Long-term follow-up of renal function in patients treated with migalastat for Fabry disease

Abstract

The effect of migalastat on long-term renal outcomes in enzyme replacement therapy (ERT)-naive and ERT-experienced patients with Fabry disease is not well defined. An integrated posthoc analysis of the phase 3 clinical trials and open-label extension studies was conducted to evaluate long-term changes in renal function in patients with Fabry disease and amenable GLA variants who were treated with migalastat for ≥2 years during these studies. The analysis included ERT-naive (n = 36 [23 females]; mean age 45 years; mean baseline estimated glomerular filtration rate (eGFR), 91.4 mL/min/mL/1.73 m²) and ERT-experienced (n = 42 [24 females]; mean age, 50 years; mean baseline eGFR, 89.2 mL/min/1.73m²) patients with amenable variants who received migalastat 123 mg every other day for ≥2 years. The annualized rate of change from baseline to last observation in estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation (eGFR_CKD-EPI) was calculated by both simple linear regression and a random coefficient model. In ERT-naive patients, mean annualized rates of change from baseline in eGFR_CKD-EPI were - 1.6 mL/min/1.73 m² overall and - 1.8 mL/min/1.73 m² and - 1.4 mL/min/1.73 m² in male and female patients, respectively, as estimated by simple linear regression. In ERT-experienced patients, mean annualized rates of change from baseline in eGFR_CKD-EPI were - 1.6 mL/min/1.73 m² overall and - 2.6 mL/min/1.73 m² and - 0.8 mL/min/1.73 m² in male and female patients, respectively. Mean annualized rate of change in eGFR_CKD-EPI in ERT-naive patients with the classic phenotype (defined by white blood cell alpha galactosidase A [α-Gal A] activity of <3% of normal and multiorgan system involvement) was -1.7 mL/min/1.73 m². When calculated using the random coefficient model, which adjusted for sex, age, and baseline renal function, the annualized eGFR_CKD-EPI change was minimal (mean: -0.1 and 0.1 mL/min/1.73 m² in ERT-naive and ERT-experienced patients, respectively). In conclusion, patients with Fabry disease and amenable GLA variants receiving long-term migalastat treatment (≤8.6 years) maintained renal function irrespective of treatment status, sex, or phenotype.

Keywords: Chaperone; Classic phenotype; Efficacy; Fabry disease; GLP-HEK, Good Laboratory Practice-validated human embryonic kidney; Gb3, globotriaosylceramide; LVMi, left ventricular mass index; Migalastat; Q1, quartile 1; Q3, quartile 3; RI, renin inhibitor; Renal function; eGFRCKD-EPI, estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation; α-Gal A, α-galactosidase A.

Fig. 1

Patient flow in phase 3 studies of migalastat. ^aThe AT1001–041 study also included 12 amenable patients from phase 2 studies. ^bThe AT1001–042 study also enrolled 1 patient from a phase 2 study, for a total of 84 patients, including 1 patient who had a nonamenable GLA variant. ^cOne patient discontinued due to an adverse event, 3 patients met protocol-defined stopping criteria (ie, estimated glomerular filtration rate < 30 mL/min/1.73 m²), 1 patient was lost to follow-up, 4 patients discontinued per physician decision, and 2 patients chose to withdraw. ^dDuration of the treatment varied among patients. Patients completed the study when they switched to commercial migalastat or had access to migalastat through an alternate source. ERT, enzyme replacement therapy; QOD, every other day.

Fig. 2

Estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation over time in (A) male and (B) female patients receiving long-term migalastat treatment.