AASLD: Drug for Autoimmune Liver Disease Promising

StephenW

http://www.medpagetoday.com/MeetingCoverage/AASLD/29582?utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=WC&eun=g426768d0r&userid=426768&[email protected]&mu_id=
AASLD: Drug for Autoimmune Liver Disease Promising
By Michael Smith, North American Correspondent, MedPage Today
Published: November 10, 2011
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine.     
Click here to provide feedback
Action Points  

    Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


    Note also that the farnesoid X receptor, an endogenous sensor for bile acids, regulates a program of genes involved in bile acid biosynthesis, conjugation, and transport. The novel compound 6-ethyl chenodeoxycholic acid, a derivative of the primary human bile acid CDCA, has markedly increased agonist potency for the receptor.


    In this study, the drug significantly reduced alkaline phosphatase and GGT levels in patients with definite or probable primary biliary cirrhosis. Pruritus was the most common adverse experience.

SAN FRANCISCO – An investigational drug aimed at an autoimmune liver disease showed "clear biochemical improvement" in a short trial, a researcher said here.

The compound, dubbed obeticholic acid, is a potent agonist of the farnesoid X receptor, which plays a role in regulating bile acid levels, according to Kris Kowdley, MD, of Virginia Mason Medical Center in Seattle.

Because of that effect, the compound is thought to be a possible treatment for primary biliary cirrhosis (PBC), an autoimmune disease that mainly affects women, Kowdley said at the annual meeting of the American Association for the Study of Liver Diseases.

To test the question, Kowdley and others conducted a double-blind, placebo-controlled, dose-finding study in 60 patients with PBC, of whom 48 completed the 12-week treatment period.

The primary aims of the study were to assess the effect of two doses of the drug – 10 mg and 50 mg -- on levels of alkaline phosphatase, a marker of blocked bile ducts, as well as to describe safety.

Both doses of the compound led to a significant drop in enzyme levels after 12 weeks -- a 45% decline for the 10-mg dose and a 38% drop for the 50-mg dose. Both changes were significant at P<0.0001 compared with no change for patients on placebo.

Put another way, levels of the enzyme fell from almost four times the upper limit of normal to about twice the upper limit of normal, while placebo values did not change substantially, Kowdley reported.

During a two-week follow-up after the end of treatment, alkaline phosphatase levels rebounded slightly, he said.

The researchers found a similar effect on levels of gamma-glutamyl transpeptidase (GGT), an enzyme also used as a marker for disease of the biliary tract.

Patients on placebo saw a mean drop in GGT of just 3 IU, Kowdley reported, compared with 73 IU for the low dose and 65 IU for the high dose, differences that were significant at P=0.004 and P=0.007, respectively.

The main adverse event was pruritus, which afflicted 30% of those on placebo, but 70% of those on the low dose of the drug and 94% of those on the high dose.

All told, nine of the patients dropped out – all in the treatment arms and all because of the pruritus, Kowdley said.

But the findings warrant further study, he said, and a phase III trial is planned to start early next year.

The findings are exciting although the researchers still have to deal with the issue of pruritus, according to AASLD president Jake Liang, MD, of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md.

"This is a potentially exciting new drug for PBC and merits further study," he told reporters. But the "major drawback" is the itching associated with the compound, he added.

The compound works more quickly than the current standard-of-care drug – ursodiol (Actigall) -- and appears to be more faster-acting, Liang said. But since it will also have to be taken continuously, it will be important to reduce the pruritus, which "could be very debilitating," he said.

The study was supported by Intercept Pharmaceuticals. Kowdley reported financial links with Novartis, Gilead, Merck, Vertex, Pharmasset, BMS, Schering Plough, Intercept, Abbott, Ikaria, Mochida, Zymogenetics, and Conatus.

Liang had no disclosures.

Several of the co-authors were employees of Intercept Pharmaceuticals, the producer of 6-alpha-ethyl-chenodeoxycholic acid.


Primary source: Hepatology
Source reference:
Kowdley KV, et al "The first new monotherapy therapeutic PBC study in a decade? An international study evaluating the farnesoid x receptor agonist obeticholic acid in PBC" Hepatology 2011; 54(4): Abstract 116.

StephenW

肝病学会：自身免疫性肝病的药物有望
迈克尔史密斯，北美通讯员，MedPage今天
发布日期：2011年11月10日，
评论由Zalman的S.阿古斯，医学博士，名誉教授
宾夕法尼亚大学医学院。
点击这里提供反馈
行动要点

    请注意，这项研究是作为一个抽象的出版，并在一次会议上提出的。应考虑这些数据和结论是初步的，直到在同行评审的期刊出版。


    还要注意的法呢醇X受体，内源性胆汁酸的传感器，调节胆汁酸的生物合成共轭，和交通有关的基因方案。新化合物6 - 乙基鹅去氧胆酸，主人体胆汁酸CDCA的衍生物，显着增强受体激动剂药效。


    在这项研究中，药物显着降低，在明确或可能的原发性胆汁性肝硬化患者的碱性磷酸酶和GGT水平。瘙痒症是最常见的不良体验。

旧金山 - 在自身免疫性肝病的研究药物表现出“明确的生化改善”在很短的试验，研究人员在这里说。

的化合物，被称为obeticholic酸，是一种强效激动剂的法呢醇X受体，它起着调节胆汁酸水平的作用，根据克里斯Kowdley，医学博士，弗吉尼亚梅森医学中心在西雅图。

由于这种效应，该化合物被认为是一个可能的治疗原发性胆汁性肝硬化（PBC）是一种自身免疫性疾病，主要影响妇女，Kowdley肝病研究在美国协会年会上说。

Kowdley和其他测试的问题，进行了一项双盲，安慰剂对照，剂量调查研究在60 PBC患者，其中48个完成了12周的治疗期。

这项研究的主要目的是评估两种剂量的药物的效果 - 10毫克和50毫克 - 碱性磷酸酶水平，胆管阻塞的标志，以及描述安全。

这两种化合物12周后，在酶的水平显著下降导致的剂量 - 为10毫克剂量的45％下降为50毫克剂量的38％下降。这两个变化，P <0.0001显著，与服用安慰剂的患者没有改变相比。

换句话说，酶的水平下降了近四倍的正常正常值上限的两倍左右的上限，而服用安慰剂的值没有发生重大变化，Kowdley报道。

他说，在为期两个星期的的治疗结束后随访，碱性磷酸酶水平略有回升。

研究人员发现，γ-谷氨酰转肽酶（GGT），也用于胆道疾病的标志物酶的水平类似的效果。

服用安慰剂的患者看到了平均只有3 IU GGT的下降，Kowdley报道，73 IU低剂量和高剂量为65 IU，在P = 0.004和P = 0.007，显著的差异，分别相比。

不良事件主要是瘙痒，这折磨那些服用安慰剂的30％，但低剂量的药物的70％和94％的高剂量的。

总而言之，病人中有9个下降了 - 所有的治疗武器，因为瘙痒，Kowdley说。

但研究结果值得进一步研究，他说，第三阶段的试验计划明年年初动工。

调查结果是令人兴奋，但研究人员仍然要处理皮肤瘙痒的问题，根据肝病学会主席杰克梁，医学博士，国家糖尿病研究所，在美国马里兰州贝塞斯达，消化道和肾脏疾病

“这是一个潜在的令人兴奋的中国人民银行和值得进一步研究的新药物，他告诉记者。”他补充说，但“主要缺点”是与化合物有关的瘙痒。

复合工程速度比目前标准的保健药品 - ursodiol（Actigall） - 似乎更快效良说。不过，因为它也将不断采取将是重要的，以减少瘙痒，可以非常虚弱​​“，”他说。

这项研究是支持通过拦截药品。 Kowdley报道与诺华公司，Gilead公司，默克公司，顶点，Pharmasset，拜耳，先灵葆雅，拦截，雅培，伊卡里亚，持田，ZymoGenetics公司，并Conatus金融联系。

梁启超没有披露。

共同作者的一些拦截制药，6 -α-乙基去氧胆酸生产员工。


主要来源：肝脏
来源参考：
Kowdley千伏，等“第一单药治疗中国人民银行研究在十年内一个国际研究评估的法呢醇X受体激动剂在PBC obeticholic酸？”肝脏病杂志2011; 54（4）：摘要116。