Establishing Treatment Effectiveness in Fabry Disease: Observation-Based Recommendations for Improvement

Area of Science:

• Genetics and rare diseases
• Enzyme replacement therapy
• Pharmacology

Background:

• Fabry disease (FD) stems from pathogenic *GLA* gene variants, causing α-galactosidase A deficiency and substrate accumulation.
• FD presents with highly variable phenotypes across sexes and disease stages, complicating clinical assessment.
• Despite available therapies for two decades, robust long-term evidence of effectiveness remains elusive.

Purpose of the Study:

• To identify factors hindering robust evidence generation for FD therapies.
• To propose strategies for improving the quality and reliability of future FD treatment studies.

Main Methods:

• Review of existing literature on Fabry disease therapies, focusing on enzyme replacement therapy (ERT) and chaperone therapy.
• Analysis of factors contributing to heterogeneity in study populations and designs.
• Identification of limitations in outcome assessment and study duration.

Main Results:

• Key challenges include significant heterogeneity in patient populations (sex, age, phenotype, disease stage) and variations in study designs (control groups, outcome measures, study duration).
• These factors collectively impede the establishment of strong evidence for the long-term effectiveness of FD treatments.

Conclusions:

• Advocating for patient matching to enhance control group comparability in future FD therapy studies.
• Recommending international collaboration and harmonization through an independent FD registry.
• Proposing a stepwise approach for evaluating novel treatments, including surrogate outcomes and defined study durations.