Late Stage Development of Sustained-release Relaxin for Treating Joint Contracture

PROJECT SUMMARY/ABSTRACT Shoulder contracture or “arthrofibrosis” is a painful and gradual loss of shoulder motion caused by trauma, surgical procedures, inflammation, prolonged joint immobilization, or for no clear cause (i.e. idiopathically), as is the case in “frozen shoulder”. Shoulder arthrofibrosis occurs in 9 million individuals in the United States with more than 1.6 million seeking surgical remedies each year. Current treatment options, including intra-articular corticosteroid injections, NSAIDs, and nerve blockers, provide only marginal and temporary relief of patient symptoms and do not address the underlying cause of the disease—the accumulation of fibrotic collagenous tissue. Surgical interventions are used in more severe cases, but these procedures are fraught with complica- tions and can further aggravate symptoms. Ortholevo is developing a local injectable polymeric microparticle sustained release formulation of relaxin-2 for the treatment of shoulder arthrofibrosis. Relaxin-2 (RLX) is a 6-kDa naturally-occurring peptide hormone that is present in males and females but is especially known for temporally downregulating collagen production and upregulating matrix metalloproteases to loosen pelvic ligaments prior to childbirth. Using this peptide therapeutic for the treatment of arthrofibrosis provides an unprecedented opportunity to treat this disease with a first of its kind therapy and a resulting paradigm shift in the treatment of shoulder arthrofibrosis. Ortholevo proposes to advance its technology down the path of commercialization by the completion of the following late-stage product development proposed aims: 1) Perform pilot scale production of IND-enabling re- laxin (RLX) drug substance for use in late stage drug product development; 2) Complete late-stage manufactur- ing activities and sterilization development of sustained-release relaxin (SR-RLX) drug product, resulting in a tox batch for IND-enabling studies; 3) Conduct key rat GLP acute local toxicology studies to demonstrate a wide therapeutic window; and 4) Execute FDA regulatory strategy in support of pre-IND meeting and IND submission. To accomplish these aims, we have collected key preliminary data demonstrating efficacy using a relaxin-2 loaded microparticle formulation as well as assembled a team with expertise in science/engineering/medicine (e.g., protein therapeutics, microparticles, biomechanics, and clinical joint contracture) and translation and com- mercialization (e.g., management, regulatory, manufacturing, and marketing). With the successful completion of the specific aims in this CRP proposal, the next commercialization steps include completing remaining IND- enabling studies, producing clinical trial drug product, obtaining IND approval, and initiating clinical investigation. Achievement of these goals will lead to the first standard of care treatment for shoulder arthrofibrosis based on reversing the underlying and abnormal accumulation of fibrotic collagenous tissue that delivers the therapeutic in a sustained and controlled manner to the site of disease while keeping systemic exposure to a minimum.