Viltolarsen

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Viltolarsen
Viltolarsen.svg
Clinical data
Trade names Viltepso
Other namesNS-065/NCNP-01
AHFS/Drugs.com Monograph
License data
Routes of
administration
Intravenous
Drug class Antisense oligonucleotide
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C244H381N113O88P20
Molar mass 6924.910 g·mol−1

Viltolarsen, sold under the brand name Viltepso, is a medication used for the treatment of Duchenne muscular dystrophy (DMD). [2] [3] [1] Viltolarsen is a Morpholino antisense oligonucleotide. [2] [1]

Contents

The most common side effects include upper respiratory tract infection, injection site reaction, cough, and pyrexia (fever). [2] [3] [1]

Viltolarsen was approved for medical use in the United States in August 2020. [2] [3] After golodirsen was approved in December 2019, viltolarsen is the second approved targeted treatment for people with this type of mutation in the United States. [2] [4] Approximately 8% of people with DMD have a mutation that is amenable to exon 53 skipping. [2]

Medical uses

Viltolarsen is indicated for the treatment of Duchenne muscular dystrophy (DMD) in people who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping. [2] [1]

DMD is a rare genetic disorder characterized by progressive muscle deterioration and weakness. [2] It is the most common type of muscular dystrophy. [2] DMD is caused by mutations in the DMD gene that results in an absence of dystrophin, a protein that helps keep muscle cells intact. [2] The first symptoms are usually seen between three and five years of age and worsen over time. [2] DMD occurs in approximately one out of every 3,600 male infants worldwide; in rare cases, it can affect females. [2]

Adverse effects

The most common side effects include upper respiratory tract infection, injection site reaction, cough, and pyrexia (fever). [2] [3] [1]

Although kidney toxicity was not observed in the clinical studies, the clinical experience is limited, and kidney toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. [2]

History

Viltolarsen was developed by Nippon Shinyaku and the NCNP based on pre-clinical study conducted by Toshifumi Yokota and colleagues, [5] [6] and evaluated in two clinical studies with a total of 32 participants, all of whom were male and had genetically confirmed DMD. [2] The increase in dystrophin production was established in one of those two studies, a study that included sixteen DMD participants, with eight participants receiving viltolarsen at the recommended dose. [2] In the study, dystrophin levels increased, on average, from 0.6% of normal at baseline to 5.9% of normal at week 25. [2] Trial 1 provided data for evaluation of the benefits of viltolarsen. [3] The combined populations from both trials provided data for evaluation of the side effects of viltolarsen. [3] Trial 1 was conducted at six sites in the United States and Canada and Trial 2 was conducted at five sites in Japan. [3] All participants in both trials were on a stable dose of corticosteroids for at least three months before entering the trials. [3]

The U.S. Food and Drug Administration (FDA) concluded that the applicant's data demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in people with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping. [2] A clinical benefit of the drug has not been established. [2] In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease, and the lack of available therapies. [2]

The application for viltolarsen was granted priority review designation and the FDA granted the approval to NS Pharma, Inc. [2]

Society and culture

Economics

Viltolarsen costs around US$733,000 per year for a person that weighs 30 kilograms (66 lb). [7]

Related Research Articles

<span class="mw-page-title-main">Dystrophin</span> Rod-shaped cytoplasmic protein

Dystrophin is a rod-shaped cytoplasmic protein, and a vital part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane. This complex is variously known as the costamere or the dystrophin-associated protein complex (DAPC). Many muscle proteins, such as α-dystrobrevin, syncoilin, synemin, sarcoglycan, dystroglycan, and sarcospan, colocalize with dystrophin at the costamere. It has a molecular weight of 427 kDa

<span class="mw-page-title-main">Duchenne muscular dystrophy</span> Type of muscular dystrophy

Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy predominantly affecting boys. The onset of muscle weakness typically begins around age four, with rapid progression. Initially, muscle loss occurs in the thighs and pelvis, extending to the arms, which can lead to difficulties in standing up. By the age of 12, most individuals with Duchenne muscular dystrophy are unable to walk. Affected muscles may appear larger due to an increase in fat content, and scoliosis is common. Some individuals may experience intellectual disability, and females carrying a single copy of the mutated gene may show mild symptoms.

<span class="mw-page-title-main">Becker muscular dystrophy</span> Genetic muscle disorder

Becker muscular dystrophy (BMD) is an X-linked recessive inherited disorder characterized by slowly progressing muscle weakness of the legs and pelvis. It is a type of dystrophinopathy. The cause is mutations and deletions in any of the 79 exons encoding the large dystrophin protein, essential for maintaining the muscle fiber's cell membrane integrity. Becker muscular dystrophy is related to Duchenne muscular dystrophy in that both result from a mutation in the dystrophin gene, however the hallmark of Becker is milder in-frame deletions. and hence has a milder course, with patients maintaining ambulation till 50–60 years if detected early.

<span class="mw-page-title-main">Morpholino</span> Chemical compound

A Morpholino, also known as a Morpholino oligomer and as a phosphorodiamidate Morpholino oligomer (PMO), is a type of oligomer molecule used in molecular biology to modify gene expression. Its molecular structure contains DNA bases attached to a backbone of methylenemorpholine rings linked through phosphorodiamidate groups. Morpholinos block access of other molecules to small specific sequences of the base-pairing surfaces of ribonucleic acid (RNA). Morpholinos are used as research tools for reverse genetics by knocking down gene function.

Antisense therapy is a form of treatment that uses antisense oligonucleotides (ASOs) to target messenger RNA (mRNA). ASOs are capable of altering mRNA expression through a variety of mechanisms, including ribonuclease H mediated decay of the pre-mRNA, direct steric blockage, and exon content modulation through splicing site binding on pre-mRNA. Several ASOs have been approved in the United States, the European Union, and elsewhere.

Sarepta Therapeutics, Inc. is a medical research and drug development company with corporate offices and research facilities in Cambridge, Massachusetts, United States. Incorporated in 1980 as AntiVirals, shortly before going public the company changed its name from AntiVirals to AVI BioPharma soon with stock symbol AVII and in July 2012 changed name from AVI BioPharma to Sarepta Therapeutics and SRPT respectively. As of 2023, the company has four approved drugs.

<span class="mw-page-title-main">Ataluren</span> Duchenne muscular dystrophy medication

Ataluren, sold under the brand name Translarna, is a medication for the treatment of Duchenne muscular dystrophy. It was designed by PTC Therapeutics.

In molecular biology, exon skipping is a form of RNA splicing used to cause cells to “skip” over faulty or misaligned sections (exons) of genetic code, leading to a truncated but still functional protein despite the genetic mutation.

Prosensa was a biotechnology company engaged in the discovery, development and commercialization of RNA-modulating therapeutics. The company targets genetic disorders with a large unmet medical need, with a primary focus on neuromuscular and neurodegenerative disorders such as Duchenne muscular dystrophy (DMD), myotonic dystrophy, and Huntington's disease. Prosensa was acquired by BioMarin

Drisapersen is an experimental drug that was under development by BioMarin, after acquisition of Prosensa, for the treatment of Duchenne muscular dystrophy. The drug is a 2'-O-methyl phosphorothioate oligonucleotide that alters the splicing of the dystrophin RNA transcript, eliminating exon 51 from the mature dystrophin mRNA.

<span class="mw-page-title-main">Eteplirsen</span> Medication

Eteplirsen is a medication to treat, but not cure, some types of Duchenne muscular dystrophy (DMD), caused by a specific mutation. Eteplirsen only targets specific mutations and can be used to treat about 14% of DMD cases. Eteplirsen is a form of antisense therapy.

<span class="mw-page-title-main">Ezutromid</span> Chemical compound

Ezutromid is an orally administered small molecule utrophin modulator involved in a Phase 2 clinical trial produced by Summit Therapeutics for the treatment of Duchenne muscular dystrophy (DMD). DMD is a fatal x-linked recessive disease affecting approximately 1 in 5000 males and is a designated orphan disease by the FDA and European Medicines Agency. Approximately 1/3 of the children obtain DMD as a result of spontaneous mutation in the dystrophin gene and have no family history of the disease. Dystrophin is a vital component of mature muscle function, and therefore DMD patients have multifarious forms of defunct or deficient dystrophin proteins that all manifest symptomatically as muscle necrosis and eventually organ failure. Ezutromid is theorized to maintain utrophin, a protein functionally and structurally similar to dystrophin that precedes and is replaced by dystrophin during development. Utrophin and dystrophin are reciprocally expressed, and are found in different locations in a mature muscle cell. However, in dystrophin-deficient patients, utrophin was found to be upregulated and is theorized to replace dystrophin in order to maintain muscle fibers. Ezutromid is projected to have the potential to treat all patients suffering with DMD as it maintains the production of utrophin to counteract the lack of dystrophin to retard muscle degeneration. Both the FDA and European Medicines Agency has given ezutromid an orphan drug designation. The FDA Office of Orphan Products and Development offers an Orphan Drug Designation program (ODD) that allows drugs aimed to treat diseases that affect less than 200,000 people in the U.S. monetary incentives such as a period of market exclusivity, tax incentives, and expedited approval processes.

<span class="mw-page-title-main">Vamorolone</span> Chemical compound

Vamorolone, sold under the brand name Agamree, is a synthetic corticosteroid, which is used for the treatment of Duchenne muscular dystrophy. It is taken by mouth. It is a dual atypical glucocorticoid and antimineralocorticoid.

<span class="mw-page-title-main">Golodirsen</span> Drug of DMD

Golodirsen, sold under the brand name Vyondys 53, is a medication used for the treatment of Duchenne muscular dystrophy (DMD). It is an antisense oligonucleotide drug of phosphorodiamidate morpholino oligomer (PMO) chemistry.

<span class="mw-page-title-main">Cure Rare Disease</span>

Cure Rare Disease is a non-profit biotechnology company based in Boston, Massachusetts that is working to create novel therapeutics using gene therapy, gene editing and antisense oligonucleotides to treat people impacted by rare and ultra-rare genetic neuromuscular conditions.

Toshifumi (Toshi) Yokota is a biomedical scientist and professor of medical genetics at the University of Alberta, also holding the titles of the Friends of Garrett Cumming Research & Muscular Dystrophy Canada Endowed Research Chair and the Henri M. Toupin Chair in Neurological Science. Known for pioneering research in antisense therapy for muscular dystrophy that led to the development of an FDA-approved drug viltolarsen, research interests encompass precision medicine for muscular dystrophy and genetic diseases. Publications exceed 100 refereed papers and patents, with contributions as co-editor to three books in the Methods in Molecular Biology series from Humana Press, Springer-Nature, Roles include fellow of the Canadian Academy of Health Sciences, a member of the editorial boards for numerous journals, a member of the Medical and Scientific Advisory Committee of Muscular Dystrophy Canada, chief scientific officer of OligomicsTx, and a co-founder of the Canadian Neuromuscular Network (CAN-NMD).

<span class="mw-page-title-main">Casimersen</span> Medication

Casimersen, sold under the brand name Amondys 45, is an antisense oligonucleotide medication used for the treatment of Duchenne muscular dystrophy (DMD) in people who have a confirmed mutation of the dystrophin gene that is amenable to exon 45 skipping. It is an antisense oligonucleotide of phosphorodiamidate morpholino oligomer (PMO). Duchenne muscular dystrophy is a rare disease that primarily affects boys. It is caused by low levels of a muscle protein called dystrophin. The lack of dystrophin causes progressive muscle weakness and premature death.

Delandistrogene moxeparvovec, sold under the brand name Elevidys, is a recombinant gene therapy used for the treatment of Duchenne muscular dystrophy. It is designed to deliver into the body a gene that leads to production of Elevidys micro-dystrophin that contains selected domains of the dystrophin protein present in normal muscle cells. It is an adeno-associated virus vector-based gene therapy that is given by injection into a vein.

SGT-003 is an experimental gene therapy being tested for Duchenne's muscular dystrophy. It is hoped to be an improvement on Solid Bioscience's earlier gene therapy SGT-001.

Stephen Donald Wilton, also known as Steve Wilton, is an Australian molecular biologist and academic, serving as the Foundation Professor of Molecular Therapy at Murdoch University and adjunct professor at the University of Western Australia (UWA). He also fulfills dual roles as a Director at the Perron Institute for Neurological and Translational Science and deputy director at Murdoch's Centre for Molecular Medicine and Innovative Therapeutics (CMMIT).

References

  1. 1 2 3 4 5 6 "Viltepso- viltolarsen injection, solution". DailyMed. 12 August 2020. Retrieved 18 August 2020.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 "FDA Approves Targeted Treatment for Rare Duchenne Muscular Dystrophy Mutation". U.S. Food and Drug Administration (FDA) (Press release). 12 August 2020. Retrieved 12 August 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  3. 1 2 3 4 5 6 7 8 "Drug Trials Snapshots: Viltepso". U.S. Food and Drug Administration. 12 August 2020. Retrieved 18 August 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  4. Anwar S, Yokota T (August 2020). "Golodirsen for Duchenne muscular dystrophy". Drugs of Today. 56 (8): 491–504. doi:10.1358/dot.2020.56.8.3159186. PMID   33025945. S2CID   222183389.
  5. Yokota T, Lu QL, Partridge T, Kobayashi M, Nakamura A, Takeda S, et al. (June 2009). "Efficacy of systemic morpholino exon-skipping in Duchenne dystrophy dogs". Annals of Neurology. 65 (6): 667–76. doi:10.1002/ana.21627. PMC   5951302 . PMID   19288467.
  6. "FDA approves new drug to treat common form of muscular dystrophy based on research from University of Alberta". Mirage News. 9 October 2020. Retrieved 19 September 2021.
  7. "FDA gives speedy approval to another Duchenne drug". BioPharma Dive. Retrieved 3 August 2021.

Further reading