What is the recommended use and dosage of Givinostat (Givinostat) for Duchenne muscular dystrophy?

Givinostat for Duchenne Muscular Dystrophy

Givinostat is FDA-approved for treating Duchenne muscular dystrophy in patients 6 years and older, administered as an oral suspension twice daily with food at weight-based dosing of 20-70 mg per dose, representing the first nonsteroidal DMD treatment approved regardless of specific genetic mutation. 1

Indication and Patient Selection

• Givinostat is indicated for ambulant and non-ambulant boys with genetically confirmed DMD aged 6 years and older 1
• This represents the first approved therapy that works independently of the underlying dystrophin gene mutation, making it applicable to all DMD patients meeting age criteria 1
• Must be used in addition to systemic corticosteroids, not as monotherapy 2

Dosing Regimen

Weight-based dosing administered twice daily with food: 1, 3

• The dose is flexible and adjusted based on body weight, ranging from 20-70 mg twice daily 2, 3
• Administered as oral suspension 1
• Dose reductions are permitted if not tolerated 2
• The weight-based approach produces target systemic exposure of 554-641 ng·h/mL 3

Mechanism and Clinical Efficacy

• Givinostat is a Class I and II histone deacetylase (HDAC) inhibitor that counteracts the effects of dystrophin deficiency 4, 2
• In the pivotal EPIDYS phase 3 trial, boys receiving givinostat showed significantly less decline in four-stair climb time compared to placebo (geometric least squares mean ratio 0.86,95% CI 0.745-0.989; p=0.035) 2
• Long-term data suggest givinostat delays major disease milestones by 2.0-3.3 years, including loss of ability to rise from floor, complete 4-stair climb, and loss of ambulation (all nominal p<0.05) 4
• Maximum exposure in clinical studies exceeds 8 years 4

Safety Profile and Monitoring Requirements

Mandatory platelet monitoring is essential due to dose-dependent thrombocytopenia: 3

• Platelet counts decrease by an average of 45% from baseline, with maximum decrease occurring within 28 days of treatment initiation 3
• After 6 months of therapy, approximately 14-15% of patients have platelet counts <75 × 10⁹/L 3
• Regular platelet monitoring must be implemented throughout treatment 3

Most common adverse events: 2

• Diarrhea occurs in 36% of patients (vs 18% with placebo) 2
• Vomiting occurs in 29% of patients (vs 13% with placebo) 2
• Most adverse events are mild to moderate in severity 4
• 87.1% of patients in long-term studies reported at least one adverse event, but the safety profile remained consistent over time 4
• No treatment-related deaths have occurred 2

Critical Clinical Considerations

Dose optimization is crucial: The starting dose was reduced following interim safety analysis in the EPIDYS trial, demonstrating the importance of using the FDA-approved weight-based dosing rather than higher doses 2. Preclinical studies identified an efficacy window between 5-10 mg/kg/day, with reduced benefits at 1 mg/kg/day 5.

Integration with standard DMD care: Givinostat must be added to existing corticosteroid therapy and does not replace standard DMD management including cardiac monitoring (echocardiograms starting at age 6, annually after age 10), respiratory surveillance, and ACE inhibitor/ARB therapy initiated by age 10 6, 7.

Patient eligibility considerations: The pivotal trial enrolled boys with baseline vastus lateralis fat fraction between 5-30% on MR spectroscopy, though FDA approval does not restrict use to this population 2. All patients must have received systemic corticosteroids for at least 6 months prior to givinostat initiation 2.