Preclinical Development of Oxy200 for the Treatment of Osteoporosis

Oxy200 治疗骨质疏松症的临床前开发

• 批准号: 9790889
• 负责人: Frank Stappenbeck
• 金额: $ 97.5万
• 依托单位: MAX BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9790889
• 关键词: Acids; Acute; Address; Affect; American; Anabolic Agents; Animal Model; Animals; Biological; Biological Assay; Biological Availability; Biological Process; Blood Circulation; Bone Density; Bone Resorption; Bone Tissue; CCRL2 gene; Canis familiaris; Carbamates; Cephalic; Chemicals; Cholesterol; Cholesterol Homeostasis; Chromosome abnormality; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; Complex; Consultations; Defect; Development; Development Plans; Dose; Drug Kinetics; FDA approved; Forteo; Grant; Human; Hydroxycholesterols; In Vitro; Injections; Laboratories; Link; Maximum Tolerated Dose; Mediating; Mesenchymal Differentiation; Mesenchymal Stem Cells; Micronucleus Tests; Modeling; Mutagenesis; Mutation; Oral; Oral Administration; Oryctolagus cuniculus; Osteoblasts; Osteogenesis; Osteoporosis; PTH gene; Patients; Peripheral Blood Lymphocyte; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology Study; Phase; Phenotype; Physiological; Postmenopausal Osteoporosis; Property; Public Health; Rattus; Reporting; Research; Research Activity; Risk; Rivers; Safety; Small Business Innovation Research Grant; Sprague-Dawley Rats; Structure-Activity Relationship; Temperature; Tissues; Toxic effect; Vertebral column; Water; acute toxicity; albino rat; base; bisphosphonate; bone; bone loss; bone metabolism; bone quality; calcification; chemical synthesis; clinical investigation; cost; design; drug development; drug mechanism; fracture risk; genotoxicity; improved; in vitro activity; in vivo; inhibitor/antagonist; lipid biosynthesis; novel; older men; osteoblast differentiation; osteogenic; oxidation; preclinical development; side effect; skeletal tissue; smoothened signaling pathway; standard of care; subcutaneous; success; targeted delivery; therapeutic candidate; therapeutic development; therapy development

ABSTRACT Osteoporosis directly affects 10 million Americans and another 34 million are osteopenic and at risk for developing osteoporosis. Postmenopausal osteoporosis is most common, but osteoporosis does also frequently affect older men. At MAX BioPharma, we are developing new and improved therapies for osteoporosis that aim to rebalance both bone formation and resorption based on a dual therapy approach. Bisphosphonate drugs, for example, alendronic acid (ALN, Fosamax) can improve bone density and reduce fracture risk by slowing osteoclastic bone resorption; however, many of the existing anti-resorptive therapies are plagued with untoward side effects and limited duration of clinical benefits. Complementary to anti- resorptive therapy, transient activation of anabolic bone formation could become part of a new treatment paradigm. Presently, there are only two FDA approved bone anabolic agents, Forteo and Tymlos, which confer significant clinical benefits in osteoporosis with daily subcutaneous administration, but their use is severely restricted due to safety concerns. Several years ago, we discovered that specific oxysterols induce osteogenesis when applied to mesenchymal stem cells (MSCs) while inhibiting their adipogenesis. The most promising bone anabolic oxysterol to date, OXY133, potently induces osteogenic differentiation in vitro, including in primary rat, rabbit and human MSCs, and stimulates robust localized bone formation in vivo in rat and rabbit spine fusion and cranial and femoral defect models. In the context of osteoporosis, our research has addressed the targeted delivery of Oxy133 to skeletal tissues. We proposed that conjugation of Oxy133 with ALN could selectively deliver both agents to bone tissue, potentially inducing synergistic clinical benefits. Supported by the ongoing NIA-sponsored Phase II SBIR grant, we have examined chemical syntheses and biological properties of numerous Oxy133-ALN conjugates. We have identified Oxy200, a carbamate-linked Oxy133-ALN monoconjugate as a potent osteogenic compound in vitro that is highly water soluble and chemically scalable to multi-gram levels. When administered orally to ovariectomized rats, Oxy200 significantly inhibited bone loss with no evidence of toxicity or ectopic calcification. In this Phase IIB application, we propose detailed studies that seek to further appraise the qualities of Oxy200 as a therapeutic candidate for osteoporosis in IND-enabling studies. According to a therapeutic development plan that we have devised in collaboration with regulatory advisors, these studies will expand on our Phase II grant accomplishments in three Specific Aims: Aim 1: Efficacy and pharmacokinetic studies – dosing optimization studies will be performed in rats and dogs Aim 2: Genotoxicity studies – these will include in vitro and in vivo GLP mutagenesis assays to assess safety Aim 3: Acute toxicity and safety pharmacology studies – these studies will be performed on Albino rats and Beagle dogs following oral administration to further assess safety and tolerability of Oxy200

抽象的 骨质疏松症直接影响 1000 万美国人，另有 3400 万骨质疏松症患者面临骨质疏松症风险 出现骨质疏松症。绝经后骨质疏松症是最常见的，但骨质疏松症也 经常影响老年男性。在 MAX BioPharma，我们正在开发新的和改进的疗法 骨质疏松症旨在基于双重治疗方法重新平衡骨形成和骨吸收。 双膦酸盐药物，例如阿仑膦酸（ALN、Fosamax）可以提高骨密度并减少骨密度。 减缓破骨细胞骨吸收导致的骨折风险；然而，许多现有的抗再吸收疗法 受到不良副作用和临床获益持续时间有限的困扰。补充抗 再吸收疗法，合成代谢骨形成的瞬时激活可能成为新疗法的一部分 范例。目前，FDA 批准的骨合成代谢药物只有 Forteo 和 Tymlos 两种， 每日皮下注射对骨质疏松症具有显着的临床益处，但其用途是 出于安全考虑，受到严格限制。几年前，我们发现特定的氧甾醇会诱导 当应用于间充质干细胞（MSC）时成骨，同时抑制其脂肪生成。最 迄今为止有前途的骨合成代谢氧甾醇 OXY133 在体外有效诱导成骨分化， 包括原代大鼠、兔和人类 ​​MSC，并刺激大鼠体内强健的局部骨形成 以及兔脊柱融合以及颅骨和股骨缺损模型。在骨质疏松症的背景下，我们的研究 已经解决了 Oxy133 向骨骼组织的靶向递送。我们提出 Oxy133 的缀合 与 ALN 一起使用可以选择性地将两种药物递送至骨组织，从而可能产生协同临床效益。 在 NIA 资助的第二阶段 SBIR 资助的支持下，我们研究了化学合成和 多种 Oxy133-ALN 缀合物的生物学特性。我们已经鉴定出 Oxy200，一种氨基甲酸酯连接的 Oxy133-ALN 单缀合物是一种有效的体外成骨化合物，具有高度水溶性和 化学上可扩展至数克水平。当给切除卵巢的大鼠口服给药时，Oxy200 显着抑制骨质流失，没有毒性或异位钙化的证据。在本阶段IIB 应用中，我们提出了详细的研究，旨在进一步评估 Oxy200 作为治疗药物的品质 IND 支持研究中骨质疏松症的候选者。根据我们的治疗开发计划 这些研究是与监管顾问合作设计的，将扩展我们的第二阶段拨款 在三个具体目标方面取得的成就： 目标 1：功效和药代动力学研究——将在大鼠和狗中进行剂量优化研究 目标 2：基因毒性研究 – 这些研究将包括体外和体内 GLP 诱变测定以评估安全性 目标 3：急性毒性和安全药理学研究——这些研究将在白化大鼠和 比格犬口服给药后进一步评估 Oxy200 的安全性和耐受性