Response to "Oral Chaperone Therapy Migalastat for the Treatment of Fabry Disease: Potentials and Pitfalls of Real-World Data".

Abstract

We thank Dr Körver and colleagues for their interest in our work.1 We absolutely agree that validity of current amenability criteria arguably might still be subject to discussion. From the clinical viewpoint, the cutoff values of 1.2-fold relative and 3% absolute increase in alpha galactosidase activity chosen in the recent multicenter trials might be questionable particularly in patients with polymorphism-like genotypes, such as the benign variant D313Y, presenting with near-normal wild-type enzyme activity but currently still categorized as amenable.2, 3 Limitations in knowledge on the genotype-dependent absolute and relative changes in enzyme activity in the clinical setting, and the question which cutoff value might be most suitable to forecast therapy success, represent a clinical dilemma for the treating physicians. This was one of the main drivers for execution of the current investigations. Given the exceptional bandwidth of genotypes and phenotypes in Fabry disease, it is not surprising that not only chaperone therapy but also alternative specific treatment options—namely enzyme replacement but also substrate reduction therapy—have shown marked variance in individual patients’ treatment response.4, 5 However, we disagree with the claim that lyso-Gb3 represents the ideal biomarker to determine amenability or therapy success, and neither can support the hypothesis that an increase in lyso-Gb3 in one patient switched from enzyme replacement therapy to migalastat verifies non-amenability in this particular mutation or even patient. Obviously, as also pointed out by Dr Körver et al., laboratory as well as imaging biomarkers, such as left ventricular mass derived by echocardiography, can show substantial variability over time. Importantly, such variance does not necessarily reflect methodological limitations or measurement errors, but at least in part can be explained by varying biological parameters, which often strongly affect numerical data even when extreme care is taken to avoid any technical bias. With regard to echocardiography data in our study, it is important to stress the fact that blinded analysis revealed no relevant changes in left ventricular mass in the previously non-hypertrophic hearts but a strong effect in the cases with prevalent hypertrophy. Individual absolute and relative enzyme activity changes over time correlated with respective changes in left ventricular mass index are shown in Figure 1. Given the fact that—despite limited patient numbers—our study reveals a robust correlation between the increase in alpha galactosidase enzyme activity and reduction of left ventricular mass index in response to therapy, we see strong evidence and, therefore, confirm our claim that migalastat does improve cardiac integrity in amenable patients with Fabry disease. Answering the question which specific patients might benefit most also in the long run and how migalastat therapy compares with other specific therapeutic options with regard not only to organ involvement and symptoms but also genotype and additional individual disease-modifying factors will certainly require additional investigations from larger trials. No funding was received for this work. J.M. received speaker honoraria by Sanofi/Genzyme and travel support by Amicus Therapeutics, Sanofi/Genzyme, and Shire/Takeda. P.N. received advisory board/speaker honoraria and travel support by Amicus Therapeutics, Greenovation Biotech, Idorsia, Sanofi/Genzyme, and Shire/Takeda. Research support was given to the institution by Amicus Therapeutics, Idorsia, Sanofi/Genzyme, and Shire/Takeda.