Identification

Name
Golodirsen
Accession Number
DB15593
Type
Biotech
Groups
Approved
Biologic Classification
Gene Therapies
Antisense oligonucleotides
Description

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

Synonyms
  • Golodirsen
External IDs
NG-12-0163 / SRP-4053 / WHO 10355
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Vyondys 53Injection50 mg/1mLIntravenousSarepta Therapeutics, Inc.2019-12-12Not applicableUs
Additional Data Available
  • Application Number
    Application Number

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  • Product Code
    Product Code

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International/Other Brands
Vyondys 53
Categories
UNII
033072U4MZ
CAS number
1422959-91-8

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

Associated Conditions
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 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

TargetActionsOrganism
ADystrophin
inducer
Humans
Additional Data Available
Adverse Effects

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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

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.

Affected organisms
Not Available
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.
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Golodirsen which could result in a higher serum level.
AcarboseAcarbose may decrease the excretion rate of Golodirsen which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Golodirsen which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Golodirsen which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Golodirsen which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Golodirsen which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Golodirsen which could result in a higher serum level.
AclidiniumAclidinium may decrease the excretion rate of Golodirsen which could result in a higher serum level.
AcrivastineAcrivastine may decrease the excretion rate of Golodirsen which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Golodirsen which could result in a higher serum level.
Additional Data Available
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Food Interactions
Not Available

References

General References
  1. 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. [PubMed:30171533]
  2. 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. [PubMed:29301272]
  3. Yiu EM, Kornberg AJ: Duchenne muscular dystrophy. Neurol India. 2008 Jul-Sep;56(3):236-47. doi: 10.4103/0028-3886.43441. [PubMed:18974549]
  4. 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. [PubMed:26140716]
  5. 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. [PubMed:15544491]
  6. 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. [PubMed:31257147]
  7. Baker DE: Eteplirsen. Hosp Pharm. 2017 Apr;52(4):302-305. doi: 10.1310/hpj5204-302. [PubMed:28515510]
  8. Kinter J, Sinnreich M: Molecular targets to treat muscular dystrophies. Swiss Med Wkly. 2014 Feb 19;144:w13916. doi: 10.4414/smw.2014.13916. [PubMed:24554202]
  9. 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. [PubMed:31576784]
  10. 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. [PubMed:28974147]
  11. 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. [PubMed:27398133]
  12. Vijay Venugopal; Steven Pavlakis (2019). Duchenne Muscular Dystrophy. StatPearls Publishing.
  13. FDA grants accelerated approval to first targeted treatment for rare Duchenne muscular dystrophy mutation [Link]
  14. FDA label, Golodirsen [Link]
  15. Muscular dystrophy UK [Link]
  16. MSDS: Golodirsen [Link]
  17. Eteplirsen FDA label [Link]
External Links
RxNav
2267207
Wikipedia
Golodirsen
FDA label
Download (396 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2CompletedTreatmentDuchenne's Muscular Dystrophy (DMD)1
2Enrolling by InvitationTreatmentDuchenne's Muscular Dystrophy (DMD)1
3Enrolling by InvitationTreatmentDuchenne's Muscular Dystrophy (DMD)1
3RecruitingTreatmentDMD / Duchenne's Muscular Dystrophy (DMD) / Muscular Dystrophy1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
InjectionIntravenous50 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US9416361No2016-08-162021-05-04Us
US10266827No2019-04-232025-06-28Us
US10227590No2019-03-122025-06-28Us
US9994851No2018-06-122025-06-28Us
US9024007No2015-05-052025-06-28Us
US10421966No2019-09-242025-06-28Us
USRE47691No2019-11-052025-06-28Us
US10533174No2001-05-042021-05-04Us
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

Classification
Not classified

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
  1. 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. [PubMed:29301272]
  2. Kinter J, Sinnreich M: Molecular targets to treat muscular dystrophies. Swiss Med Wkly. 2014 Feb 19;144:w13916. doi: 10.4414/smw.2014.13916. [PubMed:24554202]
  3. 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. [PubMed:30171533]
  4. 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. [PubMed:31576784]
  5. FDA label, Golodirsen [Link]
  6. Muscular dystrophy UK [Link]

Drug created on December 16, 2019 15:21 / Updated on March 01, 2020 22:10

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