Fabry therapy switch linked to less pain, lower biomarker in boy

Switching from the enzyme replacement therapy (ERT) agalsidase alfa to Fabrazyme (agalsidase beta) was associated with reduced pain and lower levels of a disease biomarker in a boy with classic Fabry disease, according to a case report from Japan.

The boy was diagnosed through newborn screening and started agalsidase alfa in childhood. He later developed recurring pain in his hands and feet, while levels of globotriaosylsphingosine (lyso-Gb3), a biomarker of Fabry disease, remained persistently high. After switching to Fabrazyme, his pain eased, and lyso-Gb3 levels fell substantially.

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The researchers said, to their knowledge, “this is the first pediatric case” documenting the switch from agalsidase alfa to Fabrazyme due to insufficient efficacy, highlighting “the importance of monitoring symptoms and biomarkers in Fabry disease.”

The report, “Clinical and Biochemical Improvement After Switching From Agalsidase Alfa to Beta in a Boy With Classic Fabry Disease: A Case Report,” was published in the journal Clinical Case Reports.

Fabry is caused by mutations in the GLA gene that reduce the activity of alpha-galactosidase A (alpha-Gal A), an enzyme that helps break down certain fatty molecules. When alpha-Gal A activity is too low, these fatty molecules build up inside cells, especially in structures called lysosomes, and can eventually damage tissues and organs. Blood levels of lyso-Gb3, one of the fatty molecules that can accumulate in Fabry disease, can be measured to help monitor the disease and response to treatment.

Boys and men with classic Fabry disease generally have very low enzyme activity and may begin developing symptoms during childhood. These can include burning or tingling pain in the hands and feet (called acroparesthesia), reduced sweating, gastrointestinal problems, and skin lesions called angiokeratomas. Over time, Fabry can also damage the kidneys, heart, and blood vessels.

ERT, a standard Fabry treatment, provides a lab-made version of alpha-Gal A to help reduce the buildup of fatty molecules and slow damage to organs.

Agalsidase alfa, sold as Replagal, and Fabrazyme are two forms of ERT. Fabrazyme is approved in the U.S., while agalsidase alfa is approved in the European Union and several other countries but not in the U.S.

Although several ERT options are available, it remains unclear which is the most appropriate for children with classic Fabry disease.

Switch followed insufficient response to initial enzyme therapy

This report describes the clinical and biochemical course of the switch from agalsidase alfa to Fabrazyme, which was prompted by an insufficient response to the initial treatment.

The boy was diagnosed with Fabry through newborn screening in Japan after testing showed low alpha-Gal A activity. Genetic testing identified a GLA mutation known to cause classic Fabry disease. His mother carried the same variant and had experienced acroparesthesia.

At age 6, routine monitoring detected mulberry bodies — tiny, round clumps of fat — in his urine, a finding that can signal Fabry-related organ involvement. A cardiac MRI also showed an abnormal area in the heart muscle, although there was no evidence of heart muscle swelling or abnormal wall motion. His kidney function was normal, and he had no protein in his urine.

These findings suggested that Fabry was already affecting his organs even though he had no symptoms. He therefore started ERT with agalsidase alfa at 0.2 mg/kg every two weeks. At that time, his lyso-Gb3 level was 76.4 nanomoles per liter (nmol/L).

About a year later, he began experiencing recurrent acroparesthesia triggered by exercise or infection. The pain typically lasted several days and was medically managed, but continued despite ongoing agalsidase alfa.

Lyso-Gb3 levels fell somewhat but remained around 50 nmol/L — about 35% below the pretreatment level — without a clear continued decline. Antibodies against the ERT, which can interfere with the response to treatment, were also detected when he was 9.5 years old.

Together, the persistent pain and persistently elevated lyso-Gb3 suggested that he was not responding well enough to agalsidase alfa. As a result, the boy was switched at age 10.9 to Fabrazyme, at 1 mg/kg every two weeks.

Pain and Fabry biomarker improved after treatment switch

After the switch, his acroparesthesia gradually eased. By the latest follow-up, the pain typically improved within about a day. His lyso-Gb3 levels also fell to approximately 35 nmol/L — about 54% below the level measured before ERT was started.

Although antibodies against the ERT were still detected about nine months after the switch, his pain and lyso-Gb3 levels had both diminished. Since Fabrazyme is administered at a substantially higher standard dose than agalsidase alfa — 1 mg/kg versus 0.2 mg/kg every two weeks — it may maintain higher enzyme activity even in the presence of antibodies.

At the latest evaluation, when he was 12.8 years old, an echocardiogram showed no abnormalities, and kidney function remained normal.

Overall, this case report highlights how “switching to [Fabrazyme] may improve outcomes in patients with [Fabry disease] when the effect of agalsidase alfa is insufficient,” the researchers wrote.

However, the researchers noted that the natural course of acroparesthesia could not be completely ruled out as a reason for the improvement in pain. They also cautioned that, because lyso-Gb3 levels vary according to GLA variant, disease type, and sex, “caution is warranted when interpreting treatment response based on this biomarker alone.”