Skip to main content
SpringerLink
Log in

Viltolarsen: From Preclinical Studies to FDA Approval

  • Protocol
  • First Online:
Muscular Dystrophy Therapeutics

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2587))

Abstract

Viltolarsen is a phosphorodiamidate morpholino antisense oligonucleotide (PMO) designed to skip exon 53 of the DMD gene for the treatment of Duchenne muscular dystrophy (DMD), one of the most common lethal genetic disorders characterized by progressive degeneration of skeletal muscles and cardiomyopathy. It was developed by Nippon Shinyaku in collaboration with the National Center of Neurology and Psychiatry (NCNP) in Japan based on the preclinical studies conducted in the DMD dog model at the NCNP. After showing hopeful results in pre-clinical trials and several clinical trials across North America and Japan, it received US Food and Drug Administration (FDA) approval for DMD in 2020. Viltolarsen restores the reading frame of the DMD gene by skipping  exon 53 and produces a truncated but functional form of dystrophin. It can treat approximately 8-10% of the DMD patient population. This paper aims to summarize the development of viltolarsen from preclinical trials to clinical trials to, finally, FDA approval, and discusses the challenges that come with fighting DMD using antisense therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 299.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Mendell JR, Shilling C, Leslie ND et al (2012) Evidence-based path to newborn screening for duchenne muscular dystrophy. Ann Neurol 71:304–313. https://doi.org/10.1002/ana.23528

    Article  CAS  PubMed  Google Scholar 

  2. Moser H (1984) Duchenne muscular dystrophy: pathogenetic aspects and genetic prevention. Hum Genet 66:17–40. https://doi.org/10.1007/BF00275183

    Article  CAS  PubMed  Google Scholar 

  3. Mercuri E, Muntoni F (2013) Muscular dystrophies. Lancet 381:845–860. https://doi.org/10.1016/S0140-6736(12)61897-2

    Article  CAS  PubMed  Google Scholar 

  4. Bushby K, Finkel R, Birnkrant DJ et al (2010) Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol 9:77–93. https://doi.org/10.1016/S1474-4422(09)70271-6

    Article  PubMed  Google Scholar 

  5. Manzur AY, Kinali M, Muntoni F (2008) Update on the management of Duchenne muscular dystrophy. Arch Dis Child 93:986–990. https://doi.org/10.1136/adc.2007.118141

    Article  CAS  PubMed  Google Scholar 

  6. Emery AE (2002) The muscular dystrophies. Lancet 359:687–695. https://doi.org/10.1016/S0140-6736(02)07815-7

    Article  CAS  PubMed  Google Scholar 

  7. Muntoni F, Torelli S, Ferlini A (2003) Dystrophin and mutations: one gene, several proteins, multiple phenotypes. Lancet Neurol 2:731–740. https://doi.org/10.1016/S1474-4422(03)00585-4

    Article  CAS  PubMed  Google Scholar 

  8. Koenig M, Hoffman EP, Bertelson CJ et al (1987) Complete cloning of the duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell 50:509–517. https://doi.org/10.1016/0092-8674(87)90504-6

    Article  CAS  PubMed  Google Scholar 

  9. Roberts RG, Coffey AJ, Bobrow M, Bentley DR (1993) Exon structure of the human dystrophin gene. Genomics 16:536–538. https://doi.org/10.1006/geno.1993.1225

    Article  CAS  PubMed  Google Scholar 

  10. Bladen CL, Salgado D, Monges S et al (2015) The TREAT-NMD DMD global database: analysis of more than 7,000 duchenne muscular dystrophy mutations. Hum Mutat 36:395–402. https://doi.org/10.1002/humu.22758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Carter JC, Sheehan DW, Prochoroff A, Birnkrant DJ (2018) Muscular dystrophies. Clin Chest Med 39:377–389. https://doi.org/10.1016/j.ccm.2018.01.004

    Article  PubMed  Google Scholar 

  12. Oudet C, Hanauer A, Clemens P et al (1992) Two hot spots of recombination in the DMD gene correlate with the deletion prone regions. Hum Mol Genet 1:599–603. https://doi.org/10.1093/hmg/1.8.599

    Article  CAS  PubMed  Google Scholar 

  13. Hoffman EP, Brown RH, Kunkel LM (1987) Dystrophin: the protein product of the duchenne muscular dystrophy locus. Cell 51:919–928. https://doi.org/10.1016/0092-8674(87)90579-4

    Article  CAS  PubMed  Google Scholar 

  14. Gao QQ, McNally EM (2015) The dystrophin complex: structure, function, and implications for therapy. Comprehensive Physiology, Wiley, pp 1223–1239

    Google Scholar 

  15. Ervasti JM (2007) Dystrophin, its interactions with other proteins, and implications for muscular dystrophy. Biochim Biophys Acta - Mol Basis Dis 1772:108–117. https://doi.org/10.1016/j.bbadis.2006.05.010

    Article  CAS  Google Scholar 

  16. Nichols B, Takeda S, Yokota T (2015) Nonmechanical roles of dystrophin and associated proteins in exercise, neuromuscular junctions, and brains. Brain Sci 5:275–298. https://doi.org/10.3390/brainsci5030275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ervasti JM, Campbell KP (1991) Membrane organization of the dystrophin-glycoprotein complex. Cell 66:1121–1131. https://doi.org/10.1016/0092-8674(91)90035-W

    Article  CAS  PubMed  Google Scholar 

  18. Yokota T, Lu Q, Partridge T et al (2009) Efficacy of systemic morpholino exon-skipping in duchenne dystrophy dogs. Ann Neurol 65:667–676. https://doi.org/10.1002/ana.21627

    Article  PubMed  PubMed Central  Google Scholar 

  19. Lu QL, Mann CJ, Lou F et al (2003) Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse. Nat Med 9:1009–1014. https://doi.org/10.1038/nm897

    Article  CAS  PubMed  Google Scholar 

  20. Echigoya Y, Lim KRQ, Melo D et al (2019) Exons 45–55 skipping using mutation-tailored cocktails of antisense morpholinos in the DMD gene. Mol Ther 27:2005–2017. https://doi.org/10.1016/j.ymthe.2019.07.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Koenig M, Beggs AH, Moyer M et al (1989) The molecular basis for duchenne versus becker muscular dystrophy: correlation of severity with type of deletion. Am J Hum Genet 45(4):498

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Mendell JR, Rodino-Klapac LR, Sahenk Z et al (2013) Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. https://doi.org/10.1002/ana.23982

  23. O’Keefe L (2020) FDA approves targeted treatment of rare Duchenne muscular dystrophy mutation. FDA news release

    Google Scholar 

  24. Aartsma-Rus A, Corey DR (2020) The 10th oligonucleotide therapy approved: golodirsen for duchenne muscular dystrophy. Nucleic Acid Ther 30:67–70. https://doi.org/10.1089/nat.2020.0845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shirley M (2021) Casimersen: first approval. Drugs. https://doi.org/10.1007/s40265-021-01512-2

  26. Bylo M, Farewell R, Coppenrath VA et al (2020) A review of deflazacort for patients with duchenne muscular dystrophy. Ann Pharmacother 54(8):788–794. https://doi.org/10.1177/1060028019900500

  27. Moxley RT, Ashwal S, Pandya S et al (2005) Practice parameter: corticosteroid treatment of duchenne dystrophy: report of the quality standards subcommittee of the American academy of neurology and the practice committee of the child neurology society. Neurology 64(1):13–20. https://doi.org/10.1212/01.WNL.0000148485.00049.B7

  28. Moxley RT, Pandya S, Ciafaloni E et al (2010) Change in natural history of duchenne muscular dystrophy with longterm corticosteroid treatment: implications for management. J Child Neurol 25(9):1116–1129. https://doi.org/10.1177/0883073810371004

  29. Roshmi RR, Yokota T (2019) Viltolarsen for the treatment of Duchenne muscular dystrophy. Drugs Today 55:627. https://doi.org/10.1358/dot.2019.55.10.3045038

    Article  CAS  Google Scholar 

  30. Dhillon S (2020) Viltolarsen: First Approval. Drugs 80:1027–1031. https://doi.org/10.1007/s40265-020-01339-3

    Article  CAS  PubMed  Google Scholar 

  31. Watanabe N, Nagata T, Satou Y et al (2018) NS-065/NCNP-01: an antisense oligonucleotide for potential treatment of exon 53 skipping in duchenne muscular dystrophy. Mol Ther Nucleic Acids 13:442–449. https://doi.org/10.1016/j.omtn.2018.09.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Echevarría L, Aupy P, Goyenvalle A (2018) Exon-skipping advances for Duchenne muscular dystrophy. Hum Mol Genet 27:R163–R172. https://doi.org/10.1093/hmg/ddy171

    Article  CAS  PubMed  Google Scholar 

  33. Komaki H, Nagata T, Saito T et al (2018) Systemic administration of the antisense oligonucleotide NS-065/NCNP-01 for skipping of exon 53 in patients with Duchenne muscular dystrophy. Sci Transl Med 10:eaan0713. https://doi.org/10.1126/scitranslmed.aan0713

    Article  CAS  PubMed  Google Scholar 

  34. Yokota T, Lu Q, Partridge T et al (2009) Efficacy of systemic morpholino exon-skipping in duchenne dystrophy dogs. Ann Neurol 65(6):667–676. https://doi.org/10.1002/ana.21627

  35. Inxight: drugs. In: U.S. Department of Health and Human Services. https://drugs.ncats.io/drug/SXA7YP6EKX

  36. Dhillon S (2020) Viltolarsen: first approval. Drugs 80(10):1027–1031. https://doi.org/10.1007/s40265-01339-3

  37. Pharma NS, Fda N, Dystrophy DM, et al (2020) NEWS RELEASE NS Pharma’s VILTEPSOTM (viltolarsen) injection Now FDA-approved in the U.S. for the treatment of duchenne muscular dystrophy in patients amenable to exon 53 skipping therapy. 1–4

    Google Scholar 

  38. Clemens PR, Rao VK, Connolly AM et al (2020) Safety, tolerability, and efficacy of viltolarsen in boys with duchenne muscular dystrophy amenable to exon 53 skipping. JAMA Neurol 77:982. https://doi.org/10.1001/jamaneurol.2020.1264

    Article  PubMed  Google Scholar 

  39. Komaki H, Takeshima Y, Matsumura T et al (2018) DMD CLINICAL THERAPIES II. Neuromuscul Disord 28:S68. https://doi.org/10.1016/j.nmd.2018.06.157

    Article  Google Scholar 

  40. Komaki H, Takeshima Y, Matsumura T et al (2020) Viltolarsen in Japanese Duchenne muscular dystrophy patients: a phase 1/2 study. Ann Clin Transl Neurol 7:2393–2408. https://doi.org/10.1002/acn3.51235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Study to Assess the Efficacy and Safety of Viltolarsen in Ambulant Boys With DMD (RACER53), clinicaltrials.gov, ClinicalTrials.gov Identifier: NCT04060199 (2019)

    Google Scholar 

  42. (2020) Nippon Shinyaku Co. Ltd. Viltepso injection 250 mg: Japanese prescribing information. https://www.pmda.go.jp/

  43. Clemens PR, Rao VK, Connolly AM (2018) A phase II, dose-finding study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of NS-065/NCNP-01 in boys with Duchenne muscular dystrophy (DMD). 13th New Directions Biol Dis Skelet Muscle

    Google Scholar 

  44. Extension Study of NS-065/NCNP-01 in Boys With Duchenne Muscular Dystrophy (DMD). In: ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/record/NCT03167255

  45. Rodrigues M, Yokota T (2018) An overview of recent advances and clinical applications of exon skipping and splice modulation for muscular dystrophy and various genetic diseases. pp 31–55

    Google Scholar 

  46. Himič V, Davies KE (2021) Evaluating the potential of novel genetic approaches for the treatment of Duchenne muscular dystrophy. Eur J Hum Genet. https://doi.org/10.1038/s41431-021-00811-2

  47. Nakamura H, Kimura E, Mori-Yoshimura M et al (2013) Characteristics of Japanese Duchenne and Becker muscular dystrophy patients in a novel Japanese national registry of muscular dystrophy (Remudy). Orphanet J Rare Dis 8(1):60. https://doi.org/10.1186/1750-1172-8-60

  48. Echigoya Y, Lim KRQ, Melo D et al (2019) Exons 45–55 skipping using mutation-tailored cocktails of antisense morpholinos in the DMD gene. Mol Ther 27(11):2005–2017. S1525001619303259. https://doi.org/10.1016/j.ymthe.2019.07.012

  49. Lim KRQ, Woo S, Melo D et al (2022) Development of DG9 peptide-conjugated single- and multi-exon skipping therapies for the treatment of Duchenne muscular dystrophy. Proc Natl Acad Sci 119(9):e2112546119. https://doi.org/10.1073/pnas.2112546119

  50. Meyers TA, Townsend D (2019) Cardiac pathophysiology and the future of cardiac therapies in duchenne muscular dystrophy. Int J Mol Sci 20(17):4098. https://doi.org/10.3390/ijms20174098

  51. Echigoya Y, Nakamura A, Nagata T et al (2017) Effects of systemic multiexon skipping with peptide-conjugated morpholinos in the heart of a dog model of Duchenne muscular dystrophy. Proc Natl Acad Sci 114(16):4213–4218. https://doi.org/10.1073/pnas.1613203114

  52. Jearawiriyapaisarn N, Moulton HM, Buckley B et al (2008) Sustained dystrophin expression induced by peptide-conjugated morpholino oligomers in the muscles of mdx mice. Mol Ther 16(9):1624–1629. S1525001616320615. https://doi.org/10.1038/mt.2008.120

  53. Sheikh O, Yokota T (2022) Pharmacology and toxicology of eteplirsen and SRP-5051 for DMD exon 51 skipping: an update. Arch Toxicol 96(1):1–9. https://doi.org/10.1007/s00204-021-03184-z

  54. Tyler KL (2003) Origins and early descriptions of ?Duchenne muscular dystrophy? Muscle Nerve 28:402–422. https://doi.org/10.1002/mus.10435

    Article  PubMed  Google Scholar 

  55. Lim KRQ, Echigoya Y, Nagata T et al (2019) Efficacy of multi-exon skipping treatment in duchenne muscular dystrophy dog model neonates. Mol Ther 27:76–86. https://doi.org/10.1016/j.ymthe.2018.10.011

    Article  CAS  PubMed  Google Scholar 

  56. Yin H, Moulton HM, Seow Y et al (2008) Cell-penetrating peptide-conjugated antisense oligonucleotides restore systemic muscle and cardiac dystrophin expression and function. Hum Mol Genet 17:3909–3918. https://doi.org/10.1093/hmg/ddn293

    Article  CAS  PubMed  Google Scholar 

  57. Yokota T, Nakamura A, Nagata T et al (2012) Extensive and prolonged restoration of dystrophin expression with vivo-morpholino-mediated multiple exon skipping in dystrophic dogs. Nucleic Acid Ther 22:306–315. https://doi.org/10.1089/nat.2012.0368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Min Y-L, Bassel-Duby R, Olson EN (2019) CRISPR correction of Duchenne muscular dystrophy. Annu Rev Med 70:239–255. https://doi.org/10.1146/annurev-med-081117-010451

    Article  CAS  PubMed  Google Scholar 

  59. Hakim CH, Wasala NB, Pan X et al (2017) A five-repeat micro-dystrophin gene ameliorated dystrophic phenotype in the severe DBA/2J-mdx model of Duchenne muscular dystrophy. Mol Ther Methods Clin Dev 6:216–230. https://doi.org/10.1016/j.omtm.2017.06.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada

    Rohini Roy Roshmi & Toshifumi Yokota

  2. The Friends of Garrett Cumming Research & Muscular Dystrophy Canada, HM Toupin Neurological Science Research Chair, Edmonton, Canada

    Toshifumi Yokota

Authors
  1. Rohini Roy Roshmi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toshifumi Yokota
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toshifumi Yokota .

Editor information

Editors and Affiliations

  1. Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada

    Rika Maruyama

  2. Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada

    Toshifumi Yokota

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Roshmi, R.R., Yokota, T. (2023). Viltolarsen: From Preclinical Studies to FDA Approval. In: Maruyama, R., Yokota, T. (eds) Muscular Dystrophy Therapeutics. Methods in Molecular Biology, vol 2587. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-2772-3_2

Download citation

  • DOI: https://doi.org/10.1007/978-1-0716-2772-3_2

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-2771-6

  • Online ISBN: 978-1-0716-2772-3

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation