Replagal is an enzyme replacement therapy (ERT) for people with Fabry disease, providing them with the functional enzyme they are missing in a form that their body can use. It is being developed by the biotechnology company Shire (now owned by Takeda).
Although in use in many countries, including Canada, Russia, the United Kingdom, Mexico, Israel, and many members of the European Union, Replagal has not been approved by the U.S. Food and Drug Administration (FDA).
How Replagal works
Fabry disease is a rare genetic disorder where affected individuals lack the enzyme alpha-galactosidase A and cannot break down a fat molecule called globotriaosylceramide (Gb3 or GL-3). When this enzyme is not present or is malfunctioning, this fat molecule damages the body by building up inside cells. Symptoms include extreme pain in the hands and feet, progressive kidney damage, and damage to the heart leading to an increased risk of stroke and heart attack. This damage to the heart can manifest as portions of the heart muscle such as the left ventricle, which pumps blood to the whole body, being enlarged.
Replagal is a concentrated form of the enzyme alpha-galactosidase A that is administered via infusion into the bloodstream. The formulation, which includes sodium phosphate, monohydrate, polysorbate 20, sodium chloride, and sodium hydroxide, allows the enzyme to enter the cells easily where it can break down Gb3 and clear it out of the cell. As the levels of Gb3 decrease in the cells, the symptoms of the disease should improve.
Replagal in clinical trials
The safety and effectiveness of several dosing regimens of Replagal on heart function in adults with Fabry disease were evaluated in a Phase 3 clinical trial (NCT00864851). Three different dosing regimens were tested: 0.2 mg/kg once weekly, 0.2 mg/kg every other week, and a higher dose of 0.4 mg/kg once a week. Results published in the scientific journal Drug Design, Development, and Therapy, showed that all dosages were able to reduce the size of the enlarged heart muscles and alleviate symptoms associated with it. The frequency of adverse events and the improvement of the symptoms measured through oxygen usage during a brisk walking exercise were not found to be affected by the dose or frequency of the treatment.
Replagal also evaluated 17 children with Fabry disease, ages 7 to 17, in a Phase 2 clinical trial (NCT00084084) called TKT029. Patients were given 0.2 mg/kg of Replagal every week for 52 weeks. No serious adverse effects were seen over the course of the study.
Two Phase 2 trials tested the effect of Replagal manufactured in a different way, in adult male Fabry patients (HGT-REP-082) and in children with Fabry disease (NCT01363492). In both cases, there was no apparent difference in the effectiveness or safety of the enzyme produced, according to the new method.
A separate Phase 3 clinical trial (NCT01298141) to confirm the safety of Replagal manufactured with the new method is currently recruiting up to 200 participants in Canada.
The main concern with Replagal is a possible severe allergic reaction. Other known side effects are non-life-threatening and include chills, cough, headache, nausea, fever, shaking or sweating, facial flushing, tiredness, low blood pressure, unsteadiness, and trouble breathing. Hearing problems such as tinnitus (ringing in the ears), chest pain, and tightness in the chest and throat also have been reported.
More severe side effects include heart rhythm problems, ischemia (reduced blood flow to the heart), and heart failure, though these are caused by the infusion and not by the medication itself.
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