Subcutaneous Drug Development for Portal Hypertension Ascites

门静脉高压腹水的皮下药物开发

基本信息

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
项目类别：
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

项目摘要

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：无论何种原因，所有类型腹水的患病率为 10 万人中 41.7 人其中80%是由于肝硬化造成的。腹水可通过限盐饮食和药物治疗来治疗利尿剂。然而，5% 至 10% 的腹水患者对药物治疗变得难治。一半晚期肝硬化出现顽固性腹水的患者，如果没有肝脏，一年内就会死亡移植，因此建议快速转诊进行肝移植。临时治疗等待期间包括大容量腹腔穿刺术、经颈静脉肝内门体分流术 (TIPS) 和腹腔静脉分流手术。这些手术的并发症可能会进一步增加死亡包括腹腔穿刺引起的循环功能障碍（PICD）和慢性肝性脑病来自提示。可以阻止进展或延长生存期的药物疗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) 的无活性前体药物，可缓慢释放活性 LVP 最大限度地减少可能导致缺血性副作用的 LVP 峰值。 LVP 降低门静脉压力，恢复平衡血流动力学，是治疗门脉高压性腹水的有效方法。因为LVP慢释放，特利加压素具有良好的耐受性，并且比人类天然加压素具有更好的安全性（[8- Arg]加压素）。过去二十年来，静脉注射特利加压素已在欧洲上市，并且治疗静脉曲张出血和肝肾出血最具成本效益和经济的药物之一综合征（HRS）可改善生存率，这是有据可查的。尽管其安全性良好概况来看，特利加压素的使用目前仅限于急性护理环境，因为半衰期短（26 分钟），需要每 4-6 小时静脉推注一次。我们开发了一种新的特利加压素 LVP 释放速度慢得多的衍生物 (dTer)，被发现是诱导肝硬化的有效大鼠模型每天一次推注皮下注射时会出现门静脉高压性腹水。该产品可以有在美国有一个重要的市场机会，特别是在门诊环境中（这将减少总体治疗肝硬化难治性腹水的医疗费用（通过消除住院费用）门脉高压性腹水。该产品 (dTer) 提供活性 LVP 的持续释放和表现出显着更长的血液存在时间和更低的 LVP Cmax（消除缺血副作用）比特利加压素。该提案旨在收集 IND 授权数据包以提交给 FDA 开始临床试验。我们已经获得了在肝硬化患者中使用 dTer 的孤儿药地位诱发腹水。 PharmaIN 公司机密信息