AASLD肝脏会议: Intercept制药 -阶段2A门静脉高压症的数据

StephenW

http://www.menafn.com/menafn/d3ca7ed2-2fb2-405f-8f1e-3f76080da65d/Intercept-Pharmaceuticals-to-Present-Phase-2a-Portal-Hypertension-Data-at-AASLDs-Liver-Meeting?src=main
Intercept制药: 阶段2A门静脉高压症的数据，在AASLD肝脏会议

NEW YORK, Nov 8, 2012 (Menafn - GlobeNewswire via COMTEX) --Intercept Pharmaceuticals, Inc. ICPT (Intercept), a clinical stage biopharmaceutical company focused on the development and commercialization of novel therapeutics to treat chronic liver diseases, today announced initial results from PESTO, an open-label Phase 2a trial evaluating the effects of obeticholic acid (OCA) for the treatment of portal hypertension. Twelve patients with established alcoholic cirrhosis and portal hypertension were administered a 10mg daily dose of OCA for seven days. The drug was well tolerated in all twelve patients and, of the eight patients assessed for changes in portal pressure, five met the primary efficacy endpoint with a clinically significant improvement in hepatic venous pressure gradient (HVPG), the standard measurement of portal pressure in such patients.

The initial results from PESTO will be presented at the American Association for the Study of Liver Disease (AASLD)'s annual Liver Meeting in Boston as a late-breaking poster on Monday, November 12, 2012. The abstract is available at www.aasld.org.

PESTO Trial Results

The rationale for the PESTO trial is based on previously obtained results in an animal model of cirrhosis, demonstrating that five days of OCA therapy can reverse portal hypertension via a local nitric oxide induced mechanism with no concomitant change in systemic blood pressure [Hepatology 2009, Vol 50, 74A]. PESTO is designed to evaluate OCA's ability to reduce hepatic portal venous pressure in patients with liver cirrhosis, first testing a 10mg dose and then proceeding with a 25mg dose (still ongoing). The first four patients enrolled were assessed for drug safety alone; the subsequent eight patients were then assessed for efficacy as well by measuring HVPG.

The primary efficacy endpoint of the trial is to lower HVPG after seven days of treatment by 15% or more, or to less than 12 mm Hg, a level at which the risk of adverse clinical outcomes has been shown to be significantly reduced. Five of the eight patients in the efficacy cohort met at least one of these endpoint criteria, while a sixth patient experienced slightly more than a 14% reduction in HVPG. Among these six patients who experienced a reduction in HVPG, the mean baseline HVPG was 16 mm Hg which decreased to 12 mm Hg at the end of therapy, reflecting a mean 24% reduction (range:14% to 38%). Systemic mean arterial blood pressure (MAP) increased slightly in the six patients, with the mean baseline MAP at 84 mm Hg rising to 97 mm Hg at the end of therapy. All patients tolerated OCA therapy and no significant changes were seen in aminotransferases, creatinine, bilirubin or coagulation.

"The available results so far from the PESTO trial are encouraging," commented Dr. Raj Mookerjee from University College London, the investigator conducting the trial. "It is believed that portal hypertension is caused at least to some degree by a reduction in available intra-hepatic nitric oxide, and we have previously shown in an animal model that OCA can significantly increase nitric oxide in the liver. The aim of PESTO is to assess the ability of OCA to similarly reduce portal hypertension in patients acutely, after only a week of treatment, via a mechanism independent of any longer term anti-fibrotic effects. Indeed, the data from the 10mg dose cohort suggest that OCA may rapidly improve portal hypertension in patients without reducing systemic blood pressure. These results merit further study of OCA in longer term, controlled trials as a potential novel portal hypertension treatment."

About Portal Hypertension

Portal hypertension results from increased pressure in the portal vein, which feeds most of the blood supply to the liver. Clinically significant portal hypertension is defined as an HVPG >10 mm Hg (1 mm to 5 mm HVPG is normal). It is a common cause of morbidity and mortality in patients with cirrhosis, seen at the end stage of all chronic liver diseases. One manifestation of portal hypertension is the development of esophageal varices, which are distended and weakened veins in the lower part of the esophagus that can burst and cause catastrophic bleeding. More than 40% of patients with cirrhosis have varices at the time of diagnosis. Patients with an HVPG  greater than or equal to  12 mm Hg are at particularly high risk of variceal bleeding, with each episode carrying an approximate 20% mortality risk, and a goal of therapeutic intervention is therefore to lower portal pressure ideally below this threshold. There are no approved therapies for the treatment of portal hypertension, although beta blockers are commonly used. However, they are effective in only approximately one third of portal hypertension patients and present significant safety issues in advanced disease. One challenge with beta blockers is that they lower systemic blood pressure in these patients who already tend to have low blood pressure (hypotension) and therefore are at risk of fainting and reduced perfusion of critical organs.

About Intercept

Intercept is a biopharmaceutical company focused on the development and commercialization of novel therapeutics to treat orphan and more prevalent liver diseases utilizing its expertise in bile acid chemistry. The company's lead product candidate, obeticholic acid, or OCA, is a bile acid analog and first-in-class agonist of the farnesoid X receptor (FXR). OCA is initially being developed for the second line treatment of primary biliary cirrhosis (PBC) in patients with an inadequate response to, or who are unable to tolerate, ursodiol, the only approved therapy for this indication. PBC is a chronic autoimmune liver disease that may progress to cirrhosis and liver failure, and it is currently the fifth leading indication for liver transplant in the United States. OCA has orphan drug designation in both the United States and Europe for the treatment of PBC. Intercept owns worldwide rights to OCA outside of Japan and China, where it has outlicensed the product candidate to Dainippon Sumitomo Pharma (DSP). For more information about Intercept, please visit the Company's website at: www.interceptpharma.com.

StephenW

纽约11月8，2012（Menafn通过COMTEX  - 中国商业电讯） - 拦截制药公司ICPT（拦截），专注于开发和商业化的创新疗法治疗慢性肝脏疾病的一个临床阶段的生物制药公司，今天宣布PESTO的初步结果，开放标签2A期试验，评估的影响obeticholic酸（OCA）用于治疗门静脉高压症。 12例酒精性肝硬化和门静脉高压症，服用10mg，每日剂量的亚奥理事会七天。该药物的耐受性良好，在所有12例患者中，8例门静脉压力的变化进行评估，达到主要疗效终点与肝静脉压力梯度（HVPG），标准测量门静脉压力在这样一个临床显着改善患者。

从PESTO的初步结果将发表在美国肝病研究协会（AASLD）肝脏在波士顿举行的年度作为2012年11月12日（星期一）的最新海报。
文摘是在www.aasld.org。

PESTO试验结果

基本原理为香蒜试验的基础上的肝硬化动物模型中得到的结果，表明通过当地的一氧化氮诱导机制没有随之而来的变化在全身血压[肝脏2009年，第5天的OCA治疗可以逆转门脉高压症50，74A]。PESTO的目的是评估OCA的能力，以减少肝硬化患者，肝门静脉压力测试10mg剂量，然后用25毫克剂量（仍在进行中）。第4例患者进行了评估药品安全单独随后的8例患者的疗效进行评估，以及通过测量HVPG。

的试验的主要疗效终点是降低HVPG的后7天的治疗，15％或更多，或至小于12毫米汞柱，已被证明在哪一级的不良的临床结果的风险被显着降低。五的8个患者中的疗效队列遇到这些端点的标准中的至少一个，而六分之一患者经历了略多于在HVPG减少了14％。经历了减少在HVPG的其中6个患者中，平均基线HVPG是降低至12毫米汞柱，在治疗结束时，反映了平均减少24％（范围：14％至38％）的16毫米汞柱。全身平均动脉压（MAP）略有增加的6例患者中，平均基线MAP在84毫米汞柱上升到97毫米汞柱，在治疗结束。所有患者的耐受性OCA治疗并没有显着的变化，在转氨酶，胆红素，肌酐或凝固。

“至今PESTO试验的查询结果是令人鼓舞的，拉吉慕克吉博士评论说：”从伦敦大学学院（University College London），研究者进行试验。 “这被认为至少在一定程度上由可用帧内肝一氧化氮的减少，门静脉高压症引起，我们先前已经在动物模型中所示，OCA可以显着增加在肝脏中的一氧化氮的目的香蒜事实上，评估的能力，亚奥理事会，同样降低门静脉高压症患者剧烈，只有一个星期的治疗后，通过一个独立于任何较长期的抗肝纤维化作用的机制。10mg剂量队列的数据显示，OCA可能会迅速提高门静脉高压症患者不降低全身血压。这些结果值得进一步研究的亚奥理事会长远来看，作为一个潜在的新的门静脉高压症治疗的对照试验。“

关于门静脉高压症

门静脉高压导致门静脉压力，供给到肝脏的血液供应增加。临床上显着的门静脉高压症的定义为HVPG> 10毫米汞柱（1毫米至5毫米的HVPG是正常的）。这是一个常见的​​原因，出现在所有慢性肝病的终末期肝硬化患者的发病率和死亡率。门静脉高压症的一种表现形式是，这是在下部食道，可能会爆油炸并导致灾难性的出血静脉扩张，削弱食管静脉曲张的发展。超过40％的肝硬化患者有静脉曲张的诊断时间。 HVPG的大于或等于12毫米汞柱的患者是在特别高的静脉曲张出血的风险，与每集载体的近似20％的死亡风险，因此，治疗性干预的一个目标是降低门脉压力最好低于该阈值。有没有批准用于治疗门静脉高压症的治疗，虽然β受体阻滞剂常用的。然而，他们中只有约三分之一的门静脉高压症和当前重大的安全问题，在先进的疾病是有效的。 β受体阻滞剂的一大挑战是，他们全身血压降低，在这些患者中，已经倾向于有低血压（低血压），因此昏厥和重要器官灌注减少的风险。

关于Intercept
Intercept是一家生物制药公司，专注于开发和商业化的创新疗法治疗孤儿和更普遍的肝脏疾病，利用其专业知识，胆汁酸的化学性质。公司的主导产品候选人，obeticholic酸，或OCA，是胆汁酸的模拟和第一级的法尼酯衍生物X受体（FXR）激动剂。亚奥理事会最初被开发的第二线治疗原发性胆汁性肝硬化（PBC）患者与反应不足，或者是无法容忍的，熊去氧胆酸，唯一批准用于此适应症的治疗。 PBC是一种慢性自身免疫性肝病，可能进展为肝硬化和肝功能衰竭，这是目前进行肝脏移植手术在美国的第五大指示。亚奥理事会在美国和欧洲孤儿药治疗PBC。拦截拥有全球亚奥理事会的权利外，日本和中国，它已outlicensed候选产品，大日本住友制药（DSP）。拦截的更多信息，请访问该公司网站：www.interceptpharma.com。