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 treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.4
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- Contraindications & Blackbox Warnings
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- Pharmacodynamics
The pharmacodynamic effects of inotersen were studied in hereditary transthyretin-mediated amyloidosis (hATTR) amyloidosis patients treated with 284 mg of inotersen via subcutaneous injection once weekly. With repeated dosing, the mean percentage decreases from baseline in serum TTR (transthyretin) from week 13 to Week 65 of treatment were measured from 68%-74% (median range: 75% to 79%). Similar TTR reductions were seen regardless of TTR mutation, sex, age, or race.4
- 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.4
Target Actions Organism ATransthyretin mRNA inhibitorHumans - Absorption
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.4
- Volume of distribution
Rapidly distributes broadly to tissues, with the highest concentrations observed in the kidney and liver. This drug does not cross the blood-brain barrier.4
- Protein binding
Inotersen is highly bound to human plasma proteins (>94%) and the fraction bound is independent of drug concentration.4
- Metabolism
Inotersen is metabolized by nucleases to nucleotides of various lengths.4
- Route of elimination
Mainly cleared through metabolism.4
- Half-life
The terminal elimination half-life is 32.3 (29.4, 35.5) days.4
- 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.4
- Adverse Effects
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- Toxicity
Thrombocytopenia
Inotersen causes reductions in platelet count that can result in sudden and unpredictable thrombocytopenia that can be life-threatening. Monitor CBC at regular intervals and adjust/pause treatment as necessary. Do not initiate treatment with this drug in patients with a platelet count below 100 x 10^9/L.4
Glomerulonephritis and Renal Toxicity
Inotersen can cause glomerulonephritis that may result in dialysis-dependent renal failure4,3. It may also exacerbate pre-existing renal dysfunction. Monitor kidney function before and during treatment.4
Stroke and Cervicocephalic Arterial Dissection
Inotersen may cause stroke and cervicocephalic arterial dissection.4
Inflammatory and Immune Effects
Inflammatory and immune changes are an expected side effect of some antisense oligonucleotide drugs, including inotersen. In clinical studies, serious inflammatory and immune adverse reactions occurred in Inotersen-treated patients, including immune thrombocytopenia and glomerulonephritis, as well as one case of antineutrophil cytoplasmic autoantibody (ANCA)- positive systemic vasculitis.4
Liver Effects
The liver is a possible site of accumulation of antisense oligonucleotides. In clinical studies, 8% of inotersen-treated patients had an increased alanine aminotransferase (ALT) at least 3 times the upper limit of normal (ULN), compared to 3% of patients on placebo; 3% of inotersen-treated patients had an ALT at least 8 times the upper limit of normal, compared to no patient on placebo. Monitor liver function tests as indicated on the FDA label.4
Hypersensitivity Reactions/Antibody Formation
Most of these reactions occur within 2 hours of administration of inotersen and included headache, chest pain, hypertension, chills, flushing, dysphagia, palmar erythema, eosinophilia, involuntary choreaform movements, arthralgia, myalgia, and flu-like symptoms.4
Reduced Serum Vitamin A Levels
Inotersen treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance of vitamin A is advised for patients taking this drug .4
Cardiac QT prolongation
Formal QTc studies have not been conducted with this drug. The risk of QTc prolongation with inotersen was evaluated in a randomized, placebo-controlled trial in healthy volunteers. No major changes in the mean QTc interval (>20 ms) were detected in the trial. In the 66-week controlled efficacy trial, 5.4% of the treated patients showed 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.4
Effects on pregnancy
There are no or limited amount of data from the use of inotersen in pregnant women. Animal studies are insufficient with respect to reproductive toxicity. There are no or limited amount of data from the ingestion of inotersen in pregnant women. Animal studies are not sufficient with respect to reproductive toxicity.4
- 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. Aceclofenac The risk or severity of nephrotoxicity can be increased when Aceclofenac is combined with Inotersen. Acemetacin The risk or severity of nephrotoxicity can be increased when Acemetacin is combined with Inotersen. Acetaminophen Inotersen may decrease the excretion rate of Acetaminophen which could result in a higher serum level. Acetylsalicylic acid The risk or severity of nephrotoxicity can be increased when Acetylsalicylic acid is combined with Inotersen. Aclidinium Inotersen may decrease the excretion rate of Aclidinium which could result in a higher serum level. Acrivastine The risk or severity of QTc prolongation can be increased when Acrivastine is combined with Inotersen. Acyclovir The risk or severity of nephrotoxicity can be increased when Acyclovir is combined with Inotersen. Adefovir dipivoxil The risk or severity of nephrotoxicity can be increased when Adefovir dipivoxil is combined with Inotersen. Adenosine The risk or severity of QTc prolongation can be increased when Inotersen is combined with Adenosine. Identify potential medication risksEasily compare up to 40 drugs with our drug interaction checker.Get severity rating, description, and management advice.Learn more - Food Interactions
- No interactions found.
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, Inc. 2019-01-07 Not applicable Canada Tegsedi Injection, solution 284 mg Subcutaneous Akcea Therapeutics Ireland Limited 2020-12-16 Not applicable EU Tegsedi Injection, solution 284 mg/1.5mL Subcutaneous Akcea Therapeutics, Inc. 2018-10-05 Not applicable US Tegsedi Injection, solution 284 mg Subcutaneous Akcea Therapeutics Ireland Limited 2020-12-16 Not applicable EU
Categories
- ATC Codes
- N07XX15 — Inotersen
- Drug Categories
- Antisense Elements (Genetics)
- Antisense Oligonucleotides
- Compounds used in a research, industrial, or household setting
- Decreased RNA Integrity
- DNA, Antisense
- Increased Protein Breakdown
- Laboratory Chemicals
- 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]
- Tegsedi EMA label [File]
- External Links
- FDA label
- Download (1.51 MB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Active Not Recruiting Treatment Hereditary Transthyretin-Mediated Amyloid Polyneuropathy 1 2 Active Not Recruiting Treatment Amyloidosis 1 2 Withdrawn Treatment Amyloidosis 1 2, 3 Completed Treatment Amyloidosis / Familial Amyloid Polyneuropathy (FAP) / FAP / Transthyretin / TTR 1 Not Available Approved for Marketing Not Available Amyloidosis, Hereditary 1 Not Available Recruiting Not Available Hereditary Transthyretin-mediated Amyloidosis With Polyneropathy / Pregnancy 1
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

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]
- Tegsedi EMA label [File]
Drug created at October 09, 2018 16:02 / Updated at May 22, 2022 04:54