Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 225.00K | Year: 2015
DESCRIPTION provided by applicant Glucocorticoids GCandapos s such as prednisolone are used frequently to induce remission and treat rheumatoid arthritis RA Despite effectiveness many GC mediated detrimental side effects including osteoporosis and muscle atrophy limit long term chronic treatment of RA patients In addition juvenile arthritis patients suffer from th side effect of significant stunting of linear growth These side effects are believed to be mediated by well described glucocorticoid response element GRE mediated transcriptional properties transactivation whereas efficacy is mediated by transrepression of NFkB pro inflammatory pathways ReveraGen BioPharma has identified a lead compound VBP that is a novel dissociative steroid designed to maintain the anti inflammatory efficacy of traditional steroids through NFkB inhibition and GR translocation yet has lost GRE mediated transcriptional activities leading to much less side effects typically associated with traditional glucocorticoid drugs no osteopenia growth stunting or steroid myopathy Importantly VBP has been shown to reduce inflammatory activity in vivo across multiple murine models of disease Furthermore we have demonstrated in a pilot study that VBP significantly reduces the severity of disease in the collagen antibody induced mouse model of arthritis preliminary data Thus VBP may represent a safer and more effective alternative to traditional glucocorticoids in the treatment of RA where treatment of elderly RA patients may show efficacy with loss of osteopenia and steroid myopathy side effects and loss of growth stunting side effects important in juvenile RA The goal of this STTR research is to extend preclinical evaluation of VBP with a blinded study of efficacy endpoints in a chronic collagen induced mouse model of arthritis CIA using published recommendations for pre clinical studies We hypothesize that VBP treatment after disease onset will result in similar anti inflammatory activity compared to prednisolone but possess a much reduced side effect profile As VBP has already entered Phase clinical trials in adult healthy volunteers transition to RA trials would likely ensure shortly after the successful completion of the proposed STTR grant PUBLIC HEALTH RELEVANCE The goal of this STTR research is to extend preclinical evaluation of VBP with a blinded study of efficacy endpoints in a chronic collagen induced mouse model of arthritis using published recommendations for pre clinical studies VBP may represent a safer and more effective alternative to traditional glucocorticoids in the treatment of rheumatoid arthritis
Reveragen Biopharma, Inc. | Date: 2012-11-29
The present invention relates to compounds and methods which may be useful as treatments of diseases.
Reveragen Biopharma, Inc. | Date: 2014-01-27
The present invention relates to compounds and methods which may be useful as treatments of neuromuscular diseases such as muscular dystrophy, and as inhibitors of NF-B for the treatment or prevention of muscular wasting disease, including muscular dystrophy.
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 225.00K | Year: 2014
? DESCRIPTION (provided by applicant): Glucocorticoids (e.g. prednisolone) are prescribed frequently to treat inflammatory bowel disease (IBD). Despite effectiveness, adverse side effects believed to be caused by GRE-mediated transcriptional propertieslimit long term use of glucocorticoids in IBD patients. Furthermore, these GRE-mediated transcriptional activities have been previously shown to be responsible for glucocorticoid-induced impaired healing of the intestinal epithelium. This may explain whyglucocorticoids do not appear to be effective in maintaining remission of disease. ReveraGen BioPharma has identified a novel dissociative steroidal compound (VBP15) designed that retains the anti-inflammatory efficacy of traditional steroids (via NFkB inhibition), but has lost GRE-mediated transcriptional activities. VBP15 treatment has been shown to reduce inflammatory activity in vivo in multiple models of disease including the TNBS-induced mouse model of colitis (preliminary data) and result in a much m
Reeves E.K.M.,Reveragen Biopharma, Inc. |
Hoffman E.P.,Reveragen Biopharma, Inc. |
Hoffman E.P.,Center for Genetic Medicine Research |
Hoffman E.P.,George Washington University |
And 6 more authors.
Bioorganic and Medicinal Chemistry | Year: 2013
Δ9,11 modifications of glucocorticoids (21-aminosteroids) have been developed as drugs for protection against cell damage (lipid peroxidation; lazaroids) and inhibition of neovascularization (anecortave). Part of the rationale for developing these compounds has been the loss of glucocorticoid receptor binding due to the Δ9,11 modification, thus avoiding many immunosuppressive activities and deleterious side effect profiles associated with binding to glucocorticoid and mineralocorticoid receptors. We recently demonstrated that anecortave acetate and its 21-hydroxy analog (VBP1) do, in fact, show glucocorticoid and mineralocorticoid receptor binding activities, with potent translocation of the glucocorticoid receptor to the cell nucleus. We concluded that Δ9,11 steroids showed novel anti-inflammatory properties, retaining NF-κB inhibition, but losing deleterious glucocorticoid side effect profiles. Evidence for this was developed in pre-clinical trials of chronic muscle inflammation. Here, we describe a drug development program aimed at optimizing the Δ9,11 chemistry. Twenty Δ9,11 derivatives were tested in in vitro screens for NF-κB inhibition and GR translocation to the nucleus, and low cell toxicity. VBP15 was selected as the lead compound due to potent NF-κB inhibition and GR translocation similar to prednisone and dexamethasone, lack of transactivation properties, and good bioavailability. Phamacokinetics were similar to traditional glucocorticoid drugs with terminal half-life of 0.35 h (mice), 0.58 h (rats), 5.42 h (dogs), and bioavailability of 74.5% (mice), and 53.2% (dogs). Metabolic stability showed ≥80% remaining at 1 h of VBP6 and VBP15 in human, dog, and monkey liver microsomes. Solubility, permeability and plasma protein binding were within acceptable limits. VBP15 moderately induced CYP3A4 across the three human hepatocyte donors (24-42%), similar to other steroids. VBP15 is currently under development for treatment of Duchenne muscular dystrophy. © 2013 Elsevier Ltd. All rights reserved. Source