NAV

Eplontersen

Identification

Summary

Eplontersen is a transthyretin antisense oligonucleotide used to treat polyneuropathy of hereditary transthyretin-mediated amyloidosis.

Brand Names
Wainua
Generic Name
Eplontersen
DrugBank Accession Number
DB16199
Background

Eplontersen is a transthyretin-directed antisense oligonucleotide with 3 covalently linked e N-acetyl galactosamine residues for hepatic delivery. It was previously investigated as a potential treatment for hereditary transthyretin-mediated amyloidosis.2 Hereditary transthyretin-mediated amyloidosis is caused primarily by pathogenic variants of the TTR gene, leading to the formation and thus accumulation of insoluble and misfolded amyloid in multiple organs, although wild-type misfolded TTR has also been observed to contribute to the disease pathophysiology.3 As eplontersen targets both the WT and mutant TTR, it poses tremendous promises as a treatment.4

On December 21, 2023, the FDA approved eplontersen under the brand name WAINUA for the treatment of adult polyneuropathy of hereditary transthyretin-mediated amyloidosis. This approval was based on positive results demonstrated in the 35-week interim analysis from the Phase 3 NEURO-TTRansform study, where a consistent improvement in the Neuropathy Impairment Score +7 (mNIS+7) and the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) Score were observed.6

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Gene Therapies
Antisense oligonucleotides
Synonyms
  • Akcea ttr lrx
  • AKCEA-TTR-LRx
  • Eplontersen
  • Ion-ttr-lrx
  • Ionis-ttr-lrx
External IDs
  • ION-682884 FREE ACID
  • ISIS-682884 FREE ACID
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Pharmacology

Indication

Eplontersen is indicated for the treatment of polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults.5

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofPolyneuropathies caused by hereditary transthyretin-mediated amyloidosis••••••••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

In Study 1, following administration of the recommended eplontersen dosage every 4 weeks to patients with hATTR amyloidosis, a decrease in serum transthyretin (TTR) levels was observed at the first assessment and the (least square) mean serum TTR at Week 35 was reduced by 81% from baseline. Similar TTR reductions were observed across subgroups including Val30Met variant status, body weight, sex, age, or race. Eplontersen also reduced the mean steady-state serum vitamin A by 71% by Week 37.5

At a dose 2.7-times the maximum recommended dose for eplontersen, clinically significant QTc interval prolongation was not observed.5

Mechanism of action

Eplontersen is an antisense oligonucleotide-GalNAc conjugate 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

The pharmacokinetic (PK) properties of WAINUA were evaluated following subcutaneous administration of single and multiple doses (once every 4 weeks) in healthy subjects and multiple doses (once every 4 weeks) in patients with hATTR amyloidosis. Eplontersen Cmax and AUC showed a slightly greater than dose-proportional increase following single subcutaneous doses ranging from 45 to 120 mg (i.e., 1- to 2.7- times the recommended dose) in healthy volunteers.5

Population estimates (mean ± SD) of steady-state maximum concentrations (Cmax), and area under the curve (AUCτ) were 283 ± 152 ng/mL, and 2190 ± 689 ng/mL, respectively, following 45 mg monthly dosing in patients with hATTR amyloidosis. No accumulation of eplontersen Cmax and AUC was observed in repeated dosing (once every 4 weeks).5

Following subcutaneous administration, eplontersen is absorbed with the time to maximum plasma concentrations of approximately 2 hours, based on population estimates.5

Volume of distribution

Eplontersen is expected to distribute primarily to the liver and kidney cortex after subcutaneous dosing. The population estimate for the apparent central volume of distribution is 12 L and the apparent peripheral volume of distribution is 11,100 L.5

Protein binding

Eplontersen is bound to human plasma proteins (>98%) in vitro.5

Metabolism

Eplontersen is metabolized by endo- and exonucleases to short oligonucleotide fragments of varying sizes within the liver.5

Route of elimination

The mean fraction of unchanged antisense oligonucleotide (ASO) eliminated in urine was less than 1% of the administered dose within 24 hours.5

Half-life

The terminal elimination half-life is approximately 3 weeks.5

Clearance

The clearance was estimated at 22.6 L/h based on the population pharmacokinetic model.1

Adverse Effects
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Toxicity

There are no available data on WAINUA use in pregnant women to inform drug-associated risk of adverse developmental outcomes. Eplontersen treatment leads to a decrease in serum vitamin A levels and vitamin A supplementation is advised for patients taking eplontersen. Vitamin A is essential for normal embryofetal development; however, excessive vitamin A levels are associated with adverse developmental effects. The effect of vitamin A supplementation on the fetus in the setting of a reduction in maternal serum TTR caused by eplontersen administration is unknown.5

No adverse developmental effects were observed when eplontersen or a mouse-specific surrogate was administered to mice prior to mating and continuing throughout organogenesis.5

No dose adjustment is required in patients ≥65 years of age. In Study NCT04136184, 44 (31%) patients were 65 to 74 years of age, and 8 (5.6%) patients were ≥75 years of age. No overall differences in safety or effectiveness were observed between these patients and younger adult patients, but a greater sensitivity of some older individuals cannot be ruled out.5

Carcinogenicity studies have not been conducted with eplontersen.5

Eplontersen was negative for genotoxicity in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster lung cells) and in vivo (mouse bone marrow micronucleus) assays.5

Subcutaneous administration of eplontersen (0, 5, 25, or 75 mg/kg) or a mouse-specific surrogate (25 mg/kg) to male and female mice weekly prior to and during mating and continuing in females throughout the period of organogenesis resulted in 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.
Not Available
Food Interactions
  • Administer vitamin supplements. Inform patients that eplontersen treatment leads to a decrease in vitamin A levels, and supplementation of vitamin A at the recommended daily allowance is recommended.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Eplontersen sodiumWSP2DHR2BDNot AvailableNot applicable
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
WainuaInjection, solution45 mg/45mgSubcutaneousAstraZeneca Pharmaceuticals LP2023-12-21Not applicableUS flag

Categories

Drug Categories
Not Available
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
0GRZ0F5XJ6
CAS number
1637600-16-8

References

General References
  1. Diep JK, Yu RZ, Viney NJ, Schneider E, Guo S, Henry S, Monia B, Geary R, Wang Y: Population pharmacokinetic/pharmacodynamic modelling of eplontersen, an antisense oligonucleotide in development for transthyretin amyloidosis. Br J Clin Pharmacol. 2022 Dec;88(12):5389-5398. doi: 10.1111/bcp.15468. Epub 2022 Aug 7. [Article]
  2. Coelho T, Waddington Cruz M, Chao CC, Parman Y, Wixner J, Weiler M, Barroso FA, Dasgupta NR, Jung SW, Schneider E, Viney NJ, Dyck PJB, Ando Y, Gillmore JD, Khella S, Gertz MA, Obici L, Berk JL: Characteristics of Patients with Hereditary Transthyretin Amyloidosis-Polyneuropathy (ATTRv-PN) in NEURO-TTRansform, an Open-label Phase 3 Study of Eplontersen. Neurol Ther. 2023 Feb;12(1):267-287. doi: 10.1007/s40120-022-00414-z. Epub 2022 Dec 16. [Article]
  3. Viney NJ, Guo S, Tai LJ, Baker BF, Aghajan M, Jung SW, Yu RZ, Booten S, Murray H, Machemer T, Burel S, Murray S, Buchele G, Tsimikas S, Schneider E, Geary RS, Benson MD, Monia BP: Ligand conjugated antisense oligonucleotide for the treatment of transthyretin amyloidosis: preclinical and phase 1 data. ESC Heart Fail. 2021 Feb;8(1):652-661. doi: 10.1002/ehf2.13154. Epub 2020 Dec 7. [Article]
  4. Obici L, Mussinelli R: Current and Emerging Therapies for Hereditary Transthyretin Amyloidosis: Strides Towards a Brighter Future. Neurotherapeutics. 2021 Oct;18(4):2286-2302. doi: 10.1007/s13311-021-01154-y. Epub 2021 Nov 30. [Article]
  5. FDA Approved Drug Products: WAINUA™ (eplontersen) injection, for subcutaneous use [Link]
  6. WAINUA™ (eplontersen) granted regulatory approval in the U.S. for the treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis [Link]
RxNav
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Wikipedia
Eplontersen

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentTransthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM)1
3CompletedTreatmentHereditary Transthyretin-Mediated Amyloid Polyneuropathy1
3RecruitingTreatmentHereditary Transthyretin-Mediated Amyloid Polyneuropathy1
3RecruitingTreatmentTransthyretin (TTR) Amyloid Cardiomyopathy1
3RecruitingTreatmentTransthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionSubcutaneous45 mg/45mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8101743No2012-01-242025-04-01US flag
US10683499No2014-08-252034-08-25US flag
US9127276No2014-05-012034-05-01US flag
US9181549No2014-05-012034-05-01US flag

Properties

State
Solid
Experimental Properties
Not Available

Drug created at December 15, 2020 18:15 / Updated at February 15, 2024 07:14