Introduction

Eplontersen is transthyretin-directed antisense oligonucleoside used in the treatment of the polyneuropathy caused by hereditary transthyretin-mediated amyloidosis. Eplontersen has been associated with minor liver test abnormalities during therapy but has not been linked instances of clinically apparent liver injury.

Background

Eplontersen (e plon’ ter sen) is an antisense oligonucleoside directed against transthyretin, a serum protein made in the liver whose major function is transport of vitamin A and thyroxine. Rare mutations in the transthyretin gene result in misfolding of the protein and accumulation of large amyloid deposits of transthyretin molecules, most prominently in peripheral nerves and the heart. Patients with hereditary transthyretin amyloidosis typically present with polyneuropathy or autonomic dysfunction followed by cardiomyopathy, which if untreated is usually fatal within 5 to 12 years. Eplontersen causes degradation of transthyretin and decreases production of both wild type and mutant forms in the liver resulting in lower serum concentrations and decreased accumulation in nerves and heart. Eplontersen is bound to a ligand with three N-acetyl galactosamine residues that direct the molecule for uptake by hepatocytes, where the majority of transthyretin is produced. In preregistration open label studies, eplontersen decreased transthyretin levels and led to improvements in symptoms of neuropathy as well as general quality of life, at least as compared to untreated historical controls. Studies in experimental animal models and in preliminary trials in humans suggest that long term therapy with eplontersen can prevent worsening of amyloid associated heart disease. Eplontersen was approved for use in the United States as treatment of polyneuropathy of hereditary transthyretin mediated amyloidosis in adults in 2023. It is available in solution as 45 mg in 0.8 mL in single use autoinjectors under the brand name Wainua. The usual dose regimen is 45 mg subcutaneously once per month. Side effects are infrequent but can include vomiting, proteinuria, injection site reactions, and blurred vision. Transthyretin is a vitamin A carrier involved in its transport and uptake. As a consequence, vitamin A levels decrease in patients receiving eplontersen. For that reason, while on treatment, patients should take supplements with the recommended daily allowance of vitamin A. Rare potential adverse events associated with eplontersen therapy include vitamin A deficiency and embryo-fetal toxicity.

Hepatotoxicity

In the registration trial of eplontersen, liver test abnormalities occurred in 7.6% of treated patients, but the elevations were mild and no more frequent than was observed in a historical control group (6.7%). There were no ALT elevations above 3 times the upper limit of normal (ULN) and no case of aminotransferase elevations accompanied by jaundice or symptoms. Since its approval, clinical experience with eplontersen has been limited, but there have been no published case reports of clinically apparent liver injury attributed to its use.

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

Mechanism of Injury

The mechanism by which eplontersen might cause liver injury is not clear. Eplontersen is an oligonucleotide and is metabolized to short sequences or individual nucleotides by plasma and intracellular nucleases. Eplontersen is not metabolized by P450 enzymes and has no effect on their level of activity and no significant drug-drug interactions.

Outcome and Management

The serum aminotransferase elevations that occur on eplontersen therapy are unlikely to be due to the drug therapy and rarely require dose modification or discontinuation. Persistent ALT or AST elevations arising during therapy should lead to evaluation of their possible causes. There is no information on cross sensitivity to liver injury among the various other therapies for transthyretin-associated amyloidosis.

Drug Class: Genetic Disorder Agents

Drugs for Hereditary Transthyretin Amyloidosis: Acoramidis, Inotersen, Patisiran, Tafamidis, Vutrisiran