An Early Start With Fabrazyme Might be Better for Fabry Patients

Observational study included men, women younger than 30 with Fabry

Joana Vindeirinho, PhD avatar

by Joana Vindeirinho, PhD |

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Male patients with Fabry disease who started treatment with Fabrazyme (agalsidase beta) at an earlier age had a slower decline in kidney function compared with older patients with more severe disease, according to a study assessing data from the Fabry Registry.

Continued treatment in female and male patients who were younger than 30 with Fabry disease led to a modest decline in kidney function, stable heart-related parameters, and some improvements in self-reported symptoms after at least 2.5 years of follow-up.

“The greater decline in [kidney function] among older … males [with severe kidney disease] may suggest a benefit of earlier treatment,” the research team wrote. “The findings emerging from this comprehensive analysis of clinical outcomes substantially contribute to bridging the gap in understanding the clinical outcomes associated with agalsidase beta [Fabrazyme] treatment among pediatric, adolescent, and young adult patients with this complex genetic disorder, which is progressive if left untreated.”

The study, “Clinical outcomes among young patients with Fabry disease who initiated agalsidase beta treatment before 30 years of age: An analysis from the Fabry registry,” was published in the journal Molecular Genetics and Metabolism. Research was funded by Sanofi, the registry’s sponsor.

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Fabry disease is caused by mutations in the GLA gene that lead to the absence or malfunction of the enzyme alpha-galactosidase A. This causes fatty molecules — mainly Gb3 and lyso-Gb3 — to build up to toxic levels in several organs and systems, including the kidneys, heart, and nervous system.

Progression of Fabry disease, especially in the kidneys and heart, can become life-threatening. The disease occurs in both sexes, but it is frequently more severe in males.

The standard treatment for Fabry is enzyme replacement therapy (ERT). Fabrazyme was the first ERT specifically developed to treat Fabry. Its active ingredient is agalsidase beta, a version of the missing enzyme alpha-galactosidase A.

The importance of an early Fabry diagnosis and early treatment initiation is being increasingly recognized.

Although the first clinical symptoms of Fabry disease usually appear in childhood, few studies have assessed the effect of treatment in young patients.

Most clinical studies of Fabry disease therapies are done in patients who started treatment at a relatively late age. Such a late start might mean that irreversible organ damage has already occurred.

Study eyes effects of early, sustained treatment for Fabry disease

Because of this, a multinational team of researchers planned this observational study to add much needed evidence on the effects of early and sustained treatment for Fabry disease.

They used Sanofi’s Fabry Registry, an ongoing multinational observational program (NCT00196742) that tracks routine clinical outcomes of enrolled patients.

Researchers assessed clinical data of 524 male and 261 female patients who started Fabrazyme therapy between the ages of 5 and 30. These participants had a GLA mutation associated with classic Fabry disease or a GLA mutation not yet classified.

Participants were classified as having low renal involvement (LRI) or high renal involvement (HRI), according to their levels of excess proteins in urine (proteinuria), which are an indicator of poor kidney function.

The primary goals of the study were the assessment of kidney function, signs of cardiomyopathy (heart disease), and self-reported symptoms of Fabry disease after long-term treatment.

Kidney function was evaluated by using the estimated glomerular filtration rate (eGFR). Lower eGFR values indicate increasing kidney damage. Signs of cardiomyopathy were evaluated with the use of echocardiographic assessments made during an echocardiogram, an imaging test that allows doctors to examine the heart.

Evaluated self-reported symptoms included abdominal pain, diarrhea, chronic peripheral pain, and acute pain crises.

Results for male vs. female patients

Researchers found male participants with LRI were younger at diagnosis than those with HRI (median age of 16.1 vs. 20.1 years). Males with LRI started Fabrazyme therapy significantly earlier, at a median age of 19.9 years, than those with HRI, who initiated treatment at a median age of 26.7 years.

Male participants with LRI had a lower decline in eGFR than those with HRI. Males with LRI had a mean decline of −1.18 mL/min/1.73 m2 per year over a median follow-up of 6.3 years, while those with HRI had a mean decline of 2.39 mL/min/1.73 m2 per year over a median period of 5.6 years.

Data for female participants were hampered by the small number of participants with HRI (seven), so no comparisons between groups were made. Females with LRI had a mean rate of eGFR change of −0.92 mL/min/1.73 m2 per year over a median follow-up of five years.

Echocardiographic signs of cardiomyopathy remained stable overall during follow-up, especially in male and younger female participants.

Changes in the level of self-reported Fabry disease symptoms were more evident in male participants.

“After longer follow-up, reports of all analyzed [Fabry disease] symptoms [were] significantly reduced,” the researchers wrote.

For female participants, although reports of diarrhea and acute pain crises were significantly lower after at least half a year of follow-up, these reductions were no longer statistically significant after a longer period of time.

Conversely, reports of abdominal pain were significantly reduced in female participants only after a longer follow-up of at least five years.

“These findings extend the current limited clinical data regarding therapeutic outcomes among young [Fabry disease] patients and suggest an overall improvement of the analyzed variables after sustained treatment in patients in this age category,” the research team wrote. “However, the findings merit caution in their interpretations, given the study limitations, and warrant larger longitudinal studies.”

Limitations to study

These limitations included the lack of a control group and the lack of detail on the clinical presentation of patients before the start of treatment. The low number of female participants in several of the measures analyzed was also pointed out as a limitation.

Similarly, the Fabry Registry did not have the information necessary for researchers to assess biochemical responses to treatment or the use of other medications for pain or gastrointestinal symptoms.

Such limitations could be overcome with a more detailed, longitudinal study. Such a study would follow patients with repeated observations of carefully chosen measures over a long period of time.

Nonetheless, “the observed trends are informative for clinical care decisions for these young patients directed toward reducing the burden of [Fabry disease] and improving the overall clinical outcomes,” the research team wrote.