New drug Vida-5 for treating chronic kidney disease progression

治疗慢性肾病进展的新药Vida-5

基本信息

批准号：
8195768
负责人：
Jinshyun Ruth Wu-Wong
金额：
$ 21.91万
依托单位：
VIDASYM, INC.
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-20 至 2013-03-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8195768
关键词：
Adverse effects Albuminuria Americas Anemia Angiotensin-Converting Enzyme Inhibitors Animals Annual Reports Biological Markers Blood flow Brain Budgets Calcitriol Calcium Cardiovascular Diseases Cardiovascular system Chronic Chronic Kidney Failure Clinical Clinical Trials Creatinine Data Deterioration Development Dialysis patients Dialysis procedure Disease Disease Progression Dose Doxercalciferol Drug Kinetics Drug Prescriptions Enalapril Foundations Future Generic Drugs Glomerular Filtration Rate Goals Health Healthcare Healthcare Systems Homeostasis Hormones Human Hypercalcemia Immune Individual Information Systems Kidney Kidney Diseases Knowledge Marketing Medical Medicare Metabolism Modality Muscle Contraction Nerve Oral Outcome Parathyroid gland Patients Penetration Pharmaceutical Preparations Pharmacologic Substance Phase Play Process Proteinuria Protocols documentation Rattus Renal Osteodystrophy Renal function Resuscitation Risk Safety Sales Secondary Hyperparathyroidism Serum Small Business Innovation Research Grant Staging Survival Rate Symptoms Time Toxic effect Toxicology Treatment Cost Vasodilator Agents Vitamin D3 Receptor Work Zemplar bone commercial application drug discovery experience improved mortality novel patient population phase 1 study phase 2 study pressure scale up standard of care technological innovation

项目摘要

DESCRIPTION (provided by applicant): Twenty-six million people in America have chronic kidney disease (CKD). Anemia, cardiovascular diseases, secondary hyperparathyroidism, renal osteodystrophy and other complications are common in CKD. 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 CKD patients and also provide survival benefits for CKD patients. Despite encouraging data on VDRM's potential renal and survival benefits for the CKD patients, currently in the CKD field VDRM is only indicated for managing 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. Therefore, 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 little or no hypercalcemic toxicity in the efficacious dose range that could reduce PTH and slow kidney disease progression. Vidasym has taken a unique drug discovery/development approach to discover novel VDRMs that are highly differentiated from existing VDRMs. Vidasym's Vida-5 has no detectable hypercalcemic toxicity in the dose range that suppresses PTH to the normal level (vs. other VDRMs with overlapping dose ranges for efficacy and toxicity). With Vida-5's superior safety and efficacy profiles established, the next step is to determine the feasibility of using Vida-5 to treat kidney disease progression and also its long-term side effect potential in animal studies. The specific aims of this Phase I study are: (1) to conduct an animal study to show the synergistic effect of Vida-5 and an ACE inhibitor on reducing biomarkers (such as serum creatinine and proteinuira) indicative of kidney disease progression; (2) to conduct a toxicity animal study to prepare Vida-5 for Phase II studies. Once this phase I study is completed the data will allow the advancement of Vida-5 into Phase II IND-enabling studies including Vida-5 synthesis scale-up, process development and pharmacokinetics, metabolism, safety and toxicology. The completion of Phase II studies will allow Vida-5 to enter human clinical trials. Vidasym plans to develop Vida-5 into a reimbursable prescription new drug to treat kidney disease progression. Once developed, such a drug will not only reduce the mortality rate of CKD, but also reduce the need for dialysis. Current VDRMs for secondary hyperparathyroidism alone achieve US$1+ billion in annual sales in 2009. Zemplar and Hectorol dominate the US dialysis market (>80%) due to their slightly less hypercalcemic toxic profile (~2-4 fold less toxic than generic Calcijex, the endogenous hormone calcitriol,). A novel VDRM such as Vida-5 for treating kidney disease progression could easily achieve an annual US sales at $1+ billion. PUBLIC HEALTH RELEVANCE: Vidasym's phase I SBIR study will determine the feasibility of using Vida-5 to treat chronic kidney disease (CKD) progression. 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. Limitations of current therapy demonstrate that a new treatment approach such as Vida-5 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)。贫血、心血管疾病、继发性甲状旁腺功能亢进、肾性骨营养不良等并发症在CKD中很常见。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 CKD 患者的蛋白尿/白蛋白尿，并为 CKD 患者提供生存益处。尽管有关 VDRM 对 CKD 患者潜在的肾脏和生存益处的数据令人鼓舞，但目前在 CKD 领域，VDRM 仅适用于治疗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。因此，一种保留了现有 VDRM 共有的功效而没有毒性的新型 VDRM 将具有显着的临床益处。理想的 VDRM 在有效剂量范围内应具有很少或没有高钙毒性，从而降低 PTH 并减缓肾脏疾病的进展。 Vidasym 采用独特的药物发现/开发方法来发现与现有 VDRM 高度不同的新型 VDRM。 Vidasym 的 Vida-5 在将 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（与具有重叠剂量范围的功效和毒性的其他 VDRM 相比）。随着 Vida-5 卓越的安全性和有效性特征的确立，下一步是确定使用 Vida-5 治疗肾脏疾病进展的可行性及其在动物研究中的长期副作用潜力。这项I期研究的具体目标是：（1）进行动物研究，以显示Vida-5和ACE抑制剂在降低指示肾脏疾病进展的生物标志物（例如血清肌酐和蛋白尿）方面的协同作用； (2)进行毒性动物研究，为Vida-5的II期研究做好准备。一旦这项 I 期研究完成，这些数据将允许 Vida-5 进入 II 期 IND 支持研究，包括 Vida-5 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Vida-5进入人体临床试验。 Vidasym 计划将 Vida-5 开发成一种可报销的处方新药，用于治疗肾脏疾病进展。一旦开发出来，这样的药物不仅会降低 CKD 的死亡率，还会减少透析的需要。目前仅用于治疗继发性甲状旁腺功能亢进症的 VDRM 在 2009 年的年销售额就达到了 1 亿美元以上。Zemplar 和 Hectorol 由于其高钙血症毒性稍低（比仿制药 Calcijex 的毒性低约 2-4 倍），在美国透析市场占据主导地位 (>80%)。内源性激素骨化三醇，）。用于治疗肾脏疾病进展的新型 VDRM（例如 Vida-5）可以轻松实现美国年销售额超过 10 亿美元。公共健康相关性：Vidasym 的 I 期 SBIR 研究将确定使用 Vida-5 治疗慢性肾脏病 (CKD) 进展的可行性。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。尽管有多种治疗 CKD 的方法和药物，但 CKD 患者的死亡率仍然很高（~33%），并且透析 CKD 的数量患者不断增加。医学界迫切需要开发一种有效且新颖的复苏方法来治疗 CKD。当前治疗的局限性表明，Vida-5 等新的治疗方法可以减少透析需求并降低 CKD 死亡率，为改善结果提供了重要机会，并具有巨大的社会效益。