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. 2025 Apr 11:43:101215.
doi: 10.1016/j.ymgmr.2025.101215. eCollection 2025 Jun.

Two decades of experience of the Fabry Outcome Survey provides further confirmation of the long-term effectiveness of agalsidase alfa enzyme replacement therapy

Uma Ramaswami  1 , Guillem Pintos-Morell  2 , Christoph Kampmann  3 , Kathleen Nicholls  4 , Dau-Ming Niu  5 , Ricardo Reisin  6 , Michael L West  7 , Christina Anagnostopoulou  8 , Jaco Botha  8 , Dalia Jazukeviciene  8 , Jörn Schenk  8 , Derralynn A Hughes  1 , Roberto Giugliani  9
Affiliations

Two decades of experience of the Fabry Outcome Survey provides further confirmation of the long-term effectiveness of agalsidase alfa enzyme replacement therapy

Uma Ramaswami et al. Mol Genet Metab Rep. .

Abstract

Background: Analyses of up to 20 years of data from the Fabry Outcome Survey (FOS) assessed the long-term effectiveness of agalsidase alfa enzyme replacement therapy.

Methods: The impact of agalsidase alfa treatment on renal, cardiac, morbidity, and mortality outcomes in FOS was compared with untreated external Fabry disease (FD) cohorts.

Results: A total of 2171 FOS patients (1014 men, 919 women, 163 boys, 75 girls) received agalsidase alfa (median [range] duration of treatment: 5.38 [0.0-20.8] years). Annual rates of decline in estimated glomerular filtration rate improved in treated patients versus untreated external cohorts regardless of sex or baseline urinary protein levels. Annual left ventricular mass index rates were stable in treated patients regardless of sex or baseline left ventricular hypertrophy status, and better than in untreated external cohorts. The mean age at which 50 % of patients had their first composite morbidity event was later in the agalsidase-alfa-treated population than in the untreated external cohort (51.7 vs 41 years [males]; 60.8 vs 53 years [females]). After 24 months of treatment, the probability of a composite morbidity event was ∼34 % in treated patients and ∼ 45 % in untreated patients. Treated patients were older at death than untreated patients (mean [range]: 61.7 [26.2-87.6] vs 50.3 [34.5-70.1] years). The mean age at which 50 % of male patients were still alive was higher in treated patients than in untreated external cohorts (75.5 vs 60.0 years).

Conclusions: Long-term treatment with agalsidase alfa may provide renal, cardiac, and overall survival protection in FD.

Keywords: Agalsidase alfa; Clinical outcomes; Fabry disease; Long-term data; Registry data.

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Conflict of interest statement

UR reports honoraria for speaking and/or advisory boards from Amicus Therapeutics, Sanofi Genzyme, and Takeda, and research grants from Amicus Therapeutics, Intrabio, and Takeda. She is a member of the FOS Steering Committee. GP-M reports honoraria from Alexion, Amicus Therapeutics, BioMarin, Chiesi, Kyowa-Kirin, Lucane, Sanofi, and Takeda, and unrestricted grants from Sanofi and Takeda to the Vall d'Hebron 10.13039/100005930Research Foundation for funding research on rare diseases. He is a member of the FOS Steering Committee. CK reports honoraria for speaking and/or advisory boards from Amicus Therapeutics, BioMarin, Gore, and Takeda. He is a member of the FOS Steering Committee. KN reports honoraria from Amicus Therapeutics, Sanofi Genzyme, and Takeda. She is a member of the FOS Steering Committee. D-MN reports honoraria and speaker fees from Sanofi Genzyme and Takeda, and research grants from BioMarin, Sanofi Genzyme, and Takeda. He is a member of the FOS Steering Committee. RR reports honoraria, speaker fees, and consulting fees from Amicus Therapeutics, CSL Behring, Gador, Novartis, Sanofi Genzyme, and Takeda. He is a member of the FOS Steering Committee. MLW reports grants, personal fees, and travel support from 10.13039/100006396Alexion, Alnylam, 10.13039/100015362Amicus Therapeutics, Chiesi, Idorsia, Moderna, Protalix, 10.13039/100013995Sanofi Genzyme, and Takeda. He is a member of the FOS Steering Committee. CA is a former employee of Takeda Pharmaceuticals International AG and a current employee of Medison Pharma, Switzerland. JB is an employee of Takeda Pharmaceuticals International AG and is a stockholder of Takeda Pharmaceuticals Company Limited. DJ is an employee of Takeda Pharmaceuticals International AG and is a stockholder of Takeda Pharmaceuticals Company Limited. JS is a former employee of Takeda Pharmaceuticals International AG and a current employee of Kalvista Pharmaceuticals, Switzerland. DAH reports honoraria from Amicus Therapeutics, Chiesi, Freeline Therapeutics, Idorsia, Protalix, Sanofi Genzyme, and Takeda. She is a member of the FOS Steering Committee. RG reports honoraria, consulting fees, speaker fees, research funding, and/or travel reimbursement from Alexion, Allievex, Alnylam, Amicus Therapeutics, Astellas, Azafaros, BioMarin, Chiesi, JCR, Lysogene, Novartis, Paradigm, PassageBio, Pfizer, Praxis, PTC, Regenxbio, Sanofi, Takeda, and Ultragenyx. He is a member and the current chair of the FOS Steering Committee.

Figures

Fig. 1
Fig. 1
FOS patient cohorts and untreated external cohorts used throughout the current set of analyses. eGFR, estimated glomerular filtration rate; FOS, Fabry Outcome Survey; LVMI, left ventricular mass index. a FOS patients were included in every sub-cohort for which they filled the inclusion criteria.
Fig. 2
Fig. 2
Annualized eGFR change in treated population stratified by sex and time on treatment. A) Treated patients, B) treated patients with < 10 years of treatment, C) treated patients with ≥ 10 years of treatment, D) treated males, < 10 years of treatment vs ≥ 10 years of treatment, and E) treated females, < 10 years of treatment vs ≥ 10 years of treatment. Baseline is defined as the most recent value within 12 months of the earliest start of agalsidase alfa. CI, confidence interval; eGFR, estimated glomerular filtration rate; FOS, Fabry Outcome Survey; SE, standard error; y, year.
Fig. 3
Fig. 3
Morbidity outcomes in the treated population stratified by sex. A) Age at first renal, cardiac, or stroke event, or death, in treated patients, and B) time to first renal, cardiac, or stroke event, or death, in treated patients. CI, confidence interval; FOS, Fabry Outcome Survey. a Owing to the wide differences in range of event rate data between the FOS population and the published comparator, and to ensure that both data sets are being represented appropriately, the axis ranges used in the graphs of panel B differ from each other.
Fig. 4
Fig. 4
Survival over time in treated and untreated patients stratified by sex. A) Treated FOS patients stratified by sex, and B) the untreated external cohort published by Schiffmann et al. [35] CI, confidence interval; FOS, Fabry Outcome Survey.
Fig. 5
Fig. 5
Outcomes for treated FOS patients with classic or non-classic FD. A) Annualized eGFR change, B) time to first renal, cardiac, or stroke event, or death, and C) survival curves. Data points represent individual patient data. CI, confidence interval; eGFR, estimated glomerular filtration rate; FD, Fabry disease; FOS, Fabry Outcome Survey; NA, not available; SE, standard error; y, year.
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