Novel Drug VS-105 for Treatment of Osteoporosis

描述（由申请人提供）：骨质疏松症是一个主要的公共健康威胁。国家骨质疏松基金会估计，2005年美国国家用于骨质疏松性髋部骨折的直接支出为170亿美元，到2025年将增加到250亿美元。目前骨质疏松症的治疗包括几种抗吸收（或抗分解代谢）和一些合成代谢药物。骨化三醇等vdrm目前在美国以外的一些国家用于治疗骨质疏松症。VDRMs通过调节肠道钙吸收、甲状旁腺激素、核因子- kb配体受体激活剂影响骨代谢，并直接影响成骨细胞和破骨细胞。尽管VDRM在治疗骨质疏松症方面的数据令人鼓舞，但在美国，VDRM并未用于骨质疏松症患者，可能是因为目前市场上的VDRM具有严重的高钙血症毒性，会干扰钙稳态。市场上所有治疗骨质疏松的VDRMs都是高钙的，需要频繁的血钙监测和剂量滴定。理想的VDRM应在有效剂量范围内很少或没有高钙血症毒性。由于众所周知VDRM对骨骼有合成代谢作用，无高钙毒性的VDRM治疗骨质疏松症将为接受标准护理的患者提供显着益处。Vidasym采用了独特的方法来发现和开发新的vdrm。来自大量动物研究的数据表明，VS-105具有非常宽的治疗指数（TI），达到50倍（比较疗效与副作用）。我们假设VS-105在刺激合成代谢骨形成和增加骨矿物质密度（BMD）方面比骨化三醇表现出更好的功效，而且高钙血症的副作用更少。本I期研究的具体目的是：(1)比较VS-105和骨化三醇对去卵巢雌性大鼠骨密度和骨参数的影响。(2)比较VS-105与骨化三醇对小鼠颅骨骨原代器官培养骨吸收和骨形成的影响。一旦I期研究完成，这些数据将允许VS-105进入II期ind研究，包括VS-105合成放大、工艺开发和药代动力学、代谢、安全性和毒理学。II期研究的完成将允许VS-105进入人体临床试验。Vidasym计划将VS-105开发成一种可报销的处方药，用于治疗接受标准治疗的骨质疏松症患者。根据EvaluatePharma提供的信息，2011年骨质疏松症药物的全球年销售额达到130多亿美元。根据对患者数量增加的预测，这一数字可能会增加。开发VS-105治疗骨质疏松症的方法一旦投入市场，将使椎体骨折的发生率降低至少25%（基于目前市场上针对骨质疏松症的vdrm的信息），这将转化为美国每年约40亿美元的医疗保健节省。假设Vidasym的VS-105在骨质疏松症市场的渗透率为5%，预计年销售额将达到6亿美元以上。

DESCRIPTION (provided by applicant): Osteoporosis is a major public health threat. National Osteoporosis Foundation estimated that the US national direct expenditures for osteoporotic hip fractures were at $17 billion in 2005 and it would increase to $25 billion in 2025. Current treatments for osteoporosis include several anti-resorptive (or anti-catabolic) and some anabolic agents. VDRMs such as calcitriol are currently used to treat osteoporosis in several ex-US countries. VDRMs influence bone metabolism through regulation of intestinal calcium absorption, parathyroid hormone, receptor activator of nuclear factor-kB ligand, and also via direct effects on osteoblasts and osteoclasts. Despite encouraging data on VDRM's benefits for treating osteoporosis, VDRMs are not used in osteoporosis patients in the US likely due to the fact that those currently on the market have substantial hypercalcemic toxicity that interferes with calcium homeostasis. All VDRMs on the market for osteoporosis are hypercalcemic, and require frequent serum calcium monitoring and dose titration. An ideal VDRM should be with little or no hypercalcemic toxicity in the efficacious dose range. Since VDRMs are well known to have anabolic effects on the bone, a VDRM without hypercalcemic toxicity for the treatment of osteoporosis will provide significant benefits to patients receiving the standard of care. Vidasym has taken a unique approach to discover and develop novel VDRMs. Data from extensive animal studies show that VS-105 has an exceptionally wide therapeutic index (TI) at >50-fold (comparing efficacy vs. side effect). We hypothesize that VS-105 will exhibit better efficacy than calcitriol in stimulating anabolic bone formation and also in increasing bone mineral density (BMD) with less hypercalcemic side effects. The specific aims of this Phase I study are: (1) To compare the effects between VS-105 and calcitriol on BMD and bone parameters in ovariectomized female rats. (2) To compare the effects between VS-105 and calcitriol on bone resorption and formation in mouse calvariae bone primary organ culture. Once this phase I study is completed, the data will allow the advancement of VS-105 into Phase II IND-enabling studies including VS-105 synthesis scale-up, process development and pharmacokinetics, metabolism, safety and toxicology. The completion of Phase II studies will allow VS-105 to enter human clinical trials. Vidasym plans to develop VS-105 into a reimbursable prescription drug to treat osteoporosis in patients receiving the standard of care. Based on the information provided by EvaluatePharma, osteoporosis medications achieved US$13+ billion in annual worldwide sales in 2011. This number is likely to increase based on the projections of increased patient numbers. The approach of developing VS-105 for osteoporosis, once introduced into the market, will decrease the incidence of vertebral fractures by at least 25 % (based on information from current on-the-market VDRMs for osteoporosis), which shall translate into ~$4 billion in annual health care savings in the US. Assuming Vidasym's VS-105 has a modest 5% penetration into the osteoporosis market, the estimated annual sales will be US$0.6+ billion.