Dataset Information

Assessment of plasma lyso-Gb₃ for clinical monitoring of treatment response in migalastat-treated patients with Fabry disease.

ABSTRACT:

Purpose

To assess the utility of globotriaosylsphingosine (lyso-Gb₃) for clinical monitoring of treatment response in patients with Fabry disease receiving migalastat.

Methods

A post hoc analysis evaluated data from 97 treatment-naive and enzyme replacement therapy (ERT)-experienced patients with migalastat-amenable GLA variants from FACETS (NCT00925301) and ATTRACT (NCT01218659) and subsequent open-label extension studies. The relationship between plasma lyso-Gb₃ and measures of Fabry disease progression (left ventricular mass index [LVMi], estimated glomerular filtration rate [eGFR], and pain) and the relationship between lyso-Gb₃ and incidence of Fabry-associated clinical events (FACEs) were assessed in both groups. The relationship between changes in lyso-Gb₃ and kidney interstitial capillary (KIC) globotriaosylceramide (Gb₃) inclusions was assessed in treatment-naive patients.

Results

No significant correlations were identified between changes in lyso-Gb₃ and changes in LVMi, eGFR, or pain. Neither baseline lyso-Gb₃ levels nor the rate of change in lyso-Gb₃ levels during treatment predicted FACE occurrences in all patients or those receiving migalastat for ?24 months. Changes in lyso-Gb₃ correlated with changes in KIC Gb₃ inclusions in treatment-naive patients.

Conclusions

Although used as a pharmacodynamic biomarker in research and clinical studies, plasma lyso-Gb₃ may not be a suitable biomarker for monitoring treatment response in migalastat-treated patients.

SUBMITTER: Bichet DG

PROVIDER: S-EPMC7790748 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Assessment of plasma lyso-Gb<sub>3</sub> for clinical monitoring of treatment response in migalastat-treated patients with Fabry disease.

Bichet Daniel G DG Aerts Johannes M JM Auray-Blais Christiane C Maruyama Hiroki H Mehta Atul B AB Skuban Nina N Krusinska Eva E Schiffmann Raphael R

Genetics in medicine : official journal of the American College of Medical Genetics 20200930 1

<h4>Purpose</h4>To assess the utility of globotriaosylsphingosine (lyso-Gb<sub>3</sub>) for clinical monitoring of treatment response in patients with Fabry disease receiving migalastat.<h4>Methods</h4>A post hoc analysis evaluated data from 97 treatment-naive and enzyme replacement therapy (ERT)-experienced patients with migalastat-amenable GLA variants from FACETS (NCT00925301) and ATTRACT (NCT01218659) and subsequent open-label extension studies. The relationship between plasma lyso-Gb<sub>3< ...[more]

PMID: 32994552

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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.