Enabling Studies for the Treatment of Frozen Shoulder Using Relaxin

项目摘要/摘要 冻结的肩或“肩关节纤维化”是一种痛苦的和渐进性的丧失肩部活动引起的 创伤、外科手术、炎症或长时间的关节制动。肩关节纤维化9例 在美国，每年有超过160万人寻求手术治疗。当前 治疗方案，包括关节内注射皮质类固醇、非甾体抗炎药和神经阻滞剂，只能提供 患者症状的轻微和暂时缓解，并且没有解决疾病的根本原因- 纤维性胶原组织堆积。手术干预用于更严重的病例，但这些 手术充满了并发症，可能会进一步加重症状。奥托列沃正在开发一种当地的 松弛素-2可注射聚合物微粒缓释剂治疗肩周炎 纤维化症。人松弛素-2(RLX)是一种6 kDa的自然产生的生殖荷尔蒙多肽，它暂时地 在分娩前下调胶原蛋白的生成，上调基质金属蛋白酶。利用这一鼓舞士气- 浪潮疗法为治疗关节纤维化提供了前所未有的机会 首创此类疗法的疾病，以及由此导致的肩部治疗范式的转变 关节纤维化。 Ortholevo提议通过完成 以下Direct第二阶段提出的目标是：1)将我们的微粒封装工艺转移到路博润生命 科学健康，以建立产品规格并评估灭菌和货架稳定性；2)阻止- 地雷体内最小有效剂量(MED)、最大耐受量(MTD)和重复剂量毒性 (3)测定大鼠体内药代动力学(PK)和药代动力学参数。 松弛蛋白-2微粒在犬关节挛缩症模型中的作用。为了实现这些目标， 我们已经收集了关键的初步数据，证明了使用松弛素-2微粒子制剂的有效性 以及组建了一支具有科学/工程专业知识的团队(例如，蛋白质疗法、微粒、 生物力学和肩部冻伤)以及翻译和商业化(例如，管理、监管、人- 制造和营销)。随着这一直接第二阶段SBIR PRO的具体目标的圆满完成， Posal，下一步包括IND前会议，获得IND/IRB临床站点批准，然后是第一阶段First 人体临床安全性试验。这些目标的实现将导致首个护理治疗标准。 基于逆转纤维性胶原潜在异常堆积的肩关节纤维化 以持续和受控的方式将治疗药物输送到疾病部位的组织。

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.