Introduction
Fabry disease is a rare progressive X-linked lysosomal disorder, in which mutations of the
GLA gene impair the activity of the lysosomal enzyme alpha-galactosidase A (α-Gal A), resulting in a devastating condition [
1]. In Fabry disease, accumulation of substrates of α-Gal A, such as globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb
3), in various organs and tissues causes dysfunction that can lead to premature death. Cardiac complications are the primary cause of death in men and women both, although some data indicate that the primary cause of death is renal complications in men and cerebrovascular disease in women [
2,
3]. The estimated prevalence of Fabry disease ranges between 1 in 476,000 and 1 in 117,000 worldwide, although its actual prevalence is thought to be higher [
3]. In Japan, the estimated prevalence is 1 in 7000 newborns based on the results of neonatal screening [
4].
Phenotypic expression of Fabry disease is highly variable. Initial symptoms of the classic disease generally appear in childhood, and symptoms progress if the condition is not treated [
3]. Enzyme replacement therapy (ERT) with agalsidase alfa or agalsidase beta is the mainstay of treatment [
5]. Results of previous clinical studies have shown efficacy and good tolerability of ERT in some Japanese patients with Fabry disease [
6,
7]. However, several challenges remain, including infusion-associated reactions, reduced quality of life associated with lifelong parenteral treatment, and the decrease in efficacy after development of circulating antibodies to the enzyme [
8,
9].
Migalastat is a low-molecular-weight iminosugar that can act as a pharmacologic chaperone by binding selectively and reversibly to the active site of specific mutant forms of α-Gal A, the genotype of which is referred to as amenable
GLA mutations. Migalastat binds to mutant forms of α-Gal A in the endoplasmic reticulum and promotes trafficking to the lysosomes, increasing lysosomal enzyme activity [
10‐
12]. The efficacy of migalastat has been verified in patients with amenable mutations [
13]. Migalastat was discovered in Japan [
14] and was approved for the treatment of patients with Fabry disease 16 years or older in Japan, [
16] Australia, Europe, Israel, South Korea and Switzerland and in adult patients in Canada and the United States [
10,
15].
A phase I pharmacokinetic study showed similar dose-proportional pharmacokinetics and a similar safety profile of migalastat in Japanese and non-Japanese populations [
17]. The phase III ATTRACT study compared efficacy and safety of migalastat with ERT in patients with Fabry disease with amenable mutations who were previously treated with ERT [
18]. During an 18-month treatment period, migalastat and ERT both had a similar effect on renal function. From baseline to month 18, the left ventricular mass index (LVMi) decreased significantly in the migalastat group, but there was no significant decrease in the ERT group [
18]. We report the results of analyses performed in the Japanese subgroup, including data from the open-label extension study (OLE).
Methods
Patients and study design
ATTRACT was a global, open-label, randomized trial with a 30-month treatment period (18-month open-label comparison of migalastat with ERT, and 12-month OLE with migalastat; AT1001-012, ClinicalTrials.gov, NCT01218659) in patients with Fabry disease who were previously treated with ERT. Full methods are described in the primary paper [
18]. Primary inclusion criteria were men and women between 16 and 74 years of age with Fabry disease and a migalastat-amenable
GLA mutation, as detected by the preliminary human embryonic kidney (HEK) 293 cell-based assay [
19]. Other inclusion criteria were initiation of ERT ≥ 12 months before the baseline visit, maintenance of a stable ERT dose for ≥ 3 months before baseline assessment (at least 80% of the dose specified in the package insert), and an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m
2 (calculated by the modification of diet in renal disease equation) at screening. In patients receiving an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, or renin inhibitor, doses of these drugs had to be stable for ≥ 4 weeks before screening.
Eligible patients were randomly assigned 1.5:1 using interactive response technology (Almac Clinical Technologies, Craigavon, UK) to receive either oral migalastat hydrochloride (150 mg every other day) or continue previous ERT (biweekly infusions of either agalsidase alfa 0.2 mg/kg or agalsidase beta 1.0 mg/kg) during the 18-month open-label treatment period [
18]. Patients who completed the open-label comparison period could continue treatment with migalastat (150 mg every other day) for an additional 12 months. During this OLE period, patients in the migalastat group continued to receive migalastat, whereas patients in the ERT group discontinued ERT and switched to migalastat. Patients who completed both parts of the ATTRACT study were eligible for enrollment in the OLE study (AT1001-042, ClinicalTrials.gov, NCT02194985).
End points
Coprimary end points of the ATTRACT study were the annual rate of change from baseline in eGFR calculated using the chronic kidney disease epidemiology collaboration equation (eGFR
CKD-EPI) and measured GFR determined by clearance of iohexol (mGFR
iohexol) [
18]. Key secondary end points were changes from baseline in LVMi and composite clinical outcome (renal, cardiac, cerebrovascular events, and death). Other secondary end points were leukocyte α-Gal A activity, plasma lyso-Gb3 level, and safety.
The efficacy analysis was performed in the modified intention-to-treat population, which included all randomly assigned patients who received at least 1 dose of study drug and had baseline and postbaseline GFR measurements, excluding patients with
GLA mutations later found nonamenable in a new and good laboratory practice-validated HEK assay [
13]. The safety population included all randomly assigned patients who received ≥ 1 dose of the study medication.
Statistical analysis
Leukocyte α-Gal A activity was measured at baseline, months 1 and 3, and every 3 months thereafter up to month 30. Annualized rates of change in eGFRCKD-EPI and mGFRiohexol were analyzed by analysis of covariance, considering the treatment group, sex, age, baseline GFR, and baseline 24-h urine protein excretion as covariates. Descriptive statistics, including least squares mean values and 95% confidence intervals (CIs), were determined with this model. Annualized rates of change of GFR were calculated from the slopes obtained by linear regression. LVMi was evaluated centrally (Cardiocore, Rockville, MD, USA) by 2-dimensional or M-mode echocardiography in a blinded manner every 6 months. The long-term effect of migalastat on LVMi was evaluated by calculating the change from baseline to final assessment in each patient. Composite clinical outcome was evaluated based on the number of patients who experienced a prespecified renal event, cardiac event, cerebrovascular event or who died. The plasma level of lyso-Gb3 was quantified by liquid chromatography–mass spectrometry at baseline and months 6, 12, 18, and 30.
Safety was evaluated based on the type, frequency, and severity of adverse events (AEs), as well as changes in vital signs, laboratory data, and physical findings. AEs were coded according to the Medical Dictionary for Regulatory Activities (MedDRA version 8.0 or more recent versions).
Discussion
Migalastat is an oral agent that acts as a pharmacologic chaperone for α-Gal A. In previous studies, migalastat provided clinical benefit with good tolerability in patients with Fabry disease and amenable
GLA mutations [
18,
21]. In the phase III FACETS study, migalastat was administered to patients with Fabry disease who had not received ERT. Results showed a decrease in renal interstitial capillary GL-3 inclusions and plasma lyso-Gb
3 level due to migalastat treatment, along with stabilization of renal function, a decrease in cardiac mass, and improvement in gastrointestinal symptoms [
21]. In the phase III ATTRACT study, migalastat is a treatment option for ERT-experienced patients [
18].
No racial differences have been reported with regard to Fabry disease, and its clinical phenotypes are likely similar among races [
2,
6,
22]. Therefore, it is meaningful that this subanalysis of Japanese patients showed that the efficacy of migalastat was not affected by race; there were also no unexpected safety concerns. The pharmacokinetics of migalastat was similar in the Japanese patients and the overall ATTRACT population, suggesting that migalastat’s therapeutic efficacy is not affected by intrinsic factors or race [
17]. In addition, efficacy and safety of migalastat were comparable in the Japanese and the overall patient populations.
Regarding the pharmacodynamic effects of migalastat, male Japanese patients with Fabry disease showed an increase in leukocyte α-Gal A activity, and the median change was within the range for the overall ATTRACT population. In Japanese patients with amenable mutations, migalastat treatment also stabilized renal function and decreased LVMi, as observed in the overall patient population. In addition, the plasma lyso-Gb
3 level remained low and stable throughout migalastat treatment in the Japanese patients and in the overall ATTRACT population. Additionally, individual patient data in migalastat group (Table
2) showed that eGFR range was relatively wide which might be due to either varied eGFR level of patients at baseline or concomitant treatment such as ACEI/ARB received by patients. However, given the small sample size in this study, the definitive cause could not be determined.
In the AT1001-042 OLE study, the beneficial effects of migalastat on renal function and LVMi were maintained in the Japanese patients through month 48 and month 42, respectively. In addition to demonstrating efficacy, migalastat was also safe and well tolerated by Japanese patients. The types and frequencies of AEs were similar in both the Japanese and the overall patient populations.
Only a few prospective studies have been performed in Japanese patients with Fabry disease, highlighting the importance of the current findings, despite the small sample size. A recently reported observational study conducted in 36 previously untreated Japanese patients showed that ERT can stabilize renal function and prevent deterioration of cardiac function [
6]. The patients in this recent study were relatively young (mean age 27 and 45 years for men and women, respectively), whereas the Japanese patients in the ATTRACT study were older (mean age 55 years), had previously been treated with ERT for 12 months or more before enrollment, and had a high disease burden. Use of migalastat achieved favorable outcomes in patients previously treated with ERT in the ATTRACT study, which included an open-label comparison with ERT and an OLE period [
18]. Therefore, these findings are important when considering treatment options for Japanese patients with Fabry disease.
The ATTRACT study was characterized by a prospective design and by enrolling typical Japanese patients with Fabry disease. However, given the small sample size of the Japanese patient population, the results should be interpreted with caution when considering migalastat therapy.
With the caveat of the aforementioned study limitations, migalastat seems effective for Japanese patients with Fabry disease who have amenable GLA mutations. In addition, migalastat demonstrated similar efficacy and safety in Japanese patients with Fabry disease who had previously been treated with ERT compared with the overall ATTRACT patient population. Therefore, our findings confirm the pharmacologic actions and efficacy of migalastat in Japanese patients.
Acknowledgements
The authors thank all those who participated in this study, including the patients, their families, fabry patients advocacy organizations in Japan, and health care providers. The authors also thank Sally Mitchell and Dana Francis of ApotheCom (Yardley, PA, United States) provided writing and editing support. Medical writing support was provided by MedPro Clinical Research.
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