Vamorolone for DMD
(2026)Objective
To evaluate the safety, tolerability, and pharmacokinetics of vamorolone (2 or 6 mg/kg/d) in corticosteroid-naive boys with Duchenne muscular dystrophy aged 2-<4 years, with exploratory motor efficacy.
Study Summary
• Dose-dependent adrenal suppression: 50% of 6 mg/kg/d patients had morning cortisol ≤65 nmol/L vs 20% at 2 mg/kg/d; no clinical adrenal insufficiency
• Stable growth trajectories (height, weight, BMI) over 12 weeks and ~2 years of EAP follow-up; 8/19 developed BMI-score change >0.5 suggesting excessive weight gain
• Dose-dependent motor improvement: median Bayley-III gross motor scaled score change from baseline was 0.0 (2 mg/kg/d) vs 2.5 (6 mg/kg/d) at week 12
• Dose-dependent PK with rapid absorption (Tmax ~2 h) and no drug accumulation; bone turnover and glucose metabolism biomarkers unchanged
Intervention
Oral vamorolone suspension 2 mg/kg/d or 6 mg/kg/d once daily for 12 weeks
Inclusion Criteria
Boys aged 2-<4 years with genetically or biopsy-confirmed Duchenne muscular dystrophy, corticosteroid-naive, with evidence of varicella zoster immunity
Study Design
Arms: Vamorolone 2 mg/kg/d vs Vamorolone 6 mg/kg/d (sequential, open-label, nonrandomized)
Patients per Arm: 10 vs 10
Outcome
• Adrenal suppression (cortisol ≤65 nmol/L) at week 12: 20% (2 mg/kg/d) vs 40% (6 mg/kg/d); no adrenal crises
• Exploratory efficacy: median Bayley-III GMSS change from baseline 0.0 (2 mg/kg/d) vs 2.5 (6 mg/kg/d)
• PK: dose-dependent exposure (Cmax day 1: 246.8 ng/mL [2 mg] vs 781.7 ng/mL [6 mg]); no accumulation; Tmax ~2 h
Clinical Question
In corticosteroid-naive boys aged 2-<4 years with Duchenne muscular dystrophy, are 2 or 6 mg/kg/d of oral vamorolone safe, tolerable, and associated with favorable pharmacokinetics and motor function outcomes over 12 weeks (with EAP extension)?
Bottom Line
In 20 corticosteroid-naive boys aged 2-<4 years with DMD, 12 weeks of vamorolone (2 or 6 mg/kg/d) was well tolerated with no serious adverse events and stable growth, dose-dependent adrenal suppression (asymptomatic), dose-dependent pharmacokinetics, and dose-dependent gross motor improvement favoring 6 mg/kg/d.
Major Points
- Phase II, open-label, nonrandomized, multiple-dose study at 5 Canadian sites; 10 patients each received vamorolone 2 mg/kg/d then 6 mg/kg/d sequentially for 12 weeks, followed by an Expanded Access Protocol (EAP) with data snapshot at ~2 years of exposure.
- Safety: 70% (2 mg/kg/d) and 90% (6 mg/kg/d) had at least one TEAE; no deaths, no serious TEAEs, no discontinuations; most TEAEs were mild GI events (80% at 6 mg/kg/d) and infections (50% at 2 mg/kg/d, mainly nasopharyngitis).
- Adrenal suppression (morning cortisol ≤65 nmol/L) at week 12 occurred in 20% (2/10) at 2 mg/kg/d and 40% (4/10) at 6 mg/kg/d; all asymptomatic; 3 patients required hydrocortisone stress dosing during study.
- Growth: stable height, weight, and BMI z-scores over 12 weeks; ~2 years of EAP follow-up showed median CBL height-score 0.066, BMI-score 0.234; 8/19 patients had BMI-score change >0.5 suggesting excessive weight gain.
- Pharmacokinetics: dose-dependent Cmax and AUC with rapid absorption (Tmax ~2 h); no accumulation between day 1 and week 2; profile consistent with prior data in 4-<7 year-olds.
- Exploratory efficacy: median Bayley-III gross motor scaled score change from baseline to week 12 was 0.0 (2 mg/kg/d) vs 2.5 (6 mg/kg/d), suggesting dose-dependent motor benefit favoring 6 mg/kg/d.
- Bone turnover biomarkers (osteocalcin, CTX1, P1NP) and glucose metabolism markers (fasting glucose, HbA1c, insulin) remained stable at both doses.
- Class IV evidence given the small (n=20), open-label, nonrandomized design; no formal hypothesis testing was planned.
Study Design
- Study Type
- Phase II, open-label, nonrandomized, multiple-dose clinical trial
- Randomization
- No
- Blinding
- Open-label
- Sample Size
- 20
- Follow-up
- 12 weeks (primary); ~2 years median in EAP Canada extension
- Centers
- 5
- Countries
- Canada
Primary Outcome
Definition: Safety and tolerability: TEAEs, SAEs, and change from baseline to week 12 in height, weight, and BMI
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 2 mg/kg/d: 70% (7/10) had ≥1 TEAE (18 events); 0 SAEs; median CBL height-score -0.04, weight-score -0.01, BMI-score 0.12 | 6 mg/kg/d: 90% (9/10) had ≥1 TEAE (39 events); 0 SAEs; median CBL height-score 0.09, weight-score 0.13, BMI-score -0.13 | - (Not applicable (descriptive)) | Not applicable (descriptive) |
Limitations & Criticisms
- Small sample size (n=20; 10 per arm) limits precision of safety and efficacy estimates
- Open-label, nonrandomized, single-country (Canada) design provides only Class IV evidence
- Sequential (not concurrent) allocation to dose groups introduces potential temporal confounding
- No placebo or classic corticosteroid comparator; efficacy interpretation relies on historical controls
- Short 12-week primary treatment period is insufficient to fully evaluate long-term growth, bone health, or motor function; EAP follow-up used routine-care data quality only
- Bayley-III is validated only up to 3.5 years, but was used in all participants; efficacy signal driven partly by patients above the validated age range
- PK terminal half-life and AUC-infinity could not be calculated due to sparse sampling; high interpatient variability
- Industry-sponsored study (Santhera/ReveraGen); several coauthors are company employees
- Age distribution skewed toward the upper end of the 2-<4 y range (median 3.4 y), limiting generalizability to the youngest patients
- Fasting insulin data unavailable for 2 mg/kg/d group due to central-laboratory sample-handling oversight
Citation
Neurology 2026;106(11):e218066