New drug Vida-5 for treating chronic kidney disease progression

描述（由申请人提供）：美国有2600万人患有慢性肾脏疾病（CKD）。贫血、心血管疾病、继发性甲状旁腺功能亢进、肾性骨营养不良等并发症是CKD的常见并发症。目前包括ACE抑制剂在内的CKD患者的治疗主要集中在控制症状和疾病并发症。尽管有多种可用的治疗方法，但5年生存率约为33%，死亡风险随着肾脏疾病的进展和继发性甲状旁腺功能亢进而增加。维生素D受体调节剂（VDRMs）已被证明可以减少CKD患者的蛋白尿/白蛋白尿，并为CKD患者提供生存益处。尽管VDRM对CKD患者潜在的肾脏和生存益处的数据令人鼓舞，但目前在CKD领域，VDRM仅用于治疗继发性甲状旁腺功能亢进（PTH升高）。干扰钙稳态和损害身体功能的高钙中毒是市场上vdrm扩大使用的限制因素。因此，一种新的VDRM，既保留了现有VDRM的疗效，又没有现有VDRM的毒性，将具有重要的临床价值。理想的VDRM应该在有效剂量范围内很少或没有高钙血症毒性，可以减少甲状旁腺激素和减缓肾脏疾病的进展。Vidasym采用独特的药物发现/开发方法来发现与现有vdrm高度不同的新型vdrm。Vidasym的Vida-5在抑制PTH至正常水平的剂量范围内没有可检测到的高钙血症毒性（与其他剂量范围重叠的VDRMs相比，其疗效和毒性）。随着Vida-5卓越的安全性和有效性的确立，下一步是确定使用Vida-5治疗肾脏疾病进展的可行性及其在动物研究中的长期副作用潜力。该I期研究的具体目的是：(1)开展动物研究，以证明Vida-5和ACE抑制剂在降低指示肾脏疾病进展的生物标志物（如血清肌酐和蛋白尿）方面的协同作用；(2)进行毒性动物研究，为维达-5的II期研究做准备。一旦I期研究完成，数据将允许将Vida-5推进到II期IND-enabling研究，包括Vida-5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Vida-5进入人体临床试验。Vidasym计划将Vida-5开发成可报销的处方药，用于治疗肾脏疾病的进展。一旦开发出来，这种药物不仅可以降低CKD的死亡率，还可以减少透析的需要。目前仅用于继发性甲状旁腺功能亢进的VDRMs在2009年的年销售额就达到了10亿美元以上。Zemplar和Hectorol在美国透析市场占据主导地位（约80%），因为它们的高钙血症毒性略低（毒性比普通的钙化杰克斯（内源性激素骨化三醇）低2-4倍）。一种新的VDRM，如用于治疗肾脏疾病进展的Vida-5，在美国的年销售额很容易达到10亿美元以上。

DESCRIPTION (provided by applicant): Twenty-six million people in America have chronic kidney disease (CKD). Anemia, cardiovascular diseases, secondary hyperparathyroidism, renal osteodystrophy and other complications are common in CKD. Current treatments including ACE inhibitors for CKD patients mainly focus on managing symptoms and disease complications. Despite the various treatments available, the five-year survival rate is ~33% and the mortality risk increases with kidney disease progression and secondary hyperparathyroidism. Vitamin D receptor modulators (VDRMs) have been shown to reduce proteinuria/albuminuria in CKD patients and also provide survival benefits for CKD patients. Despite encouraging data on VDRM's potential renal and survival benefits for the CKD patients, currently in the CKD field VDRM is only indicated for managing secondary hyperparathyroidism (with elevated PTH). Hypercalcemic toxicity that interferes with calcium homeostasis and detriments body functions is the limiting factor to expanded use of on-market VDRMs. Therefore, a novel VDRM which retains the efficacy without the toxicity shared by current VDRMs would have significant clinical benefit. An ideal VDRM should be with little or no hypercalcemic toxicity in the efficacious dose range that could reduce PTH and slow kidney disease progression. Vidasym has taken a unique drug discovery/development approach to discover novel VDRMs that are highly differentiated from existing VDRMs. Vidasym's Vida-5 has no detectable hypercalcemic toxicity in the dose range that suppresses PTH to the normal level (vs. other VDRMs with overlapping dose ranges for efficacy and toxicity). With Vida-5's superior safety and efficacy profiles established, the next step is to determine the feasibility of using Vida-5 to treat kidney disease progression and also its long-term side effect potential in animal studies. The specific aims of this Phase I study are: (1) to conduct an animal study to show the synergistic effect of Vida-5 and an ACE inhibitor on reducing biomarkers (such as serum creatinine and proteinuira) indicative of kidney disease progression; (2) to conduct a toxicity animal study to prepare Vida-5 for Phase II studies. Once this phase I study is completed the data will allow the advancement of Vida-5 into Phase II IND-enabling studies including Vida-5 synthesis scale-up, process development and pharmacokinetics, metabolism, safety and toxicology. The completion of Phase II studies will allow Vida-5 to enter human clinical trials. Vidasym plans to develop Vida-5 into a reimbursable prescription new drug to treat kidney disease progression. Once developed, such a drug will not only reduce the mortality rate of CKD, but also reduce the need for dialysis. Current VDRMs for secondary hyperparathyroidism alone achieve US$1+ billion in annual sales in 2009. Zemplar and Hectorol dominate the US dialysis market (>80%) due to their slightly less hypercalcemic toxic profile (~2-4 fold less toxic than generic Calcijex, the endogenous hormone calcitriol,). A novel VDRM such as Vida-5 for treating kidney disease progression could easily achieve an annual US sales at $1+ billion. PUBLIC HEALTH RELEVANCE: Vidasym's phase I SBIR study will determine the feasibility of using Vida-5 to treat chronic kidney disease (CKD) progression. Globally > 350 million individuals have CKD and this number is projected to increase to >550 million by 2025. Although various modalities and substances are available for CKD, the mortality rate for CKD patients remains high (~33%) and the number of dialysis CKD patients keeps increasing. There is an urgent medical need for the development of an effective and novel resuscitation approach for the treatment of CKD. Limitations of current therapy demonstrate that a new treatment approach such as Vida-5 to reduce the need for dialysis and also reduce the mortality rate of CKD offers a significant opportunity for improved outcomes with substantial societal benefit.