Eplontersen

Eplontersen is an antisense oligonucleotide-GalNAc conjugate that causes degradation of mutant and wild-type TTR mRNA through binding to the TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in tissues.

In Study 1, following administration of the recommended eplontersen dosage every 4 weeks to patients with hATTR amyloidosis, a decrease in serum TTR levels was observed at the first assessment and the (least square) mean serum TTR at Week 35 was reduced by 81% from baseline. Similar TTR reductions were observed across subgroups including Val30Met variant status, body weight, sex, age, or race.

Eplontersen also reduced the mean steady state serum vitamin A by 71% by Week 37.

Cardiac Electrophysiology

At a dose 2.7-times the maximum recommended dose for eplontersen, clinically significant QTc interval prolongation was not observed.

The pharmacokinetic (PK) properties of eplontersen were evaluated 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 hATTR amyloidosis.

Eplontersen C_max 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.

Population estimates (mean ± SD) of steady state maximum concentrations (C_max), and area under the curve (AUC_τ) were 283 ± 152 ng/mL, and 2190 ± 689 ng/mL, respectively, following 45 mg monthly dosing in patients with hATTR amyloidosis. No accumulation of eplontersen C_max and AUC was observed in repeated dosing (once every 4 weeks).

Absorption

Following subcutaneous administration, eplontersen is absorbed with the time to maximum plasma concentrations of approximately 2 hours, based on population estimates.

Distribution

Eplontersen is expected to distribute primarily to the liver and kidney cortex after subcutaneous dosing. Eplontersen is bound to human plasma proteins (>98%) in vitro. The population estimate for the apparent central volume of distribution is 12 L and the apparent peripheral volume of distribution is 11,100 L.

Elimination

The terminal elimination half-life is approximately 3 weeks.

Metabolism

Eplontersen is metabolized by endo- and exonucleases to short oligonucleotide fragments of varying sizes within the liver.

Excretion

The mean fraction of unchanged ASO eliminated in urine was less than 1% of the administered dose within 24 hours.

Specific Populations

Population pharmacokinetic and pharmacodynamic analysis showed no clinically meaningful differences in the pharmacokinetics or pharmacodynamics of eplontersen based on age, body weight, sex, race, Val30Met variant status, mild and moderate renal impairment (eGFR ≥30 to <90 mL/min), or mild hepatic impairment (total bilirubin ≤1 x ULN and AST >1 x ULN, or total bilirubin >1.0 to 1.5 x ULN and any AST). Eplontersen has not been studied in patients with severe renal impairment, end-stage renal disease, or in patients with moderate to severe hepatic impairment, or in patients with prior liver transplant.

Drug Interaction Studies

No clinical drug-drug interaction studies have been performed with eplontersen. In vitro studies show that eplontersen is not a substrate or inhibitor of transporters, does not interact with highly plasma protein bound drugs, and is not an inhibitor or inducer of cytochrome P450 (CYP) enzymes. Oligonucleotide therapeutics, including eplontersen, are not typically substrates of CYP enzymes. Therefore, eplontersen is not expected to cause or be affected by drug-drug interactions mediated through drug transporters, plasma protein binding or CYP enzymes.