Subcutaneous Drug Development for Portal Hypertension Ascites

摘要：无论原因如何，所有类型腹水的患病率为每10万人中有41.7人患有腹水 其中80%是由于肝硬变。腹水的治疗是用盐限制的饮食和药物治疗 利尿剂。然而，在5%到10%的腹水患者中，药物治疗变得难治。一半的人 晚期肝硬变导致顽固性腹水的患者将在没有肝脏的情况下在一年内死亡 建议进行肝移植，因此建议加快肝移植的转诊。临时治疗 等待期间包括大容量穿刺术、经颈静脉肝内门体分流术(TIPS)和 腹膜静脉分流术的外科手术。这些手术的并发症可能会进一步增加 死亡率包括穿刺性循环功能障碍(PICD)和慢性肝性脑病 来自小费。可以阻止病情发展或延长生存时间的药物疗法 因此，迫切需要通往肝移植的治疗桥梁。特利加压素，三甘氨基[8-赖氨酸] 加压素是赖氨酸加压素(LVP)的一种非活性前体药物，它能缓慢释放活性LVP 尽量减少可能导致缺血副作用的LVP峰值。LVP降低门静脉压力，恢复 血液动力学平衡，是治疗门脉高压性腹水的有效方法。因为LVP速度慢 释放，特利加压素耐受性良好，安全性远远好于人的天然加压素([8- Arg]加压素)。静脉注射特利加压素在欧洲已经有20年的历史了，它是 治疗静脉曲张和肝肾出血的最具成本效益和最经济的药物之一 综合征(HRS)与存活率的改善，这是很好的记录。尽管它的安全性很好 特利加压素的使用目前仅限于急性护理环境，因为较短的半衰期(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 具有慢得多的LVP释放的衍生物(Dter)，被发现是有效的肝硬变大鼠模型 门脉高压症每天一次皮下注射时会出现腹水。此产品可以拥有 在美国有巨大的市场机会，特别是在门诊方面(这将减少总体 消除住院费用的医疗保健费用)治疗肝硬变顽固性腹水- 诱发性门脉高压腹水。本产品(Dter)提供活性LVP的持续释放和 表现出更长的血液存在时间和更低的LVP Cmax(消除缺血副作用) 而不是特利加压素。该提案旨在收集IND支持数据包以提交给FDA 开始临床试验。我们已经获得了在肝硬变患者中使用dter的孤儿药物地位。 诱发腹水。 Pharmain Corp.机密信息

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