OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Golodirsen – Vyondys 53®

DRUG CLASS

Genetic Disorder Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO	MOLECULAR FORMULA	STRUCTURE
Golodirsen	1422959-91-8	C305-H481-N138-O112-P25

ANNOTATED BIBLIOGRAPHY

References updated: 01 December 2022

Abbreviations: siRNA, small interfering RNA; RNAi, RNA interference.

• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al. United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology. 2015;148:1340–52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, no cases were attributed to siRNA or antisense therapies or medications for muscular dystrophy).
• Chi X, Gatti P, Papoian T. Safety of antisense oligonucleotide and siRNA-based therapeutics. Drug Discov Today. 2017;22:823–33. [PubMed: 28159625]

  (Oligonucleotide and siRNA based treatments are currently being evaluated in several diseases and have been found to have unexpected toxicities including antisense thrombocytopenia [mipomersen, drisapersen] and peripheral neuropathy [revusiran]; no discussion of hepatotoxicity).
• Levin AA. Treating disease at the RNA level with oligonucleotides. N Engl J Med. 2019;380:57–70. [PubMed: 30601736]

  (Review of the mechanism of action, current status and future promise of RNA based therapies that use synthetic oligonucleotides to modulate RNA function and have been applied to diseases ranging from hemophilia, amyloidosis, muscular dystrophy and hyperlipidemia).
• Messina S, Vita GL. Clinical management of Duchenne muscular dystrophy: the state of the art. Neurol Sci. 2018;39:1837–45. [PubMed: 30218397]

  (Review of current optimal clinical management of Duchenne muscular dystrophy focusing upon standard respiratory, cardiovascular, orthopedic and nutritional support as well as recent innovative approaches to therapy including exon and premature stop codon suppression).
• Setten RL, Rossi JJ, Han SP. The current state and future directions of RNAi-based therapeutics. Nat Rev Drug Discov. 2019;18:421–46. [PubMed: 30846871]

  (Extensive review of gene silencing using RNA interference pathways and the potential of RNAi therapeutics which have promise in many genetic and acquired diseases including transthyretin amyloidosis [transthyretin], HIV infection [CCR5], HBV [HBV mRNA], alpha-1-antitrypsin deficiency [zz A1AT], hypercholesterolemia [PCSK9]).
• Verhaart IEC, Aartsma-Rus A. Therapeutic developments for Duchenne muscular dystrophy. Nat Rev Neurol. 2019;15:373–86. [PubMed: 31147635]

  (Review of mechanisms of action, challenges, and clinical efficacy of new molecular approaches to therapy of muscular dystrophy including gene therapy with viral vectors, exon skipping using antisense oligonucleotides [casimersen, eteplirsen, drisapersen, golodirsen], stop coding readthrough [ataluren], gene addition, CRISPR-Cas9 genome editing, and myoblast transplantation).
• FDA Multi-Disciplinary Review and Evaluation. Golodirsen. 2019. Available at: https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2019/211970Orig1s000MedR.pdf.

  (The FDA clinical review of golodirsen for efficacy and safety found minor increases in dystrophin levels in muscle biopsies but no improvement in clinical measures such as 6 minute walk test distances; therapy required intravenous infusions once weekly and insertion of a venous access port, but there were no serious adverse events attributable to the medication and no hepatic related serious adverse events or discontinuations because of liver toxicity; no mention of changes in ALT levels during therapy).
• Heo Y-A. Golodirsen: first approval. Drugs. 2020;80:329–33. [PubMed: 32026421]

  (Review of the mechanism of action, history of development, clinical efficacy and safety of golodirsen shortly after its approval for use in Duchenne muscular dystrophy mentions that in the registration trial, all patients showed exon 53 skipping responses and the mean dystrophin levels from muscle biopsies increased from baseline, but that clinical improvement rates were not reported, while adverse events in treated vs control subjects included headache [41% vs 10%], fever [41% vs 14%], falls [29% vs 19%], abdominal pain [27% vs 10%], cough [27% vs 19%], and nausea [20% vs 10%], but does not mention ALT elevations or hepatotoxicity).
• Aartsma-Rus A, Corey DR. The 10th oligonucleotide therapy approved: golodirsen for Duchenne muscular dystrophy. Nucleic Acid Ther. 2020;30:67–70. [PMC free article: PMC7133412] [PubMed: 32043902]

  (Review of the efficacy and safety of 10 oligonucleotide therapies approved in the US or Europe, including specific discussions of fomivirsen, mipomersen, eteplirsen, nusinersen, patisiran, givosiran and golodirsen).
• Frank DE, Schnell FJ, Akana C, El-Husayni SH, Desjardins CA, Morgan J, Charleston JS, et al. SKIP-NMD Study Group. Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy. Neurology. 2020;94:e2270–e2282. [PMC free article: PMC7357297] [PubMed: 32139505]

  (Among 25 boys with Duchenne muscular dystrophy treated with golodirsen for 48 weeks, dystrophin levels increased from approximately 0.10% of normal to 1.02%, and all had evidence of increased exon skipping).
• Golodirsen (Vyondys 53) for Duchenne muscular dystrophy. Med Lett Drugs Ther. 2020;62(1603):119–120. [PubMed: 32728014]

  (Concise summary of the mechanism of action, clinical efficacy and safety of golodirsen shortly after its approval for use in Duchenne muscular dystrophy in the US; adverse effects included headache, fever, abdominal pain, cough, nasopharyngitis, nausea, rash and urticaria; no mention of ALT elevations or hepatotoxicity).
• Alhamadani F, Zhang K, Parikh R, Wu H, Rasmussen TP, Bahal R, Zhong XB, Manautou JE. Adverse drug reactions and toxicity of the Food and Drug Administration-approved antisense oligonucleotide drugs. Drug Metab Dispos. 2022;50:879–887. [PubMed: 35221289]

  (Review of the adverse side effects of oligonucleotide therapies approved in the US or Europe, including specific discussions of fomivirsen, mipomersen, nusinersen, inotersen, eteplirsen, golodirsen, viltolarsen and casimersen; hepatotoxicity has been described with use of mipomersen [now withdrawn] and inotersen, but not with the agents used for Duchenne muscular dystrophy).
• Servais L, Mercuri E, Straub V, Guglieri M, Seferian AM, Scoto M, Leone D, et al. SKIP-NMD Study Group. Long-term safety and efficacy data of golodirsen in ambulatory patients with Duchenne muscular dystrophy amenable to exon 53 skipping: a first-in-human, multicenter, two-part, open-label, phase 1/2 trial. Nucleic Acid Ther. 2022;32:29–39. [PMC free article: PMC8817703] [PubMed: 34788571]

  (Among 25 boys with Duchenne muscular dystrophy enrolled in a phase 1 randomized placebo controlled trial followed by an open label study of golodirsen [30 mg/kg intravenously once weekly] for 168 weeks, dystrophin levels increased over the first 48 weeks but there was a steady decline in 6 minute walk time distance and forced vital capacity on yearly determinations, although the amount of change was less than in a matched historical control group).