Acoramidis

Breast Feeding; Lactation; Milk, Human

EMA approved medicines: Human medicine

Warning

H315 (100%): Causes skin irritation [Warning Skin corrosion/irritation]

P261, P264, P264+P265, P271, P280, P302+P352, P304+P340, P305+P351+P338, P319, P321, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

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.

C - Cardiovascular system

QC - Cardiovascular system

At the recommended dosage, near-complete _in vitro_ transthyretin (TTR) stabilization was observed as early as Day 28 and through completion of a 30-month study of patients with ATTR-CM (wild-type and variant). Acoramidis may decrease serum concentrations of free thyroxine without an accompanying change in thyroid stimulating hormone - this is an effect common to TTR stabilizers, and is likely due to reduced thyroxine binding to (or displacement from) TTR.

The first and rate-limiting step in transthyretin (TTR) amyloidogenesis is the dissociation of the TTR tetramer into its constituent monomers. This is followed by misfolding of the resulting monomer and their subsequent aggregation, leading to build-ups of larger oligomers and amyloid fibrils. When these build-ups aggregate in the heart, they can lead to heart dysfunction (transthyretin amyloidosis cardiomyopathy; ATTR-CM). Acoramidis is a highly selective stabilizer of TTR. It exerts its therapeutic effects by binding to TTR at thyroxine binding sites and stabilizing it in its tetrameric form, thereby slowing the rate-limiting step in amyloidogenesis.

Acoramidis is primarily metabolized by glucuronidation via UGT1A9, UGT1A1, and UGT2B7. The predominant circulating metabolite is acoramidis-β-D-glucuronide (acoramidis acylglucuronide; acoramidis-AG), comprising 8% of total circulating drug-related moieties. The pharmacological activity of acoramidis-AG is approximately 1/3 that of acoramidis parent drug and thus does not significantly contribute to overall pharmacological activity.