Acoramidis

Transthyretin amyloid cardiomyopathy is initiated by the dissociation of the transthyretin (TTR) tetramer into its constituent monomers. These misfold and aggregate as oligomeric amyloid precursors that deposit in the heart where they assemble into amyloid fibrils.

Acoramidis is a specific stabiliser of TTR. Acoramidis was designed to mimic the disease protective genetic variant (T119M), through the formation of hydrogen bonds with adjacent serine residues within both thyroxine binding sites of the tetramer. This interaction enhances the stability of the tetramer, inhibiting its dissociation into monomers, thus slowing the amyloidogenic process that results in ATTR-CM.

Near-complete transthyretin stabilisation was observed with acoramidis in wild-type and in all amyloidogenic variant genotypes tested, including the most prevalent genotypes V30M (p.V50M), T60A (p.T80A), and V122I (p.V142I). In the ATTRibute-CM study, in patients (wild-type and variant ATTR) treated with acoramidis (712 mg twice daily), near-complete (≥90%) TTR stabilisation was observed at the first post-dose initiation assessment (Day 28) and sustained through Month 30. For all post-baseline measurements (from Day 28 through Month 30), the TTR level was higher in the acoramidis group compared with placebo (at Month 30, mean change from baseline 9.1 mg/dL with acoramidis versus 1.3 mg/dL with placebo).

In ATTRibute-CM, the increase in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) at Month 30 favoured acoramidis and was about half the increase seen with placebo. A lower increase in troponin I was also observed with acoramidis versus placebo.

In ATTRibute-CM, the mean serum creatinine (and estimated GFR) at baseline was 110.0 μmol/L (eGFR: 60.9 mL/min/1.73 m²) in the acoramidis group and 109.0 μmol/L (eGFR: 61.0 mL/min/1.73 m²) in the placebo group. At Day 28, there was a change from baseline in the mean serum creatinine (eGFR) that was greater in the acoramidis group (observed values on Day 28 serum creatinine: 129.3 μmol/L, eGFR: 52.4 mL/min/1.73 m²) compared with the placebo group (observed values on Day 28 serum creatinine: 110.6 μmol/L, eGFR: 60.0 mL/min/1.73 m²). After Day 28, serum creatinine (eGFR) remained stable in the acoramidis group for the remainder of the study. There was a progressive rise in serum creatinine, and corresponding progressive decrease in eGFR, in the placebo group from baseline through Month 30. At Month 30, serum creatinine was 123.4 μmol/L (eGFR: 55.1 mL/min/1.73 m²) and 117.2 μmol/L (eGFR: 57.2 mL/min/1.73 m²) for acoramidis and placebo respectively. The observed increase in serum creatinine, and corresponding decrease in eGFR, observed in acoramidis treated patients was reversible in the event of an interruption of therapy.

Cardiac electrophysiology

The maximum dose of acoramidis, 1 780 mg, studied as a single dose in healthy adult volunteers did not have a clinically relevant effect on cardiac conduction or repolarisation (no concentration-QTc effect was observed). These observations indicate a low risk of pro-arrhythmia.

Absorption

The increase in exposure parameters (area under the concentration-time curve [AUC] and maximum concentration [C_max]) was less than dose-proportional over single (up to 1 780 mg) or multiple (up to 712 mg) twice daily dosing.

Following oral administration, acoramidis is rapidly absorbed and peak plasma concentration of unchanged acoramidis is usually achieved within 1 hour. Increases in plasma concentration were observed for acoramidis doses from 44.5 mg once daily to 712 mg once daily. Plasma exposures appeared to saturate at acoramidis doses over 712 mg to 1 068 mg. A steady state is achieved by 10 days of dosing with 712 mg twice daily, and repeated dosing results in minor (approximately 1.3- to 1.6-fold) accumulation of acoramidis.

The absolute bioavailability is not known; however at least 75-80% of orally administered single 712 mg dose is absorbed based on a human ADME (absorption, distribution, metabolism, excretion) study.

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

Distribution

The apparent steady state volume of distribution of 712 mg acoramidis dosed twice daily is 654 litres. In vitro binding of acoramidis to human plasma proteins is 96.4%. Acoramidis primarily binds to TTR.

Biotransformation

The metabolism of acoramidis was characterised following the administration of a single oral dose of [¹⁴C]acoramidis to healthy adult volunteers. Acoramidis is metabolised predominantly by glucuronidation, with acoramidisβ-D-glucuronide (acoramidis-AG) being the predominant metabolite (7.6% of total circulating radioactivity). Acoramidis-AG is approximately 3-fold less pharmacologically active than acoramidis, has a low potential for covalent binding, and does not meaningfully contribute to pharmacological activity.

Elimination and excretion

The terminal half-life of acoramidis is approximately 27 hours after a single dose. At steady state, the apparent oral clearance of acoramidis is 15.6 L/h.

After administration of a single oral dose of [¹⁴C]-acoramidis to healthy adult volunteers, approximately 34% of dose radioactivity was recovered in faeces (acoramidis being the major component) and approximately 68% was recovered in urine. The percent of unchanged acoramidis in the urine was <10%.

Special populations

No clinically significant differences in the pharmacokinetics of acoramidis were observed based on age (18.0-89.3 years), race/ethnicity (including Japanese and non-Japanese), sex, or renal impairment (eGFR 25.4-157 mL/min/1.73 m²).

Based on population PK modelling, steady-state acoramidis AUC was 37% higher for healthy subjects than for the patient population. Also, relative to White subjects, steady-state AUC was 23% higher for Black subjects and 38% higher for non-White, non-Black subjects. These effects are within the range of inter-individual variability (CV=38%). The model also predicted lack of clinically significant differences in the pharmacokinetics of acoramidis due to body weight, within the body weights range of 50.9 to 133 kg.

A dedicated renal-impairment study was not conducted because acoramidis is not substantially eliminated by the renal route. However, despite the main metabolite (acoramidis-AG) having no clinically relevant contribution to pharmacological activity in the studied population, data in patients with severe renal impairment (creatinine clearance <30 mL/min) are limited and there are no data for patients on dialysis. Clearance of the acoramidis metabolite acoramidis-AG might be affected by severe renal impairment resulting potentially in higher systemic exposure of acoramidis-AG. While this potential increase in acoramidis-AG exposure is not expected to have a clinically meaningful contribution to pharmacologic activity, acoramidis should be used with caution in patients with severe renal impairment.

Acoramidis has not been studied in patients with hepatic impairment.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, developmental and reproductive toxicology (fertility and embryo-foetal development).

In the rat pre- and postnatal development study with acoramidis, decreased pup survival, reduced pup weights, and learning deficits were observed following maternal dose administration during pregnancy and lactation with acoramidis at 1 000 mg/kg/day. Severe maternal toxicity including mortalities and weight loss during the period of organogenesis was also observed at this dose. The no-observed-adverse-effect-level (NOAEL) in pre- and postnatal development toxicity study in rats were established at the tested dose of 350 mg/kg/day acoramidis, (AUC values were approximatively 21-fold the human exposure at the clinical dose of acoramidis).

Placental transfer and milk excretion studies in animals were not performed.