ERT Before Age 16 May Slow Classic Fabry Progression
Beginning enzyme replacement therapy (ERT) before age 16 is associated with reduced kidney and heart damage — relative to no treatment — in males with classic Fabry disease, according to a small study from the Netherlands.
These early findings, concerning 10 years of treatment with Fabrazyme (agalsidase beta), suggest that starting ERT early slows disease progression in boys with classic Fabry, supporting such therapeutic approach.
However, longer follow-up studies are needed to confirm its effects on later disease-associated events, such as kidney failure and heart problems, the researchers noted.
The study, “Low-dose agalsidase beta treatment in male pediatric patients with Fabry disease: A 5-year randomized controlled trial,” was published in the journal Molecular Genetics and Metabolism.
Fabry disease is caused by absent or markedly reduced activity of the alpha-galactosidase A (Gal A) enzyme due to mutations in the GLA gene. Gal A deficiency leads to the toxic accumulation of two fatty molecules — Gb3 and lyso-Gb3 — in tissues and organs such as the kidneys, heart, nervous system, eyes, and skin.
Patients with the classic, more severe form of the disease are typically male, have a Gal A activity lower than 3%, and develop symptoms during childhood. While at this stage fatty molecules are building up in tissues, patients do not show clinical signs of kidney, heart, or cerebral complications.
Such complications are developed only during adolescent and early adulthood, and can cause kidney and/or heart failure, as well as cerebrovascular events. All contribute to reduced life expectancy.
ERT, a mainstay Fabry treatment, involves the delivery of a lab-made version of Gal A directly to a patient’s bloodstream, restoring its normal function. Currently, two versions of the enzyme are available commercially — Fabrazyme and Replagal (agalsidase alfa). Only Fabrazyme is approved in the U.S.
In boys with classic Fabry, it is recommended that ERT be initiated early, before the development of clear clinical kidney or heart manifestations, as this approach was shown to be more effective at slowing disease progression.
However, “with the clinically asymptomatic [symptoms absent] progression of [kidney], cardiac and cerebral disease manifestations spanning decades, optimal timing of ERT initiation remains unclear,” the researchers wrote.
To address this, a team of researchers in the Netherlands, along with a colleague in Norway, retrospectively analyzed the demographic and clinical data of seven adolescents and men with classic Fabry who started Fabrazyme treatment before age 16.
These patients, with a median age of 24 (range, 14–26), had begun Fabrazyme about 10 years before within a Phase 3 clinical trial called FIELD (NCT00701415), which evaluated the effects of five years of treatment with two suboptimal dosing regimens.
All patients continued treatment after completing the trial, and all but one switched to the approved Fabrazyme regimen (1 mg/kg every other week) after a median of nine years (range 8.3–10 years).
Given that the trial did not include a group of untreated patients, the researchers compared the participants’ data with those of 23 untreated classic Fabry male patients with similar ages (median age of 22 range 13–27). Untreated patients’ data were collected from a clinical database of one of the medical centers that participated in the FIELD study.
There were no significant differences between the two groups of patients in terms of age at evaluation and clinical symptoms at diagnosis, but the treated group had significantly higher blood lyso-Gb3 levels at the time of Fabrazyme initiation.
Results showed that albuminuria, or higher-than-normal levels of albumin protein in urine — one of the strongest risk factors of kidney failure — occurred at an older age and less frequently, and was significantly less pronounced in the treated group relative to the untreated group.
While median estimated glomerular filtration rate, another measure of kidney function, was similar between the groups, 30% of untreated patients showed abnormal values versus none in the treated group.
Untreated patients also showed significantly higher muscle mass in the left side of the heart. Abnormal thickening of the heart’s left side is a common heart manifestation of Fabry disease that may lead to heart failure. Other heart abnormalities also were more common in the untreated group.
Brain involvement was minimal in both groups, and brain lesions were more frequent among untreated patients (27.3% vs. 14.3%), but this difference did not reach statistical significance.
Four (57.1%) of the treated patients developed neutralizing antibodies against Fabrazyme, which is a common event in males that can trigger adverse side effects and limit the therapy’s effectiveness. Notably, these patients showed a trend for higher blood lysoGb3 levels during treatment relative to those without these antibodies.
Fabrazyme caused serious infusion-related fever and cold chills in one patient, who started needing immunosuppressive treatment prior to infusions to continue treatment.
“This study is the first to provide clinical evidence that treatment of male [classic Fabry disease] patients before the age of 16 has a beneficial impact on progression of clinical [kidney] and cardiac manifestations,” the researchers wrote.
The team also noted the fact that these patients were treated most of this time with a suboptimal dose of Fabrazyme suggests that treatment with the approved dose likely results in greater benefits.
“Confirmation that this approach delays or even prevents [kidney] failure and cardiac events requires another decade of follow-up,” the researchers wrote.
Still, the risk of developing neutralizing antibodies against ERT and “potential infusion reactions should also be taken into account when weighing the pros and cons of ERT, especially in pediatric patients,” they added.
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