Dr. Deb Talukdar is a medical doctor from New Delhi, India. His research interest includes cancer therapeutics, Parkinson’s Disease, inflammatory and immunosuppressive drugs, COVID-19 predictive modeling and vaccination program, public health research associated with DHS and rare diseases such Pulmonary arterial hypertension (PAH). Previously, he was involved in AI research at Yale University. Currently, he is affiliated with All Saints University School of Medicine in Dominica.
Vyondys 53™ (golodirsen) is a medication indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation in the DMD gene that is amenable to exon 53 skipping. According to clinical studies, Vyondys 53 received accelerated approval due to the increased dystrophin production noted in the skeletal muscles. The drug received continued approval due to verification of its clinical benefits in confirmatory trials. Monitoring renal toxicity and evaluating glomerular filtration are critical. The recommended dosage for Vyondys 53 is 30 mg/kg administered via an intravenous infusion over 25 to 60 minutes. If a dose is missed, it can be administered as soon as possible after the scheduled dose. Vyondys 53 is supplied as a preservative-free concentrated solution in a single-dose vial that requires dilution before administration. It should be visually inspected for any discoloration or particulate matter before administration. The total dose of Vyondys 53 is calculated based on the recommended dosage of 30 mg/kg and the weight of the patient. The correct number of vials and total volume of Vyondys 53 required can then be determined. Vyondys 53 vials need to be warmed to room temperature prior to administration. The contents of each vial should be inverted 2 to 3 times and mixed gently without shaking. The solution of each vial should be inspected visually to confirm that it is an opalescent, clear, and colorless liquid. It can be administered via a noncoring 21-gauge or smaller needle fitted to a syringe.1
The dosage of Vyondys 53 varies from 4 to 30 mg/kg/week. The exposure to Vyondys 53 in patients with DMD increases proportionally with the number of doses. Minimal accumulation of Vyondys 53 occurs with weekly administration. The area under the concentration-time curve for Vyondys 53 ranged from 34% to 44%, and the maximum plasma concentration (Cmax) ranged from 38% to 72%. The plasma protein binding of Vyondys 53 is 33% to 39% (concentration-dependent), and the mean steady-state volume of distribution is 668 mL/kg for a 30 mg/kg intravenous infusion. It is metabolically stable, and no metabolites are detected in the plasma or urine. It has an elimination half-life of 3.4 hours, and it is excreted primarily in the urine. Renal impairment based on estimated glomerular filtration rate (GFR) can cause a reduced renal clearance rate for Vyondys 53. The plasma clearance of Vyondys 53 is 346 mL/h/kg for an intravenously administered dose of 30 mg/kg. DMD patients with renal impairment (based on GFR) can suffer from reduced skeletal muscle mass according to creatinine measurements. No specific adjustment of the Vyondys 53 dosage is recommended for such patients. They should be closely monitored during treatment with Vyondys 53.2
Get detailed prescribing information on the Vyondys 53 monograph page at MPR.
Hypersensitivity reactions such as pruritus, urticaria, pyrexia, skin exfoliation, and dermatitis are associated with Vyondys 53 administration. In the case of a hypersensitivity reaction, it is recommended to slow or interrupt Vyondys 53 therapy. Kidney toxicity was reported in animal models administered Vyondys 53 therapy. Clinical studies with Vyondys 53 are limited. Potentially fatal glomerulonephritis and kidney toxicity are observed after the administration of antisense oligonucleotides. Monitoring kidney function is recommended for patients taking Vyondys 53. Creatinine is not a reliable kidney function test for patients with DMD, as they suffer from reduced skeletal muscle mass. Measurements of urine protein to creatinine ratio, serum cystatin C, and urine dipstick are recommended before starting Vyondys 53 therapy. During treatment, these tests should be performed every 3 months. Glomerular filtration rate can be measured using exogenous filtration markers before Vyondys 53 therapy.3
Increased Dystrophin Production
Dystrophin production was evaluated in patients with DMD in a first-in-human, multicenter clinical trial that involved exon 53 skipping. The treatment duration was 48 weeks, with weekly intravenous Vyondys 53 infusions. At week 48, dystrophin was localized in the muscle biopsies of patients with DMD. Based on previous experience with eteplirsen, an antisense phosphorodiamidate morpholino oligomer (PMO) targeting exon 51 of the DMD gene, sufficient time was allowed for dystrophin to be produced. Robust pharmacologic activity was observed for Vyondys 53 using 3 independent complementary methods, as most of the patients demonstrated an increase in exon 53 skipping with target engagement by Vyondys 53. The study was statistically significant because there was a 16-fold increase compared to baseline in de novo dystrophin protein as measured by western blot at week 48. The primary biological endpoint of the study was achieved, as dystrophin protein maintained a mean of 1.019% of normal and a range of 0.09% to 4.30% in patients with DMD .4
Food and Drug Administration Approval
The US Food and Drug Administration (FDA) approved Vyondys 53 to treat DMD patients with eligible mutations. A lack of functional dystrophin protein can cause severe progressive muscle wasting, as mutations that allow partial production of dystrophin protein result in a less progressive disease. Vyondys 53 is part of an antisense oligonucleotide-mediated splicing modulation that allows patients with DMD to produce Becker muscular dystrophy (BMD)-like dystrophin protein. This specific approach is mutation-specific, as patients with DMD do not all carry the same mutation. For example, exon 53 mutations occur in 8% of patients with DMD. Exon 51 and 45 mutations occur in 14% and 9% of patients with DMD, respectively. Vyondys 53 is a PMO developed by Sarepta Therapeutics that involves the skipping of exon 53 in patients with DMD.5
Drug Trials Overview
Vyondys 53 drug trials involved 2 clinical studies in patients with DMD. Data from trial 1 were used to evaluate the side effects and benefits of Vyondys 53 as a treatment modality for patients with DMD. Trial 2 evaluated the side effects only. All patients involved in the clinical studies were taking corticosteroids for 6 months before entering the trials. Patients with DMD were randomly assigned to receive Vyondys 53 or a placebo once a week in the first double-blinded clinical trial. The results of the trial were calculated by measuring the dystrophin protein before and after 48 weeks of treatment. In the second trial, patients received Vyondys 53 or placebo once a week for 96 weeks.6
- Vyondys 53 (golodirsen). Package insert. Sarepta Therapeutics, Inc.; 2019. Accessed August 18, 2021.
- Heo YA. Golodirsen: first approval. Drugs. 2020;80(3):329-333. doi:10.1007/s40265-020-01267-2
- Vyondys 53. RxList. Updated March 1, 2021. Accessed August 18, 2021.
- Frank DE, Schnell FJ, Akana C, et al.; SKIP-NMD Study Group. Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy. Neurology. 2020;94(21):e2270-e2282. doi:10.1212/WNL.0000000000009233
- Aartsma-Rus A, Corey DR. The 10th oligonucleotide therapy approved: golodirsen for Duchenne muscular dystrophy. Nucleic Acid Ther. 2020;30(2):67-70. doi:10.1089/nat.2020.0845
- Drug trials snapshots: Vyondys 53. FDA. Accessed August 18, 2021.
Reviewed by Harshi Dhingra, MD, on 8/16/2021.