Santhera: Publication of long-term clinical data in patients with Duchenne Muscular Dystrophy

This publication in the journal PLOS Medicine [1] provides peer-reviewed and detailed open-label data in patients with DMD treated for 18 months with vamorolone. A multi-center, open-label, 24-week trial (VBP15-003; [2, 3]) with a total 24-month long-term extension (VBP15-LTE; [4]) was conducted by the Cooperative International Neuromuscular Research Group (CINRG) and evaluated drug-related effects of vamorolone on motor outcomes and corticosteroid-associated safety concerns. This publication covers the 24-week Phase 2a trial (VBP15-003) and the first 12 months of the open-label extension trial (VBP15-LTE) adding up to a total treatment period of 18 months.

“This long-term study showed significant continued clinical improvement of all outcomes measured over an 18-month follow-up period,” said Edward C. Smith, MD, Associate Professor of Pediatrics, Duke University, Durham (North Carolina, USA), clinical investigator and lead-author of the publication. “Treatment-related efficacy responses with vamorolone were similar to those seen in an external control group with corticosteroid-treated patients. Both 4-stair climb and 10-meter run/walk tests were significantly improved when compared to steroid-naïve natural history control subjects.”

“Importantly, we also found that vamorolone did not show stunting of growth seen with deflazacort and prednisone, and vamorolone also showed fewer physician-reported adverse events such as mood disturbance, excessive hair growth, and Cushingoid appearance,” noted Eric Hoffman, PhD, Vice President of Research at ReveraGen BioPharma, Inc. and co-author of the study.

DMD trial participants (4 to <7 years at entry) treated with 2.0 or 6.0 mg/kg/day vamorolone for the full 18-month period (n=23) showed clinical improvement of all motor outcomes from baseline to month 18 (time to stand velocity, p = 0.012 [95% CI 0.010, 0.068 event/second]; run/walk 10 meters velocity, p < 0.001 [95% CI 0.220, 0.491 meters/second]; climb 4 stairs velocity, p = 0.001 [95% CI 0.034, 0.105 event/second]; 6-minute walk test, p = 0.001 [95% CI 31.14, 93.38 meters]; North Star Ambulatory Assessment, p < 0.001 [95% CI 2.702, 6.662 points]). Outcomes in vamorolone-treated DMD patients (n = 46) were compared to group-matched participants in the CINRG Duchenne Natural History Study (corticosteroid-naïve, n = 19; corticosteroid-treated, n = 68) over a similar 18-month period. Time to stand was not significantly different between vamorolone-treated and corticosteroid-naïve participants (p = 0.088; least squares [LS] mean 0.042 [95% CI –0.007, 0.091]), but vamorolone-treated participants showed significant improvement compared to group-matched corticosteroid-naïve participants for run/walk 10 meters velocity (p = 0.003; LS mean 0.286 [95% CI 0.104, 0.469]) and climb 4 stairs velocity (p = 0.027; LS mean 0.059 [95% CI 0.007, 0.111]). The vamorolone-related improvements were similar in magnitude to corticosteroid-related improvements. Corticosteroid-treated participants showed stunting of growth, whereas vamorolone-treated trial participants did not (p < 0.001; LS mean 15.86 [95% CI 8.51, 23.22]). Physician-reported incidences of adverse events (AEs) for Cushingoid appearance, hirsutism, weight gain, and behavior change were less for vamorolone than published incidences for prednisone and deflazacort.

References

[1]   Smith E, et al. (2020). Efficacy and safety of vamorolone in Duchenne muscular dystrophy: an
18-month interim analysis of a non-randomized open-label extension study. PLOS Medicine, Link

[2]   Clinicaltrials.gov: An Extension Study to Assess Vamorolone in Boys with Duchenne Muscular Dystrophy (DMD), Link

[3]   Hoffman EP et al. (2019). Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function. Neurology 93: e1312-e1323.

[4]   Clinicaltrials.gov: Long-term Extension Study to Assess Vamorolone in Boys with Duchenne Muscular Dystrophy (DMD), Link

[5]   Heier CR at al. (2013). VBP15, a novel anti‐inflammatory and membrane‐stabilizer, improves muscular dystrophy without side effects. EMBO Mol Med 5: 1569–1585.

[6]   Reeves EKM, et al (2013) VBP15: preclinical characterization of a novel anti-inflammatory delta 9,11 steroid. Bioorg Med Chem 21(8):2241-2249

[7]   Heier CR et al. (2019). Vamorolone targets dual nuclear receptors to treat inflammation and dystrophic cardiomyopathy. Life Science Alliance DOI 10.26508/lsa.201800186.

[8]   Liu X et al. (2020). Disruption of a key ligand-H-bond network drives dissociative properties in vamorolone for Duchenne muscular dystrophy treatment. Proc Natl Acad Sci USA. Link 

[9]   Press release “Santhera Exercises Option to Obtain Worldwide Rights to Vamorolone in Duchenne Muscular Dystrophy and All Other Indications”, September 2, 2020, Link

[10] Clinicaltrials.gov: A Study to Assess the Efficacy and Safety of Vamorolone in Boys with Duchenne Muscular Dystrophy (DMD), Link

[11] Press release “Santhera Announces Full Enrollment of ReveraGen’s Pivotal VISION-DMD Study with Vamorolone in Duchenne Muscular Dystrophy”, September 11, 2020, Link