Peringatan Keamanan

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.L49479

No adverse developmental effects were observed when eplontersen or a mouse-specific surrogate was administered to mice prior to mating and continuing throughout organogenesis.L49479

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.L49479

Carcinogenicity studies have not been conducted with eplontersen.L49479

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.L49479

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.L49479

Eplontersen

DB16199

biotech approved investigational

Deskripsi

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.A262975 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.A262985 As eplontersen targets both the WT and mutant TTR, it poses tremendous promises as a treatment.A262990

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.L49525

Struktur Molekul 2D

Struktur tidak tersedia

Peta Jejaring Molekuler
Legenda: ObatTargetGenEnzim(Panah → menunjukkan arah efek / relasi)TransporterCarrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) The terminal elimination half-life is approximately 3 weeks.[L49479]
Volume Distribusi 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.[L49479]
Klirens (Clearance) The clearance was estimated at 22.6 L/h based on the population pharmacokinetic model.[A262970]

Absorpsi

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.L49479 Population estimates (mean ± SD) of steady-state maximum concentrations (Cmax), and area under the curve (AUC?) 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).L49479 Following subcutaneous administration, eplontersen is absorbed with the time to maximum plasma concentrations of approximately 2 hours, based on population estimates.L49479

Metabolisme

Eplontersen is metabolized by endo- and exonucleases to short oligonucleotide fragments of varying sizes within the liver.L49479

Rute Eliminasi

The mean fraction of unchanged antisense oligonucleotide (ASO) eliminated in urine was less than 1% of the administered dose within 24 hours.L49479

Interaksi Makanan

1 Data
  • 1. 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.

Interaksi Obat

0 Data
Tidak ada data.

Target Protein

Transthyretin mRNA

Referensi & Sumber

Artikel (PubMed)
  • PMID: 35869634
    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.
  • PMID: 36525140
    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.
  • PMID: 33283485
    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.
  • PMID: 34850359
    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.

Contoh Produk & Brand

Produk: 2 • International brands: 0
Produk
  • Wainua
    Solution • 45 mg / 0.8 mL • Subcutaneous • Canada • Approved
  • Wainua
    Injection, solution • 45 mg/45mg • Subcutaneous • US • Approved

Sekuens Gen/Protein (FASTA)

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