Golodirsen

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Golodirsen
Clinical data
Trade names Vyondys 53
Other namesSRP-4053
AHFS/Drugs.com Monograph
License data
Routes of
administration 		Intravenous
Drug class Antisense oligonucleotide
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
UNII
KEGG
Chemical and physical data
Formula C305H481N138O112P25
Molar mass 8647.401 g·mol−1

Golodirsen, sold under the brand name Vyondys 53, is a medication used for the treatment of Duchenne muscular dystrophy (DMD). [2] It is an antisense oligonucleotide drug of phosphorodiamidate morpholino oligomer (PMO) chemistry. [1] [3]

Contents

The most common side effects include headache, fever, fall, cough, vomiting, abdominal pain, cold symptoms (nasopharyngitis) and nausea. [2] [1]

Medical uses

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

Mechanism of action

Golodirsen has been provisionally approved for approximately 8% of all DMD patients amenable to exon 53 skipping. [3] It works by inducing exon skipping in the dystrophin gene and thereby increasing the amount of dystrophin protein available to muscle fibers. [3]

Adverse effects

The most common side effects include headache, fever, fall, cough, vomiting, abdominal pain, cold symptoms (nasopharyngitis) and nausea. [2] [1] In animal studies, no significant changes were seen in the male reproductive system of monkeys and mice following weekly subcutaneous administration. [3] According to the reports obtained from the clinical trials, pain at the site of intravenous administration, back pain, oropharyngeal pain, sprain in ligaments, diarrhea, dizziness, contusion, flu, ear infection, rhinitis, skin abrasion, tachycardia, and constipation occurred at an elevated frequency in the treatment group, as compared to their placebo counterparts. [3] Hypersensitivity reactions, including rash, fever, itching, hives, skin irritation (dermatitis) and skin peeling (exfoliation), have occurred in people who were treated with golodirsen. [2]

Renal toxicity was observed in animals who received golodirsen. [2] [4] Although renal toxicity was not observed in the clinical studies with golodirsen, potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. [2] Renal function should be monitored in those taking golodirsen. [2] [5] [6]

Pharmacology

Pharmacokinetics

Following single or multiple intravenous infusions, the majority of drug elimination occurs within 24 hours of intravenous administration. The elimination half-life of golodirsen, in parity with eteplirsen was 3 to 6 hours. [3]

Clinical benefits

As a first-generation drug, golodirsen is far away from being curative; clinical trial outcomes have demonstrated the drug to have a marginal effect on ameliorating DMD pathology. [3] As of December 2019, golodirsen is approved for therapeutic use in the United States, as well as in the countries that automatically recognize the decisions of the US Food and Drug Administration, under the condition that its benefit will be demonstrated in a confirmatory clinical trial.

Society and culture

Golodirsen is one of the very few FDA-approved exon-skipping therapy for Duchenne muscular dystrophy (DMD), although the clinical benefits of the drug are yet to established. [1] [3] While the development of golodirsen needed huge financing, it is only applicable to a small subset of DMD patients. Sarepta Therapeutics has announced that golodirsen will cost in parity with eteplirsen, another drug of a similar kind, which may be as high as US$300,000 a year. Whether the patients should spend so much on a drug with questioned efficacy raises concerns. Also, the accelerated approval of golodirsen has paved the way for the patients to have early access to the drug, at the same time, it shrouded with controversy over a number of issues. [3] A double-blind placebo-controlled confirmatory trial (NCT02500381) is ongoing to resolve the issues.

History

Golodirsen was developed by collaborative research led by Prof. Steve Wilton and Prof. Sue Fletcher in the Perron Institute and licensed to Sarepta Therapeutics by the University of Western Australia. [3]

In the pivotal clinical trial of golodirsen, dystrophin levels increased, on average, from 0.10% of normal at baseline to 1.02% of normal after 48 weeks of treatment with the drug or longer. [2] The change was a surrogate endpoint and the trial did not establish clinical benefit of the drug, including changes to the subject's motor function. [2]

The pharmacological assessment of golodirsen did not include special population groups, e.g., pregnant and lactating women, the elderly, and patients with concurrent disease states. As DMD predominantly affects male children and young adults, and golodirsen is indicated for the treatment of pediatric patients, but primarily not for adult women, the elderly, and patients with comorbidity, it was not evaluated on them. [3]

The US Food and Drug Administration (FDA) approved golodirsen in December 2019, [2] [7] [8] under the accelerated approval pathway. [2] The application for golodirsen was granted fast track designation, priority review designation, orphan drug designation, and a rare pediatric disease priority review voucher. [2]

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 that primarily affects boys. Muscle weakness usually begins around the age of four, and worsens quickly. Muscle loss typically occurs first in the thighs and pelvis followed by the arms. This can result in trouble standing up. Most are unable to walk by the age of 12. Affected muscles may look larger due to increased fat content. Scoliosis is also common. Some may have intellectual disability. Females with a single copy of the defective gene may show mild symptoms.

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

Becker muscular dystrophy is an X-linked recessive inherited disorder characterized by slowly progressing muscle weakness of the legs and pelvis. It is a type of dystrophinopathy. This is caused by mutations in the dystrophin gene, which encodes the protein dystrophin. Becker muscular dystrophy is related to Duchenne muscular dystrophy in that both result from a mutation in the dystrophin gene, but has a milder course.

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.

The dystrophin-associated protein complex, also known as the dystrophin-associated glycoprotein complex is a multiprotein complex that includes dystrophin and the dystrophin-associated proteins. It is one of the two protein complexes that make up the costamere in striated muscle cells. The other complex is the integrin-vinculin-talin complex.

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

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">Marathon Pharmaceuticals</span> Former U.S. rare disease drug company

Marathon Pharmaceuticals LLC was a privately held biopharmaceuticals company focused on drugs for people with rare diseases. The Illinois-based company developed and manufactured therapeutics and brought them to market. It employed 100 people in four global locations. In 2017, PTC Therapeutics acquired rights to Marathon Pharmaceuticals' drug Emflaza (deflazacort) for $140 million after criticism about their plan to sell the drug at a list price of $89,000 per year to sufferers despite the fact that the same drug was available in Canada and the UK for around $1,000 per year.

<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.

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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.

References

  1. 1 2 3 4 5 6 "Vyondys 53- golodirsen injection". DailyMed. 31 March 2020. Retrieved 6 August 2020.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 "FDA grants accelerated approval to first targeted treatment for rare Duchenne muscular dystrophy mutation". U.S. Food and Drug Administration (FDA) (Press release). 12 December 2019. Archived from the original on 13 December 2019. Retrieved 12 December 2019.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 9 10 11 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.
  4. ↑ "Safety risks highlighted in FDA letter on Sarepta's Vyondys". BioPharma Dive. 22 January 2020. Retrieved 22 January 2020.
  5. ↑ Terry M (22 January 2020). "FDA Publishes Initial Rejection Letter of Sarepta's Vyondys 53 for DMD". BioSpace. Retrieved 22 January 2020.
  6. ↑ Unger EF (19 August 2019). "NDA 211970 Other action letter" (PDF). U.S. Food and Drug Administration (FDA). Retrieved 22 January 2020.
  7. ↑ "Drug Approval Package: Vyondys 53 (golodirsen)". U.S. Food and Drug Administration (FDA). 21 January 2020. Retrieved 22 January 2020.
  8. ↑ "Drug Trials Snapshots: Vyondys 53". U.S. Food and Drug Administration (FDA). 12 December 2019. Retrieved 24 January 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
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