Galafold Found to Stabilize Kidney Function in Patients for Over 8 Years

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by Steve Bryson PhD |

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Fabry disease patients treated with Galafold (migalastat) had stable kidney (renal) function for up to eight and a half years — regardless of treatment status, sex, or disease characteristics — an analysis of clinical trials found.

Notably, the treatment — designed only for people with certain mutations in the GLA gene that cause Fabry — was found to work both in patients treated with standard enzyme replacement therapy (ERT) and those who were not.

Based on these results, the researchers said it was “imperative” that treatment with Galafold be started “before substantial [kidney] damage occurs.”

“Early treatment should be encouraged to stabilize or slow the decline in renal function in patients with Fabry disease,” the investigators wrote.

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The analysis, “Long-term follow-up of renal function in patients treated with migalastat for Fabry disease,” was published in the journal Molecular Genetics and Metabolism Reports.

Fabry disease is caused by a lack or deficiency of the enzyme alpha-galactosidase A (alpha-gal A), caused by mutations (variants) in the encoding GLA gene. This leads to the toxic buildup of fatty substances called globotriaosylceramide or Gb3, which progressively damages tissues and organs.

Gb3 may accumulate in the multiple kidney cell types, causing inflammation and scarring that damages the glomeruli — the tiny network of small blood vessels in the kidneys that filter waste and remove extra fluids. Glomerular injury results in elevated protein levels in the urine and a decline in the glomerular filtration rate (GFR), a common measure of kidney function that estimates how much blood passes through the glomeruli each minute.

Enzyme replacement therapy, called ERT, is the current standard treatment for Fabry patients, and deals with the disease’s underlying cause. It delivers a functional, lab-made copy of the alpha-galactosidase A (alpha-gal A) enzyme to the bloodstream.

Certain Fabry patients — those with specific mutations in the GLA gene — also may be treated with Galafold, an oral chaperone therapy designed to restore the activity of faulty forms of Gal A that carry specific GLA mutations.

Galafold’s renal efficacy was demonstrated in Phase 3 clinical trials, in which the treatment reduced Gb3 levels in kidney cells and stabilized kidney function. The treatment received regulatory approval in the U.S. in 2018. It also is approved for use in the EU, Japan, Switzerland, Israel, Australia, South Korea, Canada, and Argentina.

To evaluate the long-term impact of Galafold on kidney function, a team of researchers based at the University of Montréal, in Québec, Canada, examined data collected from Fabry patients who participated in clinical trials and were treated with the therapy for at least two years.

Data were extracted from the FACETS (NCT00925301) and ATTRACT (NCT01218659) Phase 3 clinical trials that treated Fabry patients with Galafold every other day for two or more years. Additionally, eligible patients completing these trials entered open-label extension (OLE) studies for up to five years (NCT01458119, NCT02194985).

Participants in the FACETS trial had never received ERT or had not been treated with ERT for at least six months — and were dubbed “ERT-naive” in this analysis — whereas ATTRACT patients had received ERT for at least one year. These patients were identified as “ERT-experienced” here.

To assess kidney function, bloodstream creatinine values were used to calculate the estimated GFR (eGFR), measured before Galafold treatment (baseline) and every six months until each study was complete. A bigger decline in eGFR values is synonymous with deteriorated kidney function.

Researchers selected 78 Fabry patients who had at least two years of Galafold therapy. Among them, 36 participants (23 females) were ERT-naive, and 42 (24 females) were ERT-experienced. In the ERT-naive group, the mean age at the study’s start was 45.1 years, versus 50.1 years in the ERT-experienced group. Overall, 78% of participants had disease involvement in multiple organs.

The duration of Galafold treatment of ERT-naive patients ranged from 2.0 to 8.6 years (median 7.0 years) and 2.1 to 7.2 years (median 5.1 years) for ERT-experienced patients.

Over the long-term follow-up, kidney function generally stabilized in both ERT-naive and ERT-experienced participants for both females and males. The mean annual eGFR change was -1.6 milliliters per minute per square meter (mL/min/1.73 meters m2) for both ERT-naive and ERT-experienced patients.

After adjusting for sex, age, baseline kidney function, and the time since diagnosis, the mean annual change in eGFR for the ERT-naive group was −0.1 mL/min/1.73 m2 and 0.1 mL/min/1.73 m2 in ERT-experienced patients.

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For females with Fabry, the mean eGFR change was 0.1 mL/min/1.73 m2 (ERT-naive) and 0.5 mL/min/1.73 m2 (ERT-experienced). For males, the change was −0.5 mL/min/1.73 m2 (ERT-naive) and − 0.4 mL/min/1.73 m2 (ERT-experienced).

A statistical analysis found that baseline eGFR was a significant predictor of further kidney function decline, followed by age. Elevated baseline urine protein was a moderate predictor but was not statistically significant. Other assessed factors were not significant.

Finally, annual eGFR change data for 10 male ERT-naive patients treated with Galafold for two or more years in FACETS were available, considered to have classic disease, defined by residual alpha-Gal A activity of less than 3% and involvement in two or more organs.

The mean annual change in eGFR was −1.7 mL/min/1.73 m2 in this group of male patients with the classic disease and −1.5 mL/min/1.73 m2 in other patients in FACETS over the long term. After adjustments, eGFR changes were −0.5 mL/min/1.73 m2 in these ERT-naive and 0.0 mL/min/1.73 m2 in other FACETS participants. Similar results were seen on ERT-experienced individuals with multiorgan involvement alone.

“In summary, the results of this … analysis suggest that patients with Fabry disease and amenable GLA variants had stable renal function during long-term [Galafold] treatment [up to 8.6 years] irrespective of treatment status, sex, or phenotype [disease characteristics],” the researchers wrote.

The team noted that “long-term data are especially important when assessing” the effects of different therapies, adding that “published real-world evidence can also be helpful in guiding treatment decisions.”

Early treatment with Galafold should be considered, according to the researchers.

“Treatment before substantial renal damage occurs is imperative because renal function may not be restored” after such damage has occurred, they wrote.