Identification

Name

Inotersen

Accession Number

DB14713

Description

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

Not Available

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

Associated Conditions

• Polyneuropathies caused by Hereditary transthyretin-mediated amyloidosis

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	inhibitor	Humans

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 failure^4,3. 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

Affected organisms

• Humans

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abacavir	Inotersen may decrease the excretion rate of Abacavir which could result in a higher serum level.
Acarbose	Inotersen may decrease the excretion rate of Acarbose which could result in a higher serum level.
Acebutolol	The risk or severity of QTc prolongation can be increased when Inotersen is combined with Acebutolol.
Aceclofenac	Inotersen may decrease the excretion rate of Aceclofenac which could result in a higher serum level.
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	Inotersen may decrease the excretion rate of Acrivastine which could result in a higher serum level.
Acyclovir	Inotersen may decrease the excretion rate of Acyclovir which could result in a higher serum level.

Additional Data Available

Extended Description
Extended Description
Extended description of the mechanism of action and particular properties of each drug interaction.
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Severity
Severity
A severity rating for each drug interaction, from minor to major.
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Evidence Level
Evidence Level
A rating for the strength of the evidence supporting each drug interaction.
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Action
Action
An effect category for each drug interaction. Know how this interaction affects the subject drug.
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Food Interactions

No interactions found.

Products

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
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Tegsedi	Injection, solution	284 mg/1.5mL	Subcutaneous	Akcea Therapeutics, Inc.	2018-10-05	Not applicable
Tegsedi	Solution	284 mg	Subcutaneous	Akcea Therapeutics Inc	2019-01-07	Not applicable

Additional Data Available

Application Number
Application Number
A unique ID assigned by the FDA when a product is submitted for approval by the labeller.
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Product Code
Product Code
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.
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Categories

ATC Codes

N07XX15 — Inotersen

• N07XX — Other nervous system drugs
• N07X — OTHER NERVOUS SYSTEM DRUGS
• N07 — OTHER NERVOUS SYSTEM DRUGS
• N — NERVOUS SYSTEM

Drug Categories

• Antisense Elements (Genetics)
• Carbohydrates
• Compounds used in a research, industrial, or household setting
• Decreased RNA Integrity
• Diagnostic Uses of Chemicals
• DNA
• DNA, Antisense
• Glycosides
• Increased Protein Breakdown
• Laboratory Chemicals
• Miscellaneous Central Nervous System Agents
• Molecular Probes
• Nephrotoxic agents
• Nervous System
• Nucleic Acid Probes
• Nucleic Acids
• Nucleic Acids, Nucleotides, and Nucleosides
• Nucleotides
• Oligodeoxyribonucleotides, Antisense
• Oligonucleotides
• Oligonucleotides, Antisense
• Polynucleotides
• Potential QTc-Prolonging Agents
• QTc Prolonging Agents
• Transthyretin-directed RNA Interaction

Classification

Not classified

Chemical Identifiers

UNII

0IEO0F56LV

CAS number

1492984-65-2

References

General References

1. 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. [PubMed:29972757]
2. 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. [PubMed:29240946]
3. 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. [PubMed:29185862]
4. FDA Approved Drug Products: Tegsedi (inotersen) for subcutaneous injection [Link]
5. Tegsedi EMA label [File]

External Links

RxNav

2099289

Wikipedia

Inotersen

AHFS Codes

• 28:92.00 — Miscellaneous Central Nervous System Agents

FDA label

Download (1.51 MB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Recruiting	Treatment	Hereditary Transthyretin-Mediated Amyloid Polyneuropathy	1
2	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	Cutaneous	284 MG
Injection, solution	Subcutaneous	284 mg/1.5mL
Solution	Subcutaneous	284 mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
Unlock Additional Data
US7015315	No	2006-03-21	2023-03-21
US7101993	No	2006-09-05	2023-09-05
US9399774	No	2016-07-26	2031-04-29
US9061044	No	2015-06-23	2031-04-29
US8697860	No	2014-04-15	2031-04-29
US8101743	No	2012-01-24	2025-04-01

Additional Data Available

Filed On
Filed On
The date on which a patent was filed with the relevant government.
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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

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Drug created on October 09, 2018 10:02 / Updated on September 26, 2020 20:49