3 Da. It has the following structural formula:
Chemical Structure
The molecular formula of inotersen free base is C230H318N69O121P19S19 and its molecular weight is 7183.08.
TEGSEDI is a sterile, preservative-free, aqueous solution for subcutaneous injection. It is supplied in a prefilled syringe (PFS). Each PFS contains 1.5 mL of solution containing 284 mg inotersen (equivalent to 300 mg inotersen sodium salt) TEGSEDI is formulated in Water for Injection and may include hydrochloric acid and/or sodium hydroxide for pH adjustment to 7.5-8.5.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
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.
12.2 Pharmacodynamics
The pharmacodynamic effects of TEGSEDI were eva luated in hATTR amyloidosis patients treated with 284 mg TEGSEDI 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 [see Warnings and Precautions (5.6)].
Cardiac Electrophysiology
Formal QTc studies have not been conducted with TEGSEDI. The potential for QTc prolongation with inotersen was eva luated 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 TEGSEDI-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.
12.3 Pharmacokinetics
Following subcutaneous administration, systemic exposure to inotersen increase in a dose-proportional manner over the range of 150-400 mg of inotersen sodium salt. At the recommended TEGSEDI 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.
Absoption
Following subcutaneous administration, TEGSEDI 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.
Distribution
TEGSEDI 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), TEGSEDI rapidly distributes broadly to tissues, with the highest concentrations observed in the kidney and liver. TEGSEDI does not cross the blood-brain barrier. The apparent volume of distribution of TEGSEDI at steady-state (mean and 90% confidence interval) is 293 (268, 320) L in patients with hATTR.
Elimination
The terminal elimination half-life (mean and 90% confidence interval) fo |
