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

描述（由申请人提供）：美国有2600万人患有慢性肾脏疾病（CKD）。尽管CKD患者可接受多种治疗，但5年生存率约为33%。CKD患者血清磷酸盐水平控制不当可导致多种具有临床重要性的病理，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结合剂存在严重的缺点：(1)磷酸盐结合效果不佳且效率低下；(2)药片负担高（每天服药量大），口感不佳，因此依从性低；(3)价格昂贵，尤其是无钙磷酸盐结合剂；(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采用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，在吸收胃肠道中的磷酸盐和其他矿物质方面非常有效，而不会产生全身毒理学效应。为了确认VS-501优越的安全性和有效性，一个重要的步骤是在临床验证的5/6肾切除（NX）尿毒症大鼠模型中对VS-501和sevelamer（目前市场上首选的磷酸盐粘合剂）进行正面比较。因此，本I期研究的具体目的是：(1)比较VS-501与碳酸西维拉默对5/6 NX尿毒症大鼠的治疗效果。验收标准：VS-501疗效更好，副作用更小；(2)阐明CKD中磷酸盐控制对肾脏和心血管的益处。验收标准：VS-501比sevelamer具有更好的心脏和肾脏保护作用。实现这些目标将证实VS-501作为治疗CKD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II期ind研究（安全性和毒理学）。II期研究的完成将允许VS-501进入人体临床试验。Vidasym计划将VS-501开发成治疗慢性肾病的可报销处方新药。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，磷酸盐粘合剂的全球年销售额达到10亿美元以上，主要用于透析患者。仅Sevelamer一家公司的全球年销售额就达到了7.5亿美元。从销售数字估计，约90%的透析患者接受磷酸盐结合剂治疗，但在美国接受治疗的3/4期CKD患者不到1%。假设VS-501在3/4/5期CKD患者群体（约2000万患者）中渗透率为3%，年治疗费用为2000美元（Sevelamer为3000美元），预计美国年销售额将达到12亿美元。

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.