabry disease: A Chinese monocentric real-world study. Orphanet J. Rare Dis.; 2024; 19, 422. [DOI: https://dx.doi.org/10.1186/s13023-024-03441-1] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/39529120]

204. Holida, M.; Linhart, A.; Pisani, A.; Longo, N.; Eyskens, F.; Goker-Alpan, O.; Wallace, E.; Deegan, P.; Tøndel, C.; Feldt-Rasmussen, U. . A phase III, open-label clinical trial evaluating pegunigalsidase alfa administered every 4 weeks in adults with Fabry disease previously treated with other enzyme replacement therapies. J. Inherit. Metab. Dis.; 2025; 48, e12795. [DOI: https://dx.doi.org/10.1002/jimd.12795] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/39381863]

Word count: 32105

Show less

© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Objectives: This systematic literature review aimed to identify studies assessing the clinical efficacy and real-world effectiveness of current and emerging treatments for Fabry disease. Methods: Searches of the MEDLINE, EMBASE, and Cochrane library databases, as well as relevant congress proceedings, were conducted to identify publications reporting on studies in patients of any age, sex, race, or ethnicity who received any approved or experimental treatment for Fabry disease, published before 17 June 2024. Results: Of 1881 publications screened, 234 reported data on renal, cardiac, cerebrovascular, and disease severity outcomes from 225 studies. The majority of reported studies were observational in nature (n = 150; 67%) and involved only adults (n = 172; 74%). Study designs and patient populations were highly heterogeneous, and cross-study conclusions about the effectiveness of different therapies could not be made. Enzyme replacement therapy (ERT) with agalsidase alfa or agalsidase beta stabilized renal function and cardiac structure in patients with Fabry disease. Early initiation of ERT in childhood or young adulthood was associated with better renal and cardiac outcomes than treatment initiation at a later age. The small number of comparator studies of agalsidase alfa and agalsidase beta suggested similar efficacy. Patients treated with migalastat and pegunigalsidase alfa also maintained stable renal function and cardiac structure. Conclusions: Overall, current treatments slow the progression of renal and cardiac decline in patients with Fabry disease. Large cohort studies with long-term follow-up and baseline stratification based on clinical phenotype are needed to address evidence gaps and provide clinicians with robust data to inform treatment decisions.

Details

Title
Clinical Efficacy and Real-World Effectiveness of Fabry Disease Treatments: A Systematic Literature Review
Author
Jovanovic, Ana 1 ; Miller-Hodges, Eve 2   VIAFID ORCID Logo  ; Castriota Felicia 3 ; Obaro, Evuarherhe 4 ; Olulade, Ayodele 3   VIAFID ORCID Logo  ; Hughes Derralynn 5   VIAFID ORCID Logo  ; Pintos-Morell Guillem 6   VIAFID ORCID Logo  ; Giugliani Roberto 7   VIAFID ORCID Logo  ; Feriozzi Sandro 8   VIAFID ORCID Logo  ; Siffel Csaba 9   VIAFID ORCID Logo 

1  The Mark Holland Metabolic Unit, Northern Care Alliance NHS Foundation Trust, Salford M6 8HD, UK 
2  Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK 
3  Global Evidence and Outcomes, Data and Quantitative Sciences Institute, Takeda Development Center Americas, Inc., Cambridge, MA 02142, USA 
4  Oxford PharmaGenesis Ltd., Tubney OX13 5QJ, UK 
5  Lysosomal Storage Disorders Unit, Royal Free London NHS Foundation Trust, University College London, London WC1E 6BT, UK 
6  Vall d’Hebron Institute of Research, Vall d’Hebron Barcelona Hospital Campus, MPS-Lisosomales Medical Committee, 08035 Barcelona, Spain 
7  Department of Genetics, Federal University of Rio Grande do Sul (UFRGS), Medical Genetics Service, Hospital de Clinicas de Porto Alegre (HCPA), Dasa Genomics, and Casa dos Raros, Porto Alegre 90610-261, Brazil 
8  Nephrology Department, University Campus Bio-Medico, University of Rome, 00128 Rome, Italy 
9  Global Evidence and Outcomes, Data and Quantitative Sciences Institute, Takeda Development Center Americas, Inc., Cambridge, MA 02142, USA, College of Allied Health Sciences, Augusta University, Augusta, GA 30912, USA 
First page
5131
Publication year
2025
Publication date
2025
Publisher
MDPI AG
e-ISSN
20770383
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.3390/jcm14145131
ProQuest document ID
3233225863
Copyright
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.