r TEGSEDI 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.
Metabolism
Inotersen is metabolized by nucleases to nucleotides of various lengths.
Excretion
Less than 1% of the administered dose of inotersen is excreted unchanged into urine within 24 hours.
Specific Populations
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/1.73m2) 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. TEGSEDI 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.
Drug Interaction Studies
No formal clinical drug interaction studies have been performed. TEGSEDI 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. TEGSEDI is not expected to cause drug-drug interactions or to be affected by inhibitors or inducers of cytochrome P450 enzymes.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 26-week carcinogenicity study in transgenic (TgRasH2) mice, weekly subcutaneous administration of inotersen (0, 10, 30, or 80 mg/kg) or a rodent-specific (pharmacologically active) surrogate (30 mg/kg) did not result in an increase in tumors.
Inotersen was negative for genotoxicity in in vitro (bacterial mutagenicity, chromosomal aberration in Chinese hamster lung) and in vivo (mouse bone marrow micronucleus) assays.
Subcutaneous administration of inotersen (0, 3, 15, or 25 mg/kg) or a rodent-specific surrogate (15 mg/kg) to male and female mice every other day prior to and during mating and continuing in females throughout the period of organogenesis produced no adverse effects on fertility.
14 CLINICAL STUDIES
The efficacy of TEGSEDI was demonstrated in a randomized, double-blind, placebo-controlled, multicenter clinical trial in adult patients with polyneuropathy caused by hATTR amyloidosis (Study 1; NCT 01737398). Patients were randomized in a 2:1 ratio to receive either TEGSEDI (284 mg inotersen) (N=113) or placebo (N=60), respectively, as a subcutaneous injection administered once per week for 65 weeks (3 doses were administered during the first week of treatment). Seventy seven percent of TEGSEDI-treated patients and 87% of patients on placebo completed 66 weeks of the assigned treatment.
The co-primary efficacy endpoints were the change from baseline to Week 66 in the modified Neuropathy Impairment Scale+7 (mNIS+7) composite score and the Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) total score
The mNIS+7 is an objective assessment of neuropathy, and comprises the NIS and Modified +7 composite scores. In the version of the mNIS+7 used in the trial, the NIS objectively measures deficits in cranial nerve function, muscle strength, reflexes, and sensations, and the Modified +7 assesses heart rate response to deep breathing, postural blood pressure, quantitative sensory testi |
