Potential DMD Therapy Vamorolone Shows Positive Effects in Phase 2a Trial, Study Reports

Vamorolone, a Duchenne muscular dystrophy (DMD) treatment candidate, showed anti-inflammatory activity and an improved safety profile over the glucocorticoid prednisolone in a Phase 2a clinical trial for boys 4 to 6 years old.

Findings from the trial were published in the study, “Phase IIa trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug,” in the journal Pharmacological Research.

Treatment of DMD with anti-inflammatory glucocorticoid prednisone and Emflaza (deflazacort) delays disease progression, but is associated with serious adverse effects, such as increased bone fragility, delayed puberty, mood changes, and metabolic disturbances. Due to concerns over these side effects, about half of U.S. and European patients do not receive this standard of care.

ReveraGen BioPharma’s vamorolone is a steroidal product highly similar in its chemistry and 3D structure to glucocorticoids, but it induces reduced pro-inflammatory gene expression when bound to the glucocorticoid receptor.

This difference may boost its anti-inflammatory effects while lessening the typical side effects of glucocorticoids, as shown in animal models and a Phase 1 trial, which makes vamorolone a so-called “dissociative” steroidal therapy.

Destabilized membranes of myofibers — a type of muscle cell — occur as a result of DMD’s hallmark loss of the protein dystrophin. Vamorolone was designed to have a superior ability over prednisolone in stabilizing myofiber membranes while inhibiting NF-ĸB, a pro-inflammatory protein complex that controls gene expression and is activated in the muscle of DMD patients at birth, years before clinical symptoms.

Aiming to further explore vamorolone’s effectiveness and safety, researchers conducted the multicenter, open-label Phase 2a trial (NCT02760264), sponsored by ReveraGen, in 48 ambulant boys with DMD not previously treated with glucocorticoids. The two-week study assessed ascending daily doses of the oral therapy — 0.25, 0.75, 2, and 6 mg/kg, with 12 patients receiving each dose — followed by two weeks of no treatment.

The team also analyzed pharmacodynamic (the relationship between the concentration of a medication at a specific site and its effects) biomarkers of clinical safety concerns of glucocorticoids, namely insulin resistance, adrenal glands suppression — or insufficient production of cortisol — and changes in bone turnover, which refers to the total volume of bone that is reabsorbed and formed over a period of time.

In addition, seven pro-inflammatory serum proteins whose levels are reduced with glucocorticoid treatment in children with DMD and inflammatory bowel disease, were evaluated as markers of effectiveness, and six serum biomarkers significantly increased by glucocorticoids were assessed as markers of safety.

Results showed that vamorolone was safe and well-tolerated through the highest dose, measured by clinical laboratory analyses, physical examinations, vital sign measurements, and electrocardiograms.

A total of 46 treatment-emergent adverse events (TEAEs) were noted, the most common being upper respiratory tract infection (12.5%), diarrhea (8.3%), pain in extremity (6.3%), and vomiting (6.3%). Eight participants (16.7%) had TEAEs considered possibly or probably related to vamorolone, but no TEAE was confirmed as being definitely related to the therapy. Most TEAEs were mild, and there were no severe TEAEs.

Vamorolone did not cause persistent elevations in the enzymes glutamate dehydrogenase and gamma-glutamyl transferase, suggesting it does not cause acute or subacute liver toxicity. The analysis also showed that the pharmacokinetics — drug absorption, distribution, metabolism, and excretion in the body — of vamorolone were similar to prednisolone.

Vamorolone demonstrated improved safety over glucocorticoids, illustrated by reduced insulin resistance, less bone resorption and formation (only at the highest dose), and a milder decrease in adrenal suppression — measured by first-in-morning cortisol — compared with prior data in adult volunteers.

Analysis of serum biomarkers showed dose-dependent decreases of pro-inflammatory proteins and creatine kinase activity, a biomarker of muscle disease activity, indicating the potential to stabilize the myofiber membrane, the team observed.

“We demonstrate the development of the first dissociative steroid that preserves anti-inflammatory efficacy and decreases steroid-associated safety concerns,” the investigators wrote.

In addition to DMD patients, this anti-inflammatory property of vamorolone should also benefit individuals with Becker MD, they added.

After the study’s completion, the patients could enroll in the six-month open label VBP15-003 extension study (NCT02760277), and then the 24-month, open-label, long-term VBP15-LTE extension trial (NCT03038399).

Of note, seven of the study’s authors are employees of ReveraGen. Three are co-founders of ReveraGen and own founder shares. Five received payment from ReveraGen for statistical analysis and consultancy.