Effects of Current Therapies on Disease Progression in Fabry Disease: A Narrative Review for Better Patient Management in Clinical Practice

Abstract

Fabry disease (FD) is a rare lysosomal storage disorder that is characterized by renal, neurological, and cardiovascular dysfunction. Four treatments are currently available for patients with FD; three enzyme replacement therapies (ERTs; agalsidase alfa, agalsidase beta, and pegunigalsidase alfa) and one pharmacological chaperone (migalastat). This review focuses on the evidence for the benefits of ERTs and migalastat, and provides an overview of their impact on disease manifestations and quality of life (QoL). Agalsidase beta is associated with renal, neurological, and cardiovascular benefits, and may prevent renal disease progression. Agalsidase alfa provides stabilizing effects across all main organ systems, although minor sex-specific differences exist in patients with more advanced baseline disease. The benefits of agalsidase alfa and agalsidase beta are similar but depend on the extent of baseline disease. Some data indicate that agalsidase beta may be preferable over the longer term. Both agalsidase alfa and agalsidase beta are associated with improved gastrointestinal and pain symptoms, as well as improved QoL. Patients with advanced end-organ damage tend not to respond as optimally to ERTs as those who initiate ERTs before irreversible organ fibrosis develops, highlighting the need for early treatment initiation. Migalastat, which is only approved for patients with amenable missense gene variants, generally stabilizes renal parameters and provides cardiovascular benefits. Migalastat also improves diarrhea and pain, and stabilizes QoL (although ERT may be more effective for pain management), but the neurological effects of migalastat have not been studied. Real-world data raise concerns about effective in vivo amenability of some genetic variants. Future studies with direct treatment comparisons in patients with FD are needed.

Keywords: Agalsidase alfa; Agalsidase beta; Cardiovascular outcomes; Enzyme replacement therapy; Fabry disease; Neurological outcomes; Pegunigalsidase alfa; Quality of life; Renal outcomes.

Fig. 1

Representation of the overall progressive nature of Fabry disease in the cardiac system, showing the expected clinical progression, relevant imaging biomarkers, main means to diagnosis, and in relation to expected treatment efficacy with ERT [10]. Reproduced from [10] with permission from Elsevier. ECG electrocardiography, ERT enzyme replacement therapy, GLS global longitudinal strain, LGE late gadolinium enhancement, LysoGb3 globotriaosylsphingosine, MBF myocardial blood flow, NT-proBNP NT-probrain natriuretic peptide, T1 T1-weighted magnetic resonance image, T2 T2-weighted magnetic resonance image

Fig. 2

Respective cumulative onset of cardiac conditions, including left ventricular hypertrophy (LVH) in a men and b women, and late-gadolinium enhancement (LGE) in c men and d women with Fabry disease, separated by age group. The green line indicates cumulative penetrance [80]. Reproduced from [80] with permission from Elsevier. No. number, NT-proBNP N-terminal pro-brain natriuretic peptide

Fig. 3

Estimated glomerular filtration rate (eGFR) and response to treatment in adult patients with Fabry disease [106]. Reproduced from [106] with permission from Oxford University Press and the European Renal Association. ERT enzyme replacement therapy, FD Fabry disease