How does vamorolone work?
DMD is caused by mutations in the DMD gene that cells need to make dystrophin. Dystrophin is a protein that helps protect muscles while they contract. Mutations in the DMD gene lead to cells not being able to produce working dystrophin protein. This causes damage to muscle cells at each contraction. Over time, this leads to fibrosis (scar tissue) formation in the muscles.
DMD is typically managed with corticosteroids like deflazacort and prednisone. The aim is to reduce inflammation and strengthen muscles. Corticosteroids often have a number of side effects, however, including fluid retention, high blood pressure and weight gain, among others.
Vamorolone is a dissociative steroid. It works in a similar way to other corticosteroids by activating certain pathways within the cell and inhibiting others. For example, it inhibits the NF-kB pathway, which is linked to inflammation. It also binds to and helps stabilize the membranes around cells without causing transactivation. Transactivation is the increase of gene expression that glucocorticoid response elements (GRES) cause. It results in many of the side effects of corticosteroid treatment. Vamorolone also may help preserve heart function in DMD patients through the inhibition of mineralocorticoid receptors.
Vamorolone in clinical trials
Researchers first investigated the safety of vamorolone in 86 healthy men in a Phase 1 clinical trial (NCT02415439). Participants received single ascending doses and multiple ascending doses of the treatment to establish the maximum tolerated dose.
The results of the study were published in the journal Steroids in 2018. They showed that vamorolone did not lead to safety concerns up to the maximum dose of 20 mg/kg per day.
Researchers also studied vamorolone in an open-label Phase 2a clinical trial (NCT02760264) in 48 boys with DMD, ages 4 to 7. They divided the patients into four groups of 12. Each group received one of four oral doses or treatment (0.25, 0.75, 2.0, or 6.0 mg/kg per day) for 14 days. The goal was to assess the safety, pharmacokinetics (movement in the body), and pharmacodynamics (effects on the body) of vamorolone.
Results showed that patients tolerated all four dose levels well. The pharmacokinetics of the treatment was similar to prednisone. The study also found a decrease in biomarkers of inflammation along with lower insulin resistance, positive changes to bone breakdown, and less adrenal gland inhibition.
The 48 patients then continued treatment in an extension study (NCT02760277) in which they continued to take the same dose of treatment for 24 weeks. The extension study continued to monitor safety. It also assessed changes in each patient’s body mass index (BMI) and their performance in a time-to-stand test (TTSTAND).
The results were published in the journal Neurology and showed that all four dose levels were safe and well-tolerated. Patients also showed dose- and time-dependent improvements in the TTSTAND test at 12 and 24 weeks. They also had dose-dependent improvements in other functional measures. These included the time to climb a set of stairs, time to walk/run 10 meters (11 yards), the six-minute walk test, and the North Star Ambulatory Test, which is used to measure functional motor abilities. The analysis of biomarkers continued to show that patients did not experience changes in bone mass, reduction in adrenal gland function, or insulin resistance that corticosteroids normally cause.
Patients from the previous Phase 2 trials continued on to another extension trial (NCT03038399) for 24 more months of treatment at the same four dose levels that they received earlier.
Researchers published interim data from 23 patients who had reached at least 18 months of treatment. They showed that patients continued to improve in motor outcomes such as the TTSTAND and the time to run/walk 10 meters.
Researchers also compared patients receiving vamorolone against a group of DMD patients who did not receive any corticosteroid treatment in another study (NCT00468832). The patients who received treatment did not score better on the TTSTAND test. However, they were faster on the time to run/walk 10 meters and time-to-climb stairs test.
Ongoing clinical trials
Santhera announced in a press release that the extension trial was complete and that all 46 patients who completed it wished to continue receiving vamorolone. Those in the U.S., Canada, and Israel have the opportunity to transition to the expanded access program (NCT03863119). Those in the U.K., Sweden, or Australia have access to a compassionate use program. Of the 41 patients who attended the end-of-trial visit, 27 (66%) finished the trial at the highest dose (6 mg/kg per day). Researchers reported no serious adverse side effects related to vamorolone over the 2.5 years of investigation.
VISION-DMD, a Phase 2b clinical trial (NCT03439670), is further investigating vamorolone in DMD patients. Prior to the study, researchers screen patients for five weeks. They then assign them randomly to one of six treatment groups to receive either 2 mg/kg/day of vamorolone, 6 mg/kg/day of vamorolone, 0.75 mg/kg/day of prednisone, or a placebo for 24 weeks. Then patients receiving vamorolone or placebo continue to receive the same doses for four weeks while the prednisone group tapers dosage to zero. At that point, researchers will divide the prednisone and placebo groups into two with one half receiving 2 mg/kg/day and the other receiving 6 mg/kg/day of vamorolone. All patients will then continue to receive vamorolone for another 20 weeks.
The primary outcome is the TTSTAND test score between the higher vamorolone dose and the placebo group at 24 weeks. Researchers will record TTSTAND results for the other treatment groups and also at 48 weeks. They also will perform additional functional testing.
The study has completed the enrollment of 121 patients, ages 4 to 7. Researchers estimate completing the study in the first quarter of 2021 with topline results becoming available in the second quarter.
Vamorolone received orphan drug designation in the U.S. and Europe, plus fast track and rare pediatric disease designations in the U.S. Vamorolone also has received the promising innovative medicine designation in the U.K.
ReveraGen BioPharma received a grant worth $3.3 million from the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health (NIH) to support further development of vamorolone.
Last updated: Feb. 2, 2021
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