Evaluating the relationship between antidrug antibodies and efficacy and safety outcomes in patients with Fabry disease receiving enzyme replacement therapy: a systematic literature review

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BACKGROUND: Fabry disease is a lysosomal storage disorder caused by deficient activity of the enzyme α-galactosidase A, resulting in progressive accumulation of globotriaosylceramide (Gb3) and widespread tissue and organ damage. Enzyme replacement therapy (ERT) can slow disease progression but may elicit antidrug antibody (ADA) responses. The impact of ADA status on long-term ERT efficacy and safety remains incompletely understood. OBJECTIVE: We conducted a systematic literature review (SLR) to examine the impact of ADA status on outcomes in patients with Fabry disease receiving ERT. We aimed to evaluate associations between ADA status and specific outcomes, and to identify remaining evidence needs. METHODS: Systematic searches were conducted in MEDLINE and Embase (up to March 4, 2025), supplemented by searches of the Cochrane Library and clinical trial registries. Eligible publications reported data on the relationship between ADA status and Fabry disease-related biomarkers (Gb3, globotriaosylsphingosine [lyso-Gb3]), efficacy (renal and cardiovascular) outcomes, and safety (adverse events [AEs] and infusion-related reactions [IRRs]) outcomes. RESULTS: Of 1763 articles screened, 24 were included (19 reported disease-related biomarkers, 10 renal outcomes, 4 cardiovascular, and 9 AE/IRR data). Most analyses of disease-related biomarkers (17/18) reported statistically significant positive associations (p < 0.05) between ADA positivity and elevated biomarkers: plasma lyso-Gb3 (4/8 studies), plasma Gb3 (1/3 studies), and urine Gb3 (6/6 studies). Some renal data sets (2/9) reported evidence suggesting a potential association between more rapid decline in estimated glomerular filtration rate in ADA-positive (vs ADA-negative) patients. Four out of 9 studies reported statistically significant associations between ADA positivity and IRR occurrence; most studies stratifying IRR rates by ADA status (5/7) reported higher rates among ADA-positive (vs ADA-negative) subgroups. CONCLUSION: This SLR found evidence that ADA positivity may be associated with increased IRR risk and may have a negative effect on some measures of ERT efficacy. Inconsistencies in the identified data were likely driven by study design differences, including prior ERT exposure, follow-up time, and ADA assessment protocols. Additional prospective studies with standardized ADA assessments and accounting for patient baseline characteristics and disease severity, are needed to better understand the clinical implications of ADA formation on ERT outcomes, including an assessment of causality.

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