Viltolarsen Phase 2 in DMD
(2020)Objective
To evaluate the safety, tolerability, and efficacy of viltolarsen in boys with DMD amenable to exon 53 skipping
Study Summary
• De novo dystrophin production of 5.7% (40 mg/kg) and 5.9% (80 mg/kg) of normal on Western blot
• Significant improvements in timed function tests vs 65 age-matched natural history controls
• Significant improvements in timed function tests vs 65 age-matched natural history controls
Intervention
Viltolarsen 40 mg/kg or 80 mg/kg IV weekly
Inclusion Criteria
Boys aged 4-9 years with DMD amenable to exon 53 skipping
Study Design
Arms: Viltolarsen 40 mg/kg, Viltolarsen 80 mg/kg
Patients per Arm: 8 per arm (16 total)
Outcome
• Dystrophin production: 5.7% (40 mg/kg) and 5.9% (80 mg/kg) of normal
• 6-minute walk test improved 28.9 m vs decline of 65.3 m in natural history controls
• No serious adverse events or treatment discontinuations
• 6-minute walk test improved 28.9 m vs decline of 65.3 m in natural history controls
• No serious adverse events or treatment discontinuations
Bottom Line
Viltolarsen induced dystrophin production of ~5.7-5.9% of normal and was associated with significant improvements in timed function tests vs natural history controls, with no serious adverse events.
Major Points
- Viltolarsen (exon 53 skipping ASO) increased dystrophin production in DMD: 5.7% of normal at 24 weeks (40mg group) vs 0% at baseline.
- Dose-dependent dystrophin increase: 40 mg/kg/week > 80 mg/kg/week (paradoxical — may reflect small sample).
- 16 boys with DMD amenable to exon 53 skipping. Phase 2, dose-finding, open-label.
- Timed function tests: 6MWT improved in 40 mg group; stable/improved in 80 mg group.
- Western blot confirmed de novo dystrophin expression in all treated patients.
- Well tolerated: injection site reactions most common AE. No serious AEs.
- Published JAMA Neurology 2020. NS Pharma/Nippon Shinyaku.
- FDA approved viltolarsen (Viltepso) 2020 via accelerated approval based on dystrophin increase.
- Third exon-skipping ASO approved for DMD (specific to exon 53 amenable mutations, ~8% of DMD).
- Confirmatory Phase 3 (RACER53) ongoing for clinical benefit.
Study Design
- Study Type
- Phase 2, multicenter trial; 4-week randomized double-blind placebo-controlled period + 20-week open-label treatment
- Randomization
- Yes
- Blinding
- Double-blind for weeks 1-4 (3:1 randomization); open-label weeks 5-24; muscle biopsies blinded for dystrophin analysis
- Sample Size
- 16
- Follow-up
- 24 weeks (4-week blinded + 20-week open-label)
- Centers
- 6
- Countries
- United States, Canada
Primary Outcome
Definition: Safety, tolerability, and de novo dystrophin production by Western blot (% of normal)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Natural history controls (n=65, CINRG DNHS) | Low-dose (40 mg/kg): 5.7% of normal (range 3.2-10.3%); High-dose (80 mg/kg): 5.9% of normal (range 1.1-14.4%); both p<0.01 from baseline | - (94% achieved >2% of normal; 88% achieved >3% of normal) | Both doses p<0.01 vs baseline |
Limitations & Criticisms
- Very small sample size (16 patients, 8 per dose group)
- Open-label treatment phase after initial 4-week blinded period
- Efficacy comparison used external historical natural history controls rather than randomized placebo arm
- Short duration (24 weeks) -- long-term functional benefit uncertain
- Variability in functional assessments given small sample size
- Manufacturer-funded (NS Pharma involved in study design and analysis)
Citation
Clemens PR et al. JAMA Neurol. 2020 Aug 1;77(8):982-991. DOI: 10.1001/jamaneurol.2020.1264. PMID: 32453377. PMCID: PMC7251505. NCT02740972