Galafold (migalastat) is an effective treatment for certain Japanese people with Fabry disease, with no apparent differences in response to treatment due to race, a new analysis of data from the ATTRACT study suggests.
The findings were published in the Orphanet Journal of Rare Diseases in the paper “Efficacy and safety of migalastat in a Japanese population: a subgroup analysis of the ATTRACT study.”
Fabry disease is caused by mutations in the GLA gene, which provides instructions to produce the protein alpha-galactosidase A (Gal A). Hundreds of disease-causing mutations in GLA have been described, all of which ultimately reduce the ability of Gal A to function. Some of these mutations cause the protein to become too unstable to work correctly.
Galafold is a chaperone therapy; it helps to stabilize these mutant versions of Gal A. As such, the therapy works only for people with Fabry disease who have certain kinds of mutations, referred to as amenable mutations. So far, of more than 700 Gal A mutations, 269 have been identified as amenable.
Galafold, developed by Amicus Therapeutics, was approved in Japan in 2018, based in part on data from the Phase 3 ATTRACT study (NCT01218659). This study compared Galafold to enzyme replacement therapy (ERT): either Fabrazyme (agalsidase beta) or Replagal (agalsidase alfa). ERT involves administering a replacement version of the Gal A enzyme and has been the mainstay of Fabry disease treatment.
The study recruited people with Fabry disease who had been on ERT for at least a year. Participants were assigned randomly to continue treatment with ERT or to switch to Galafold for 18 months. Participants then had the option of continuing into a second phase, where all participants took Galafold for a year. After completion of the 30-month-long study, participants had the option of enrolling in a separate open-label extension trial (NCT02194985), in which they continued to be monitored and treated with Galafold.
Results from the overall group were reported in 2018. Broadly, the findings suggested that Galafold and ERT both had comparable effects at preserving kidney health, and Galafold treatment significantly reduced heart size, while ERT did not, suggesting the effectiveness of Galafold.
In the new study, researchers analyzed the subgroup of trial participants who were Japanese. Fabry disease is estimated to occur in about one out of every 7,000 births in Japan, whereas the global incidence is estimated at one in 100,000.
Of the 57 trial participants included in the initial analysis, seven were Japanese. The researchers noted that “The shortage of agalsidase beta in Japan between 2009 and 2012 made it difficult to find patients who met the enrollment criteria [being on ERT for at least a year].”
Of the seven Japanese participants, five (three male, two female) were assigned randomly to treatment with Galafold. All of these completed ATTRACT and enrolled in the open-label extension; four currently remain in the extension, while one withdrew due to kidney health concerns.
The other two Japanese participants (both female) received ERT treatment. One was found to have a non-amenable mutation after the first 18 months of the study, so the patient discontinued treatment and was not included in the analysis. The other completed the study, but did not enroll in the open-label extension due to heart problems.
The findings in the Japanese subpopulation were not remarkably different from those found in the group as a whole. For instance, the yearly rate of change in one measurement of glomerular filtration rate (an indicator of kidney function) was −0.4 mL/min/1.73 m2 on average in the Galafold group in the overall population. This value was of −1.8 mL/min/1.73 m2 in the respective Japanese subpopulation. Statistical comparison revealed these values to be within a normal range based on the group overall.
Similarly, average left ventricular mass index (a measure of heart size) decreased by an average of 6.6 g/m in the overall Galafold-treated population and by 13.8 g/m2 in the Japanese subpopulation.
There also was evidence for similar effects on Gal A itself and on reducing substrate accumulation.
Additionally, no new safety concerns were raised in this subgroup analysis. Although all five Galafold-treated participants experienced at least one adverse event (side effect), all were described as mild or moderate, with the most common being colds.
“[I]t 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 researchers wrote.
They noted that this wasn’t necessarily surprising, given that “No racial differences have been reported with regard to Fabry disease.”
Given that this was an analysis of a very small sample, the results should be interpreted with appropriate caution; but the study suggests that Galafold is beneficial for people with amenable mutations, regardless of race.