Introduction

Migalastat is pharmacologic chaperone of alpha-galactosidase the intrahepatic enzyme that is deficient in Fabry disease. Clinical experience with migalastat is limited, but it not been linked to serum enzyme elevations during therapy or to instances of clinically apparent acute liver injury.

Background

Migalastat (me' gal a stat) is a small molecule chaperone of alpha-galactosidase A (GLA) the enzyme that is deficient in Fabry disease. The enzyme deficiency results in the intra-lysosomal accumulation of glycosphingolipids in multiple cell types including endothelial, renal and nerve cells, causing damage to kidneys, heart, brain, gastrointestinal tract and peripheral nerves. The disease has an X-linked inheritance, but both males and females can be affected, and the frequency and severity of clinical features vary greatly, apparently dependent upon the amount of residual GLA enzyme activity. In severe cases, the disease presents in childhood with abdominal pain, diarrhea and peripheral neuropathy followed by renal dysfunction that progresses to end stage renal disease in adulthood. Other complications include cardiovascular and cerebrovascular complications including arrhythmias, myocardial infarction, transient ischemic attacks and stoke. Disease severity correlates with amount of accumulation of GLA substrate in affected tissue. Migalastat is a small molecule chaperone which increases GLA activity in cells by directing the enzyme to the proper location in lysosomes. However, only a proportion of patients with Fabry disease have a beneficial response to migalastat, which generally correlates with specific mutations in the GLA gene that can be shown to be responsive to migalastat in vitro as well as in vivo. In several clinical trials, therapy with migalastat was associated with decrease in substrate accumulation in kidney tissue in subjects with gene mutations that could be shown to be amenable to migalastat in vitro. Responses to migalastat were greatest in patients with severe disease, but improvements were measured by changes in substrate accumulation and not by improvement in clinical symptoms or disease outcomes. Migalastat was given accelerated approval in 2018 as oral therapy of Fabry disease in patients who have a variant of the GLA gene that is amenable to its effects. Migalastat is available in tablets of 123 mg under the brand name Galafold. The recommended dose regimen is 123 mg every other day at the same time of day. Side effects are not common but can include headache, upper respiratory symptoms, urinary tract infection, nausea and fever.

Hepatotoxicity

In placebo-controlled trials, liver test abnormalities were rare and no more common with migalastat than with placebo treatment. What abnormalities occurred were mild and resolved spontaneously without need for dose interruption. During these premarketing clinical trials and since its more widespread clinical availability, no instances of acute liver injury with jaundice have been reported attributable to migalastat. However, the total clinical experience with its use has been limited.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which migalastat might cause serum aminotransferase elevations or liver injury is not known. Migalastat is extensively metabolized by the liver via the cytochrome P450 system (predominantly CYP 2D6 and 3A) and is susceptible to drug-drug interactions with agents that induce or inhibit these enzymes.

Outcome and Management

The serum aminotransferase elevations that occur on migalastat therapy are usually self-limited and do not require dose modification or discontinuation of therapy. No instances of severe hepatitis, acute liver failure or vanishing bile duct syndrome due to migalastat have been reported.

Drug Class: Genetic Disorder Agents