Evaluating the relationship between anti-drug antibodies and clinical efficacy in patients with Fabry disease receiving enzyme replacement therapy: A systematic literature review

Derralynn Hughes; John A. Bernat; Patricio Aguiar

doi:10.1016/j.ymgme.2025.109473

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Evaluating the relationship between anti-drug antibodies and clinical efficacy in patients with Fabry disease receiving enzyme replacement therapy: A systematic literature review

Abstract

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Evaluating the relationship between anti-drug antibodies and clinical efficacy in patients with Fabry disease receiving enzyme replacement therapy: A systematic literature review

Derralynn Hughes, John A. Bernat and Patricio Aguiar

Molecular genetics and metabolism, Vol.147(2), 109473

02/2026

DOI: 10.1016/j.ymgme.2025.109473

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Abstract

The relationship between anti-drug antibodies (ADAs) and efficacy of enzyme replacement therapies (ERT) in patients with Fabry disease (FD) is poorly understood. We conducted a systematic literature review to synthesize the available evidence. Literature searches were conducted in MEDLINE and Embase up to March 4, 2025. Studies were included if they reported disease biomarkers (globotriaosylceramide [Gb3], globotriaosylsphingosine [lysoGb3]), renal outcomes, and/or cardiovascular outcomes stratified by ADA status in patients with FD receiving ERT. Of 1183 records screened, 20 were included: 18 reported biomarker analyses, 10 renal outcomes and 4 cardiovascular outcomes. ADA-positivity was consistently associated with elevated disease biomarker levels: 17/18 studies reported statistically significant positive associations (p < 0.05) between ADA-positivity and elevated plasma lyso-Gb3 (9/10 studies), plasma Gb3 (4/6 studies), and urine Gb3 (5/6 studies; additionally, 1/6 studies observed a numerical trend [p > 0.05)]). The relationship between ADA status and renal outcomes was less clear; most studies (7/10) reported no significant associations. The most assessed renal outcome (9/10 studies) was annualized estimated glomerular filtration rate (eGFR). Across studies evaluating annualized eGFR: two reported a statistically significantly positive association (p < 0.05) between ADA-positivity and rate of eGFR decline, one a non-significant trend (p = 0.05-0.10), one a numerical increase (no statistical test), and five no association. The relationship between ADA-positivity and cardiovascular outcomes was also equivocal with 2/4 studies reporting significant positive associations (one left ventricular mass, p = 0.02; one intraventricular wall thickness, p < 0.05) and two studies reporting no associations. This literature review found evidence to suggest ADA-positivity may attenuate certain clinical response measures of ERT however inconsistency in reports may result from important differences in study design (including prior ERT exposure, follow-up time and ADA assessment protocols) as well as sensitivity of clinical outcomes and confounding variables such as baseline disease severity. Additional studies using standardized methods are needed to clarify this relationship.

Details

Title: Subtitle: Evaluating the relationship between anti-drug antibodies and clinical efficacy in patients with Fabry disease receiving enzyme replacement therapy: A systematic literature review
Creators: Derralynn Hughes - University College London
John A. Bernat - University of Iowa
Patricio Aguiar - Centro Hospitalar Lisboa Norte
Resource Type: Abstract
Publication Details: Molecular genetics and metabolism, Vol.147(2), 109473
DOI: 10.1016/j.ymgme.2025.109473
ISSN: 1096-7192
eISSN: 1096-7206
Publisher: Elsevier Inc; SAN DIEGO
Language: English
Date published: 02/2026
Academic Unit: Stead Family Department of Pediatrics; Medical Genetics and Genomics
Record Identifier: 9985139462602771

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