Acoramidis

Acoramidis is a new substance from the substance group of transthyretin stabilizers (TTR stabilizers), which is used to treat cardiomyopathy in ATTR amyloidosis.

Significance: After tafamidis, acoramidis is the second approved substance in the substance group of transthyretin stabilizers. It was approved in the EU in February 2025 for the treatment of cardiomyopathy in wild-type and hereditary forms of transthyretin amyloidosis (wtATTR-CM and hATTR-CM).

Acoramidis is a so-called orphan drug. Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a rare disease.

(For orphan drugs and approval of orphan drugs, see also: BfArM Orphan Drugs and BfArM Drugs for Rare Diseases).

The final benefit assessment of the G-BA (Federal Joint Committee) with regard to an additional benefit compared to the existing standard therapy with Tafimidis is expected in September 2025.

Acoramidis is a specific TTR stabilizer.

Mechanism of action: Acoramidis increases the stability of the TTR tetramer, inhibits its dissociation into monomers and thus slows down the amyloidogenic process leading to ATTR-CM. It mimics the mode of action of the protective T119M gene variant of the TTR protein by forming hydrogen bonds with neighboring serine residues within both thyroxine binding sites of the tetramer. This interaction increases the stability of the tetramer and inhibits its dissociation into monomers.

Under acoramidis, almost complete transthyretin stabilization was observed in wild type and in all tested amyloidogenic genotype variants, including the most prevalent genotypes V30M (p.V50M), T60A (p.T80A) and V122I (p.V142I).

In patients (wild-type and hereditary ATTR) treated with acoramidis (712 mg twice daily), almost complete (≥ 90 %) TTR stabilization was achieved and maintained over the entire observation period of 30 months (ATTRibute-CM study)(Gillmore JD et al 2024). TTR levels in the acoramidis group were consistently higher than in the placebo group (at month 30 mean change from baseline 9.1 mg/dl with acoramidis vs. 1.3 mg/dl with placebo).

Values for NT-proBNP and troponin I showed a lower increase with acoramidis than with placebo (ATTRibute-CM study).

The ATTRibute-CM study, RCT in 632 patients, Acoramidis 2:1 versus placebo, showed a significantly lower overall mortality, hospitalization rate and better quality of life with treatment with Acoramidis compared to placebo. The difference was detectable from 3 months after the start of treatment (Gillmore JD et al 2024). The study is currently being continued as an open label extension (OLE) study (Judge DP et al 2024). A comparative study with Tafimidis (head to head comparison) has not yet been conducted.

Absorption: after oral administration, Acoramidis is rapidly absorbed; maximum plasma concentration of unchanged Acoramidis usually within 1 hour; in vitro binding of Acoramidis to human plasma proteins is 96.4%.

The overall extent of absorption of acoramidis is not influenced by food intake.

No specific in vivo interaction study with gastric acid reducing drugs has been performed. The influence of these drugs on the pharmacokinetics of Acoramidis is therefore not known. The solubility of Acoramidis is strongly pH-dependent in the physiological pH range. However, in the Phase 3 study, no differences in systemic acoramidis exposure or pharmacodynamic marker (TTR stabilization) were observed between patients taking gastric acid-reducing drugs and patients not taking gastric acid-reducing drugs.

Metabolism: Acoramidis is metabolized predominantly by glucuronidation, primarily to acoramidis-β-D-glucuronide (acoramidis-AG predominant metabolite). Acoramidis-AG exhibits approximately 3-fold less pharmacologic activity than acoramidis, has a low potential for covalent binding, and does not contribute significantly to pharmacologic activity.

Elimination: After application of a single oral dose of [14C]-acoramidis in healthy adult volunteers, about 34% of the dose radioactivity was recovered in the feces (with acoramidis as the major component) and about 68% in the urine. The proportion of unchanged acoramidis in urine was < 10 %.

HWZ approx. 27 hours.

for further details see technical info.

Acoramidis is indicated for the treatment of the wild-type or hereditary form of transthyretin amyloidosis (wtATTR and hATTR) in adult patients with cardiomyopathy (ATTR-CM).

The diagnosis of wild-type ATTR cardiomyopathy or hereditary ATTR cardiomyopathy must be confirmed and AL amyloidosis must be reliably excluded as the cause.

Acoramidis is not relevant for children and adolescents.

Pharmaceutical form: Film-coated tablet, for oral administration; 1 tablet contains acoramidis hydrochloride, equivalent to 356mg acoramidis.

The recommended daily dose of Acoramidis is 1424 mg divided into 712 mg twice daily, i.e. 2 tablets of 356 mg each time (total daily dose 1424 mg).

The tablets must be swallowed whole; intake independent of food.

Treatment should be administered by a physician experienced in transthyretin amyloidosis and cardiomyopathy (ATTR-CM).

No efficacy data are available for patients with New York Heart Association (NYHA) Class IV.

No dose adjustment is required in elderly patients (≥ 65 years).

In patients with renal impairment: due to the low renal clearance of acoramidis, dose adjustment is not required.

In severe renal impairment (creatinine clearance < 30 ml/min) only limited data are available; no data are available for dialysis patients. Acoramidis should therefore be used with caution in these patients.

In patients with hepatic impairment: Acoramidis has not been studied in hepatic impairment and is therefore not recommended in hepatic impairment.

Acoramidis has been shown to inhibit CYP2C8 and CYP2C9 in vitro. No in vivo study was conducted. The concomitant use of CYP2C8 and CYP2C9 substrates with a narrow therapeutic range should be used with caution.

Based on preclinical studies to date, inhibition of the organic anion transporters OAT 1 and OAT 3 is not expected to lead to clinically relevant drug interactions with OAT 1 and OAT 3 substrates.

Similarly, according to previous studies, no drug interactions are expected at clinically relevant concentrations with concomitantly applied substrates of the breast cancer resistant protein (BCRP).

Acoramidis is a BCRP substrate. Based on an in vitro study, no clinically relevant interactions with BCRP inhibitors are expected.

Acoramidis Fachinfo ^Bayonttra® 356mg (Distributed in Germany by Bayer).

Gillmore JD, Judge DP, Cappelli F et. al. for the ATTRibute-CM Investigators (2024). Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy. N Engl J Med;390:132-142 doi/full/10.1056/NEJMoa2305434.

Judge DP, Gillmore JP, Alexander KM. Long-Term Efficacy and Safety of Acoramidis in ATTR-CM: Initial Report From the Open-Label Extension of the ATTRibute-CM Trial. CirculationVolume 151, 9, 4;601-611. doi/10.1161/CIRCULATIONAHA.124.072771.

Rapezzi C, Quarta CC, Riva L, et al. (2010). Transthyretin-related amyloidoses and the heart: a clinical overview. Nat Rev Cardiol;7:398-408. doi.org/10.1038/nrcardio.2010.67.