Novel drug VS-105 for treatment of diabetic nephropathy

治疗糖尿病肾病新药VS-105

基本信息

批准号：
8313361
负责人：
Yan Chun LI
金额：
$ 15.96万
依托单位：
VIDASYM, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8313361
关键词：
Accounting Adolescent Adrenergic beta-Antagonists Affect Albuminuria Americas Angiotensin-Converting Enzyme Inhibitors Animal Model Annual Reports Brain Budgets Calcitriol Calcium Cardiovascular Physiology Cardiovascular system Chicago Chronic Kidney Failure Clinical Clinical Data Clinical Management Clinical Research Clinical Trials Data Development Diabetes Mellitus Diabetic Nephropathy Diabetic mouse Diagnosis Dialysis patients Dialysis procedure Disease Disease Progression Dose Doxercalciferol Drug Kinetics Drug Prescriptions Epidemic Exhibits Experimental Models Foundations Generic Drugs Goals Healthcare Homeostasis Hormones Human Hypercalcemia Individual Inflammation Information Systems Kidney Kidney Diseases Kidney Failure Knowledge Lead Marketing Medical Medicare Metabolic syndrome Metabolism Methods Modality Modeling Molecular Muscle Contraction Nerve Non-Insulin-Dependent Diabetes Mellitus Osteogenesis Outcome Parathyroid gland Pathway interactions Patients Penetration Pharmaceutical Preparations Pharmacologic Substance Phase Physiological Population Prevalence Process Proteinuria Rattus Renin-Angiotensin System Resuscitation Risk Safety Sales Secondary Hyperparathyroidism Small Business Technology Transfer Research Staging Streptozocin Survival Rate Symptoms Therapeutic Toxic effect Toxicology Treatment Cost Treatment Efficacy Universities Vitamin D3 Receptor Zemplar clinical care commercial application cost db/db mouse diabetic diabetic patient improved inhibitor/antagonist mortality novel novel therapeutics paricalcitol patient population phase 1 study phase 2 study pre-clinical scale up standard of care technological innovation type I and type II diabetes

项目摘要

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.

描述（由申请人提供）：美国有 2600 万人患有慢性肾病 (CKD)。迄今为止，糖尿病是 CKD（糖尿病肾病）的主要原因，占新透析病例的 44%（2005 年）。目前针对 CKD 患者的治疗（包括 ACE 抑制剂）主要集中于控制症状和疾病并发症。尽管有多种治疗方法，但五年生存率约为 33%，死亡风险随着肾脏疾病进展和继发性甲状旁腺功能亢进症而增加。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/白蛋白尿，还可以为 CKD 患者提供心血管和生存益处。尽管有关 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（PTH 升高）。高钙毒性会干扰钙稳态并损害身体功能，是扩大市售 VDRM 使用的限制因素。一种新型 VDRM 保留了现有 VDRM 所具有的功效而没有毒性，将具有显着的临床益处。理想的 VDRM 在有效剂量范围内应不存在高钙血症毒性，从而降低 PTH 并提供心血管益处。 Vidasym 采用独特的方法来发现与现有 VDRM 高度不同的新型 VDRM。在经过临床验证的 5/6 肾切除尿毒症大鼠模型中，Vidasym 的 VS-105 在改善心血管功能并将 PTH 抑制至正常水平的剂量范围内没有可检测到的高钙血症毒性（与功效和毒性重叠剂量范围的其他 VDRM 相比）。 Vidasym 计划将 VS-105 开发成可报销处方新药，用于治疗 CKD 患者。 VS-105 临床研究的最初重点是 CKD 患者的糖尿病肾病。因此，合理的步骤是确定 VS-105 在糖尿病肾病动物模型中的功效。这项I期研究的具体目的是：（1）比较VS-105和帕立骨化醇（目前美国市场份额最大的VDRM）在1型和2型糖尿病肾病实验模型中阻断糖尿病肾病进展的疗效。 2型糖尿病。 (2)阐明VS-105的肾脏保护作用的机制。这一第一阶段研究的数据将使 VS-105 进入第二阶段 IND 支持研究，包括 VS-105 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 年的年销售额就达到了 1 亿美元以上。Zemplar（帕立骨化醇）和 Hectorol 主导着美国透析市场 (>80%)，因为它们的高钙血症毒性稍低（比其他药物低约 2 至 4 倍）通用名 Calcijex，内源性激素骨化三醇）。一个用于治疗 CKD 的新型 VDRM（例如 VS-105）可能会在美国实现年销售额超过 10 亿美元。公共健康相关性：Vidasym 的 I 期 STTR 研究将调查使用 VS-105 治疗与糖尿病（糖尿病肾病）相关的慢性肾脏病 (CKD) 的可行性。糖尿病是 CKD 的主要原因。根据国家肾脏基金会的数据，约 30% 的 1 型（青少年发病）糖尿病患者和高达 40% 的 2 型（成人发病）糖尿病患者最终将遭受肾衰竭。 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 CKD。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，这主要是由于代谢综合征和糖尿病的日益流行。尽管有多种治疗 CKD 的方法和药物，但糖尿病 CKD 患者的数量不断增加，且 CKD 患者的死亡率仍然很高（约 33%）。医学上迫切需要开发一种有效且新颖的复苏方法来治疗糖尿病肾病。当前治疗的局限性表明，诸如 VS-105 之类的新治疗方法可以减少透析需求并降低 CKD 死亡率，为改善预后提供了重要机会，并具有巨大的社会效益。