SBIR-STTR Award

Direct to Phase II

Frozen shoulder or "shoulder arthrofibrosis" is a painful and gradual loss of shoulder motion caused bytrauma, surgical procedures, inflammation, or prolonged joint immobilization. Shoulder arthrofibrosis occurs in 9million individuals in the United States with more than 1.6 million seeking surgical remedies each year. Currenttreatment options, including intra-articular corticosteroid injections, NSAIDs, and nerve blockers, provide onlymarginal and temporary relief of patient symptoms and do not address the underlying cause of the disease-theaccumulation of fibrotic collagenous tissue. Surgical interventions are used in more severe cases, but theseprocedures are fraught with complications and can further aggravate symptoms. Ortholevo is developing a localinjectable polymeric microparticle sustained release formulation of relaxin-2 for the treatment of shoulder arthro-fibrosis. Human relaxin-2 (RLX) is a 6-kDa naturally-occurring reproductive hormone peptide that temporallydownregulates collagen production and upregulates matrix metalloproteases prior to childbirth. Using this pep-tide therapeutic for the treatment of arthrofibrosis provides an unprecedented opportunity to treat thisdisease with a first of its kind therapy and a resulting paradigm shift in the treatment of shoulderarthrofibrosis. Ortholevo proposes to advance its technology down the path of commercialization by the completion of thefollowing Direct Phase II proposed aims: 1) Transfer our microparticle encapsulation process to Lubrizol LifeScience Health in order to establish product specifications and assess sterilization and shelf-stability; 2) Deter-mine in vivo Minimum Effective Dose (MED), Maximum Tolerated Dose (MTD), and Repeated Dose Toxicity(RDT) of relaxin-2 loaded microparticles in an in vivo rat model; and 3) Determine pharmacokinetics (PK) andefficacy of relaxin-2 loaded microparticles in an in vivo canine joint contracture model. To accomplish these aims,we have collected key preliminary data demonstrating efficacy using a relaxin-2 loaded microparticle formulationas well as assembled a team with expertise in science/engineering (e.g., protein therapeutics, microparticles,biomechanics, and frozen shoulder) and translation and commercialization (e.g., management, regulatory, man-ufacturing and marketing). With the successful completion of the specific aims in this Direct Phase II SBIR pro-posal, the next steps include pre-IND meeting, attaining IND/IRB clinical site approval, followed by Phase I first-in-human clinical safety trial. Achievement of these goals will lead to the first standard of care treatment forshoulder arthrofibrosis based on reversing the underlying and abnormal accumulation of fibrotic collagenoustissue that delivers the therapeutic in a sustained and controlled manner to the site of disease.

Public Health Relevance Statement:
PROJECT NARRATIVE Current surgical and non-surgical treatment options for patients suffering from "frozen shoulder" or shoulder arthrofibrosis are limited in scope and effectiveness, with a significant number of patients never regaining full joint function. Ortholevo has developed a unique treatment for frozen shoulder. This first of its kind therapy delivers the protein, relaxin-2, using a sustained release polymeric microparticle formulation to restore the range of motion and reduce shoulder contracture.

Project Terms:
Achievement ; Achievement Attainment ; Adrenal Cortex Hormones ; Corticoids ; Corticosteroids ; Affect ; Anesthesia procedures ; Anesthesia ; Animals ; Ankle ; Regio tarsalis ; Tarsal Bone ; Tarsus ; Non-Steroidal Anti-Inflammatory Agents ; NSAIDs ; Non Steroidal Antiinflammatory Agents ; Nonsteroidal Anti-Inflammatory Agents ; Nonsteroidal Antiinflammatory Agents ; Nonsteroidal Antiinflammatory Drug ; non-steroidal anti-inflammatory drugs ; non-steroidal antiinflammatory drugs ; nonsteroidal anti-inflammatory drugs ; Biological Sciences ; Biologic Sciences ; Bioscience ; Life Sciences ; Biomechanics ; biomechanical ; Birth ; Parturition ; articular cartilage ; Chemistry ; Collagen ; Contracture ; Diabetes Mellitus ; diabetes ; Disease ; Disorder ; Canis familiaris ; Canine Species ; Dogs ; Dogs Mammals ; canine ; domestic dog ; Down-Regulation ; Downregulation ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Engineering ; Experimental Designs ; Fibroblasts ; Fibrosis ; Freezing ; Goals ; Half-Life ; Hip region structure ; Coxa ; Hip ; Human ; Modern Man ; Immobilization ; orthopedic freezing ; In Vitro ; Incidence ; Inflammation ; Intra-Articular Injections ; Intraarticular Injections ; Joints ; Knee ; Marketing ; Metalloproteases ; Metallopeptidases ; Metalloproteinases ; Microspheres ; Microbeads ; Motion ; Motivation ; Nerve ; Pain ; Painful ; Patients ; Peat ; Drug Kinetics ; Pharmacokinetics ; Polymers ; Production ; Proteins ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Relaxin ; Risk ; Safety ; Science ; Shoulder ; Technology ; Testing ; Tissues ; Body Tissues ; Translations ; United States ; Wrist ; Articular Range of Motion ; Joint Range of Motion ; range of motion ; Drug Delivery Systems ; Drug Delivery ; Injectable ; Schedule ; base ; Organ ; improved ; Procedures ; Peripheral ; Distal ; Site ; Clinical ; Phase ; Histologic ; Histologically ; Ensure ; Individual ; Development Plans ; Collaborations ; Therapeutic ; Morphology ; Frequencies ; Protocol ; Protocols documentation ; Operative Procedures ; Surgical ; Surgical Interventions ; Surgical Procedure ; surgery ; Operative Surgical Procedures ; meetings ; particle ; Peptide Hormone Gene ; peptide hormone ; Performance ; reproductive hormone ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; Toxicities ; Toxic effect ; General Public ; General Population ; Regaine ; Rogaine ; Maximal Tolerated Dose ; Maximally Tolerated Dose ; Maximum Tolerated Dose ; Modeling ; Property ; native protein drug ; pharmaceutical protein ; protein drug agent ; therapeutic protein ; Early-Stage Clinical Trials ; Phase 1 Clinical Trials ; phase I protocol ; Phase I Clinical Trials ; Physiatric Procedure ; Physical Medicine Procedure ; Physical Therapeutics ; Physiotherapy ; Physical therapy ; child birth ; Childbirth ; Effectiveness ; Address ; Dose ; Symptoms ; Data ; Health Sciences ; in vivo ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Process ; joint function ; clinical research site ; clinical site ; Biodistribution ; manufacturing process ; Trauma ; commercialization ; standard of care ; preclinical evaluation ; pre-clinical evaluation ; product development ; Sterilization ; Institutional Review Boards ; IRB ; IRBs ; individualized medicine ; customized therapy ; customized treatment ; individualized patient treatment ; individualized therapeutic strategy ; individualized therapy ; individualized treatment ; patient specific therapies ; patient specific treatment ; tailored medical treatment ; tailored therapy ; tailored treatment ; unique treatment ; clinical investigation ; Formulation ; peptide drug ; therapeutic peptide ; reduce symptoms ; alleviate symptom ; ameliorating symptom ; decrease symptom ; fewer symptoms ; relieves symptoms ; symptom alleviation ; symptom reduction ; symptom relief ; efficacy study ; Injections ; first-in-human ; first in man ;