What is the role of exon 4 skipping therapy, such as golodirsen, in managing Duchenne muscular dystrophy?

Exon Skipping Therapy in Duchenne Muscular Dystrophy

Golodirsen (VYONDYS 53) is FDA-approved for treating DMD patients with confirmed mutations amenable to exon 53 skipping, administered as 30 mg/kg IV once weekly, though this approval is based on surrogate endpoints (dystrophin production) rather than proven clinical benefit on morbidity or mortality. 1

Understanding the Indication and Limitations

The FDA granted accelerated approval for golodirsen based on increased dystrophin production in skeletal muscle, not on improvements in functional outcomes, quality of life, or survival 1. Continued approval is contingent upon verification of clinical benefit in confirmatory trials 1. This is a critical distinction—the drug increases a biomarker (dystrophin protein) but lacks definitive evidence for improving what matters most: muscle function, ambulation, cardiac outcomes, or lifespan.

Patient Selection Criteria

Golodirsen is indicated exclusively for DMD patients with:

• Genetically confirmed DMD mutation amenable to exon 53 skipping 1
• This represents approximately 8-10% of all DMD patients 2, 3
• Age range studied: 6-13 years at study entry 1

Common pitfall: Do not prescribe golodirsen without genetic confirmation that the patient's specific mutation would benefit from exon 53 skipping. Other exon-skipping drugs target different exons (eteplirsen for exon 51, casimersen for exon 45, viltolarsen for exon 53) 2, 3.

Dosing and Administration

• Dose: 30 mg/kg IV once weekly 1
• Administered as intravenous infusion after dilution 1
• Treatment is chronic and ongoing 1

Safety Profile and Monitoring

Common Adverse Reactions (≥20% incidence):

• Headache (41%) 1
• Pyrexia (41%) 1
• Falls (29%) 1
• Abdominal pain (27%) 1
• Nasopharyngitis (27%) 1
• Cough (27%) 1
• Vomiting (27%) 1
• Nausea (20%) 1

Serious Concerns:

• Hypersensitivity reactions including anaphylaxis have been reported postmarketing 1
• Renal toxicity: Juvenile rat studies showed dose-dependent renal tubular degeneration, fibrosis, and impairment at all doses tested, with no identified no-effect dose 1
• Monitor renal function closely in patients with known renal impairment, though no specific dosage adjustment can be recommended due to reduced muscle mass affecting creatinine measurements in DMD 1

Integration with Standard DMD Management

Exon skipping does NOT replace glucocorticoid therapy, which remains the only medication with proven benefit for slowing muscle strength decline, prolonging ambulation, reducing scoliosis risk, and stabilizing pulmonary function. 4

Recommended Concurrent Therapies:

• Glucocorticoids (prednisone 0.75 mg/kg/day or deflazacort 0.9 mg/kg/day) should be initiated and maintained 4
• Cardiac monitoring: Annual ECG and echocardiography, with cardiac MRI preferred for comprehensive assessment 4
• Pulmonary function testing every 6 months 4
• Physical and occupational therapy assessments every 4 months 4

Cardiac Considerations in Clinical Trials

When DMD patients receiving exon-skipping therapy are monitored, cardiac function must be carefully evaluated to detect concomitant benefits or toxicity 4. Cardiac MRI with late gadolinium enhancement is preferred over echocardiography for assessing cardiac status, measuring degree and pattern of late gadolinium enhancement, myocardial strain, and extracellular volume 4.

Critical caveat: Typical heart failure symptoms like exercise limitation or dyspnea are often absent in DMD patients due to skeletal muscle impairment, so do not rely on symptoms alone to guide cardiac management 4.

Evidence Quality and Clinical Reality

Current real-world data suggests exon-skipping ASOs have a broad safety profile and may delay muscle deterioration, but exon-skipping efficacy and dystrophin protein production remain limited 2. Multiple newer-generation ASOs with improved cellular uptake and nuclear import are in development, showing better molecular efficacy in early trials, though their safety profiles may differ from first-generation compounds 2.

The fundamental limitation: Exon skipping addresses only patients with specific mutations (approximately 14% for exon 51 skipping, smaller percentages for other exons), and even in these patients, the clinical benefit on functional outcomes remains unproven 2, 3.

Practical Algorithm for Exon Skipping Therapy

1. Confirm genetic mutation via next-generation sequencing or multiplex ligation-dependent probe amplification 3
2. Match mutation to appropriate exon-skipping drug (golodirsen for exon 53-amenable mutations) 1
3. Initiate or optimize glucocorticoid therapy first—this has proven mortality/morbidity benefit 4
4. Establish baseline renal function before starting golodirsen 1
5. Administer 30 mg/kg IV weekly with monitoring for hypersensitivity 1
6. Monitor renal function serially, especially in patients with baseline impairment 1
7. Continue comprehensive DMD care including cardiac monitoring, pulmonary support, and physical therapy 4

Bottom line: Golodirsen is a mutation-specific therapy with FDA approval based on surrogate endpoints, not proven clinical benefit. It should be used as an adjunct to, not replacement for, glucocorticoid therapy and comprehensive multidisciplinary DMD management.