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.

抽象的脊柱融合通常是各种脊柱条件的选择，包括退化性脊柱，创伤，肿瘤和畸形。该程序的目的是通过填充空隙并促进来弥合缺陷骨再生。假性关节炎是脊柱融合的主要挑战之一，报告的发生率是 5-35％，需要进一步的手术干预才能纠正缺陷。脊柱手术器的改进技术，仪器，嫁接材料和对骨生物学的理解有助于更好然而，结果，实现100％融合的挑战仍然是未满足的医疗需求。发现 BMP2作为有效的骨骼生长因子和RHBMP2的发展，以实现100％的融合率LED 在2002年获得了FDA批准Alif。但是，其使用已扩展到其他程序后腰椎融合和颈椎融合。不幸的是，严重威胁生命的不利据报道，RHBMP2的影响包括软组织水肿和与其在可以导致气道妥协和吞咽困难的颈椎。使用RHBMP2的其他缺点被注意到，例如其高成本，新骨的质量较低，通常包含大量脂肪细胞，骨吸收和溶解性和异位骨形成。需要替代对于在刺激骨形成方面相同或更有效的RHBMP2，但更有利安全性概况和较低的成本。我们以前报道说，Oxy133是一种有效的半合成专有骨诱导氧甲醇刺激骨源细胞的成骨分化，包括间充质干细胞，体外和在局部骨形成的动物模型中诱导稳健的骨形成，包括脊柱融合和大鼠和兔子的颌面和颅骨再生。 oxy133的这些活动显示为等于或优于RHBMP2，而没有任何明显的不良反应，例如脂肪生成，渗透融合质量中的炎性细胞和异位骨形成。 Oxy133生产高度可扩展而且比RHBMP2便宜得多，并且可以通过胶原蛋白作为药物磁盘组合交付遵循与RHBMP2相同的协议（Infuse）在手术室中的海绵。继续 Oxy133用于脊柱融合的治疗性开发，在直接到第2阶段SBIR应用中，我们提出包括配方优化，功效测试以及辅助安全性和毒理学研究在内的研究基于FDA III类药物设备组合的指南。鉴于已知的特征和品质 Oxy133作为小分子骨诱导氧甲醇，其成功的发育将提供骨科外科医生和神经外科医生是RHBMP2的更安全，更有效的替代品，用于进行脊柱融合他们的病人。