Subcutaneous Drug Development for Portal Hypertension Ascites

门静脉高压腹水的皮下药物开发

• 批准号: 10469005
• 负责人: Gerardo M. Castillo
• 金额: $ 98.23万
• 依托单位: PHARMAIN CORPORATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-22 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10469005
• 关键词: Acute; Alcoholism; American; Animals; Ascites; Binding; Blood; Bolus Infusion; Cessation of life; Chronic; Cirrhosis; Clinical Trials; Confidential Information; Creation of peritoneovascular shunt; Data; Diuretics; Dose; Equilibrium; Europe; Excipients; Fluid overload; Formulation; Functional disorder; Funding; Furosemide; Greater sac of peritoneum; Half-Life; Health Care Costs; Hemorrhage; Hepatic Encephalopathy; Hepatorenal Syndrome; Hospital Costs; Human; Infusion procedures; Injections; Intravenous; Intravenous Bolus; Lead; Liquid substance; Liver Cirrhosis; Liver diseases; Lysine; Medical; Modeling; Modification; Necrosis; No-Observed-Adverse-Effect Level; Operative Surgical Procedures; Orphan Drugs; Outpatients; Paracentesis; Patients; Peritoneal Fluid; Pharmaceutical Preparations; Pharmacology; Phase; Portal Hypertension; Portal vein structure; Practice Guidelines; Prevalence; Procedures; Prodrugs; Quality of life; Rattus; Recommendation; Refractory; Safety; Secure; Small Business Innovation Research Grant; Sodium Chloride; Sodium-Restricted Diet; Spironolactone; Survival Rate; Testing; Therapeutic; Therapeutic Index; Time; Tissues; Toxic effect; Transjugular intrahepatic portosystemic shunt procedure; Transplant Recipients; Urine; Varicosity; Vasopressins; Viral hepatitis; acute care; analytical method; base; cost effective; dietary restriction; drug development; effective therapy; efficacy testing; hemodynamics; infection risk; lead candidate; liquid formulation; liver transplantation; meetings; method development; mortality; nonalcoholic steatohepatitis; pharmacokinetics and pharmacodynamics; phase 1 study; preference; pressure; receptor; side effect; subcutaneous; success

ABSTRACT: The prevalence of all types of ascites, irrespective of the cause, is 41.7 in 100,000 with 80% of these due to cirrhosis. Ascites is treated with a salt restricted diet and pharmacologic therapy using diuretics. However, in 5% to 10% of patients with ascites becomes refractory to medical therapy. Half of patients who develop refractory ascites due to advanced liver cirrhosis will die within a year without a liver transplant and therefore expedited referral for liver transplantation is recommended. Temporary treatment while waiting includes large volume paracentesis, transjugular intrahepatic portasystemic shunt (TIPS), and peritoneovenous shunt surgical procedures. Complications from these procedures that can further increase mortality include paracentesis-induced circulatory dysfunction (PICD) and chronic hepatic encephalopathy from TIPS. Pharmacological therapies that can stop the progression or extend survival and act as a therapeutic bridge to liver transplantation are thus desperately needed. Terlipressin, tri-glycyl [8-lys] vasopressin, is an inactive pro-drug of Lysine-vasopressin (LVP) that releases active LVP slowly to minimize LVP spike that can cause ischemic side effect. LVP reduces portal vein pressure, restores hemodynamic balance, and is an effective treatment for portal hypertension ascites. Because of slow LVP release, terlipressin is well tolerated and has a far better safety profile than human native vasopressin ([8- Arg] vasopressin). Intravenous terlipressin has been available in Europe for the past twenty years and it is one of the most cost-effective and economical drugs for treating bleeding varices and hepatorenal syndrome (HRS) with improvement in survival rates that is well documented. Despite its good safety profile, the use of terlipressin is currently limited to the acute care setting because the short half-life (26 min) that necessitates administration by IV bolus injection every 4-6h. We developed a new terlipressin derivative (dTer) that has much slower LVP release and found to be effective rat model of cirrhosis induced portal hypertension ascites when administered subcutaneously as once-daily bolus. This product can have a significant market opportunity in the U.S. especially in an outpatient setting (which will reduce overall health care cost by eliminating cost of hospitalization) for the treatment of refractory ascites from cirrhosis- induced portal hypertension ascites. This product (dTer) provides sustained release of active LVP and demonstrated a substantially longer blood presence with lower LVP Cmax (eliminating ischemic side effect) than terlipressin. This proposal is intended to collect IND enabling data package for submission to the FDA to begin clinical trial. We already secured an orphan drug status for the use of dTer in patient with cirrhosis induced ascites. PharmaIN Corp. Confidential Information

摘要：所有类型的腹水的流行率，无论原因如何，在100,000中为41.7 其中80％是由于肝硬化。使用盐限饮食和药理治疗治疗腹水 利尿剂。但是，在5％至10％的腹水患者中，对药物治疗难治性。一半 由于晚期肝肝硬化而导致难治性腹水的患者将在一年内死亡，而无需肝脏 建议进行移植，因此建议进行肝移植的快速转诊。临时治疗 等待时包括大容量的超肠，经循环肝内的Portasytystystys分流（TIPS）和 腹膜分流手术程序。这些程序的并发症可以进一步增加 死亡率包括可穿梭化引起的循环功能障碍（PICD）和慢性肝脑病 从提示。可以阻止进展或延长生存并充当的药理疗法 因此，迫切需要进行肝移植的治疗桥。 Terlipressin，Tri--糖基[8-Lys] 加压素，是一种赖氨酸 - 毒素（LVP）的无活性促血管，可缓慢释放活性LVP 最小化LVP尖峰会导致缺血性副作用。 LVP降低门静脉压力，恢复 血液动力学平衡，是门户高血压腹水的有效治疗方法。由于LVP缓慢 释放，terlipressin的耐受性良好，安全性概况远胜于人类本地加压素（[8-- Arg]加压素）。静脉静脉发脂素在过去的二十年中在欧洲可用，这是 用于治疗出血和肝的最具成本效益，最经济的药物之一 综合征（HRS），其存活率提高了，这有充分的记录。尽管安全性很好 个人资料，Terlipressin的使用目前仅限于急性护理环境，因为短期寿命（26 最小）需要每4-6H注射IV推注。我们开发了一种新的terlipressin LVP释放速度较慢，发现是肝硬化诱导的大鼠模型的衍生物（DTER） 当下以每天一次的大麻地下施用时，门静脉高血压腹水。该产品可以有 在美国，尤其是在门诊环境中的大量市场机会（这将减少总体 通过消除住院费用来治疗肝硬化的难治性腹水 - 诱发门户高血压腹水。该产品（DTER）提供了活跃的LVP的持续释放，并且 表现出较长的血液存在和较低的LVP CMAX（消除缺血性副作用） 比terlipressin。该建议旨在收集IND启用数据包以提交FDA 开始临床试验。我们已经确保了在肝硬化患者中使用DTER的孤儿药物状态 诱发腹水。 Pharmain Corp.机密信息