2025/08/11 by Eleonora Riccio, Antonio Pisani · 1 voice
Chemistry · Medicine · #Carbohydrate Chemistry and Synthesis #Glycogen Storage Diseases and Myoclonus #Lysosomal Storage Disorders Research
paper · pdf · doi:10.1002/jimd.70080
openalex publication_date 2025/08/11 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/22
Since its EU approval in 2016, the oral pharmacological chaperone migalastat has been available as a treatment option for Fabry disease (FD) patients with amenable GLA mutations; real-world data are crucial for better defining its effectiveness and its role in clinical practice. Two recent studies published in the Journal of Inherited Metabolic Disease—by Hughes et al. [1] and Pisani et al. [2] offer contrasting insights into the effects of migalastat in a real-world setting. Notably, the study by Hughes et al. [1] was funded by Amicus Therapeutics, while the study by Pisani et al. [2] was supported by Sanofi. Hughes et al. [1] analyzed 125 patients from the followME Pathfinder Registry (age at enrolment ≥ 12 years; median 58 years), ~75% of whom were treatment-naïve and ~25% had received ERT for ≤ 2 years. Only patients receiving ≥ 3 years of uninterrupted migalastat therapy were included. The reported annualized eGFR change was −0.9 mL/min/1.73 m2/year (95% confidence interval [CI]: −10.8, 9.9), with a low incidence of Fabry-associated clinical events (FACEs) (20.0%: 19.2% cardiac, 0.8% renal), suggesting favorable long-term outcomes. However, the broad CI and exclusion of patients treated for < 3 years may reflect a survivorship bias, potentially overestimating treatment benefit. In contrast, Pisani et al. [2] evaluated 83 patients (median age at ERT initiation: 44 years; at switch to migalastat: 50 years) who switched from ≥ 1 year of agalsidase beta to migalastat for ≥ 6 months. The authors observed a mean eGFR decline of −1.96 mL/min/1.73 m2/year after the switch, with increasing lyso-Gb3 levels, particularly in patients with the classic phenotype. Classic males experienced notable worsening in proteinuria and cardiac biomarkers. Key differences in patient selection, baseline characteristics, and methodology are critical to interpreting these findings. First, Hughes included predominantly treatment-naïve subjects with a median age of 58 years at treatment initiation, likely reflecting a milder disease course. In addition, patients treated with migalastat for ≤ 3 years were excluded, potentially overestimating effectiveness by excluding those who discontinued before 3 years due to inefficacy or intolerance. Conversely, Pisani's cohort comprised exclusively previously treated patients, with a median age of 50 years at switch to migalastat (and 44 years at first FD-treatment), and a higher proportion of classic males (38.6% vs. 6.7% in Hughes), a group known to have more severe manifestations. Moreover, Pisani analyzed a broader, more representative population, including both patients who successfully responded to migalastat and those who required to switch back to ERT. Again, variant amenability in Hughes may be overestimated, as some included mutations had high residual enzyme activity or uncertain pathogenicity. Conversely, Pisani did not report specific GLA variants or baseline α-Gal A activity, limiting interpretation of migalastat's clinical effect. Moreover, neither study accounted for supportive therapies (e.g., ACE inhibitors, ARBs), which may influence outcomes. Methodological differences further limit direct comparison: Hughes employed simple linear regression, while Pisani applied linear mixed models, which better account for intra-patient variability and repeated measures. Additionally, the wide 95% CI of mean eGFR annualized rate reported by Hughes (−10.8 to +9.9) underscores substantial variability and questions the interpretation of “stable” renal function. Finally, registry-based limitations, including data completeness and selection bias, also apply to both studies. In summary, Hughes provides useful data on migalastat's efficacy in selected, stable long-term responders. Pisani, however, offers a more heterogeneous and clinically relevant perspective, especially for patients with more advanced or classic disease. These findings underscore the importance of contextualizing real-world data according to patient characteristics to guide personalized treatment decisions. Importantly, based on these comparative data, migalastat does not appear to be a suitable treatment option for male patients with the classic phenotype, who consistently show unfavorable outcomes following therapy initiation or switch. A.P. had the original idea; E.R. wrote the paper; both the authors revised the paper and approved the final version. Prof. Antonio Pisani has served as PI in clinical trials involving investigational therapies for Fabry disease; received research grant, travel grant; and has been a member of the Advisory Board for Sanofi-Genzyme, Amicus, Chiesi-Protalix, and Takeda. The data that support the findings of this study are available from the corresponding author upon reasonable request.