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

Abstract

Fabry disease (FD, OMIM #301500) is caused by pathogenic GLA gene (OMIM #300644) variants, resulting in a deficiency of the α-galactosidase A enzyme with accumulation of its substrate globotriaosylceramide and its derivatives. The phenotype of FD is highly variable, with distinctive disease features and course in classical male patients but more diverse and often nonspecific features in non-classical and female patients. FD-specific therapies have been available for approximately two decades, yet establishing robust evidence for long-term effectiveness remains challenging. This review aims to identify the factors contributing to this lack of robust evidence for the treatment of FD with enzyme replacement therapy (ERT) (agalsidase-alfa and -beta and pegunigalsidase alfa) and chaperone therapy (migalastat). Major factors that have been identified are study population heterogeneity (concerning sex, age, phenotype, disease stage) and differences in study design (control groups, outcomes assessed), as well as the short duration of studies. To address these challenges, we advocate for patient matching to improve control group compatibility in future FD therapy studies. We recommend international collaboration and harmonization, facilitated by an independent FD registry. We propose a stepwise approach for evaluating the effectiveness of novel treatments, including recommendations for surrogate outcomes and required study duration.

Keywords: Fabry disease; chaperone therapy; clinical outcomes; enzyme replacement therapy (ERT); treatment effectiveness.

Figure 1

(A) Proposed stepwise approach for evaluating therapeutic effectiveness. In each study phase, patients initiating the investigational therapy are paired with a matched counterpart based on prognostic factors. During the initial short-term phase, this counterpart may be an active comparator (e.g., a family member). For the longer follow-up, a registry-matched counterpart is considered. Additionally, a minimum follow-up period per outcome category of interest has been suggested for each phase. (B) Hierarchy of clinical relevance in Fabry disease outcomes. In the figure, we recommend outcomes to evaluate therapeutic effectiveness in Fabry disease-related renal and cardiac disease. The outcomes displayed in the top layer of the figure require a shorter follow-up duration to detect changes; however, changes in these outcomes are of lower clinical relevance. For the more clinically relevant outcomes in the bottom layer, fewer events occur, necessitating longer follow-up durations. Abbreviations: Gb3 = globotriaosylceramide, LAVI = left atrial volume index, ECG = electrocardiography, CPEX = cardiopulmonary exercise testing, GLS = global longitudinal strain, EF = ejection fraction, NYHA = New York Heart Association.

Figure 2

Illustration of the infrastructure of an independent international Fabry disease registry. The registry collects a standardized core set of variables and predefined outcome measures. Harmonization of these data enables structured analysis to support diverse research and clinical objectives.