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Migalastat: A Review in Fabry Disease.

ABSTRACT: Fabry disease is a rare lysosomal disorder characterized by deficient or absent ?-galactosidase A activity resulting from mutations in the GLA gene. Migalastat (Galafold™), a pharmacological chaperone, stabilizes and facilitates trafficking of amenable mutant forms of ?-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.

SUBMITTER: McCafferty EH

PROVIDER: S-EPMC6647464 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Migalastat: A Review in Fabry Disease.

McCafferty Emma H EH Scott Lesley J LJ

Drugs 20190401 5

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 ≥ ...[more]

PMID: 30875019

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Project description: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 (eGFRCKD-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 eGFRCKD-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 eGFRCKD-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 eGFRCKD-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 eGFRCKD-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.

Project description:Background: Fabry cardiomyopathy is characterized by left ventricular hypertrophy, myocardial fibrosis, arrhythmia, and premature death. Treatment with migalastat, an oral pharmacological chaperone, was associated with a stabilization of cardiac biomarkers and a reduction in left ventricular mass index, as measured by echocardiography. A recent study, using cardiac magnetic resonance (CMR) as the gold standard, found a stable course of myocardial involvement after 18 months of treatment with migalastat. Our study aimed to provide long-term CMR data for the treatment with migalastat. Methods: A total of 11 females and four males with pathogenic amenable GLA mutations were treated with migalastat and underwent 1.5T CMR imaging for routine treatment effect monitoring. The main outcome was a long-term myocardial structural change, reflected by CMR. Results: After migalastat treatment initiation, left ventricular mass index, end diastolic volume, interventricular septal thickness, posterior wall thickness, estimated glomerular filtration rate, and plasma lyso-Gb3 remained stable during the median follow-up time of 34 months (min.: 25; max.: 47). The T1 relaxation times, reflecting glycosphingolipid accumulation and subsequent processes up to fibrosis, fluctuated over the time without a clear trend. No new onset of late gadolinium enhancement (LGE) areas, reflecting local fibrosis or scar formation of the myocardium, could be detected. However, patients with initially present LGE showed an increase in LGE as a percentage of left ventricular mass. The median α-galactosidase A enzymatic activity increased from 37.3% (IQR 5.88-89.3) to 105% (IQR 37.2-177) of the lower limit of the respective reference level (p = 0.005). Conclusion: Our study confirms an overall stable course of LVMi in patients with FD, treated with migalastat. However, individual patients may experience disease progression, especially those who present with fibrosis of the myocardium already at the time of therapy initiation. Thus, a regular treatment re-evaluation including CMR is needed to provide the optimal management for each patient.

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Migalastat: A Review in Fabry Disease.

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Migalastat: A Review in Fabry Disease.

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