Peringatan Keamanan

Viltolarsen administered by subcutaneous injection in juvenile male mice resulted in deaths due to renal toxicity at high doses; in animals administered either 240 or 1200 mg/kg viltolarsen, dose-dependent increases in the incidence and severity of renal tubular effects were observed. Although renal toxicity in humans has not been observed, it is recommended to measure urine dipstick every month and serum cystatin C and urine protein-to-creatinine ratio every three months to detect renal toxicity.L15526

Viltolarsen

DB15005

biotech approved investigational

Deskripsi

Duchenne muscular dystrophy (DMD) is an X-linked recessive allelic disorder characterized by a lack of functional dystrophin protein, which leads to progressive ambulatory, pulmonary, and cardiac function and is invariably fatal. A related, albeit a less severe, form of muscular dystrophy known as Becker muscular dystrophy (BMD) is characterized by the production of shortened and partially functional dystrophin protein. Although corticosteroids are effective in slowing disease progression in both DMD and BMD patients, they do not address the underlying molecular pathogenesis.A218171, A218176, A218191

The application of antisense oligonucleotides in DMD patients with specific mutations allows for exon skipping, which retains a productive reading frame and results in the production of truncated BMD-like dystrophin proteins.A218161, A218166, A218171, A218176, A218181, A218191, L15526 These shortened forms of dystrophin can restore partial muscle function and slow the progression of DMD. Viltolarsen is a phosphorodiamidate morpholino oligonucleotide (PMO); PMOs are oligonucleotides in which the five-membered ribofuranosyl ring is replaced with a six-membered morpholino ring, and the phosphodiester links between nucleotides are replaced with a phosphorodiamidate linkage.A218186, L15526 In this manner, PMOs are much less susceptible to endo- and exonucleases and exhibit drastically reduced metabolic degradation compared to traditional synthetic oligonucleotides.A218186 Hence, viltolarsen is similar to another PMO, eteplirsen, which gained FDA approval on September 19, 2016; however, eteplirsen is specific for exon 51 skipping while viltolarsen is specific for exon 53 skipping.A218176

Viltolarsen was granted accelerated FDA approval on August 12, 2020, based on data showing an increase in dystrophin levels in skeletal muscle of patients treated with viltolarsen; this approval is contingent on further verification in confirmatory trials. Viltolarsen was developed by Nippon Shinyaku Co LTD and is being marketed under the name VILTEPSO™.L15526

Struktur Molekul 2D

Struktur tidak tersedia

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) Viltolarsen has a reported elimination half-life of 2.5 hours (8% CV).[L15526] When administered at either 40 or 80 mg/kg for 24 weeks, viltolarsen elimination half-life was 2.38 and 2.82 hours, respectively.[A218191]
Volume Distribusi Viltolarsen has a steady-state volume of distribution of 300 mL/kg (14% CV) when given at 80 mg/kg.[L15526] In patients given either 1.25, 5, or 20 mg/kg viltolarsen weekly for 12 weeks the volume of distribution was between 183 ± 14 and 264 ± 68 mL/kg.[A218166]
Klirens (Clearance) Viltolarsen has a reported plasma clearance of 217 mL/hr/kg (22% CV).[L15526] Patients taking 1.25, 5, or 20 mg/kg viltolarsen weekly for 12 weeks had a total clearance of between 149 ± 21 and 239 ± 97 ml/hr/kg.[A218166]

Absorpsi

Viltolarsen is administered by intravenous infusion and is assumed to have a bioavailability of 100%.L15526 In a phase 1 dose-escalation trial of 10 patients given either 1.25, 5, or 20 mg/kg weekly for 12 weeks, the mean Cmax was 6040 ± 300 ng/mL in the low dose group and 70,200 ± 44,900 ng/mL in the high dose group on initial dose, with the corresponding final dose values of 5640 ± 2440 and 72,800 ± 26,400 ng/mL, respectively. Similarly, the AUC0-t for the initial/final dose was 8410 ± 1310/8410 ± 3520 ng\*hr/mL for the low dose and 98,900 ± 54,100/115,000 ± 56,000 ng\*hr/mL for the high dose.A218166 The Tmax varied between 0.667 ± 0.289 and 1.00 ± 0.00 hours,A218166 and viltolarsen has a documented median Tmax of approximately one hour.L15526

Metabolisme

Viltolarsen metabolism was not detected in serum or liver-derived microsomes, and it appears not to be metabolized by either DNase I or phosphodiesterase type 1 in vitro.A218191 This lack of metabolism is consistent with what is known regarding the stability of phosphorodiamidate morpholino oligonucleotides to enzymatic cleavage.A218186

Rute Eliminasi

Viltolarsen is mainly excreted in the urine unchanged;L15526 in a phase 1/2 study of 16 Japanese DMD patients, 92.0-93.1% of a single 80 mg/kg dose of viltolarsen was recovered unchanged in the patient urine within 24 hours of administration.A218191

Interaksi Obat

0 Data
Tidak ada data.

Target Protein

DMD gene (exon 53 viltolarsen target site)

Referensi & Sumber

Synthesis reference: Watanabe N, Nagata T, Satou Y, Masuda S, Saito T, Kitagawa H, Komaki H, Takagaki K, Takeda S: NS-065/NCNP-01: An Antisense Oligonucleotide for Potential Treatment of Exon 53 Skipping in Duchenne Muscular Dystrophy. Mol Ther Nucleic Acids. 2018 Dec 7;13:442-449. doi: 10.1016/j.omtn.2018.09.017.
Artikel (PubMed)
  • PMID: 30388618
    Watanabe N, Nagata T, Satou Y, Masuda S, Saito T, Kitagawa H, Komaki H, Takagaki K, Takeda S: NS-065/NCNP-01: An Antisense Oligonucleotide for Potential Treatment of Exon 53 Skipping in Duchenne Muscular Dystrophy. Mol Ther Nucleic Acids. 2018 Dec 7;13:442-449. doi: 10.1016/j.omtn.2018.09.017. Epub 2018 Sep 27.
  • PMID: 29669851
    Komaki H, Nagata T, Saito T, Masuda S, Takeshita E, Sasaki M, Tachimori H, Nakamura H, Aoki Y, Takeda S: Systemic administration of the antisense oligonucleotide NS-065/NCNP-01 for skipping of exon 53 in patients with Duchenne muscular dystrophy. Sci Transl Med. 2018 Apr 18;10(437). pii: 10/437/eaan0713. doi: 10.1126/scitranslmed.aan0713.
  • PMID: 26022172
    Wein N, Alfano L, Flanigan KM: Genetics and emerging treatments for Duchenne and Becker muscular dystrophy. Pediatr Clin North Am. 2015 Jun;62(3):723-42. doi: 10.1016/j.pcl.2015.03.008. Epub 2015 Apr 20.
  • PMID: 31147635
    Verhaart IEC, Aartsma-Rus A: Therapeutic developments for Duchenne muscular dystrophy. Nat Rev Neurol. 2019 Jul;15(7):373-386. doi: 10.1038/s41582-019-0203-3.
  • PMID: 32453377
    Clemens PR, Rao VK, Connolly AM, Harper AD, Mah JK, Smith EC, McDonald CM, Zaidman CM, Morgenroth LP, Osaki H, Satou Y, Yamashita T, Hoffman EP: Safety, Tolerability, and Efficacy of Viltolarsen in Boys With Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A Phase 2 Randomized Clinical Trial. JAMA Neurol. 2020 May 26. pii: 2766519. doi: 10.1001/jamaneurol.2020.1264.
  • PMID: 30285540
    Smith CIE, Zain R: Therapeutic Oligonucleotides: State of the Art. Annu Rev Pharmacol Toxicol. 2019 Jan 6;59:605-630. doi: 10.1146/annurev-pharmtox-010818-021050. Epub 2018 Oct 9.
  • PMID: 32519222
    Dhillon S: Viltolarsen: First Approval. Drugs. 2020 Jul;80(10):1027-1031. doi: 10.1007/s40265-020-01339-3.

Contoh Produk & Brand

Produk: 1 • International brands: 1
Produk
  • Viltepso
    Injection, solution • 250 mg/1 • Intravenous • US • Approved
International Brands
  • Viltepso — NS Pharma, Inc.

Sekuens Gen/Protein (FASTA)

Sekuens dimuat saat dibutuhkan agar halaman tetap ringan.
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