Exon Skipping VYONDYS 53 (golodirsen) for Treatment of Duchenne Muscular Dystrophy

VYONDYS 53 (golodirsen) injection, for intravenous use 
Initial U.S. Approval: 2019 

VYONDYS 53 (golodirsen) is an antisense oligonucleotide of the phosphorodiamidate morpholino oligomer (PMO) subclass. PMOs are synthetic molecules in which the five-membered ribofuranosyl rings found in natural DNA and RNA are replaced by a six-membered morpholino ring. Each morpholino ring is linked through an uncharged phosphorodiamidate moiety rather than the negatively charged phosphate linkage that is present in natural DNA and RNA. Each phosphorodiamidate morpholino subunit contains one of the heterocyclic bases found in DNA (adenine, cytosine, guanine, or thymine). Golodirsen contains 25 linked subunits. The sequence of bases from the 5' end to 3' end is GTTGCCTCCGGTTCTGAAGGTGTTC. The molecular formula of golodirsen is C305H481N138O112P25 and the molecular weight is 8647.28 daltons.

Mechanism of Action 
Golodirsen is designed to bind to exon 53 of dystrophin pre-mRNA resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 53 skipping. Exon 53 skipping is intended to allow for the production of an internally truncated dystrophin protein in patients with genetic mutations that are amenable to exon 53 skipping [see Clinical Studies (14)]. Pharmacodynamics 
After treatment with VYONDYS 53, all patients evaluated (n=25) in Study 1 Part 2 had an increase in skipping of exon 53 demonstrated by reverse transcription polymerase chain reaction (RT-PCR), compared to baseline. In Study 1 Part 2, dystrophin levels increased from 0.10% (SD 0.07) of normal at baseline to 1.02% (SD 1.03) of normal after 48 weeks of treatment with VYONDYS 53. The mean change from baseline in dystrophin after 48 weeks of treatment with VYONDYS Reference ID: 4532753 53 was 0.92% (SD 1.01) of normal levels (p<0.001); the median change from baseline was 0.88%. This increase in dystrophin protein expression positively correlated with the level of exon skipping. Correct localization of truncated dystrophin to the sarcolemma in muscle fibers of patients treated with golodirsen was demonstrated by immunofluorescence staining.

The pharmacokinetics of golodirsen was evaluated in DMD patients following administration of intravenous doses ranging from 4 mg/kg/week to 30 mg/kg/week (i.e., recommended dosage). Golodirsen exposure increased proportionally with the dose, with minimal accumulation with once weekly dosing. Inter-subject variability (as %CV) for Cmax and AUC ranged from 38% to 72%, and 34% to 44%, respectively. Distribution Steady-state volume of distribution was similar between DMD patients and healthy subjects. The mean golodirsen steady-state volume of distribution was 668 mL/kg (%CV=32.3) at a dose of 30 mg/kg. Golodirsen plasma protein binding ranged from 33% to 39% and is not concentration-dependent. 

Golodirsen elimination half-life (SD) was 3.4 (0.6) hours, and plasma clearance was 346 mL/hr/kg at the 30 mg/kg dose.

Golodirsen is metabolically stable. No metabolites were detected in plasma or urine. 

Golodirsen is mostly excreted unchanged in the urine. The elimination half-life (t1/2) was 3.4 hours. 

  • VYONDYS 53 is an antisense oligonucleotide indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping.
  • This indication is approved under accelerated approval based on an increase in dystrophin production in skeletal muscle observed in patients treated with VYONDYS 53.
  • Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials. 

  • Measure glomerular filtration rate prior to initiation 
  • 30 milligrams per kilogram once weekly 
  • Administer as an intravenous infusion over 35 to 60 minutes 
  • Dilution required prior to administration 

Injection: 100 mg/2 mL (50 mg/mL) in a single-dose vial (3)


Hypersensitivity Reactions: 
Hypersensitivity reactions, including rash, pyrexia, pruritus, urticaria, dermatitis, and skin exfoliation have occurred in patients who were treated with VYONDYS 53. If a hypersensitivity reaction occurs, institute appropriate medical treatment and consider slowing the infusion or interrupting the VYONDYS 53 therapy. 

Renal Toxicity: 
Based on animal data, may cause renal toxicity. Renal function should be monitored; creatinine may not be a reliable measure of renal function in DMD patients.

The most common adverse reactions (incidence ≥20% and higher than placebo) were headache, pyrexia, fall, abdominal pain, nasopharyngitis, cough, vomiting, and nausea.

Reference: FDA Package Insert