Novel drug VS-105 for treatment of diabetic nephropathy

描述(申请人提供)：美国有2600万人患有慢性肾脏疾病。到目前为止，糖尿病是CKD(糖尿病肾病)的主要原因，占新的透析病例的44%(2005年)。目前对CKD患者的治疗包括血管紧张素转换酶抑制剂，主要集中在控制症状和疾病并发症。尽管治疗方法多种多样，但随着肾脏疾病的进展和继发性甲状旁腺功能亢进，五年存活率约为33%，死亡风险增加。维生素D受体调节剂(VDRM)已被证明可以减少糖尿病肾病患者的蛋白尿/蛋白尿，并为CKD患者提供心血管和生存方面的好处。尽管关于VDRM对CKD患者潜在的肾脏、心血管和生存益处的数据令人鼓舞，但目前在CKD领域，VDRM仅适用于继发性甲状旁腺功能亢进症(甲状旁腺激素升高)。高钙毒性干扰钙稳态，损害身体功能，是市场上VDRM扩大使用的限制因素。一种新型的VDRM，既能保持现有VDRM的疗效，又不会有现有VDRM的毒性，将具有显著的临床益处。理想的VDRM应该在可以降低甲状旁腺激素并提供心血管益处的有效剂量范围内没有高钙毒性。Vidasym采取了一种独特的方法来发现与现有VDRM高度不同的新型VDRM。在临床验证的5/6肾切除尿毒症大鼠模型中，Vidasym的VS-105在改善心血管功能和将PTH抑制到正常水平的剂量范围内没有可检测到的高钙毒性(与其他VDRM相比，其疗效和毒性的剂量范围重叠)。Vidasym计划将VS-105开发成一种治疗CKD患者的可报销处方药。VS-105的临床研究最初关注的是CKD患者的糖尿病肾病。因此，一个合乎逻辑的步骤是确定VS-105在糖尿病肾病动物模型中的疗效。这项第一阶段研究的具体目的是：(1)在1型和2型糖尿病的实验模型中，比较VS-105和帕利骨化醇(目前在美国拥有最大市场份额的VDRM)在阻止糖尿病肾病进展方面的疗效。(2)阐明VS-105的肾脏保护作用机制。这项第一阶段研究的数据将使VS-105进入第二阶段的IND使能研究，包括VS-105合成放大、工艺开发和药代动力学、新陈代谢、安全性和毒理学。第二阶段研究的完成将使VS-105进入人体临床试验。目前仅治疗继发性甲状旁腺功能亢进症的VDRM在2010年就实现了10亿美元以上的年销售额。Zemplar(Paricalcitol)和Hectorol主宰了美国透析市场(80%)，因为它们的高钙毒性略低(毒性比普通的Calcijex低2到4倍，后者是一种内源性激素骨化三醇)。一个 VS-105等治疗CKD的新型VDRM在美国的年销售额可能达到10亿美元以上。 公共卫生相关性：Vidasym的第一阶段STTR研究将调查使用VS-105治疗与糖尿病(糖尿病肾病)相关的慢性肾脏疾病(CKD)的可行性。糖尿病是慢性肾脏病的主要病因。根据国家肾脏基金会的数据，大约30%的1型(青少年发病)糖尿病患者和高达40%的2型(成年发病)糖尿病患者最终会患上肾衰竭。2010年，39.6%的确诊糖尿病患者和41.7%的未确诊糖尿病患者患有慢性肾脏病。全球有3.5亿人患有慢性肾脏病，预计到2025年，这一数字将增加到5.5亿人，这主要是由于代谢综合征和糖尿病的日益流行。尽管CKD的治疗方式和药物种类繁多，但糖尿病CKD患者的数量仍在不断增加，CKD患者的死亡率仍居高不下(~33%)。目前迫切需要开发一种有效的、新颖的复苏方法来治疗糖尿病肾病。目前治疗的局限性表明，一种新的治疗方法，如VS-105，可以减少透析的需要，并降低CKD的死亡率，为改善结果提供了一个重要的机会，具有重大的社会效益。

DESCRIPTION (provided by applicant): Twenty-six million people in America have chronic kidney disease (CKD). Diabetes is by far the leading cause of CKD (diabetic nephropathy), accounting for 44% of new cases of dialysis (in 2005). 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 diabetic nephropathy patients and also provide cardiovascular and survival benefits for CKD patients. Despite encouraging data on VDRM's potential renal, cardiovascular and survival benefits for the CKD patients, currently in the CKD field VDRM is only indicated for 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. 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 no hypercalcemic toxicity in the efficacious dose range that could reduce PTH and provide cardiovascular benefits. Vidasym has taken a unique approach to discover novel VDRMs that are highly differentiated from existing VDRMs. In the clinically validated 5/6 nephrectomized uremic rat model Vidasym's VS-105 has no detectable hypercalcemic toxicity in the dose range that improves cardiovascular function and suppresses PTH to the normal level (vs. other VDRMs with overlapping dose ranges for efficacy and toxicity). Vidasym plans to develop VS-105 into a reimbursable prescription new drug to treat CKD patients. Initial focus for VS-105 in clinical studies is on diabetic nephropathy in CKD patients. Thus, a logical step is to determine the efficacy of VS-105 in diabetic nephropathy animal models. The specific aims of this Phase I study are: (1) To compare the therapeutic efficacy between VS-105 and paricalcitol (the VDRM that currently has the largest US market share) in blocking the progression of diabetic nephropathy in experimental models of type 1 and type 2 diabetes. (2) To elucidate the mechanism underlying the renoprotective effect of VS-105. Data from this phase I study 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. Current VDRMs for secondary hyperparathyroidism alone achieve US$1+ billion in annual sales in 2010. Zemplar (paricalcitol) and Hectorol dominate the US dialysis market (>80%) due to their slightly less hypercalcemic toxic profile (~2 to 4 fold less toxic than generic Calcijex, the endogenous hormone calcitriol). A novel VDRM such as VS-105 for treating CKD could potentially achieve annual US sales at $1+ billion. PUBLIC HEALTH RELEVANCE: Vidasym's phase I STTR study will investigate the feasibility of using VS-105 to treat chronic kidney disease (CKD) related to diabetes (diabetic nephropathy). Diabetes is the leading causes of CKD. According to National Kidney Foundation, ~30% of patients with Type 1 (juvenile onset) diabetes and up to 40% of those with Type 2 (adult onset) diabetes eventually will suffer from kidney failure. In 2010 39.6% of people with diagnosed and 41.7% with undiagnosed diabetes had CKD. Globally > 350 million individuals have CKD and this number is projected to increase to >550 million by 2025 largely due to the growing epidemic of metabolic syndrome and diabetes. Although various modalities and substances are available for CKD, the number of diabetic CKD patients keeps increasing and the mortality rate for CKD patients remains high (~33%). There is an urgent medical need for the development of an effective and novel resuscitation approach for the treatment of diabetic nephropathy. Limitations of current therapy demonstrate that a new treatment approach such as VS-105 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.