Duchenne muscular dystrophy (DMD) affects approximately 10,000 patients in the United States and 40,000 worldwide. Characteristic muscle deterioration results in confinement to wheelchairs by age 12 and death by age 30 due to cardio-respiratory failure. Current therapy, glucocorticoid steroid injection, acts in a nonspecific manner to lessen the severity of symptoms but does not treat the muscle-specific effects of DMD. Glucocorticoids can be used only for a short time due to serious toxic side effects, including bone fragility, suppression of the immune system and suppression of growth hormone production. The purpose of this project is to develop a modified steroid treatment that will be specific to the muscles, potentially avoiding the toxic side effects of current therapy.
Chronic treatments with glucocorticoids are considered the standard of care for DMD and result in improved strength and prolonged ambulation. However, side effects, such as bone fragility and stunted growth, can be serious. Accumulating evidence suggests that side effects are mediated by drug/receptor interactions, whereas efficacy is mediated by non-receptor mechanisms. Delta 9,11 derivatives of steroids were developed to retain efficacy but eliminate side effects. Intellectual property on methods of use has been filed in multiple countries and assigned to Validus BioPharma (since renamed ReveraGen BioPharma). Funding to date has been provided by MDA Venture Philanthropy, the Department of Defense Congressionally Directed Medical Research Programs, the Foundation to Eradicate Duchenne and NIH. A lead compound, VBP15, has been selected, and in vitro and in vivo efficacy was shown in muscular dystrophy and asthma mouse models. Pharmacokinetic/absorption, distribution, metabolism, and excretion (PK/ADME) studies have been completed, and VBP15 shows excellent features. The goal of the TRND project is to complete Investigational New Drug (IND)–enabling toxicology to enable first-in-human trials in DMD. The timeline includes acute and chronic GLP toxicology studies, formulation studies, and submission of an IND in a 14- to 16-month time frame.
ReveraGen BioPharma, Inc., Rockville, Maryland
Erica Reeves, Ph.D.
Public Health Impact
DMD is a rare disease caused by mutations in the X-linked dystrophin gene, resulting in loss of function of the dystrophin protein in skeletal muscle, heart, smooth muscle, and some neurons and glia. Disease incidence is about one in 3,500 live-born males, and approximately 8,000 males are affected in the United States. Current standard therapy, glucocorticoids, can be used only for a short period due to associated serious toxicities, such as bone fragility, adrenal suppression, immune suppression and mood changes. This project aims to develop novel compounds that provide DMD patients with tissue-selective treatment. Potential tissue-selective glucocorticoids can benefit larger patient populations in the United States.
After TRND’s acceptance of the project, ReveraGen was able to secure supplemental funding from the Muscular Dystrophy Association to speed the team’s collaborative work. TRND completed confirmatory studies demonstrating the effectiveness of the candidate molecule in both cell-based assays and animal models of DMD disease, and successfully designed and executed a novel synthetic route for manufacturing the candidate molecule for human testing under Food and Drug Administration (FDA) guidelines. TRND prepared for and participated in a pre-IND meeting with the FDA in early fiscal year 2014 to receive guidance regarding clinical endpoints and other regulatory issues. TRND support generated the data package necessary for filing an IND application for VBP15. However, in late fiscal year 2014, the molecule failed to meet a key pre-clinical safety milestone within the TRND project plan. For this reason, the project has been discontinued.