Migalastat 123mg capsules

Fabry disease is a rare lysosomal disorder characterized by deficient or absent α-galactosidase A activity resulting from mutations in the GLA gene. Migalastat (Galafold™), a pharmacological chaperone, stabilizes and facilitates trafficking of amenable mutant forms of α-galactosidase A enzyme from the endoplasmic reticulum to lysosomes and increases its lysosomal activity. Oral migalastat is the first pharmacological chaperone approved for treating patients [aged ≥ 18 years (USA and Canada) or ≥ 16 years in other countries] with Fabry disease who have a migalastat-amenable GLA mutation. In the FACETS trial in enzyme replacement therapy (ERT)-naive patients with GLA mutations amenable or non-amenable to migalastat, there was no significant difference between the migalastat and placebo groups for the proportion of patients achieving a ≥ 50% reduction in the number of globotriaosylceramide (GL-3) inclusions/kidney interstitial capillary (KIC) at 6 months [primary endpoint; intent-to-treat (ITT) population]. In the modified ITT population (i.e. patients with migalastat-amenable GLA mutations), relative to placebo, migalastat treatment significantly reduced the mean number of GL-3 inclusions/KIC and plasma lyso-globotriaosylsphingosine levels at 6 months. Among evaluable patients, migalastat maintained renal function and reduced cardiac mass after ≤ 24 months’ therapy. In the ATTRACT trial in ERT-experienced patients, renal function was maintained during 18 months of migalastat or ERT; however, migalastat significantly reduced cardiac mass compared with ERT. Migalastat was generally well tolerated in both of these trials. Given its convenient oral regimen and the limited therapeutic options available, migalastat is an important treatment option for Fabry disease in patients with migalastat-amenable GLA mutations.

Abstract licence: CC BY-NC 4.0

ObjectiveThe cardiovascular manifestations of Fabry disease are common and represent the leading cause of death. Disease-specific therapy, including enzyme replacement therapy (ERT) and chaperone therapy (migalastat), is recommended for patients exhibiting cardiovascular involvement, but its efficacy for modulating cardiovascular disease expression and optimal timing of initiation remains to be fully established. We therefore aimed to systematically review and evaluate the effectiveness of disease-specific therapy compared with placebo, and to no intervention, for the cardiovascular manifestations of Fabry disease.MethodsEight databases were searched from inception using a combination of relevant medical subject headings and keywords. Randomised, non-randomised studies with a comparator group and non-randomised studies without a comparator group were included. Studies were screened for eligibility and assessed for bias by two independent authors. The primary outcome comprised clinical cardiovascular events. Secondary outcomes included myocardial histology and measurements of cardiovascular structure, function and tissue characteristics.Results72 studies were included, comprising 7 randomised studies of intervention, 16 non-randomised studies of intervention with a comparator group and 49 non-randomised studies of intervention without a comparator group. Randomised studies were not at serious risk of bias, but the others were at serious risk. Studies were highly heterogeneous in their design, outcome measurements and findings, which made assessment of disease-specific therapy effectiveness difficult.ConclusionIt remains unclear whether disease-specific therapy sufficiently impacts the cardiovascular manifestations of Fabry disease. Further work, ideally in larger cohorts, with more standardised clinical and phenotypic outcomes, the latter measured using contemporary techniques, are required to fully elucidate the cardiovascular impact of disease-specific therapy.Prospero registration numberCRD42022295989.

Abstract licence: CC BY-NC

ObjectivesFabry disease (FD) is a rare metabolic disorder which presents with considerable heterogeneity in disease characteristics. Given the absence of interventional studies comparing all available treatments, it is important for indirect treatment comparisons (ITCs) to account for potential treatment effect modifiers (TEMs). This systematic literature review (SLR) aimed to identify patient characteristics that may impact clinical outcomes by analyzing real-world evidence (RWE) in FD.MethodsAn SLR was conducted according to PRISMA guidelines, with searches performed in the EMBASE, MEDLINE, and Cochrane databases (1946-2022; with a recent update in April 2023). Full-text articles reporting clinical outcomes from RWE studies of pharmacological therapies for the treatment of FD were included.ResultsIncluding studies from the recent SLR update, a total of 119 original studies met the PICOS criteria and 25 studies provided insights into TEMS. Potential TEMs in FD were identified: sex, age, timing of treatment initiation (early/delayed), left ventricular hypertrophy (LVH), estimated glomerular filtration rate (eGFR), proteinuria, presence of anti-drug-antibodies (ADAs) at baseline, and previous enzyme replacement therapy (ERT). In three studies (two including ERT-treated patients and one study of migalastat-treated patients) males showed worse renal outcomes than females. Five studies found that younger patients and those who received initial ERT before the age of 25 years had greater reductions in plasma-lysoGb3, as well as more favorable renal, cardiac, and biochemical outcomes. Seven studies identified associations between LVH and reduced eGFR at baseline, along with an increased risk of cardiovascular, renal, and neurological events. In four studies, lower baseline eGFR and proteinuria were associated with faster annual eGFR decline despite ERT; high baseline proteinuria was a significant predictor of renal disease progression. Baseline ADAs were linked to lower eGFR, increased left ventricular mass, and reduced treatment impact on plasma/urine-lysoGb3. Migalastat was effective in treatment-naïve patients, while those previously treated with ERT experienced deteriorations in mean lysoGb3, eGFR, and left ventricular mass.ConclusionsThis SLR highlighted several patient characteristics that influence treatment effectiveness in FD. It is important to account for these characteristics in ITCs to ensure unbiased outcomes.

Abstract licence: CC BY-NC