First-in-Class Macrocyclic Peptide Therapeutic For Rheumatoid Arthritis

DESCRIPTION provided by applicant This Direct Phase II SBIR Grant application seeks support to continue the preclinical development of a paradigm changing therapeutic for rheumatoid arthritis RA RA is a chronic debilitating systemic disease that affects to of the population worldwide Despite the advent of biologic therapies it is broadly recognized that there remains a significant unmet need for more effective and safer RA treatments since approximately of RA patients are refractory to all existing therapies and current drugs are limited by severe adverse side effects Oryn Therapeutics LLC the andquot companyandquot will conduct IND enabling studies that exploit the discovery of a new class of macrocyclic immunomodulating peptides termed theta defensins defensins expressed in leukocytes of Old World primates defensin expression ceased before the emergence of humans gorillas and chimpanzees Thus the company has embarked on the development of a synthetic version of a natural defensin termed ORTD as a retro evolutionary biologic pharmaceutical for RA SBIR Phase I equivalent studies suggest that ORTD may be utilized for RA treatment in humans without the adverse side effects of currently employed RA drugs Scalable protocols for ORTD synthesis have been developed enabling the testing of multi gram batches of cGMP ORTD With this material we showed that ORTD is highly effective in two animal models of RA and the cyclic peptide is more effective than methotrexate or etanercept Enbrel r in arresting and reversing autoimmune arthritis in rats ORTD is non toxic has unexpected pharmacokinetic PK properties and is non immunogenic Further ORTD has shown no evidence of immunocompromising immunosuppression one of the adverse side effects of current RA biologics The company proposes focused studies outlined in two Specific Aims to further the development of ORTD through filing of an IND application with the FDA In Aim we will i refine a recently developed ORTD ELISA for use in GLP toxicokinetic studies ii perform multi dose ORTD PK studies in rats iii conduct PK pharmacodynamic studies in the rat pristane induced arthritis model and iv determine metabolism and route of elimination of C ORTD administered to rats In Aim we will conduct IND enabling GLP toxicity and toxicokinetic studies of injectable ORTD in rats and beagle dogs The development plan also includes ORTD formulation studies which are already underway and genotoxicity studies The development plan includes preparation of the pre IND Briefing Document and the pre IND meeting itself in the year A key milestone for the proposed studies will be filing of an IND application for ORTD as an RA therapeutic by the end of this two year project PUBLIC HEALTH RELEVANCE Rheumatoid arthritis RA is a chronic destructive inflammatory disease that affects of the population worldwide The small business entity seeks to introduce a paradigm changing treatment for RA building on the discovery of a naturally occurring cyclic peptide that arrests and reverses joint damage in animal models of RA The proposed research seeks to perform preclinical studies of efficacy and safety that will lead to the filing of an Investigational New Drug application for this first in class RA therapeuti