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：所有类型腹水的患病率（无论病因如何）为41.7/100，000， 其中80%是因为肝硬化。腹水的治疗是限盐饮食和药物治疗， 利尿剂然而，在5%至10%的腹水患者成为难治性药物治疗。半年 由于晚期肝硬化而产生顽固性腹水的患者将在一年内死亡， 肝移植，因此建议加速转诊肝移植。临时救治 等待期间包括大容量穿刺术、经颈静脉肝内门体分流术（TIPS）， 腹膜静脉分流外科手术。这些手术的并发症会进一步增加 死亡率包括穿刺引起的循环功能障碍（PICD）和慢性肝性脑病 从TIPS药物治疗可以阻止进展或延长生存期，并作为一种治疗方法。 因此迫切需要肝移植的治疗桥梁。特利加压素，三甘氨酰[8-Lys] 加压素是赖氨酸-加压素（LVP）的无活性前药，其缓慢释放活性LVP， 最小化可导致缺血性副作用的LVP尖峰。LVP降低门静脉压力，恢复 是治疗门脉高压性腹水的有效方法。由于LVP缓慢 释放后，特利加压素耐受性良好，并且具有比人天然加压素好得多的安全性（[8- 10]）。 精氨酸加压素）。静脉内特利加压素在过去二十年中已在欧洲可用， 是治疗静脉曲张出血和肝肾功能障碍的最经济有效的药物之一。 HRS综合征（HRS）与生存率的改善是有据可查的。尽管安全性很好 由于半衰期短，特利加压素的使用目前仅限于急性护理环境（26 分钟），需要每4- 6小时通过IV推注给药。我们开发了一种新的特利加压素 衍生物（dTer），具有慢得多的LVP释放，并被发现是有效的肝硬化诱导的大鼠模型 每日一次推注皮下给药时，门静脉高压腹水。该产品可以有 在美国，特别是在门诊环境中，这是一个重大的市场机会（这将减少整体 通过消除住院费用的医疗保健费用）用于治疗肝硬化的难治性腹水- 诱发门脉高压性腹水。该产品（dTer）提供活性LVP的持续释放， 证明血液存在时间显著延长，LVP Cmax较低（消除缺血性副作用） 而不是特利加压素本提案旨在收集IND启用数据包，以提交给FDA 开始临床试验。我们已经获得了dTer在肝硬化患者中使用的孤儿药地位 诱导腹水。 PharmaIN Corp.机密信息