Inotersen

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
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

TargetActionsOrganism
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 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

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.
DrugInteraction
AbacavirInotersen may decrease the excretion rate of Abacavir which could result in a higher serum level.
AcarboseInotersen may decrease the excretion rate of Acarbose which could result in a higher serum level.
AcebutololThe risk or severity of QTc prolongation can be increased when Inotersen is combined with Acebutolol.
AceclofenacInotersen may decrease the excretion rate of Aceclofenac which could result in a higher serum level.
AcemetacinThe risk or severity of nephrotoxicity can be increased when Acemetacin is combined with Inotersen.
AcetaminophenInotersen may decrease the excretion rate of Acetaminophen which could result in a higher serum level.
Acetylsalicylic acidThe risk or severity of nephrotoxicity can be increased when Acetylsalicylic acid is combined with Inotersen.
AclidiniumInotersen may decrease the excretion rate of Aclidinium which could result in a higher serum level.
AcrivastineInotersen may decrease the excretion rate of Acrivastine which could result in a higher serum level.
AcyclovirInotersen 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
IngredientUNIICASInChI Key
Inotersen sodium950736UC771432726-13-0Not applicable
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TegsediInjection, solution284 mg/1.5mLSubcutaneousAkcea Therapeutics, Inc.2018-10-05Not applicableUS flag
TegsediSolution284 mgSubcutaneousAkcea Therapeutics Inc2019-01-07Not applicableCanada flag
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
Drug Categories
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]
RxNav
2099289
Wikipedia
Inotersen
AHFS Codes
  • 28:92.00 — Miscellaneous Central Nervous System Agents
FDA label
Download (1.51 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3RecruitingTreatmentHereditary Transthyretin-Mediated Amyloid Polyneuropathy1
2RecruitingTreatmentAmyloidosis1
2WithdrawnTreatmentAmyloidosis1
2, 3CompletedTreatmentAmyloidosis / Familial Amyloid Polyneuropathy (FAP) / FAP / Transthyretin / TTR1
Not AvailableApproved for MarketingNot AvailableAmyloidosis, Hereditary1
Not AvailableRecruitingNot AvailableHereditary Transthyretin-mediated Amyloidosis With Polyneropathy / Pregnancy1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionCutaneous284 MG
Injection, solutionSubcutaneous284 mg/1.5mL
SolutionSubcutaneous284 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7015315No2006-03-212023-03-21US flag
US7101993No2006-09-052023-09-05US flag
US9399774No2016-07-262031-04-29US flag
US9061044No2015-06-232031-04-29US flag
US8697860No2014-04-152031-04-29US flag
US8101743No2012-01-242025-04-01US flag
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
PropertyValueSource
water solubilitysoluble https://www.ema.europa.eu/documents/product-information/tegsedi-epar-product-information_en.pdf

Targets

Kind
Nucleotide
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
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. Tegsedi EMA label [File]

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

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