Therapeutic Development of Osteogenic Oxysterol, Oxy133, for Spine Fusion

摘要 脊柱融合术通常是各种脊柱疾病的首选手术，包括退行性脊柱，创伤， 肿瘤和畸形。该程序的目标是通过填补空缺和促进 骨再生假关节是脊柱融合术的主要挑战之一，据报道， 5- 35%，需要进一步手术干预以纠正缺陷。脊柱手术的改进 技术、器械、移植材料和对骨生物学的理解有助于更好地 然而，实现100%融合的挑战仍然是未满足的医疗需求。发现 BMP 2作为一种有效的骨生长因子和rhBMP 2的开发实现100%融合率导致 2002年FDA批准了ALIF。然而，它的使用已经扩展到其他程序，包括 后路腰椎融合和颈椎融合。不幸的是，严重的危及生命的不良反应 已经报道了rhBMP 2的作用，包括软组织水肿和与其用于 颈椎会导致呼吸道受损和吞咽困难。使用rhBMP 2的其他缺点有 已经注意到，例如其成本高，新骨的质量差，通常含有大量的 脂肪细胞、骨吸收和骨质溶解以及异位骨形成。需要有一种替代办法 与rhBMP 2相比，rhBMP 2在刺激骨形成方面同样有效或更有效，但具有更有利的 安全性和低成本。 我们以前报道过Oxy 133，一种有效的半合成专利骨诱导氧固醇， 在体外刺激包括间充质干细胞在内的骨祖细胞的成骨分化， 在包括脊柱融合在内的局部骨形成的动物模型中诱导稳健的骨形成， 大鼠和家兔的颌面和颅骨再生。Oxy 133的这些活性被证明是 等同或上级于rhBMP 2的那些，而没有任何明显的副作用，如脂肪形成、 融合块中的炎性细胞和异位骨形成。Oxy 133生产具有高度可扩展性 并且比rhBMP 2便宜得多，它可以作为药物-装置组合通过胶原蛋白递送， 按照与rhBMP 2（Infuse）相同的方案在手术室中使用海绵。继续 Oxy 133用于脊柱融合的治疗开发，在这一直接的2期SBIR应用中，我们建议 研究，包括处方优化、疗效试验和IND启用安全性和毒理学研究 基于FDA关于III类药物-器械组合的指南。鉴于已知的特征和质量， Oxy 133作为一种小分子骨诱导性氧固醇，其成功开发将为骨科 外科医生和神经外科医生更安全，更有效的替代rhBMP 2进行脊柱融合， 他们的病人

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.