Inotersen

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

Reduce drug development failure rates
Build, train, & validate machine-learning models
with evidence-based and structured datasets.
See how
Build, train, & validate predictive machine-learning models with structured datasets.
See how
Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofHereditary transthyretin amyloidosis•••••••••••••••••••••
Treatment ofPolyneuropathies caused by hereditary transthyretin-mediated amyloidosis••••••••••••••••••••••••••
Contraindications & Blackbox Warnings
Prevent Adverse Drug Events Today
Tap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.
Learn more
Avoid life-threatening adverse drug events with our Clinical API
Learn more
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

TargetActionsOrganism
ATransthyretin mRNA
antisense oligonucleotide
Humans
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
Improve decision support & research outcomes
With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!
See the data
Improve decision support & research outcomes with our structured adverse effects data.
See a data sample
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.
DrugInteraction
AbacavirInotersen may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbciximabThe risk or severity of thrombocytopenia can be increased when Inotersen is combined with Abciximab.
AceclofenacThe risk or severity of nephrotoxicity can be increased when Inotersen is combined with Aceclofenac.
AcemetacinThe risk or severity of nephrotoxicity can be increased when Inotersen is combined with Acemetacin.
AcenocoumarolThe 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 regions
Our datasets provide approved product information including:
dosage, form, labeller, route of administration, and marketing period.
Access now
Access drug product information from over 10 global regions.
Access now
Product Ingredients
IngredientUNIICASInChI Key
Inotersen sodium950736UC771432726-13-0Not applicable
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TegsediSolution284 mg / 1.5 mLSubcutaneousAkcea Therapeutics, Inc.2019-01-07Not applicableCanada flag
TegsediInjection, solution284 mgSubcutaneousAkcea Therapeutics Ireland Ltd2020-12-16Not applicableEU flag
TegsediInjection, solution284 mg/1.5mLSubcutaneousAkcea Therapeutics, Inc.2018-10-05Not applicableUS flag
TegsediInjection, solution284 mgSubcutaneousAkcea Therapeutics Ireland Ltd2020-12-16Not applicableEU flag

Categories

ATC Codes
N07XX15 — Inotersen
Drug Categories
Classification
Not classified
Affected organisms
  • Humans

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. [Article]
  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. [Article]
  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. [Article]
  4. FDA Approved Drug Products: TEGSEDI (inotersen) injection [Link]
  5. FDA Approved Drug Products: TEGSEDI (inotersen) injection, for subcutaneous use (Jan 2024) [Link]
  6. Tegsedi EMA label [File]
RxNav
2099289
Wikipedia
Inotersen
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
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
3CompletedTreatmentAmyloidosis / Familial Amyloid Polyneuropathy (FAP) / FAP / Transthyretin / TTR1somestatusstop reasonjust information to hide
3CompletedTreatmentHereditary Transthyretin-Mediated Amyloid Polyneuropathy1somestatusstop reasonjust information to hide
2Unknown StatusTreatmentAmyloidosis1somestatusstop reasonjust information to hide
2WithdrawnTreatmentAmyloidosis1somestatusstop reasonjust information to hide
2, 3CompletedTreatmentAmyloidosis / Familial Amyloid Polyneuropathy (FAP) / FAP / Transthyretin / TTR1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionParenteral; Subcutaneous284 MG
Injection, solutionSubcutaneous284 mg/1.5mL
Injection, solutionSubcutaneous284 mg
SolutionSubcutaneous284 mg / 1.5 mL
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

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilitysoluble https://www.ema.europa.eu/documents/product-information/tegsedi-epar-product-information_en.pdf

Targets

Build, predict & validate machine-learning models
Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
Learn more
Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.
Learn more
Kind
Nucleotide
Organism
Humans
Pharmacological action
Yes
Actions
Antisense oligonucleotide
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. [Article]
  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. [Article]
  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. [Article]
  4. FDA Approved Drug Products: TEGSEDI (inotersen) injection, for subcutaneous use (Jan 2024) [Link]
  5. Tegsedi EMA label [File]

Drug created at October 09, 2018 16:02 / Updated at April 23, 2024 11:38