Galafold Safe, Effective at Reducing Heart Damage: Real-life Study

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Galafold (migalastat) is generally safe and significantly reduces disease-associated heart enlargement in Fabry disease patients carrying Galafold-amenable mutations, according to two-year data from a real-life, multicenter study in Germany.

These benefits were generally similar between patients who had previously received standard enzyme replacement therapy (ERT) and those who had not.

Patients’ kidney function did show a significant decline over the two years, particularly among patients on certain medications for high blood pressure (hypertension), suggesting they had a higher disease burden at the start of treatment.

These findings generally support Galafold for treating Fabry among eligible patients, but physicians should monitor the clinical response on a regular basis, the researchers noted.

The study, “Treatment of Fabry Disease management with migalastat—outcome from a prospective 24 months observational multicenter study (FAMOUS),” was published in the European Heart Journal – Cardiovascular Pharmacotherapy.

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Rare Autoimmune Kidney Disorder Seen With Fabry Disease

Fabry disease, which generally affects males more severely than females, is caused by the absence of the alpha-galactosidase A (Gal A) enzyme or a marked reduction of its activity, both due to mutations in the GLA gene.

This deficiency leads to the toxic buildup of two fatty molecules — Gb3 and lyso-Gb3 — in tissues and organs such as the heart, kidneys, nervous system, eyes, and skin, causing damage. Heart and kidney complications worsen with time and may become life-threatening.

Galafold, developed by Amicus Therapeutics, is an oral chaperone therapy that restores the activity of faulty forms of Gal A that carry specific GLA mutations, referred to as “amenable.” It’s estimated that 35–50% of all Fabry patients worldwide have Galafold-amenable mutations, for which the therapy is approved.

In Europe, the therapy was approved for eligible patients, 16 and older, in 2016, and extended in 2021 to children as young as 12. In the U.S., it’s only available for adults.

Galafold, taken every other day, is expected to reduce the burden of lifelong, into-the-vein infusions of ERT — Fabrazyme (agalsidase beta) or Replagal (agalsidase alfa) — every two weeks. The mainstay Fabry disease treatment, ERT involves the delivery of a lab-made version of Gal A to patients.

Previous clinical and real-world studies have shown Galafold’s safety and effectiveness in Fabry patients with amenable mutations, and significant heart improvements were also reported for those switching from ERT to Galafold.

A team of researchers in Germany, in collaboration with Amicus, conducted an  observational, multicenter study, called FAMOUS (NCT03135197), to assess the two-year safety and effectiveness of Galafold in people with Fabry in a real-world setting. Nine German Fabry centers were involved.

The study’s main goal was to assess changes in heart enlargement — as assessed with left ventricular mass (LVM) — and kidney function, measured through the mean annualized change in the estimated glomerular filtration rate (eGFR). Patient-reported outcomes and levels of Gal A activity and lyso-Gb3 were also assessed.

As of July 2020, data was available for 54 patients (26 females and 28 males), with a mean age of 45. Nearly two-thirds (61.1%) had been previously given ERT, most commonly Replagal (60.6%).

Hypertension was present in 31 (57.4%) patients and 37 (69.8%) were on anti-hypertensive medication to reduce blood pressure and/or protect the heart and the kidneys. Females tended to more often experience Fabry-associated pain than males (76.9% vs. 50%).

Results showed Galafold was generally safe and well tolerated, with no severe treatment-related side effects reported. There were 17 clinical events (all related to cardiovascular problems) and only a mild adverse event of vomiting right after Galafold was initiated, which was resolved with ongoing treatment.

This would result in an overall frequency of 0.15 total clinical events per treatment year or 153 events per 1,000 patient years.

The mass of the heart’s left ventricle was significantly reduced after two years of treatment in both female and male patients, particularly among males with heart enlargement already at the start of treatment. Similar reductions were found for ERT-naïve patients and those pre-treated with ERT.

This LVM reduction “may further verify the wide tissue distribution of [Galafold], including penetration into cardiac muscle cells,” the researchers wrote.

Both females and males had a significant decrease of eGFR within the first year of treatment, which was attenuated the following year.

Patients’ annual eGFR decline rate (2.6–4.4 milliliters per minute per square meter, mL/min/1.73 m2) was slower than that reported for untreated patients (8–12 mL/min/1.73 m2), but apparently faster than for those on ERT (0.5–2.6 mL/min/1.73 m2). Values of ERT-treated patients vary depending on the study, however, the research team noted.

The researchers also emphasized that while these findings contrast with stabilized kidney function reported with Galafold in clinical trials, they are consistent with other real-world studies (loss of 5–9 mL/min/1.73 m2 per year).

Interestingly, the 16 patients who were not on anti-hypertensive medication showed stable kidney function throughout the study, while those on RAAS blockers, a type of anti-hypertensive medication, showed a significantly greater decline, “potentially indicating their higher disease burden at [treatment start],” the team wrote.

Fabry-specific manifestations/symptoms, including pain, remained stable, as well as Gal A activity and lyso-Gb3 levels in the blood. Four male patients, carrying different amenable GLA mutations, showed significant increases in lyso-Gb3.

These findings suggest that Galafold “offers a good treatment alternative in patients with amenable mutations, but the treating physician has to monitor the clinical response on a regular basis,” the researchers wrote.

LysoGb3 levels and Gal A activity in the blood should be measured “at therapy start and after 6 months and a clinical follow-up of heart and kidney manifestations at least after 6–12 months of treatment,” they proposed.