Replagal, an ERT, Appears Safe for Use During Pregnancy and Nursing, Case Study Reports

Use of Replagal — an enzyme replacement therapy (ERT) — during pregnancy and breastfeeding by women with Fabry disease appears to be safe for them and their children, according to a case series study.

The study, “Enzyme Replacement Therapy in Pregnant Women with Fabry Disease: A Case Series,” was published in the Journal of Inherited Metabolic Disease.

Fabry disease is caused by absent or markedly reduced α-galactosidase A (GLA) enzymatic activity, which leads to the damaging accumulation of two fat molecules — Gb3 and lysoGb3 — in tissues such as the heart, kidneys, nervous system, eyes, and skin.

ERT replaces the faulty GLA enzyme and restores its normal function. Currently, two versions of the enzyme are commercially available — agalsidase alpha (or Replagal, developed by Shire) and agalsidase beta (or Fabrazyme, developed by Sanofi Genzyme) — but only Fabrazyme is approved by the U.S. Food and Drug Administration. Replagal is approved by the European Medicines Agency for use across the European Union, and approved in Canada, much of South America, and elsewhere.

Few studies have investigated ERT use in pregnant women and no experimental study has focused on ERT safety during pregnancy. So far, only nine cases of women with Fabry disease treated with Replagal during pregnancy were reported, and the results suggest that ERT is safe and can be administered or continued during pregnancy.

Researchers at the Centro de Investigación, Diagnóstico y Tratamiento de Enfermedad de Fabry (CIDTEF, Research, Diagnosis and Treatment Center for Fabry Disease) in Catamarca, Argentina, have now reported on six Fabry patients receiving Replagal during pregnancy and lactation between January 2012 and December 2017.

The team retrospectively analyzed the patients’ medical records at diagnosis and during pregnancy and lactation, and records of the newborns at birth and during follow-up for a median of two years (ranging from 1- to 5-years-old). These women were all related, sharing the c.520T>G mutation, which is associated with late-onset Fabry disease.

However, patients showed early – and distinct – signs of the disease, and their median age at diagnosis was 22. Four of six showed reduced GLA activity, and five patients had signs of kidney damage, while the sixth showed mainly peripheral nerve damage. Three women had pain crises and two of them also reported heat intolerance and acroparesthesia — abnormal sensation, such as tingling, numbness, or pins and needles, in the hands and fingers.

All six women were using Replagal — at a dose of 0.2 mg/kg every 14 days — prior to their pregnancies. Their mean age at the time of pregnancy was 26; their age range was 19 to 38.

The decision to continue or stop therapy was made with each patient and their relatives based on the careful assessment of the risks-benefits balance. All were closely followed during pregnancy.

The three patients with pain crisis discontinued therapy during the first trimester, but the recurrence of severe and untreatable pain led them to restart therapy, which substantially eased the symptoms. The other three patients continued to use Replagal during pregnancy.

One woman had two pregnancies over the time covered by this study, and she was the only one to have complications during her first pregnancy and to have her babies delivered by C-section. The researchers noted that this patient had an underlying increased risk of complications, and believed there was no association with Replagal treatment.

All babies were born within the normal gestational time, and had heights and weights within the normal range. Six of seven newborns were breastfed. Additional testing revealed that only one baby had Fabry disease.

Replagal was well-tolerated in all cases, with no adverse events or health issues potentially associated with ERT during pregnancy and breastfeeding reported in the mothers or their children.

While these results increase the number of evidence suggesting that ERT, or at least Replagal, is safe in pregnant women with Fabry disease, “there is still poor evidence to support its universal use among all pregnant women with symptomatic FD [Fabry disease],” the researchers wrote.