Inotersen
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Identification
- Summary
Inotersen is an antisense oligonucleotide used to treat polyneuropathy of hereditary transthyretin-mediated amyloidosis.
- Brand Names
- Tegsedi
- Generic Name
- Inotersen
- DrugBank Accession Number
- DB14713
- Background
Inotersen is a transthyretin-directed antisense oligonucleotide for the treatment of the polyneuropathy caused by hereditary transthyretin-mediated amyloidosis in adults. It was FDA approved in October 2018.4 Inotersen has been shown to improve the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis 1.
Hereditary transthyretin amyloidosis is caused by single-nucleotide variants in the gene encoding transthyretin (TTR), which lead to transthyretin misfolding and the deposition of amyloid substance systemically. Progressive amyloid accumulation may lead to multiorgan dysfunction and death 1.
- Type
- Biotech
- Groups
- Approved, Investigational
- Biologic Classification
- Gene Therapies
Antisense oligonucleotides - Synonyms
- Inotersen
- External IDs
- GSK-2998728
- ISIS 420915
- ISIS-420915
Pharmacology
- Indication
Inotersen is a transthyretin-directed antisense oligonucleotide indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.5
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Hereditary transthyretin amyloidosis •••••••••••• ••••••••• Treatment of Polyneuropathies caused by hereditary transthyretin-mediated amyloidosis •••••••••••• ••••• ••••••••• - Contraindications & Blackbox Warnings
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- Pharmacodynamics
The pharmacodynamic effects of inotersen were evaluated in hATTR amyloidosis patients treated with 284 mg inotersen via subcutaneous injection once weekly.5
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.5
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 65.5
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.5
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.5
- 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.5
Target Actions Organism ATransthyretin antisense oligonucleotideHumans ATransthyretin mRNA antisense oligonucleotideHumans - Absorption
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 a steady state.5
Following subcutaneous administration, inotersen is absorbed rapidly into the systemic circulation in a dose-dependent fashion, with the median time to maximum plasma concentrations (Cmax) of 2 to 4 hours.5
- Volume of distribution
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.5
- Protein binding
Inotersen is highly bound to human plasma proteins (>94%) and the fraction bound is independent of drug concentration.5
- Metabolism
Inotersen is metabolized by nucleases to nucleotides of various lengths.5
- Route of elimination
Less than 1% of the administered dose of inotersen is excreted unchanged into urine within 24 hours.5
- Half-life
The terminal elimination half-life (mean and 90% confidence interval) for inotersen is 32.3 (29.4, 35.5) days.5
- Clearance
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.5
- Adverse Effects
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- Toxicity
There are no data on the developmental risk associated with the use of inotersen in pregnant women. Inotersen treatment leads to a decrease in serum vitamin A levels, and vitamin A supplementation is advised for patients taking inotersen. Vitamin A is essential for normal embryofetal development; however, excessive levels of Vitamin A are associated with adverse developmental effects. The effects on the fetus due to a reduction in maternal serum TTR caused by inotersen and vitamin A supplementation are unknown.5
In animal studies, subcutaneous administration of inotersen to pregnant rabbits resulted in premature delivery and reduced fetal body weight at the highest dose tested, which was associated with maternal toxicity. No adverse developmental effects were observed when inotersen or a pharmacologically active surrogate was administered to pregnant mice.5
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.5
In a 94-week carcinogenicity study in rats, weekly subcutaneous administration of inotersen (0, 0.5, 2, or 6 mg/kg) resulted in an increase in tumors at or near the injection site in males at all but the lowest dose (0.5 mg/kg) tested. Subcutaneous malignant pleomorphic fibrosarcoma was increased at the mid and high doses and combined subcutaneous malignant pleomorphic fibrosarcoma and monomorphic fibrosarcoma were increased at the high dose. These tumors are considered a response to chronic tissue irritation and inflammation caused by repeated subcutaneous injection.5
Inotersen was negative for genotoxicity in in vitro (bacterial mutagenicity, chromosomal aberration in Chinese hamster lung) and in vivo (mouse bone marrow micronucleus) assays.5
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.5
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbacavir Inotersen may decrease the excretion rate of Abacavir which could result in a higher serum level. Abciximab The risk or severity of thrombocytopenia can be increased when Inotersen is combined with Abciximab. Aceclofenac The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Aceclofenac. Acemetacin The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Acemetacin. Acenocoumarol The risk or severity of thrombocytopenia can be increased when Inotersen is combined with Acenocoumarol. - Food Interactions
- Administer vitamin A supplementation. Supplementation at the recommended daily allowance of vitamin A is advised for patients taking inotersen.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Product Ingredients
Ingredient UNII CAS InChI Key Inotersen sodium 950736UC77 1432726-13-0 Not applicable - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Tegsedi Solution 284 mg / 1.5 mL Subcutaneous Akcea Therapeutics Ireland Ltd 2019-01-07 Not applicable Canada Tegsedi Injection, solution 284 mg Subcutaneous Akcea Therapeutics Ireland Ltd 2020-12-16 Not applicable EU Tegsedi Injection, solution 284 mg/1.5mL Subcutaneous Akcea Therapeutics Ireland Ltd 2018-10-05 Not applicable US Tegsedi Injection, solution 284 mg Subcutaneous Akcea Therapeutics Ireland Ltd 2020-12-16 Not applicable EU
Categories
- ATC Codes
- N07XX15 — Inotersen
- Drug Categories
- Antisense Elements (Genetics)
- Antisense Oligonucleotides
- Decreased RNA Integrity
- DNA, Antisense
- Increased Protein Breakdown
- Molecular Probes
- Nephrotoxic agents
- Nervous System
- Nucleic Acid Probes
- Nucleic Acids
- Nucleic Acids, Nucleotides, and Nucleosides
- Nucleotides
- Oligodeoxyribonucleotides, Antisense
- Oligonucleotides
- Polynucleotides
- Potential QTc-Prolonging Agents
- QTc Prolonging Agents
- Transthyretin-directed RNA Interaction
- Classification
- Not classified
- Affected organisms
- Humans
Chemical Identifiers
- UNII
- 0IEO0F56LV
- CAS number
- 1492984-65-2
References
- General References
- Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK, Plante-Bordeneuve V, Barroso FA, Merlini G, Obici L, Scheinberg M, Brannagan TH 3rd, Litchy WJ, Whelan C, Drachman BM, Adams D, Heitner SB, Conceicao I, Schmidt HH, Vita G, Campistol JM, Gamez J, Gorevic PD, Gane E, Shah AM, Solomon SD, Monia BP, Hughes SG, Kwoh TJ, McEvoy BW, Jung SW, Baker BF, Ackermann EJ, Gertz MA, Coelho T: Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018 Jul 5;379(1):22-31. doi: 10.1056/NEJMoa1716793. [Article]
- Shen X, Corey DR: Chemistry, mechanism and clinical status of antisense oligonucleotides and duplex RNAs. Nucleic Acids Res. 2018 Feb 28;46(4):1584-1600. doi: 10.1093/nar/gkx1239. [Article]
- Crooke ST, Baker BF, Pham NC, Hughes SG, Kwoh TJ, Cai D, Tsimikas S, Geary RS, Bhanot S: The Effects of 2'-O-Methoxyethyl Oligonucleotides on Renal Function in Humans. Nucleic Acid Ther. 2018 Feb;28(1):10-22. doi: 10.1089/nat.2017.0693. Epub 2017 Nov 29. [Article]
- FDA Approved Drug Products: TEGSEDI (inotersen) injection [Link]
- FDA Approved Drug Products: TEGSEDI (inotersen) injection, for subcutaneous use (Jan 2024) [Link]
- Tegsedi EMA label [File]
- External Links
- FDA label
- Download (1.51 MB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Approved for Marketing Not Available Hereditary Amyloidosis 1 somestatus stop reason just information to hide Not Available Recruiting Not Available Hereditary Transthyretin-mediated Amyloidosis With Polyneropathy / Pregnancy 1 somestatus stop reason just information to hide 3 Completed Treatment Amyloidosis / Familial Amyloid Polyneuropathy (FAP) / FAP / Transthyretin / TTR 1 somestatus stop reason just information to hide 3 Completed Treatment Hereditary Transthyretin-Mediated Amyloid Polyneuropathy 1 somestatus stop reason just information to hide 2 Unknown Status Treatment Amyloidosis 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution Parenteral; Subcutaneous 284 MG Injection, solution Subcutaneous 284 mg/1.5mL Injection, solution Subcutaneous 284 mg Solution Subcutaneous 284 mg / 1.5 mL - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US7015315 No 2006-03-21 2023-03-21 US US7101993 No 2006-09-05 2023-09-05 US US9399774 No 2016-07-26 2031-04-29 US US9061044 No 2015-06-23 2031-04-29 US US8697860 No 2014-04-15 2031-04-29 US US8101743 No 2012-01-24 2025-04-01 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility soluble https://www.ema.europa.eu/documents/product-information/tegsedi-epar-product-information_en.pdf
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antisense oligonucleotide
- General Function
- Thyroid hormone-binding protein. Probably transports thyroxine from the bloodstream to the brain
- Specific Function
- hormone activity
- Gene Name
- TTR
- Uniprot ID
- P02766
- Uniprot Name
- Transthyretin
- Molecular Weight
- 15886.88 Da
References
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
References
- Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK, Plante-Bordeneuve V, Barroso FA, Merlini G, Obici L, Scheinberg M, Brannagan TH 3rd, Litchy WJ, Whelan C, Drachman BM, Adams D, Heitner SB, Conceicao I, Schmidt HH, Vita G, Campistol JM, Gamez J, Gorevic PD, Gane E, Shah AM, Solomon SD, Monia BP, Hughes SG, Kwoh TJ, McEvoy BW, Jung SW, Baker BF, Ackermann EJ, Gertz MA, Coelho T: Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018 Jul 5;379(1):22-31. doi: 10.1056/NEJMoa1716793. [Article]
- Shen X, Corey DR: Chemistry, mechanism and clinical status of antisense oligonucleotides and duplex RNAs. Nucleic Acids Res. 2018 Feb 28;46(4):1584-1600. doi: 10.1093/nar/gkx1239. [Article]
- Crooke ST, Baker BF, Pham NC, Hughes SG, Kwoh TJ, Cai D, Tsimikas S, Geary RS, Bhanot S: The Effects of 2'-O-Methoxyethyl Oligonucleotides on Renal Function in Humans. Nucleic Acid Ther. 2018 Feb;28(1):10-22. doi: 10.1089/nat.2017.0693. Epub 2017 Nov 29. [Article]
- FDA Approved Drug Products: TEGSEDI (inotersen) injection, for subcutaneous use (Jan 2024) [Link]
- Tegsedi EMA label [File]
Drug created at October 09, 2018 16:02 / Updated at August 26, 2024 19:24