EPIDYS
(2024)Objective
To evaluate the safety and efficacy of givinostat in ambulant boys with Duchenne muscular dystrophy on corticosteroids
Study Summary
• Givinostat is the first HDAC inhibitor to demonstrate efficacy in DMD
Intervention
Givinostat oral twice daily (weight-based dosing) vs placebo
Inclusion Criteria
Ambulant males >=6 years, genetically confirmed DMD, four-stair climb <=8 seconds, corticosteroids for >=6 months
Study Design
Arms: Givinostat (2:1), Placebo
Patients per Arm: 118 givinostat, 61 placebo; Group A: 81 givinostat, 39 placebo
Outcome
• 27% worsening in givinostat vs 48% worsening in placebo at 72 weeks
• Most common AEs: diarrhea (36% vs 18%) and vomiting (29% vs 13%)
Bottom Line
Givinostat significantly slowed disease progression on four-stair climb test over 72 weeks (ratio 0.86, p=0.035) in boys with intermediate muscle fat fraction. First HDAC inhibitor to show efficacy in DMD.
Major Points
- Vamorolone (dissociative steroid) showed comparable efficacy to prednisone with fewer side effects in DMD.
- Prospective observational comparison: vamorolone vs standard-of-care corticosteroids.
- NSAA and timed function tests: vamorolone non-inferior to prednisone/deflazacort.
- Key advantage: less weight gain, less growth stunting, better bone health biomarkers.
- Vamorolone maintains anti-inflammatory effects while reducing GR transactivation (side effects).
- Published as part of vamorolone clinical development program (VISION-DMD).
- Supports vamorolone as preferred corticosteroid for DMD with better safety profile.
- FDA approved vamorolone (Agamree) for DMD in 2023.
Study Design
- Study Type
- Phase 3 randomized controlled trial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 179
- Follow-up
- 72 weeks
- Centers
- 41
- Countries
- Multiple (11 countries)
Primary Outcome
Definition: Change in four-stair climb from baseline to 72 weeks (Group A)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Geometric LSM ratio 1.48 | Geometric LSM ratio 1.27 | - (0.745-0.989 (ratio of ratios: 0.86)) | 0.035 |
Limitations & Criticisms
- Primary analysis on subgroup (Group A) rather than full ITT
- Protocol amendment reduced dose mid-trial
- GI side effects may have unblinded some participants
- 359 screened to analyze only 120 patients
Citation
Mercuri E et al. Lancet Neurol. 2024 Apr;23(4):393-403. DOI: 10.1016/S1474-4422(24)00036-X. PMID: 38508835. NCT02851797