The experimental therapy vamorolone can improve motor function significantly in boys with Duchenne muscular dystrophy (DMD), without stunting their growth and with fewer side effects compared to standard corticosteroids, according to 18-month data from a Phase 2 trial and its extension study.
Findings were reported in the study, “Efficacy and safety of vamorolone in Duchenne muscular dystrophy: An 18-month interim analysis of a non-randomized open-label extension study,” published in the journal PLOS Medicine.
Vamolorone (VBP15) is an anti-inflammatory steroid treatment that aims to slow DMD progression, while causing fewer and less-severe side effects than conventional corticosteroids, such as prednisone and Emflaza (deflazacort). The therapy is being developed by ReveraGen Biopharma and Santhera Pharmaceuticals, which holds worldwide rights to vamorolone in all indications.
Published findings included data from the open-label Phase 2 VBP15-003 trial (NCT02760277) and its long-term extension study VBP15-LTE (NCT03038399), which assessed the safety and efficacy of vamorolone in boys with DMD, ages 4–7.
The original 24-week VBP15-003 trial, which was conducted by the Cooperative International Neuromuscular Research Group (CINRG), enrolled 48 boys. After completing this study, participants had the option to continue treatment with vamorolone by enrolling in the two-year extension study, or switch over to standard treatment with prednisone or Emflaza.
All 26 patients who completed treatment opted by enrolling in the long-term extension study, where they received vamorolone at an daily dose of 2 or 6 mg/kg for up to two years.
Data from the 23 boys who completed 18-months of treatment across VBP15-003 and VBP15-LTE showed that vamorolone led to clinically meaningful improvements in all motor outcomes analyzed. These included the speed at which boys were able to stand, run or walk 10 meters (about 11 yards), and climb stairs.
“This long-term study showed significant continued clinical improvement of all outcomes measured over an 18-month follow-up period,” Edward C. Smith, MD, professor of pediatrics at Duke University, clinical investigator and lead author of the study, said in a press release.
The investigators then compared data from vamorolone-treated boys in these studies with another group of DMD boys who had been receiving corticosteroids or had never been exposed to these medications (corticosteroid-naïve patients) and were being followed in the CINRG Duchenne Natural History Study (NCT00468832).
Although the speed at which boys were able to stand did not differ between vamorolone-treated and corticosteroid-naïve patients, those receiving vamorolone were able to run or walk 10 meters and climb stairs significantly faster than patients who had never been treated with corticosteroids.
The magnitude of the benefits seen with vamorolone was identical to that seen in patients receiving standard corticosteroids.
However, boys treated with corticosteroids had stunted growth, unlike those treated with vamorolone. In addition, the incidence of side effects associated with the use of corticosteroids, including weight gain, behavioral changes, and hirsutism (excessive hair growth), was lower among boys treated with vamorolone, compared to published incidences for prednisone and Emflaza.
In a separate study performed with investigators at Emory University, Atlanta, Georgia, and the Binghamton University-State University of New York, ReveraGen explored the structural, biochemical, and pharmacological properties that set vamorolone apart from all other corticosteroids.
The study, recently published in the journal PNAS, showed that, compared to prednisone or deflazacort, vamorolone has one less point of contact with the glucocorticoid receptor, its target protein, which seems to boost therapeutic effects.
In addition, the team discovered that vamorolone seems to weaken the association of accessory proteins to the glucocorticoid receptor, lowering the activity of genes associated with side effects of corticosteroid usage.
However, the experimental therapy does not prevent co-repressor accessory proteins from interacting with the receptor, which has been found to be crucial for the anti-inflammatory properties and effectiveness of corticosteroids.
“We now understand the molecular basis of the dissociative properties of vamorolone, which retains the anti-inflammatory capacity but result in a reduced liability for undesirable side effects. Vamorolone is in advanced clinical development with the potential to offer an alternative to current standard of care treatments in young boys with DMD,” Eric Hoffman, PhD, said in another press release. Hoffman is vice president of research at ReveraGen and a study co-author.
The company also announced it has completed enrollment into VISION-DMD (VBP15-004, NCT03439670), a 48-week Phase 2b trial of the safety and efficacy of vamorolone, compared to prednisone or a placebo, in a group of 121 boys, ages 4–7, who are able to walk independently.
“We are very pleased having achieved full enrollment of our pivotal trial with vamorolone in patients with Duchenne muscular dystrophy,” Hoffman stqted in another press release. “On behalf of the entire study team we would like to thank patients and their families for their enthusiastic engagement to help advance the clinical development of vamorolone.”
During the trial, boys will be assigned randomly to receive one of two daily doses of vamorolone (2 or 6 mg/kg), prednisone (daily dose of 0.75 mg/kg), or a placebo, for 24 weeks — nearly six months. Those originally assigned to receive vamorolone then will continue treatment for another 24 weeks, while boys initially receiving prednisone or a placebo will switch over to receive one of the doses of vamorolone for 24 weeks.
The main goal of the study is to compare the effects of vamorolone, prednisone, and placebo on patients’ muscle strength and motor function. This will be assessed once patients complete the first 24 weeks of treatment by the time-to-stand test, and other motor function tests. In addition, the safety and tolerability of the different types of treatment also will be assessed.
The initial 24-week treatment period is expected to be completed in early 2021, and top-line data are expected soon after. If positive, data from VISION-DMD may support the future submission of an application to the U.S. Food and Drug Administration requesting the approval of vamorolone for the treatment of DMD by the end of next year.
“We congratulate ReveraGen on this accomplishment of fully enrolling the VISION-DMD trial, in times where the conduct of any clinical trial is very challenging for patients and families, study sites and study personnel,” said Kristina Sjöblom Nygren, MD, chief medical officer and head of development at Santhera.
“It is already clear from existing data from previous studies that vamorolone has tremendous therapeutic potential for patients with Duchenne muscular dystrophy and we are looking forward to the outcome of the 6-month randomized, placebo- and prednisone-controlled period of the VISION-DMD trial,” Nygren added.
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