Golodirsen
Identification
- Summary
Golodirsen is a drug used to treat certain mutations that cause Duchenne muscular dystrophy (DMD).
- Brand Names
- Vyondys 53
- Generic Name
- Golodirsen
- DrugBank Accession Number
- DB15593
- Background
Golodirsen is a morpholino antisense oligomer designed to treat about 8% of patients with Duchenne Muscular Dystrophy (DMD). This is an X-linked condition leading to progressive muscle degeneration that begins in early childhood, rendering many patients wheelchair-bound by age 12. Often, patients succumb to this condition by age 30 or younger due to cardiac and respiratory complications.3,12 A similar drug used in the treatment of other types of DMD is eteplirsen, which targets a different genetic mutation.17
Golodirsen was developed by Sarepta Therapeutics and granted accelerated FDA approval on December 12, 2019 due to the urgent need for this drug in patients suffering from a certain form of DMD. Continued approval of this drug will depend on the results of clinical trials that confirm its clinical benefit.13,14 Golodirsen was initially rejected for FDA approval over concerns about its potential renal toxicity, however, clinical trials did not show significant toxicity.13
- Type
- Biotech
- Groups
- Approved
- Biologic Classification
- Gene Therapies
Antisense oligonucleotides - Synonyms
- Golodirsen
- External IDs
- NG-12-0163
- SRP-4053
- WHO 10355
Pharmacology
- Indication
Golodirsen is indicated to treat Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation of the DMD gene that would benefit from exon 53 skipping. Continued FDA approval of this drug is contingent upon the results of clinical trials to confirm its benefit.13,14
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Duchenne's muscular dystrophy (dmd) •••••••••••• ••••••••• - Contraindications & Blackbox Warnings
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- Pharmacodynamics
Golodirsen masks genetic mutations that result in a cascade of events which treat Duchenne Muscular Dystrophy in about 8% of patients. Golodirsen indirectly induces the production of dystrophin, an important protein for muscle function.2,13,15 It is not yet confirmed whether motor function is improved by golodirsen, however, clinical trials are underway to examine its clinical benefits.13
A note on nephrotoxicity
Though clinical trials have not yet confirmed that golodirsen is nephrotoxic, other morpholino antisense oligonucleotides have been known to cause nephrotoxicity. Ensure to monitor renal function during golodirsen therapy.13
- Mechanism of action
The hallmark of Duchenne Muscular Dystrophy is the absence of the important muscle stabilizing protein, dystrophin, that is caused by a deletion mutation on the DMD (dystrophin) gene.12 This results in the production of a non-functional protein.15 Lack of dystrophin protein leads to progressive muscle weakness and degeneration.4
Golodirsen binds to exon 53 of dystrophin pre-mRNA on the DMD gene, excluding this protein coding unit during mRNA processing.14,15 The exclusion (or skipping) of exon 53 by golodirsen has the end result of changing out-of-frame mRNA to in-frame mRNA, inducing the production of dystrophin. The production of an imperfect dystrophin protein induced by golodirsen likely leads to a less severe condition, Becker Muscular Dystrophy (BMD), characterized by the production of a truncated dystrophin protein.11,14 Patients with BMD generally can expect a longer lifespan and improved quality of life.10,14
Target Actions Organism ADystrophin inducerHumans - Absorption
This drug is given by the intravenous route, and is likely rapidly absorbed into the circulation.14 Pharmacokinetic studies for eteplirsen determined that Cmax occur within 1.1 to 1.2 hours of infusion initiation, after the administration of doses ranging from 0.5 mg/kg/week to 50 mg/kg/week.7
- Volume of distribution
The volume of distribution at steady-state is approximately 668 mL/kg at 30 mL/kg dose of golodirsen.14
- Protein binding
The protein binding of golodirsen ranges from 33 to 39%.14
- Metabolism
Golodirsen is not extensively metabolized. There were no metabolites detected in plasma or urine during a pharmacokinetic study.14
- Route of elimination
Golodirsen is excreted primarily as unchanged drug in the urine.14
- Half-life
In a pharmacokinetic study, the elimination half-life of golodirsen was 3.4 hours with a standard deviation of 0.6 hours.14
- Clearance
This drug is rapidly cleared from the systemic circulation, like other members of its drug class.6,7 The total clearance of eteplirsen, a drug from the same class, was 339 mL/h/kg after regular doses of 30 mg/kg/week. The clearance of golodirsen is likely similar.7
- Adverse Effects
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- Toxicity
No overdose information is available, however, renal toxicity has been seen with the administration of antisense oligomers, sometimes resulting in fatal glomerulonephritis.13,14 In the case of an overdose, it is advisable to provide supportive care and monitor renal function. LD50 information is currently unavailable for this drug.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbacavir Abacavir may decrease the excretion rate of Golodirsen which could result in a higher serum level. Aceclofenac Aceclofenac may decrease the excretion rate of Golodirsen which could result in a higher serum level. Acemetacin Acemetacin may decrease the excretion rate of Golodirsen which could result in a higher serum level. Acetaminophen Acetaminophen may decrease the excretion rate of Golodirsen which could result in a higher serum level. Acetazolamide Acetazolamide may increase the excretion rate of Golodirsen which could result in a lower serum level and potentially a reduction in efficacy. - Food Interactions
- No interactions found.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- International/Other Brands
- Vyondys 53
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Vyondys 53 Injection 50 mg/1mL Intravenous Sarepta Therapeutics, Inc. 2019-12-12 Not applicable US
Categories
- ATC Codes
- M09AX08 — Golodirsen
- Drug Categories
- Antisense Elements (Genetics)
- Antisense Oligonucleotides
- Compounds used in a research, industrial, or household setting
- Drugs that are Mainly Renally Excreted
- Laboratory Chemicals
- Molecular Probes
- Musculo-Skeletal System
- Nucleic Acid Probes
- Nucleic Acids
- Nucleic Acids, Nucleotides, and Nucleosides
- Nucleotides
- Oligonucleotides
- Polynucleotides
- Classification
- Not classified
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 033072U4MZ
- CAS number
- 1422959-91-8
References
- General References
- Rodrigues M, Yokota T: An Overview of Recent Advances and Clinical Applications of Exon Skipping and Splice Modulation for Muscular Dystrophy and Various Genetic Diseases. Methods Mol Biol. 2018;1828:31-55. doi: 10.1007/978-1-4939-8651-4_2. [Article]
- Aslesh T, Maruyama R, Yokota T: Skipping Multiple Exons to Treat DMD-Promises and Challenges. Biomedicines. 2018 Jan 2;6(1). pii: biomedicines6010001. doi: 10.3390/biomedicines6010001. [Article]
- Yiu EM, Kornberg AJ: Duchenne muscular dystrophy. Neurol India. 2008 Jul-Sep;56(3):236-47. doi: 10.4103/0028-3886.43441. [Article]
- Gao QQ, McNally EM: The Dystrophin Complex: Structure, Function, and Implications for Therapy. Compr Physiol. 2015 Jul 1;5(3):1223-39. doi: 10.1002/cphy.c140048. [Article]
- Arora V, Devi GR, Iversen PL: Neutrally charged phosphorodiamidate morpholino antisense oligomers: uptake, efficacy and pharmacokinetics. Curr Pharm Biotechnol. 2004 Oct;5(5):431-9. doi: 10.2174/1389201043376706. [Article]
- Tsoumpra MK, Fukumoto S, Matsumoto T, Takeda S, Wood MJA, Aoki Y: Peptide-conjugate antisense based splice-correction for Duchenne muscular dystrophy and other neuromuscular diseases. EBioMedicine. 2019 Jul;45:630-645. doi: 10.1016/j.ebiom.2019.06.036. Epub 2019 Jun 27. [Article]
- Baker DE: Eteplirsen. Hosp Pharm. 2017 Apr;52(4):302-305. doi: 10.1310/hpj5204-302. [Article]
- Kinter J, Sinnreich M: Molecular targets to treat muscular dystrophies. Swiss Med Wkly. 2014 Feb 19;144:w13916. doi: 10.4414/smw.2014.13916. [Article]
- Hwang J, Yokota T: Recent advancements in exon-skipping therapies using antisense oligonucleotides and genome editing for the treatment of various muscular dystrophies. Expert Rev Mol Med. 2019 Oct 2;21:e5. doi: 10.1017/erm.2019.5. [Article]
- Wilson K, Faelan C, Patterson-Kane JC, Rudmann DG, Moore SA, Frank D, Charleston J, Tinsley J, Young GD, Milici AJ: Duchenne and Becker Muscular Dystrophies: A Review of Animal Models, Clinical End Points, and Biomarker Quantification. Toxicol Pathol. 2017 Oct;45(7):961-976. doi: 10.1177/0192623317734823. Epub 2017 Oct 3. [Article]
- Shimizu-Motohashi Y, Miyatake S, Komaki H, Takeda S, Aoki Y: Recent advances in innovative therapeutic approaches for Duchenne muscular dystrophy: from discovery to clinical trials. Am J Transl Res. 2016 Jun 15;8(6):2471-89. eCollection 2016. [Article]
- Vijay Venugopal; Steven Pavlakis (2019). Duchenne Muscular Dystrophy. StatPearls Publishing.
- FDA grants accelerated approval to first targeted treatment for rare Duchenne muscular dystrophy mutation [Link]
- FDA label, Golodirsen [Link]
- Muscular dystrophy UK Research: What is exon skipping and how does it work? [Link]
- MSDS: Golodirsen [Link]
- Eteplirsen FDA label [Link]
- FDA Approved Drug Products: VYONDYS 53 (golodirsen) injection [Link]
- External Links
- 2267207
- Wikipedia
- Golodirsen
- FDA label
- Download (396 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Terminated Treatment Duchenne Muscular Dystrophy (DMD) 1 3 Active Not Recruiting Treatment Duchenne Muscular Dystrophy (DMD) 1 3 Terminated Treatment Duchenne Muscular Dystrophy (DMD) 1 2 Completed Treatment Duchenne Muscular Dystrophy (DMD) 1 1, 2 Completed Treatment Duchenne Muscular Dystrophy (DMD) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection Intravenous 50 mg/1mL - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US9416361 No 2016-08-16 2021-05-04 US US10266827 No 2019-04-23 2025-06-28 US US10227590 No 2019-03-12 2025-06-28 US US9994851 No 2018-06-12 2025-06-28 US US9024007 No 2015-05-05 2025-06-28 US US10421966 No 2019-09-24 2025-06-28 US USRE47691 No 2019-11-05 2025-06-28 US US10533174 No 2020-01-14 2021-05-04 US US10995337 No 2021-05-04 2025-06-28 US US10968450 No 2021-04-06 2025-06-28 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inducer
- Curator comments
- Golodirsen binds to pre-mRNA on exon 53 of the dystrophin gene to induce the production of dystrophin protein.
- General Function
- Anchors the extracellular matrix to the cytoskeleton via F-actin. Ligand for dystroglycan. Component of the dystrophin-associated glycoprotein complex which accumulates at the neuromuscular junction (NMJ) and at a variety of synapses in the peripheral and central nervous systems and has a structural function in stabilizing the sarcolemma. Also implicated in signaling events and synaptic transmission.
- Specific Function
- Actin binding
- Gene Name
- DMD
- Uniprot ID
- P11532
- Uniprot Name
- Dystrophin
- Molecular Weight
- 426746.58 Da
References
- Aslesh T, Maruyama R, Yokota T: Skipping Multiple Exons to Treat DMD-Promises and Challenges. Biomedicines. 2018 Jan 2;6(1). pii: biomedicines6010001. doi: 10.3390/biomedicines6010001. [Article]
- Kinter J, Sinnreich M: Molecular targets to treat muscular dystrophies. Swiss Med Wkly. 2014 Feb 19;144:w13916. doi: 10.4414/smw.2014.13916. [Article]
- Rodrigues M, Yokota T: An Overview of Recent Advances and Clinical Applications of Exon Skipping and Splice Modulation for Muscular Dystrophy and Various Genetic Diseases. Methods Mol Biol. 2018;1828:31-55. doi: 10.1007/978-1-4939-8651-4_2. [Article]
- Hwang J, Yokota T: Recent advancements in exon-skipping therapies using antisense oligonucleotides and genome editing for the treatment of various muscular dystrophies. Expert Rev Mol Med. 2019 Oct 2;21:e5. doi: 10.1017/erm.2019.5. [Article]
- FDA label, Golodirsen [Link]
- Muscular dystrophy UK Research: What is exon skipping and how does it work? [Link]
Drug created at December 16, 2019 22:21 / Updated at February 03, 2022 06:26