Therapeutic Development of Osteogenic Oxysterol, Oxy133, for Spine Fusion

用于脊柱融合的成骨氧甾醇 (Oxy133) 的治疗开发

基本信息

批准号：
10478295
负责人：
FARHAD PARHAMI
金额：
$ 85.24万
依托单位：
MAX BIOPHARMA, 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：
2021-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10478295
关键词：
Address Adipocytes Adverse effects Affect Animal Model Anterior Arthritis Aspirate substance Autologous Transplantation BMP2 gene Biological Products Biology Blood Circulation Bone Formation Stimulation Bone Growth Bone Marrow Bone Matrix Bone Regeneration Bone Resorption Bone Transplantation Buffers Cells Cephalic Cervical spine Cholesterol Clinical Trials Collagen Cytochrome P450 Defect Deformity Deglutition Disorders Development Devices Dimethyl Sulfoxide Disease Edema Enzymes FDA approved Family Formulation Future Goals Growth Factor Guidelines Harvest Hemorrhage Human Hydroxyapatites Hydroxycholesterols Immune response Implant In Vitro Incentives Incidence Inferior Infiltration Inflammation Inflammatory Journals Lead Length of Stay Life Lipid Peroxidation Medical Mesenchymal Stem Cells Mixed Function Oxygenases Modeling Morbidity - disease rate Neurosurgeon Operating Rooms Operative Surgical Procedures Orthopedics Oryctolagus cuniculus Osteogenesis Osteolysis Outcome Pain Patients Peer Review Pharmaceutical Preparations Phase Porifera Pre-Clinical Model Procedures Production Property Protocols documentation Pseudarthrosis Public Health Publishing Rattus Reporting Safety Site Small Business Innovation Research Grant Spinal Structure-Activity Relationship Surgeon Techniques Technology Time Toxicology Trauma Vertebral column amorphous solid animal tissue aqueous autooxidation base bone bone fracture repair bone growth factor bone repair cost cost effective demineralization design efficacy evaluation efficacy testing human tissue improved in vivo instrumentation intervertebral disk degeneration lipid biosynthesis maxillofacial member novel osteogenic osteoprogenitor cell pre-clinical preclinical development preclinical study recombinant human bone morphogenetic protein-2 scale up small molecule soft tissue spine bone structure steroid hormone success therapeutic development tumor

项目摘要

ABSTRACT Spine fusion is often the procedure of choice for various spine conditions, including degenerative spine, trauma, tumors and deformities. The goal of the procedure is to bridge the defect by filling the void and promoting bone regeneration. Pseudarthrosis is one of the major challenges in spine fusion, with a reported incidence of 5-35%, and requires further surgical intervention to correct the defect. Improvements in spine operative techniques, instrumentations, grafting materials, and understanding of bone biology have contributed to better outcomes, however, the challenge of achieving 100% fusion remains an unmet medical need. The discovery of BMP2 as a potent bone growth factor and the development of rhBMP2 for achieving 100% fusion rates led to its FDA approval for ALIF in 2002. However, its use has since been expanded to other procedures including posterior lumbar spine fusion and cervical spine fusion. Unfortunately, significant life-threatening adverse effects of rhBMP2 have been reported including soft tissue edema and inflammation associated with its use in cervical spine that can lead to airway compromise and dysphagia. Other drawbacks of using rhBMP2 have been noted such as its high cost, inferior quality of the new bone that often contains a large number of adipocytes, bone resorption and osteolysis, and heterotopic bone formation. There is a need for an alternative to rhBMP2 that would be equally or more efficacious in stimulating bone formation but with a more favorable safety profile and lower cost. We previously reported that Oxy133, a potent semi-synthetic proprietary osteoinductive oxysterol, robustly stimulates osteogenic differentiation of osteoprogenitor cells, including mesenchymal stem cells, in vitro and induces robust bone formation in animal models of localized bone formation including spine fusion and maxillofacial and cranial bone regeneration in rats and rabbits. These activities of Oxy133 were shown to be equal or superior to those of rhBMP2 without any apparent adverse effects such as adipogenesis, infiltration of inflammatory cells in the fusion mass, and heterotopic bone formation. Oxy133 production is highly scalable and much less expensive than rhBMP2 and it can be delivered as a drug-device combination via a collagen sponge in the operating room following the same protocols as for rhBMP2 (Infuse). To continue the therapeutic development of Oxy133 for spine fusion, in this direct to Phase 2 SBIR application, we propose studies including formulation optimization, efficacy testing, and IND-enabling safety and toxicology studies based on FDA guidelines for a Class III drug-device combination. Given the known features and qualities of Oxy133 as a small molecule osteoinductive oxysterol, its successful development will provide orthopedic surgeons and neurosurgeons a safer and more efficacious alternative to rhBMP2 for performing spine fusion in their patients.

抽象的脊柱融合术通常是治疗各种脊柱疾病的首选手术，包括脊柱退行性病变、创伤、肿瘤和畸形。该程序的目标是通过填补空白和促进来弥补缺陷骨再生。假关节是脊柱融合的主要挑战之一，据报道发生率 5-35%，并且需要进一步的手术干预来纠正缺陷。脊柱手术的改进技术、仪器、移植材料以及对骨生物学的了解有助于更好地然而，实现 100% 融合的挑战仍然是一个未满足的医疗需求。发现 BMP2 作为有效的骨生长因子以及 rhBMP2 的开发以实现 100% 融合率引领 2002 年 FDA 批准 ALIF。然而，此后其用途已扩展到其他手术，包括后路腰椎融合术和颈椎融合术。不幸的是，严重危及生命的不良反应 rhBMP2 的影响已被报道，包括与其使用相关的软组织水肿和炎症颈椎可能导致气道受损和吞咽困难。使用 rhBMP2 的其他缺点有因其成本高、新骨质量差、往往含有大量的骨量而受到关注。脂肪细胞、骨吸收和骨溶解以及异位骨形成。需要一个替代方案 rhBMP2 在刺激骨形成方面同样有效或更有效，但具有更有利的作用安全性高且成本更低。我们之前报道过 Oxy133 是一种有效的半合成专有骨诱导性氧甾醇，在体外和体外刺激骨祖细胞（包括间充质干细胞）的成骨分化在局部骨形成的动物模型中诱导强健的骨形成，包括脊柱融合和大鼠和兔子的颌面部和颅骨再生。 Oxy133 的这些活性被证明与rhBMP2相同或优于rhBMP2，且无任何明显的副作用，如脂肪生成、细胞浸润等。融合块中的炎症细胞和异位骨形成。 Oxy133 生产具有高度可扩展性比 rhBMP2 便宜得多，并且可以通过胶原蛋白作为药物-设备组合进行递送按照与 rhBMP2 (Infuse) 相同的方案在手术室中使用海绵。为了继续用于脊柱融合的 Oxy133 的治疗开发，在这直接到 2 期 SBIR 应用中，我们建议研究包括配方优化、功效测试以及支持 IND 的安全性和毒理学研究基于 FDA III 类药物-器械组合指南。鉴于已知的特征和品质 Oxy133作为一种小分子骨诱导性氧甾醇，其成功研发将为骨科提供为外科医生和神经外科医生提供了 rhBMP2 的更安全、更有效的替代方案，用于在以下情况下进行脊柱融合他们的病人。