Treatment of Fabry Disease management with migalastat—outcome from a prospective 24 months observational multicenter study (FAMOUS)

Abstract

Aims Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency of the lysosomal enzyme α-galactosidase A (GLA/AGAL) resulting in lysosomal accumulation of globotriaosylceramide (Gb3). Patients with amenable GLA mutations can be treated with migalastat, an oral pharmacologic chaperone increasing endogenous AGAL activity. In this prospective observational multicenter study safety as well as cardiovascular, renal, and patient-reported outcomes and disease biomarkers were assessed after 12 and 24 months of migalastat treatment under “real world” conditions. Methods and results 54 patients (26 females) (33 of these [61.1%] pre-treated with enzyme replacement therapy) with amenable mutations were analyzed. Treatment was generally safe and well tolerated. 153 events per 1,000 patient-years were detected. Overall left ventricular mass index decreased after 24 months (all: -7.5 ± 17.4 g/m2, p = 0.0118; females: -4.6 ± 9.1 g/m2, p = 0.0554; males: -9.9 ± 22.2 g/m2, p = 0.0699). After 24 months, females and males presented with a moderate yearly loss of eGFR (-2.6 and -4.4 ml/min/1.73 m2 per year; p = 0.0317 and p = 0.0028, respectively). FD-specific manifestations/symptoms remained stable (all p > 0.05). 76.9% of females and 50% of males suffered from pain, which has not improved under treatment. FD-specific disease scores (DS3 and MSSI) remained stable during treatment. AGAL activities and plasma lyso-Gb3 values remained stable, although some male patients presented with increasing lyso-Gb3 levels over time. Conclusions Treatment with migalastat was generally safe and resulted in most patients in an amelioration of left ventricular mass. However, due to the heterogeneity of FD phenotypes, it is advisable that the treating physician monitors the clinical response regularly.

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

“…Published real-world evidence can also be helpful in guiding treatment decisions. A recent 24-month real-world cohort publication from Lenders et al in Germany provided further evidence of LVMi reduction in migalastat-treated patients with Fabry disease (primary outcome), especially in those with left ventricualr hypertrophy at baseline [ 34 ]. That publication also examined annualized eGFR slopes over 24 months and found antihypertensive medication use was associated with greater annualized eGFR decline over time, and the authors posited that either this may have been causative of the larger decline in eGFR, or that these patients were more severely affected at baseline.…”

Biomarkers for Monitoring Renal Damage Due to Fabry Disease in Patients Treated with Migalastat: A Review for Nephrologists

“…Four studies met the inclusion criteria [ 18 , 19 , 20 , 21 ]; in addition, two studies were analyzed [ 22 , 23 ] that are preliminary reports of other publications, but they are the only published studies that include the biomarker “renal histology” during the follow-up of FD patients treated with migalastat [ Table 1 ].…”

“…MEDLINE = Total n = 11, post analysis n = 2 [ 18 , 19 ]; 3 studies were excluded because they were preliminary reports of other studies [ 22 , 24 , 25 ]; 4 studies were excluded because they were sub-analysis of other studies [ 23 , 26 , 27 , 28 ] and 2 studies were excluded because they did not meet the inclusion criteria [ 29 , 30 ]. EMBASE = Total n = 0; SCOPUS = Total n = 0, Cochrane Total n = 0 and Google Academic = Total n = 191, post analysis n = 2 [ 20 , 21 ]; (11 studies were overlapped with MEDLINE, both included and excluded; 1 study was excluded because it was a preliminary report of other study [ 25 ], 1 study was excluded because it did not have renal biomarkers among its dependent variables [ 31 ]; 1 study was excluded because its sub-analysis of other studies [ 32 ]; 173 studies were excluded for not meeting inclusion criteria).…”

“…Lenders et al [ 19 ] reported results of 54 FD adult patients (mean age: 45 years) treated with migalastat during 24 months of follow-up. Similarly to the previously described studies, patients who started migalastat for FD treatment (Naive Group) and patients who had previously received ERT (Switch Group) were included.…”

“…Among the included population, 31 patients suffered from arterial hypertension at baseline, 37 patients were on anti-hypertensive medication, and 7 patients had diabetes mellitus. The study’s primary purpose was to evaluate the left ventricular mass (LVMi) and, among the secondary endpoints, included the GFR during the follow-up period [ 19 ]. This trial showed that patients with additional (cardiovascular) risk factors suffered from a more prominent eGFR decline after 1 year of migalastat treatment, an expected result due to the high prevalence of cardiovascular risk factors in the included population.…”