Introduction

Acoramidis is transthyretin stabilizer used for the treatment of adults with the cardiomyopathy of both wild-type and hereditary transthyretin-mediated amyloidosis to reduce cardiovascular morbidity and mortality. Acoramidis has been associated with minor liver test abnormalities during therapy but has not been linked instances of clinically apparent liver injury.

Background

Acoramidis (a’ co ram” i dis ) is a stabilizer of 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. Rarely, wild-type transthyretin also can result in overproduction and deposition of misfolded transthyretin in amyloid clusters. Acoramidis causes stabilization of the transthyretin molecule in the full tetrameric form such that it is less likely to break into monomers that can misfold and create amyloid clusters. In preregistration open label studies, acoramidis increased stable transthyretin levels and led to improvements all-cause mortality and decrease in cardiovascular hospitalizations. Acoramidis was the second transthyretin stabilizer to be approved for use in the United States as treatment of the cardiomyopathy of wild-type and hereditary transthyretin-mediated amyloidosis in adults in 2024 (the first being tafamidis in 2019). Acoramidis is available in tablets of 356 mg under the brand name Attruby, the recommended dose being 712 mg (2 tablets) twice daily. In clinical trials of acoramidis, side effects were uncommon and similar in frequency overall to those of placebo. Slightly more frequent with acoramidis therapy was diarrhea (23% vs 8%) and upper abdominal pain (5.5% vs 1.4%). Mild and reversable serum creatinine levels were also increased with acoramidis therapy. Transthyretin functions as a carrier and transporter of vitamin A and thyroxine, and therapy with acoramidis can alter serum concentrations of these molecules but does not appear to affect thyroid function or vitamin A status.

Hepatotoxicity

In the registration trial of acoramidis, transient mild ALT and AST elevations were not uncommon, but elevations in ALT above 3 times ULN were infrequent and no more common with acoramidis than placebo (0.9% vs 0.5%), most of which were attributed to heart failure or its treatment. No patient required drug discontinuation because of liver test abnormalities and none developed clinically apparent liver injury or elevations in serum aminotransferases accompanied by jaundice. Since its approval, clinical experience with acoramidis 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 acoramidis might cause liver injury is not clear. Acoramidis is a small molecule that binds to transthyretin and is metabolized by glucuronidation. Acoramidis is not metabolized by P450 enzymes, but drug levels may be decreased by glucuronosyltransferase inducers and strong CYP3A inducers which increase glucuronidation.

Outcome and Management

The serum aminotransferase elevations that occur on acoramidis 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: Eplontersen, Inotersen, Patisiran, Tafamidis, Vutrisiran