Galafold may reduce heart changes, boost exercise tolerance
18 months of treatment linked with stabilized measures of heart disease
In previously untreated Fabry disease patients with heart involvement, 18 months of treatment with Galafold (migalastat) stabilized measures of heart disease and was linked to a trend toward improvement in exercise tolerance, an observational study reported
These findings provide “new detailed evidence on the effect of migalastat on FD [Fabry disease] cardiomyopathy [heart disease]”, the researchers wrote. “This information can help clinicians in managing therapeutic options for patients with FD.”
The study, “Effect of Migalastat on cArdiac Involvement in FabRry Disease: MAIORA study,” was published in the Journal of Medical Genetics.
Fabry disease is caused by mutations in the GLA gene, which contains instructions for making the enzyme alpha-galactosidase A (alpha-galA). The lack or deficiency in alpha-galA causes certain fatty molecules, particularly globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3), to accumulate and damage some organs and tissues.
Heart involvement is common with Fabry disease. One feature linked to heart disease is an increase in left ventricular mass (LVM), the estimated weight of the heart’s left lower pumping chamber.
A previous study, assessing LVM by echocardiography — an ultrasound of the heart — revealed a small, but significant reduction after 18 months of Galafold, an oral chaperone therapy developed by Amicus Therapeutics that restores alpha-galA activity in patients carrying specific GLA mutations, referred to as “amenable.” A follow-up study with a large group of patients confirmed these findings.
The “gold standard” for assessing LVM is a cardiac MRI, which lets doctors evaluate heart tissues in a noninvasive way. Heart involvement in Fabry disease is known to impact circulating biomarkers as well as patients’ quality of life and ability to function. For this reason, heart involvement and the potential therapeutic benefits of Galafold require a comprehensive cardiological evaluation.
Galafold treatment on patients with heart involvement
The researchers reported findings from MAIORA (NCT03838237), an observational study to assess the effects of 18 months of Galafold on several parameters in previously untreated (treatment-naïve) patients showing signs of heart involvement.
Patients were evaluated by cardiac MRI and cardiopulmonary exercise testing (CPET) before and after treatment, which was administered at 123 mg every other day.
In total, 16 treatment-naïve patients (four women, 12 men; mean age 46.4) with a confirmed genetic diagnosis of Fabry and heart involvement enrolled in the study. They all carried genetic mutations amenable to Galafold treatment. Most (81.2%) were associated with late-onset disease.
Eleven patients were diagnosed through family screening, while a diagnosis was made in five after an unexplained hypertrophy (enlargement) was found on their left ventricle.
Eight patients (50%) had abnormally high levels of troponin T and seven (38.9%) of NT-proBNP, two heart damage markers.
Using the New York Heart Association (NYHA) scale, which classifies the extent of heart failure and where higher classes correspond to more severe heart impairments, four patients were NYHA class 2 (mild symptoms) and the remaining were class 1 (no symptoms).
At the start of the study (baseline), the median peak oxygen consumption (VO2) was 17.95 milliliters per kilogram per minute (mL/kg/min), as measured by CPET. The median percent predicted peak VO2 was 69%.
These findings “reflect the presence of severe clinical impairment in a minority of patients, with most of them exhibiting mild clinical manifestations,” the researchers said.
In line with these findings, cardiac MRI showed patients had a mild deformation in the heart’s left atrium, the upper chamber that receives oxygen-rich blood from the lungs. All had normal left and right ventricle volumes and preserved ejection fraction, which denotes the amount of blood the heart pumps on each contraction.
The left ventricular global longitudinal strain (GLS), an alternative method of assessing the heart’s ability to pump oxygen-rich blood, was mildly reduced.
Nine patients (56%) met cardiac MRI criteria for left ventricle enlargement, defined as an increase in LVM and/or having a left ventricle wall measuring 13 mm or more in thickness. Among these, eight showed late gadolinium enhancement (LGE), or signs of heart tissue scarring.
Galafold well tolerated, no serious side effects
During the 18-month treatment, Galafold was well tolerated in all patients, with no serious side effects reported. No severe cardiac events like arrythmias, heart failure, or hospitalization occurred.
No changes in LVM by cardiac MRI were detected after 18 months when compared with the the study’s start, even for LGE-positive patients. Likewise, no significant changes were observed in ventricle and atrial volumes, ejection fractions, and GLS.
A mild increase in LGE, indicative of scar tissue formation, was seen at follow-up compared with baseline (2.09% vs. 1.60%).
The researchers did find a trend for an increase in the percent predicted peak VO2, which rose from 69% at baseline to 72% at follow-up across all patients.
The seven patients (all women; mean age, 40.5) in whom LVM decreased after treatment were younger and were at an earlier disease stage compared with the remaining patients. These patients also showed fewer signs of heart damage, as indicated by lower NT-proBNP values, and exhibited greater improvements in exercise tolerance than the others.
This indicated “patients who benefit most from migalastat treatment were younger and with less severe cardiomyopathy, reflecting an earlier stage,” the researchers wrote. “It can be speculated that, in order to optimize the effect of migalastat on cardiac involvement, an early therapeutic approach should be encouraged, as previously demonstrated for ERT [enzyme replacement therapy].”
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