|Drug class||Antisense oligonucleotide|
|Main uses||Certain types of Duchenne muscular dystrophy (DMD)|
|Side effects||Headache, fever, falls, abdominal pain, runny nose, nausea|
|Typical dose||30 mg/kg q wk|
|Chemical and physical data|
|Molar mass||8647.401 g·mol−1|
Golodirsen, sold under the brand name Vyondys53, is a medication used to treat Duchenne muscular dystrophy (DMD) due to a mutation in the dystrophin gene that may be improved by exon 53 skipping. It is given by injection into a vein. While it increases dystrophin, benefit is yet to be shown as of 2021.
Common side effects include headache, fever, falls, abdominal pain, runny nose, and nausea. Other side effects may include allergic reactions and kidney problems. It is an antisense oligonucleotide that binds to exon 53 and results in mRNA that produces more functional dystrophin.
Golodirsen was approved for medical use in the United States in 2019. As of 2021 it is not approved in either Europe or the United Kingdom. In the United States it costs about 5,000 USD for a 10 kg person per week as of 2021.
Golodirsen is used to treat Duchenne muscular dystrophy (DMD) in children who have a confirmed mutation of the dystrophin gene that is amenable to exon 53 skipping. This is present in about 8 to 10% of people with DMD.
It is given at a dose of 30 mg per kg once per week.
The most common side effects include headache, fever, fall, cough, vomiting, abdominal pain, cold symptoms (nasopharyngitis) and nausea. In animal studies, no significant changes were seen in the male reproductive system of monkeys and mice following weekly subcutaneous administration. 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. Hypersensitivity reactions, including rash, fever, itching, hives, skin irritation (dermatitis) and skin peeling (exfoliation), have occurred in people who were treated with golodirsen.
Renal toxicity was observed in animals who received golodirsen. Although renal toxicity was not observed in the clinical studies with golodirsen, potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. Renal function should be monitored in those taking golodirsen.
Mechanism of action
Golodirsen has been provisionally approved for approximately 8% of all DMD patients amenable to exon 53 skipping. It works by inducing exon skipping in the dystrophin gene and thereby increasing the amount of dystrophin protein available to muscle fibers.
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. 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.
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.
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.
Golodirsen was developed by collaborative research led by Steve Wilton and Sue Fletcher in the Perron Institute and licensed to Sarepta Therapeutics by the University of Western Australia. The U.S. Food and Drug Administration (FDA) approved golodirsen in December 2019, under the accelerated approval pathway. Its approval is under the condition that its benefit will be demonstrated in a confirmatory clinical trial
Society and culture
Sarepta Therapeutics has announced that golodirsen will cost in parity with eteplirsen, another drug of a similar kind, which may be as high as 300K USD 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.
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