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

治疗慢性肾病高磷血症的新药VS-501

• 批准号: 8389307
• 负责人: Jinshyun Ruth Wu-Wong
• 金额: $ 21.74万
• 依托单位: VIDASYM, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8389307
• 关键词: Adverse effects; Albumins; Aluminum; Americas; Annual Reports; Appearance; Binding; Budgets; Calcium; Carbonates; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Chronic Kidney Failure; Clinical; Clinical Pathology; Clinical Trials; Creatinine; Deterioration; Development; Dialysis patients; Dialysis procedure; Disease; Disease Progression; Dose; Exhibits; Fibrosis; Foundations; Gastrointestinal tract structure; General Population; Goals; Health; Healthcare; Healthcare Systems; Heart; Human; Hypercalcemia; Individual; Information Systems; Kidney; Kidney Diseases; Knowledge; Lead; Link; Marketing; Medical; Medicare; Metabolism; Minerals; Modality; Modeling; Normal Range; Oral; Organ; Outcome; Patients; Penetration; Pharmaceutical Preparations; Phase; Plants; Polymers; Process; Proteins; Rattus; Renal Osteodystrophy; Renal function; Resuscitation; Risk; Safety; Sales; Sampling; Serum; Small Business Innovation Research Grant; Staging; Survival Rate; Testing; Therapeutic; Time; Toxicology; Treatment Cost; Treatment Efficacy; Urine; Weight; Western Blotting; base; cardiovascular disorder risk; commercial application; experience; food consumption; gastrointestinal; head-to-head comparison; improved; inflammatory marker; inorganic phosphate; mortality; novel; patient population; phase 1 study; phase 2 study; pill; protective effect; safety study; scale up; sevelamer; technological innovation; urinary

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.

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患者有各种治疗方法，但五年生存率约为33%。CKD患者的血清磷酸盐水平控制不佳可导致各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缺陷：（1）磷酸盐结合不理想且效率低下，（2）药丸负荷高（每天大量的药丸），不好吃，因此依从性低，（3）昂贵，特别是对于无钙的磷酸盐结合剂，和（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）副作用和在器官中积聚。Vidasym采用了独特的方法来发现VS-501，这是一种来自植物的天然聚合物，经过化学加工，可以高效吸收胃肠道中的磷酸盐和其他矿物质，而不会产生全身毒理学效应。为了证实VS-501的上级安全性和有效性，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和司维拉姆（目前市场上首选的磷结合剂）之间的头对头比较。因此，本I期研究的具体目的是：（1）比较VS-501和碳酸司维拉姆在5/6 NX尿毒症大鼠中的疗效。验收标准：VS-501将表现出比碳酸司维拉姆更好的疗效和更少的副作用;（2）阐明磷酸盐控制在CKD中的肾脏和心血管益处。验收标准：VS-501将显示出比司维拉姆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上级特征，并证明磷酸盐控制对改善CKD疾病进展和心血管并发症的疗效，这将导致VS-501的II期IND使能研究（安全性和毒理学）。II期研究的完成将使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。目前磷酸盐结合剂在全球的年销售额达到10亿美元以上，主要是在透析患者中。仅司维拉姆一项，全球年销售额就达7.5亿美元。根据销售数字估计，在美国，>90%的透析患者接受磷酸盐结合剂治疗，但<1%的3/4期CKD患者接受治疗。假设VS-501在3/4/5期CKD患者人群（约20例MM患者）中的渗透率为3%，年治疗费用为2，000美元（司维拉姆约为3，000美元），估计美国年销售额为12亿美元。 公共卫生相关性：Vidasym的I期SBIR研究将研究使用Vidasym的新型磷结合剂维达-501治疗高磷血症和改善慢性肾脏疾病（CKD）患者的肾功能和心血管功能的可行性。全球有超过3.5亿人患有CKD，预计到2025年这一数字将增加到超过5.5亿。尽管CKD有各种治疗方法和药物，但CKD患者的死亡率仍然很高（约33%），透析CKD患者的数量不断增加。目前迫切需要开发一种有效且新颖的用于治疗CKD的复苏方法。CKD患者的高磷血症与肾功能下降、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）可延迟透析时间并降低CKD的死亡率，为改善结局提供了重要机会，并具有显著的社会效益。

项目成果

VS-501: A NOVEL, NON-ABSORBED, CALCIUM- AND ALUMINUM-FREE, HIGHLY EFFECTIVE PHOSPHATE BINDER DERIVED FROM NATURAL PLANT POLYMER.

VS-501：一种新型、不被吸收、不含钙和铝、高效磷酸盐粘合剂，源自天然植物聚合物。

• DOI: 10.1002/prp2.42
• 发表时间: 2014
• 期刊: Pharmacology research & perspectives
• 影响因子: 2.6
• 作者: Wu-Wong,JRuth;Chen,Yung-Wu;Gaffin,Robert;Hall,Andy;Wong,JonathanT;Xiong,Joseph;Wessale,JerryL
• 通讯作者: Wessale,JerryL