Enabling Studies for the Treatment of Frozen Shoulder Using Relaxin

使用松弛素治疗肩周炎的研究

• 批准号: 10323754
• 负责人: Edward Ahn
• 金额: $ 78.63万
• 依托单位: ORTHOLEVO, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323754
• 关键词: Achievement; Address; Adrenal Cortex Hormones; Affect; Anesthesia procedures; Animal Model; Animals; Ankle; Articular Range of Motion; Biodistribution; Biological Sciences; Biomechanics; Birth; Canis familiaris; Chemistry; Childbirth; Clinical; Collaborations; Collagen; Contracture; Data; Development Plans; Diabetes Mellitus; Disease; Distal; Dose; Down-Regulation; Drug Delivery Systems; Drug Kinetics; Effectiveness; Engineering; Ensure; Experimental Designs; Fibroblasts; Fibrosis; Formulation; Freezing; Frequencies; General Population; Goals; Half-Life; Health Sciences; Hip region structure; Histologic; Human; Immobilization; In Vitro; Incidence; Individual; Inflammation; Injectable; Injections; Institutional Review Boards; Intra-Articular Injections; Joints; Knee; Marketing; Maximum Tolerated Dose; Metalloproteases; Microspheres; Modeling; Morphology; Motion; Motivation; Nerve; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; Organ; Pain; Patients; Peat; Performance; Peripheral; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Physical therapy; Polymers; Procedures; Process; Production; Property; Proteins; Protocols documentation; Rattus; Relaxin; Risk; Rogaine; Safety; Schedule; Science; Shoulder; Site; Small Business Innovation Research Grant; Sterilization; Symptoms; Technology; Testing; Therapeutic; Tissues; Toxic effect; Translations; Trauma; United States; Wrist; articular cartilage; base; clinical investigation; clinical research site; commercialization; efficacy study; first-in-human; improved; in vivo; individualized medicine; joint function; manufacturing process; meetings; particle; peptide drug; peptide hormone; preclinical evaluation; product development; reduce symptoms; reproductive hormone; standard of care; therapeutic protein

PROJECT SUMMARY/ABSTRACT Frozen shoulder or “shoulder arthrofibrosis” is a painful and gradual loss of shoulder motion caused by trauma, surgical procedures, inflammation, or prolonged joint immobilization. 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 complications and can further aggravate symptoms. Ortholevo is developing a local injectable 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 temporally downregulates 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 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 Direct Phase II proposed aims: 1) Transfer our microparticle encapsulation process to Lubrizol Life Science 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) and efficacy 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 formulation as 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 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.

项目概要/摘要 肩周炎或“肩关节纤维化”是由以下原因引起的肩部活动逐渐丧失的痛苦症状 外伤、外科手术、炎症或长时间关节固定。肩关节纤维化发生在9 在美国，每年有超过 160 万人寻求手术治疗。当前的 治疗方案，包括关节内皮质类固醇注射、非甾体抗炎药和神经阻滞剂，仅提供 只能暂时缓解患者症状，但不能解决疾病的根本原因—— 纤维化胶原组织的堆积。手术干预用于更严重的病例，但这些 手术充满并发症，并可能进一步加重症状。 Ortholevo 正在开发本地 用于治疗肩关节疼痛的松弛素 2 可注射聚合物微粒缓释制剂 纤维化。人松弛素 2 (RLX) 是一种 6 kDa 天然存在的生殖激素肽，可暂时 在分娩前下调胶原蛋白的产生并上调基质金属蛋白酶。使用这种活力 潮汐疗法为治疗关节纤维化提供了前所未有的机会 疾病的首个同类疗法以及由此产生的肩部治疗范式转变 关节纤维化。 Ortholevo 提议通过完成 以下直接第二阶段提出的目标： 1) 将我们的微粒封装工艺转移到 Lubrizol Life Science Health 旨在制定产品规格并评估灭菌和保质期稳定性； 2) 阻止- 体内最小有效剂量（MED）、最大耐受剂量（MTD）和重复剂量毒性 (RDT) 体内大鼠模型中负载松弛素 2 的微粒； 3) 确定药代动力学 (PK) 和 负载松弛素2的微粒在体内犬关节挛缩模型中的功效。为了实现这些目标， 我们收集了关键的初步数据，证明了使用负载松弛素 2 的微粒制剂的功效 并组建了一支具有科学/工程专业知识的团队（例如蛋白质治疗、微粒、 生物力学和肩周炎）以及翻译和商业化（例如管理、监管、人力 制造和营销）。随着直接第二阶段 SBIR 项目的具体目标的成功完成 posal，接下来的步骤包括预 IND 会议、获得 IND/IRB 临床场地批准，然后是第一阶段 - 人体临床安全性试验。这些目标的实现将带来第一个标准的护理治疗 基于逆转纤维化胶原的潜在和异常积累的肩关节纤维化 以持续和受控的方式将治疗药物输送到疾病部位的组织。