The results from a one-year extension study of the Phase 3 ATTRACT trial demonstrate the long-term safety and effectiveness of Galafold (migalastat) in people with Fabry disease with specific mutations.
Importantly, the therapy’s efficacy and safety also were observed in patients previously treated with enzyme replacement therapy (ERT) who later switched to Galafold, the results show.
The study, “Long-term efficacy and safety of migalastat treatment in Fabry disease: 30-month results from the open-label extension of the randomized, phase 3 ATTRACT study,” was published in the journal Molecular Genetics and Metabolism.
Fabry disease is caused by mutations in the GLA gene, which carries instructions to make the enzyme alpha-galactosidase A, known as alpha-gal A. A non-functional or only partially functional enzyme leads to the buildup of fatty substances called globotriaosylceramide, or GB3, and lyso-GB3, which can cause progressive organ damage affecting the kidneys and the heart.
Galafold, developed by Amicus Therapeutics, is designed to restore alpha-gal A activity in patients with specific mutations, referred to as amenable mutations. So far, of the more than 900 GLA mutations identified, 269 are amenable.
The first oral medication for Fabry, Galafold was approved by the U.S. Food and Drug Administration in August 2018. That approval was based in part on the 18-month Phase 3 ATTRACT study (NCT01218659), which compared Galafold with two enzyme replacement therapies: Fabrazyme (agalsidase beta) and Replagal (agalsidase alfa).
ERT, which involves replacing the alpha-gal A enzyme, has been the standard treatment for Fabry disease.
The ATTRACT study demonstrated the efficacy and safety of Galafold compared with ERT in amenable patients with Fabry who previously received the enzyme replacement therapy.
Now, the researchers reported the results from a subsequent 12-month, Galafold-only, open-label extension (OLE) study that followed the ATTRACT trial.
Eligible participants were between the ages of 16 and 74, with a genetically confirmed Fabry diagnosis. A total of 60 patients took part in the initial 18-month study period, in which the participants were randomly assigned to receive 150 mg of Galafold every other day or continue ERT (0.2 mg/kg Replagal or 1.0 mg/kg Fabrazyme) every other week.
Among the 52 patients who completed this randomized treatment period, 48 continued into the open-label extension study: 33 patients (31 amenable) continued to receive Galafold while 15 patients (all amenable) who had been given ERT switched to 150 mg of Galafold. Overall, 91.3% of patients with amenable mutations completed the full 30 months of treatment.
Kidney function was measured using the estimated glomerular filtration rate (eGFR), which calculates how much blood passes through the kidneys each minute. Specifically, that rate is calculated in milliliters per minute per square meter, or mL/min/1.73 m2.
Of note, patients who have yearly reductions of 3 mL/min/1.73m² or less are considered to have stable disease, while those who lose 3 to 5 mL/min/1.73m² are classified as having progressive disease. Those with annual reductions of more than 5 mL/min/1.73m² have fast-progressing disease.
A 1.7 mL/min/1.73 m2 reduction in the average eGFR per year — from the beginning of the 18-month initial study to the end of the 12-month OLE — was recorded among the patients who continued receiving Galagold.
The patients who received ERT for the first 18 months experienced a 2.0 mL/min/1.73 m2 reduction in their average eGFR, and over the extended period of 12 months, the change was consistent with a 2.1 mL/min/1.73 m2 reduction. The change for men and women was similar.
Heart (cardiac) function was assessed by echocardiogram, which measured heart size using a measure known as left ventricular mass index (LVMi).
In individuals who continued with Galafold, the LVMi was stable from the study’s start (baseline) to month 30, with an average reduction of 3.8 g/m2 (grams per meter square). In the group of patients who switched, in the first 18 months of ERT there was a reduction of 2.8 g/m2 in their LVMi. Over the 12 months on Galafold, the overall value remained unchanged (a reduction of 0.3 g/m2).
An overall composite clinical outcome was calculated as the number of patients who experienced any Fabry-associated clinical events affecting the kidneys or heart.
Among the 31 patients who continued with Galafold, six (19.4%) experienced a kidney event and one (3.2%) had a cardiac event during the initial 18-month treatment period. During the OLE, nine of these patients (29.0%) reported a kidney event but not a cardiac event, and only three patients experienced a new event relative to the initial treatment period.
During the same initial 18-month period, six (40.0%) of the 15 participants who were receiving ERT had a kidney, cardiac, or cerebrovascular event (blood flow in the brain). In the subsequent 12-month Galafold period, six of the patients experienced a composite clinical outcome.
Levels of lyso-GB3 in the blood of all participants remained low over the 30-month treatment period.
Treatment-related adverse events (AEs) were reported for 32 of the 33 patients who continued with Galafold, with most being mild or moderate. Serious AEs were reported for 11 of these patients.
All 15 patients (100%) who switched treatments experienced AEs during both periods. However, the frequency of serious AEs was greater during the initial 18 months of ERT than the remaining 12 months with Galafold (46.7% vs. 20.0%).
The most frequent AEs in participants treated for 30 months were cold infection, headache, and influenza. Cold infection was the only reported AE in the initial 18-month ERT period, with cold, vomiting, and diarrhea occurring in these patients after switching. Despite these AEs, all patients completed the study, and no deaths were reported.
“In conclusion, in patients with Fabry disease and amenable GLA variants, [Galafold] 150 mg [every other day] was well tolerated and demonstrated durable, long-term stability of renal function and reduction in LVMi,” the researchers wrote.
Overall, Galafold “efficacy was maintained over 30 months of treatment, with no new safety concerns,” they wrote.
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