Eplontersen is a N-acetylgalactosamine (GalNAc)-conjugated 2′-O-2-methoxyethyl-modified chimeric gapmer antisense oligonucleotide (ASO) with a mixed backbone of phosphorothioate and phosphate diester internucleotide linkages. The GalNAc conjugate enables targeted delivery of the ASO to hepatocytes. The selective binding of eplontersen to the transthyretin (TTR) messenger RNA (mRNA) within the hepatocytes causes the degradation of both mutant and wild type (normal) TTR mRNA. This prevents the synthesis of TTR protein in the liver, resulting in significant reductions in the levels of mutated and wild type TTR protein secreted by the liver into the circulation.
In the clinical study in patients with ATTRv-PN receiving eplontersen, a decrease in serum TTR concentrations was observed at the first assessment (Week 5) and TTR concentrations continued to decrease through Week 35. A sustained reduction of TTR concentration was observed throughout the duration of the treatment (85 weeks). Mean (SD) for serum TTR percent reduction from baseline was 82.1% (11.7) at Week 35, 83.0% (10.4) at Week 65 and 81.8% (13.4) at Week 85 when treated with eplontersen. Similar reduction from baseline in serum TTR concentrations was observed regardless of sex, race, age, region, body weight, cardiomyopathy status, previous treatment, Val30Met mutation status, disease stage, and familial amyloid cardiomyopathy clinical diagnosis at baseline.
TTR is a carrier protein for retinol binding protein 4, which is the principal carrier of vitamin A (retinol). Therefore, a reduction in plasma TTR is expected to result in the reduction of plasma retinol levels to below the lower limit of normal.
The pharmacokinetic properties of eplontersen were evaluated by measuring plasma concentrations of eplontersen following subcutaneous administration of single and multiple doses (once every 4 weeks) in healthy subjects and multiple doses (once every 4 weeks) in patients with ATTRv-PN.
Following subcutaneous administration, eplontersen is absorbed rapidly into the systemic circulation with the time to maximum plasma concentrations of approximately 2 hours, based on population estimates. Population estimates of steady state maximum concentrations (Cmax), trough concentrations (Ctrough), and area under the curve (AUCτ) were 0.218 μg/ml, 0.0002 μg/ml, and 1.95 μg h/ml, respectively, following 45 mg once every 4 weeks dosing in patients with ATTRv-PN. No accumulation of eplontersen Cmax and AUC was observed in plasma after repeated dosing (once every 4 weeks). Accumulation was observed in Ctrough, and steady-state was reached after approximately 17 weeks.
Eplontersen is highly bound to human plasma proteins (>98%). The population estimates for the apparent central volume of distribution is 12.9 l and the apparent peripheral volume of distribution is 11 100 l. Eplontersen is expected to distribute primarily to the liver and kidney cortex after subcutaneous dosing.
Eplontersen is metabolised by endo- and exonucleases into short oligonucleotide fragments of varying sizes primarily within the liver. There were no major circulating metabolites in humans. Oligonucleotide therapeutics, including eplontersen, are not metabolised by CYP enzymes.
Eplontersen is primarily eliminated by metabolism followed by renal excretion of the short oligonucleotide metabolites. The mean fraction of unchanged ASO eliminated in urine was less than 1% of the administered dose within 24 hours. The terminal elimination half-life is approximately 3 weeks based on population estimates.
Eplontersen Cmax and AUC showed a slightly greater than dose-proportional increase following single subcutaneous doses ranging from 45 to 120 mg (i.e. 1 to 2.7 times the recommended dose) in healthy volunteers.
Based on the population pharmacokinetic, body weight, sex, race, and Val30Met mutation status are unlikely to have a clinically meaningful effect on eplontersen exposure. Definitive assessments were limited in some cases as covariates were limited by the overall low numbers.
No overall differences in pharmacokinetics were observed between adult and elderly (≥65 years of age) patients.
No formal clinical studies have been conducted to investigate the effect of renal impairment on eplontersen pharmacokinetics. A population pharmacokinetic and pharmacodynamic analysis showed no clinically meaningful differences in the pharmacokinetics or pharmacodynamics of eplontersen based on mild and moderate renal impairment (eGFR ≥45 to <90 ml/min). Eplontersen has not been studied in patients with eGFR <45 ml/min or in patients with end-stage renal disease.
No formal clinical studies have been conducted to investigate the effect of hepatic impairment on eplontersen. A population pharmacokinetic and pharmacodynamic analysis showed no clinically meaningful differences in the pharmacokinetics or pharmacodynamics of eplontersen based on mild hepatic impairment (total bilirubin ≤1 × ULN and AST >1 × ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST). Eplontersen has not been studied in patients with moderate hepatic impairment (total bilirubin >1.5 to 3 × ULN and any AST) or severe hepatic impairment (total bilirubin >3 to 10 × ULN and any AST) or in patients with prior liver transplant.
Repeated administration of eplontersen at 24 mg/kg/week for 13 weeks or 25 mg/kg/month for 9 months in monkeys reduced TTR protein in plasma by 69% and 52%, respectively. There were no toxicologically relevant findings related to this pharmacologic inhibition of TTR expression.
Most of the findings observed after repeated subcutaneous dosing for up to 6 months in mice and 9 months in monkeys were non-adverse and related to the uptake and accumulation of eplontersen by various cell types in multiple organs of all tested animal species including monocytes/macrophages, kidney proximal tubular epithelia, Kupffer cells of the liver, and histiocytic cell infiltrates in lymph nodes and injection sites. In a single monkey in the 13 week toxicity study, severely decreased platelet counts associated with spontaneous haemorrhage, presented as haematoma and petechiae, were observed at the highest dose tested (24 mg/kg/week). Similar findings were not observed at the NOAEL of 6 mg/kg/week in monkeys, which corresponds to more than 70-fold the human AUC at the recommended therapeutic eplontersen dose.
Eplontersen did not exhibit genotoxic potential in vitro and in vivo and was not carcinogenic in ras.H2 transgenic mice.
Eplontersen had no effects on fertility or embryo-foetal development in mice up to 38-fold (based on human equivalent dose) to the recommended human monthly dose of 45 mg. Eplontersen is not pharmacologically active in mice. Consequently, only effects related to the chemistry of eplontersen could be captured in this study. However, no effect on fertility or embryo-foetal development was noted with a mouse-specific analogue of eplontersen in mice, which was associated with >90% inhibition of TTR mRNA expression.
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