Inotersen is an antisense oligonucleotide 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.
The pharmacodynamic effects of inotersen were evaluated in hATTR amyloidosis patients treated with 284 mg inotersen via subcutaneous injection once weekly.
With repeat dosing, the mean percent decreases from baseline in serum TTR from Week 13 to Week 65 of treatment ranged from 68% to 74% (median range: 75% to 79%). Similar TTR reductions were observed regardless of TTR mutation, sex, age, or race.
Serum TTR is a carrier of retinol binding protein, which is involved in the transport of vitamin A in the blood. Mean reductions in serum retinol binding of 71%, and serum vitamin A of 63%, were observed at Week 65.
Formal QTc studies have not been conducted with inotersen. The potential for QTc prolongation with inotersen was evaluated in a randomized, placebo-controlled trial in healthy volunteers. No large changes in the mean QTc interval (>20 ms) were detected in the trial.
In the 66-week controlled efficacy trial, 5.4% of inotersen-treated patients had evidence of QRS prolongation on their electrocardiograms (ECGs) to greater than 160 msec and greater than 25% above baseline, compared to and in 1.7% of patients on placebo.
Following subcutaneous administration, systemic exposure to inotersen increased in a dose-proportional manner over the range of 150-400 mg of inotersen sodium salt. At the recommended inotersen dosing regimen of 284 mg every week, steady state is reached after approximately 3 months. The estimated geometric mean (90% confidence interval) steady state peak concentrations (Cmax), trough concentrations (Ctrough), and area under the curve (AUCτ) were 6.39 (5.65, 7.20) µg/mL, 0.034 (0.031, 0.038) µg/mL, and 90 (82.4, 97.4) µg·h/mL, respectively. Plasma Cmax and AUC do not exhibit accumulation at steady state.
Following subcutaneous administration, inotersen is absorbed rapidly into systemic circulation in a dose-dependent fashion, with the median time to maximum plasma concentrations (Cmax) of 2 to 4 hours.
Inotersen is highly bound to human plasma proteins (>94%) and the fraction bound is independent of drug concentration. Based on animal studies (mouse, rat and monkey), inotersen rapidly distributes broadly to tissues, with the highest concentrations observed in the kidney and liver. Inotersen does not cross the blood-brain barrier. The apparent volume of distribution of inotersen at steady-state (mean and 90% confidence interval) is 293 (268, 320) L in patients with hATTR.
The terminal elimination half-life (mean and 90% confidence interval) for inotersen is 32.3 (29.4, 35.5) days. Inotersen is mainly cleared through metabolism, and the total body clearance (mean and 90% confidence interval) is 3.18 (3.08, 3.29) L/h.
Inotersen is metabolized by nucleases to nucleotides of various lengths.
Less than 1% of the administered dose of inotersen is excreted unchanged into urine within 24 hours.
Age, race, and sex had no impact on the steady state pharmacokinetics of inotersen or TTR reduction. Population pharmacokinetic and pharmacodynamic analyses indicated no impact of mild or moderate renal impairment (eGFR ≥30 to <90 mL/min/1.73 m²) or mild hepatic impairment (bilirubin less than or equal to 1.5 x ULN and/or AST less than 1.9 x ULN) on inotersen exposure or TTR reduction. Inotersen has not been studied in patients with severe renal impairment, end-stage renal disease, moderate or severe hepatic impairment, or in patients with prior liver transplant.
No formal clinical drug interaction studies have been performed. Inotersen is not a substrate or inhibitor/inducer of major CYP enzymes or a substrate or inhibitor of major transporters. In a population pharmacokinetic analysis, concomitant use of diuretics, antithrombotic, and analgesics did not impact the pharmacokinetic parameters of inotersen. Inotersen is not expected to cause drug-drug interactions or to be affected by inhibitors or inducers of cytochrome P450 enzymes.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
