TEGSEDI (Inotersen) Injection for Treatment of Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis

TEGSEDI (inotersen) injection, for subcutaneous use

Inotersen is an antisense oligonucleotide (ASO) inhibitor of human transthyretin (TTR) protein synthesis. TEGSEDI contains inotersen sodium as the active ingredient.


CLINICAL PHARMACOLOGY
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. 

Pharmacodynamics The pharmacodynamic effects of TEGSEDI were evaluated 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%, was observed at Week 65. 

Pharmacokinetics Following subcutaneous administration, systemic exposure to inotersen increase in a doseproportional 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 (AUC) 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. 

Absorption 
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) for 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.

Initial U.S. Approval: 2018

INDICATIONS AND USAGE
TEGSEDI is a transthyretin-directed antisense oligonucleotide indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. 

DOSAGE AND ADMINIS TRATION
The recommended dosage is 284 mg administered by subcutaneous injection once weekly. 
 Laboratory tests must be measured prior to treatment, continue to be monitored after treatment initiation, and for 8 weeks following discontinuation of treatment, as directed. 
 
DOSAGE FORMS AND STRENGTHS 
Injection: 284 mg/ 1.5 mL in a single-dose prefilled syringe

CONTRAINDICATIONS
  • Platelet count less than 100 x 109 /L (4, 5.1)  History of acute glomerulonephritis caused by TEGSEDI
  • Patients with a history of a hypersensitivity reaction to TEGSEDI 

WARNINGS AND PRECAUTIONS
  • Stroke and Cervicocephalic Arterial Dissection: These adverse events occurred within 2 days of the first dose and with symptoms of cytokine release. Educate patients on symptoms of stroke and central nervous system arterial dissection.
  • Inflammatory and Immune Effects: Serious neurologic adverse reactions consistent with inflammatory and immune effects occurred. 
  • Liver Effects: Monitor alanine amino transferase, aspartate aminotransferase, and total bilirubin every 4 months during treatment and in case of symptoms of hepatic dysfunction. 
  • Hypersensitivity Reactions:If these occur, discontinue and initiate appropriate therapy.
  • Uninterpretable Platelet Counts: Reaction between Antiplatelet Antibodies and ethylenediaminetetra-acetic acid: Platelet clumping can cause uninterpretable platelet measurement; repeat test if this is suspected.
  • Reduced Serum Vitamin A Levels and Recommended Supplementation: Supplement with the recommended daily allowance of vitamin A. Refer to an ophthalmologist if ocular symptoms suggestive of vitamin A deficiency occurs. 

ADVERSE REACTIONS 
The most common adverse reactions (those that occurred in at least 20% of TEGSEDI-treated patients and more frequently than on placebo) were injection site reactions, nausea, headache, fatigue, thrombocytopenia, and fever 

Reference: FDA Prescribing Information

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