New drug VS-501 for treating hyperphosphatemia in chronic kidney disease

描述(申请人提供)：美国有2600万人患有慢性肾脏疾病。尽管CKD患者有各种治疗方法，但五年存活率约为33%。慢性肾脏病患者的血磷水平控制不当会导致多种临床重要的病理改变，如肾功能进一步恶化、心血管并发症、肾性骨营养不良和死亡率增加。目前市场上的口服磷酸盐粘合剂存在严重的缺陷：(1)磷酸盐结合效果不佳和效率低下；(2)药丸负担高(每天服用大量药丸)，令人不快，因此依从性低；(3)价格昂贵，尤其是无钙磷酸盐粘合剂；(4)副作用和安全性问题，如高钙血症、铝中毒、对其他药物的负面影响、胃肠道(GI)副作用和器官蓄积。Vidasym采取了一种独特的方法来发现VS-501，这是一种从植物中提取的天然聚合物，经过化学处理后，可以高效地吸收胃肠道中的磷酸盐和其他矿物质，而不会产生系统性毒理学影响。为了证实VS-501‘S优越的安全性和有效性，重要的一步是在临床验证的5/6肾切除(NX)尿毒症大鼠模型中进行VS-501和西维拉姆(目前市场上首选的磷酸盐结合剂)的面对面比较。因此，本研究的第一阶段研究的具体目的是：(1)比较VS-501和碳酸七维拉姆对5/6 NX尿毒症大鼠的治疗效果。接受标准：VS-501将表现出比西维拉姆碳酸盐更好的疗效和更少的副作用；(2)阐明在慢性肾脏病中控制磷酸盐对肾脏和心血管的好处。验收标准：VS-501对心脏和肾脏的保护作用优于西维拉姆。实现这些目标将确认VS-501作为治疗慢性肾脏病高磷血症的临床候选药物的优势，并证明磷酸盐控制在改善CKD疾病进展和心血管并发症方面的有效性，这将导致VS-501的第二阶段IND使能研究(安全性和毒理学)。第二阶段研究的完成将使VS-501进入人体临床试验。Vidasym计划将VS-501开发成治疗CKD的可报销处方药。一旦开发出这种药物，不仅可以降低慢性肾脏病的死亡率，还可以减少透析的需要。目前的磷酸盐粘合剂在全球的年销售额达到10多亿美元，主要是在透析患者中。仅Sevelamer一家的全球年销售额就达到7.5亿美元。从销售数字估计，90%的透析患者接受磷酸盐粘合剂治疗，但在美国，1%的3/4期CKD患者得到治疗。假设VS-501在3/4/5期CKD患者(约20名MM患者)中有3%的渗透率，每年的治疗费用为2,000美元(而Sevelamer为约3,000美元)，估计美国的年销售额将为12亿美元。 公共卫生相关性：Vidasym的第一阶段SBIR研究将调查使用Vidasym的新型磷酸盐结合剂Vida-501治疗高磷血症的可行性，并改善慢性肾脏疾病(CKD)的肾脏和心血管功能。全球有3.5亿人患有慢性肾脏病，预计到2025年，这一数字将增至5.5亿。尽管CKD的治疗方式和药物种类繁多，但CKD患者的死亡率仍居高不下(~33%)，且透析CKD患者的数量持续增加。医学上迫切需要开发一种有效和新颖的复苏方法来治疗慢性肾脏病。慢性肾脏病的高磷血症与肾功能降低、心血管并发症和死亡率增加有关。目前治疗的局限性表明，一种新的治疗方法，如VS-501，可以延迟透析时间并降低CKD的死亡率，为改善预后提供了重要的机会，具有显著的社会效益。

DESCRIPTION (provided by applicant): Twenty-six million people in America have chronic kidney disease (CKD). Despite the various treatments available to CKD patients, the five-year survival rate is ~33%. Inadequately controlled serum phosphate levels in CKD can lead to various pathologies of clinical importance such as further deterioration of kidney function, cardiovascular complications, renal osteodystrophy, and increased mortality. Current oral phosphate binders on the market have serious shortcomings: (1) suboptimal and inefficient phosphate binding, (2) high pill burden (large number of pills per day), unpalatable and hence low compliance, (3) expensive, especially for the calcium-free phosphate binders, and (4) side effects and safety concerns such as hypercalcemia, aluminum toxication, negative influence on other medication, gastrointestinal (GI) side effects and accumulation in organs. Vidasym has taken a unique approach to discover VS-501, a natural polymer derived from plants that is chemically processed to become highly effective in absorbing phosphate and other minerals in the GI tract without systemic toxicology effects. To confirm VS-501's superior safety and efficacy profiles, an important step is to conduct a head-to-head comparison between VS-501 and sevelamer (the preferred phosphate binder currently on the market) in the clinically validated 5/6 nephrectomized (NX) uremic rat model. Thus, the specific aims of this Phase I study are: (1) to compare the therapeutic efficacy between VS-501 and sevelamer carbonate in the 5/6 NX uremic rats. Acceptance criteria: VS-501 will exhibit better efficacy with less side effects than sevelamer carbonate; (2) to elucidate the renal and cardiovascular benefits of phosphate control in CKD. Acceptance criteria: VS-501 will show better heart and kidney protective effects than sevelamer. Achieving these aims will confirm the superior profile of VS-501 as a clinical candidate to treat hyperphosphatemia in CKD and also demonstrate the efficacy of phosphate control on ameliorating disease progression and cardiovascular complications in CKD, which shall lead to the Phase II IND-enabling studies (safety and toxicology) for VS-501. The completion of Phase II studies will allow VS-501 to enter human clinical trials. Vidasym plans to develop VS-501 into a reimbursable prescription new drug to treat CKD. Once developed, such a drug will not only reduce the mortality rate in CKD, but also reduce the need for dialysis. Current phosphate binders achieve US$1+ billion in annual worldwide sales mainly in dialysis patients. Sevelamer alone showed US$750 million in annual worldwide sales. Estimating from the sales numbers, >90% of dialysis patients receive phosphate binders, but <1% Stage 3/4 CKD patients in US are treated. Assuming VS-501 has a modest 3% penetration into the Stage 3/4/5 CKD patient population (~20 MM patients) at an annual treatment cost of US$2,000 (vs. ~US$3000 for Sevelamer), the estimated annual US sales will be US$1.2 billion. PUBLIC HEALTH RELEVANCE: Vidasym's phase I SBIR study will investigate the feasibility of using Vida-501, Vidasym's novel phosphate binder, to treat hyperphosphatemia and to improve renal and cardiovascular functions in chronic kidney disease (CKD). 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. Hyperphosphatemia in CKD is linked to reduced kidney function, cardiovascular complications, and increased mortality. Limitations of current therapy demonstrate that a new treatment approach such as VS-501 to delay the time to dialysis and also reduce the mortality rate of CKD offers a significant opportunity for improved outcomes with substantial societal benefit.