Preclinical Development of Oxy200 for the Treatment of Osteoporosis

摘要 骨质疏松症直接影响1000万美国人，另有3400万人骨质减少， 骨质疏松症绝经后骨质疏松症是最常见的，但也 经常影响老年人。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）可以改善骨密度， 通过减缓骨吸收来降低骨折风险;然而，许多现有的抗吸收疗法 受到不良副作用和临床益处持续时间有限的困扰。与anti- 吸收疗法，合成代谢骨形成的短暂激活可能成为新治疗的一部分， 范例目前，只有两种FDA批准的骨合成代谢剂，Forteo和Tymlos， 每日皮下给药对骨质疏松症具有显著的临床益处，但它们的使用 出于安全考虑，受到严格限制。几年前，我们发现特定的氧固醇诱导 当应用于间充质干细胞（MSC）时，骨生成，同时抑制其脂肪生成。最 迄今为止有希望的骨合成代谢氧固醇，OXY 133，在体外有效诱导成骨分化， 包括在原代大鼠、兔和人MSC中，并在大鼠体内刺激稳固的局部骨形成。 以及兔脊柱融合和颅骨及股骨缺损模型。在骨质疏松症的背景下，我们的研究 已经解决了Oxy 133向骨骼组织的靶向递送。我们提出Oxy 133的缀合 ALN可以选择性地将两种药物递送到骨组织，潜在地诱导协同的临床益处。 在正在进行的国家情报局赞助的第二阶段SBIR赠款的支持下，我们研究了化学合成， 许多Oxy 133-ALN缀合物的生物学性质。我们已经确定了Oxy 200，一种与氨基甲酸酯有关的 Oxy 133-ALN单偶联物作为体外强效成骨化合物，具有高度水溶性， 在化学上可扩展到数克级别。经口给予卵巢切除大鼠时，Oxy 200 显著抑制骨丢失，没有毒性或异位钙化的证据。在本阶段IIB 应用，我们提出了详细的研究，寻求进一步评价质量的氧200作为一种治疗 IND使能研究中的骨质疏松症候选者。根据我们的治疗发展计划 这些研究是与监管顾问合作设计的，将扩大我们的第二阶段赠款 实现三个具体目标： 目的1：疗效和药代动力学研究-将在大鼠和犬中进行剂量优化研究 目的2：遗传毒性研究-包括体外和体内GLP诱变试验，以评估安全性 目的3：急性毒性和安全药理学研究-这些研究将在白化病大鼠中进行， 比格犬经口给药后进一步评估Oxy 200的安全性和耐受性

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