Treatment and prevention of osteoarthritis with an intra-articular disease-modifying regenerative therapy

通过关节内疾病修饰再生疗法治疗和预防骨关节炎

基本信息

批准号：
10256397
负责人：
Siddhesh Angle
金额：
$ 86.04万
依托单位：
REGENOSINE INC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-16 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10256397
关键词：
Acupuncture Therapy Address Adenosine Adrenal Cortex Hormones Affect Aftercare Age Aging Agonist American Animals Anti-Inflammatory Agents Biological Biomechanics Bone Density Bone Spur Canis familiaris Cartilage Cartilage Matrix Cell Proliferation Chemistry Chondrocytes Clinical Clinical Research Clinical Trials Consumption Degenerative polyarthritis Deterioration Development Disease Dose Down-Regulation Drug Kinetics Encapsulated Environment Equilibrium Exercise Female Formulation Gene Activation Genes Genetic Glucocorticoids Goals Half-Life Harvest High Pressure Liquid Chromatography Homeostasis Hospitalization Hyaluronic Acid Hypertrophy Ibuprofen Impairment In Vitro Inflammation Inflammation Mediators Injury Interleukin-1 beta Intervention Intra-Articular Injections Investigational Drugs Investigational New Drug Application Joints Kinetics Knee Laboratories Life Ligation Liposomes Liquid substance MADH2 gene Maintenance Measures Messenger RNA Methods Modeling Monitor Mus Narcotics Natural regeneration Nuclear Obesity Occupational Therapy Operative Surgical Procedures Outcome Pain Pathogenesis Pathologic Pathology Patients Pharmaceutical Preparations Phase Physical therapy Plasma Play Population Preparation Prevention Process Production Quality Control Quality of life Rattus Receptor Signaling Recovery Replacement Arthroplasty Repression Rivers Role Safety Severities Sterility Structure Synovial Fluid Technology Testing Therapeutic Time Toxicology United States Up-Regulation Variant Whole Blood Work albino rat arthropathies autocrine cartilage regeneration chronic pain commercial application cost differential expression extracellular falls first-in-human health care delivery human old age (65+)improved loss of function male manufacturing process novel novel strategies opioid injection pain reduction pain relief palliative pharmacokinetics and pharmacodynamics prevent receptor reduce symptoms regenerative therapy repaired subchondral bone subcutaneous tibia

项目摘要

Abstract Nearly one in every ten Americans, and one in every three over the age of 65 years, suffers from osteoarthritis (OA), a degenerative joint disorder that causes progressive cartilage loss. Current therapeutic options include physical and occupational therapy, acupuncture, medication, intraarticular injection, and surgery. As total joint surgery (arthroplasty) is costly and has a maximum lifetime of 15 years before requiring even more expensive and risky revision surgery, OA intervention strategies generally retain patients on the least invasive methods for as long as possible to delay the need for arthroplasty. However, the limited relief offered by palliative therapeutic options such as exercise, anti-inflammatory medications (ibuprofen, glucocorticoids), narcotics (opioids), and injections (hyaluronic acid, corticosteroids) impose a drawn-out period of suffering for OA patients to endure chronic pain from cartilage destruction, inflammation, and other pathological damages associated with the disease. Such approaches provide only symptomatic pain relief, and are not disease-modifying interventions. Although the pathogenesis of OA remains incompletely understood, we have discovered that adenosine, acting at its A2a receptor (A2aR), is a critical autocrine homeostatic factor that maintains chondrocyte and cartilage balance. Regenosine is developing Lipo-Ade, a first-in-class liposomal adenosine product in a proprietary, novel formulation for effective, prolonged treatment and for regenerating cartilage in joints in patients with established OA. We have demonstrated that use of liposomes as a mechanism to encapsulate the short-lived adenosine and its delivery into the intraarticular space enables the bioactive compound to promote cartilage regeneration, stop the progression and reverse the pathology of OA. For this Direct to Phase II project, Regenosine will continue to develop and test Lipo-Ade as an optimal OA treatment formulation in preparation for initiating our clinical trials by undertaking four specific aims: 1) conducting studies to define release kinetics and measure primary metabolites in synovial fluid and plasma, 2) performing a large animal proof-of-principal/bridge study to evaluate the safety and efficacy of Lipo-Ade in pain and joint structural change in dogs with OA, 3) characterizing an optimal, stable formulation, determining the chemistry, manufacturing, and controls (CMC) of liposomes, and undertaking the manufacturing of a pilot scale batch, and 4) conducting Investigational New Drug (IND) enabling pharmacokinetic and toxicology studies of the Lipo-Ade to satisfy requirements set by the US FDA. These assessments will validate the safety, efficacy, and feasibility of Lipo-Ade to usher the technology towards commercial application. Quality control standards such as shelf-life, sterility, batch-to-batch variation, etc. in the manufacturing process will be addressed, and more importantly the ability of Lipo-Ade to reduce pain and regenerate cartilage will be determined. As a set, these Specific Aims will address the remaining gaps in Regenosine's non-clinical development that must be filled for a successful Investigational New Drug (IND) submission, which will pave the way for a first-in-human clinical study.

抽象的每十名美国人中几乎有一个，而65岁以上的每三个人中有1个患有骨关节炎（OA），一种退化性关节疾病，会导致进行性软骨损失。当前的治疗选择包括物理和职业疗法，针灸，药物，关节内注射和手术。作为总关节手术（关节置换术）是昂贵的，最长的寿命为15年，然后需要更昂贵和风险的修订手术，OA干预策略通常将患者保留在最少的侵入性方法中尽可能延迟对关节置换术的需求。但是，姑息治疗提供的有限救济诸如运动，抗炎药（布洛芬，糖皮质激素），麻醉药（阿片类药物）等方案注射（透明质酸，皮质类固醇）为OA患者施加了痛苦的时期软骨破坏，炎症和其他病理损害造成的慢性疼痛疾病。这种方法仅提供症状性疼痛，而不是调整疾病的干预措施。尽管OA的发病机理仍未完全理解，但我们发现腺苷，作用在其A2A受体（A2AR）上，是维持软骨细胞和软骨的关键自分泌稳态因子平衡。 Remenosine正在开发Lipo-ade，这是一种在A中的第一类脂质体腺苷产品专有的，新颖的配方，用于有效，长时间治疗和关节的再生软骨在已建立的OA患者中。我们已经证明，使用脂质体作为封装的机制短寿命的腺苷及其进入关节内空间的递送使生物活性化合物促进软骨再生，停止进展并逆转OA的病理。对于直接到第二阶段项目，苯胺将继续开发和测试脂肪成果作为最佳的OA处理配方，以准备通过实现四个具体目的来启动我们的临床试验：1）进行研究以定义释放动力学和测量滑液和等离子体中的原代代谢物，2）进行大型动物的主要动物证明评估脂肪脂化在狗中的疼痛和关节结构变化中的安全性和功效的研究，3）表征最佳，稳定的配方，确定化学，制造和控制（CMC）（CMC）脂质体，并进行试验量表的制造，4）进行研究新药（IND）启用脂肪制成的药代动力学和毒理学研究，以满足美国设定的要求 FDA。这些评估将验证Lipo-Ade的安全性，功效和可行性，以引入该技术朝向商业应用。质量控制标准，例如保质期，不育，批处理变化，等等。在制造过程中将解决，更重要的是，脂肪减轻疼痛的能力并将确定再生软骨。作为一组，这些具体目标将解决为了成功的研究新药（IND）必须填补苯烷的非临床发展（IND）提交，这将为第一届人类临床研究铺平道路。