A Study of RO5024048 in Combination With Ritonavir-Boosted Danoprevir and Pegasys/Copegus in Patients With Chronic Hepatitis C Genotype 1 Who Have Failed Prior HCV Protease Inhibitor Treatment

This randomized, double blind, phase II study will evaluate the efficacy and safety of two doses of RO5024048 in combination with ritonavir-boosted danoprevir and Pegasys (peginterferon alpha-2a) and Copegus (ribavirin) in patients who failed a prior protease inhibitor containing regimen with or without pegylated interferon. Patients will be randomized to receive either a 2-week lead-in of RO5024048 (1500 mg or 1000 mg orally twice daily) in combination with Pegasys (180 mcg subcutaneously weekly) and Copegus (1000 mg or 1200 mg orally daily) followed by 24 weeks of therapy with RO5024048 in combination with danoprevir (100 mg orally twice daily) plus ritonavir (100 mg orally twice daily) and Pegasys and Copegus (QUAD therapy), or 24 weeks of therapy with RO5024048 in combination with danoprevir plus ritonavir and Pegasys and Copegus (QUAD therapy). Anticipated time on study treatment is 24 or 26 weeks, with a treatment-free follow-up of 24 weeks.

开始日期2012-07-01

申办/合作机构

Hoffmann-La Roche, Inc.

NCT01628094 / Completed临床2期

Randomized, Open-Label, Multicenter Study of Safety, Efficacy, and Tolerability of the Combination of RO5466731, RO5190591, Ritonavir, and Copegus With or Without RO5024048 in HCV Genotype 1 Infected Patients Who Are Either Treatment Naïve or Null Responders to Previous Interferon-Based Treatment

This randomized, open-label, multicenter study will evaluate the safety , efficacy and tolerability of the combination treatment RO5466731, RO5190591, ritonavir and Copegus (ribavirin) with or without RO5024048 in patients with chronic hepatitis C genotype 1. In Part 1, treatment-naïve patients will be randomized to receive treatment with RO5466731, RO5190591 plus ritonavir, and Copegus, with or without RO5024048. In Part 2, further treatment-naïve patients will receive a successful regimen from Part 1, or a reduced intensity regimen, and patients who have previously experienced null response to interferon-based treatment will be added to the study.

开始日期2012-06-01

申办/合作机构

Hoffmann-La Roche, Inc.

NCT01483742 / Completed临床2期

A Study to Evaluate Safety, Tolerability, Pharmacokinetics and Antiviral Activity of Ritonavir-Boosted DANOPREVIR and RO5024048 in Different Combinations in Null Responder or Treatment Naïve Patients With Chronic Hepatitis C and Compensated Cirrhosis

This open-label, parallel cohort study will evaluate the safety, pharmacokinetics and antiviral activity of ritonavir-boosted danoprevir in combination with Pegasys (peginterferon alfa-2a) and ribavirin in treatment-naïve patients, and with RO5024048 added to the combination treatment in prior null responder patients with chronic hepatitis C genotype 1 or 4 and compensated cirrhosis. All patients will receive danoprevir 100 mg orally twice daily (bid) , ritonavir 100 mg orally bid, Pegasys 180 mcg subcutaneously weekly and ribavirin 1000-1200 mg/kg/day orally. Prior non-responders will receive RO5024048 1000 mg orally bid additionally. Anticipated time on study treatment is 24 weeks.

开始日期2012-04-01

申办/合作机构

Hoffmann-La Roche, Inc.

100 项与美立他滨相关的临床结果

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100 项与美立他滨相关的专利（医药）

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项与美立他滨相关的文献（医药）

2020-07-01·Journal of Biological Chemistry2区 · 生物学

Resistance to excision determines efficiency of hepatitis C virus RNA-dependent RNA polymerase inhibition by nucleotide analogs

2区 · 生物学

Article

作者: Johnson, Kenneth A ; Villalba, Brian ; Li, Jiawen

NS5B is the RNA-dependent RNA polymerase that catalyzes the replication of the hepatitis C virus genome. It is a major target for antiviral drugs including nucleoside analogs, such as the prodrugs mericitabine and sofosbuvir, which get metabolized to 2'-fluoro-2'C-methylcytidine-5'-triphosphate and 2'-fluoro-2'C-methyluridine-5'-triphosphate, respectively. These analogs act as chain terminators after they are incorporated during RNA synthesis. Recently, it has been shown that NS5B can efficiently remove chain terminators by a nucleotide-mediated excision reaction that rescues RNA synthesis. In this study, we use transient-state kinetics to understand the efficiency of inhibition for five nucleoside analogs. We show that CTP analogs are readily incorporated into a growing primer by NS5B but are also efficiently excised. In contrast, although UMP analogs are more slowly incorporated, the excision of UMP is slow and inefficient, and modifications to the 2'-carbon of the UTP ribose ring further decreased rates of excision to an undetectable level. Taken together, these data suggest that the clinical effectiveness of sofosbuvir is largely a function of being intractable to nucleotide-mediated excision compared with similar nucleoside analogs.

2016-09-01·Current Treatment Options in Infectious Diseases

Zika Virus: Where Is the Treatment?

Review

作者: Boucher, Charles A B ; Koopmans, Marion P G ; Reusken, Chantal B E M ; Mumtaz, Noreen ; van Kampen, Jeroen J A

In the twenty-first century, we have seen the (re-)emergence of several RNA viruses causing severe infections in humans, like SARS and MERS coronavirus, and more recently Ebola virus and Zika virus (ZIKV). A problem with (re-)emerging virus infections is the lack of available medical countermeasures, including antiviral treatment. Therefore, the development of broadly acting antiviral compounds, as well as screening of existing drugs for potential repurposing are explored as ways to fast-track the drug development pipeline for emerging viral diseases. Here, we briefly discuss the available information on potential antiviral treatment of ZIKV infection, as well as specific challenges regarding use of antivirals. Zika virus is a positive-sense single-stranded RNA arbovirus that belongs to the genus Flavivirus of the family Flaviviridae. Based on nucleotide sequences, ZIKV can be further divided into an African lineage and an Asian lineage. The main vector for ZIKV transmission are Aedes mosquitoes. The first isolation of ZIKV was made in 1947 from serum of a febrile rhesus monkey in the Zika forest of Uganda. During the twentieth century, sporadic human cases of ZIKV infection were reported in Africa caused by the African lineage, and in Asia caused by Asian lineage. The epidemiology of ZIKV changed dramatically in the last decade, when major outbreaks of the Asian lineage of ZIKV were reported on the Island of Yap in 2007 and in French Polynesia in 2013. Subsequently, the Asian lineage of ZIKV spread to the Americas in 2015. The current outbreak of ZIKV shows new modes of transmission with mother-to-fetus transmission and sexual transmission. Furthermore, infectious ZIKV has been detected in breast milk, and there are concerns of ZIKV transmission by blood products obtained from asymptomatic viremic persons or by organ transplantation. While postnatally acquired ZIKV infections are asymptomatic or associated with mild symptoms, the recent outbreaks brought two severe complications to light: a Guillain-Barre-like syndrome (GBS), associated with paralysis, and microcephaly and other neuro-developmental problems in infants born to women infected with ZIKV during pregnancy. The rate of complications has been estimated to be around 1/4000 cases for the GBS-like syndrome, and may be considerably higher for the teratogenic effects, although much remains unknown about the precise extent of the possible sequelae in fetuses and infants. A significant contributing factor to this knowledge gap is that up to 80 % of Zika virus infections may be asymptomatic, and these ‘silently’ infected women with potentially affected fetuses and babies may go unnoticed. There are currently no drugs approved for treatment, but several nucleoside analogue drugs have some antiviral activity in cell culture such as 2′-C-methylated nucleosides like 7-deaza-2′-C-methyladenosine (7DMA) and 2′-C-methylcytidine (2CMC), and ribavirin, favipiravir, and T-1105 (Fig. 1). In addition, 7DMA shows modest anti-ZIKV activity in mice. Ribavirin and favipiravir are already approved for use as antiviral drugs in humans for other indications, but showed less in vitro antiviral effect against ZIKV than 7DMA. 7DMA and 2CMC were initially developed for treatment of hepatitis C virus (HCV) which is distantly related to ZIKV, and studies have shown that these compounds have activity against other flaviviruses much more closely related to ZIKV like dengue virus (DENV). Of interest, other anti-HCV nucleoside analogues like the approved sofosbuvir and mericitabine (in clinical trials) also showed in vitro activity against DENV. GS-5734 and BCX4430 are two very broad spectrum anti-RNA virus nucleoside analogues that are currently in phase 1 and 2 clinical trials. According to the manufacturer, BCX4430 reduced mortality in ZIKV-infected mice, but this data has yet to be published. Fig. 1 Replication mechanism of ZIKV and potential antiviral targets. Targets shown in the figure are known antiviral targets for other flaviviruses and hepatitis C virus. The above shows that there is some evidence for the use of broad spectrum antiviral drugs against ZIKV, in particular broad spectrum nucleoside analogues, but the level of evidence thus far is insufficient for licensed clinical applications. Also, a major challenge is how and when such antiviral treatment would be applied, if available. The drug should be active in cells of the nervous system; it should cross the blood-brain-barrier and the placenta, and should be safe for pregnant women, their fetuses, and infants, which are by no means trivial concerns. For example, the unfavorable toxicity profile of ribavirin including teratogenicity limits its use to treat ZIKV infections in pregnant women. In addition, a lesson learned from treating other RNA viruses is that monotherapy can cause the rapid emergence of resistant viruses, stressing the need for development of drugs with different modes of action to reduce the likelihood of selecting out resistant strains. Given the time needed to develop and approve new antiviral drugs, clinicians are currently left empty handed in terms of targeted antiviral treatment for ZIKV infection. A major lesson from this outbreak and previous (re-)emerging RNA virus outbreaks is that we need safe, broad spectrum antiviral drugs that can be tested rapidly in phase III clinical trials during outbreaks to gain the time needed for the development of other control and prevention measures, particularly vaccines.

2016-05-01·Antiviral Therapy4区 · 医学

Modelling the Interaction between Danoprevir and Mericitabine in the Treatment of Chronic HCV Infection

4区 · 医学

Article

作者: Guedj, Jeremie ; Smith, Patrick F ; Lemenuel-Diot, Annabelle ; Perelson, Alan S ; Canini, Laetitia ; Chatterjee, Anushree

Background Modelling HCV RNA decline kinetics under therapy has proven useful for characterizing treatment effectiveness. Methods Here we model HCV viral kinetics (VK) in 72 patients given a combination of danoprevir, a protease inhibitor, and mericitabine, a nucleoside polymerase inhibitor, for 14 days in the INFORM-1 trial. A biphasic VK model with time-varying danoprevir and mericitabine effectiveness and Bliss independence for characterizing the interaction between both drugs provided the best fit to the VK data. Results The average final antiviral effectiveness of the drug combination varied between 0.998 for 100 mg three times daily of danoprevir and 500 mg twice daily of mericitabine and 0.9998 for 600 mg twice daily of danoprevir and 1,000 mg twice daily of mericitabine. Using the individual parameters estimated from the VK data collected over 2 weeks, we were not able to reproduce the low sustained virological response rates obtained in a more recent study where patients were treated with a combination of mericitabine and ritonavir-boosted danoprevir for 24 weeks. Conclusions This suggests that drug-resistant viruses emerge after 2 weeks of treatment and that longer studies are necessary to provide accurate predictions of longer treatment outcomes.

项与美立他滨相关的新闻（医药）

2024-03-30

·药明康德

他救回“垃圾桶”里的药物分子，开启了治愈丙肝的新时代

▎药明康德内容团队编辑丙型肝炎病毒（HCV）是一种常见的血源性病原体，其主要感染部位是肝脏。尽管与乙肝相比，丙肝的知名度并不高，但其潜在危害却同样不容忽视。HCV可能引发急性或慢性肝炎，并增加感染者发展为肝硬化、肝功能衰竭和肝细胞癌（肝癌）的风险，且迄今为止尚未有针对性的疫苗被成功研发出来。但好消息是，2013年年底，首款无需干扰素就能高效治愈丙肝的直接抗病毒药物NS5B抑制剂索非布韦（sofosbuvir）获FDA批准上市，彻底变革了丙肝的治疗格局。在临床试验中，索非布韦展示出了对丙肝2型和3型患者100%的治愈率，其诞生是科学家在丙肝攻坚史上树立的一座里程碑。在索非布韦诞生的背后，除了有历代科学家们为HCV治疗药物的开发奠定了坚实的前期研究基础，还有一名药物研究科学家在其中发挥了关键的推动作用。他凭借扎实的化学功底、灵活的头脑、勇于挑战的个性和坚定的信念最终导致了这款被《细胞》杂志称为“这一代人在公共卫生领域取得的最重要成就之一”的疗法的诞生。在今天的文章中，药明康德内容团队将结合公开资料，为大家讲述这位开创了治愈丙肝的新时代的关键科学家迈克尔·索菲亚（Michael J. Sofia）博士的故事。▲Michael J. Sofia博士（图片来源：药明康德内容团队制作）挑战攻克一种难防难治的棘手疾病故事要从2005年索菲亚博士决定离开大型医药公司，加入一家只有15人的小型生物技术公司准备“从头再来”开始说起。在加入这家名为Pharmasset的小公司之前，索菲亚博士已在大型医药公司里贡献了自己20年的青春。很多人到了像他这样的年纪，年轻时的抱负和梦想都已在时光中被渐渐掩埋，但他却越来越按不下心中的那股冲动。索菲亚博士从博士后阶段开始就对黄病毒研究十分感兴趣，自1989年科学家首次鉴定出属于黄病毒科的丙肝病毒后，他就开始对这种与进行性肝病和癌症相关的新型人类病毒进行了小规模的研究。起初，他没想过要寻找能够治疗HCV感染的方法，只是单纯想要更好地了解这种病毒。但几年后发生的一件事改变了他的想法。那时，一名丙肝小患者的家人联系到他想向他寻求治疗丙肝的新疗法。多年来，这个家庭为了给女儿治病四处求医，在标准治疗无效的情况下，他们唯一的选择只有无奈地期盼新药的出现。当时，索菲亚博士只能对他们表示遗憾，但他想为丙肝患者做点什么的想法已经种下。当然，基于对丙肝病毒的了解，他知道这不是一件易事。▲HCV感染的自然史（图片来源：参考资料[5]）HCV是一种高度多样化的病毒，具有多种亚型，这使得科学家们不管是想要制造出一种提供广泛保护作用的疫苗还是开发一款能够全面覆盖多种亚型的疗法都十分困难。因此，最初被用于治疗丙肝的“标准方案”里的两种药物——干扰素（一种具有抗病毒、抗肿瘤和免疫调节特性的多效性细胞因子）和利巴韦林（一种广谱抗病毒药物）都不是专门用来治疗丙肝的。这种标准方案需要连续使用6至12个月，总体治愈率却只有40%左右。并且由于干扰素会产生流感样症状、抑郁和骨髓抑制等严重的副作用，许多患者根本无法坚持完整个疗程。但对丙肝患者来说，他们没有更好的选择了。时间来到了20世纪末，随着丙肝病毒体外培养的难题被攻克，转机出现了。科学家们终于有了能用来筛选丙肝药物的工具，这为开发直接抗病毒药物（direct-acting antiviral agents，DAAs）奠定了基础。索菲亚博士知道，他实现理想的机会来了。作为一名新药开发工作者，没有什么比亲手开发出一款能够造福广大无药可用的患者的有效药物更能令人感到欣慰和满足的了。为了让自己的学识和多年积累下的药物开发经验能更好地发挥其价值，也为了实现自己的一腔抱负，他毅然离开了稳定的工作环境，选择加入了一家专注于抗病毒药物开发的小公司，从搭建新的研发团队开始，尝试走一条前途未卜的路。毕竟，以前从没人能成功过。初到公司就面临棘手难题当时，许多生物技术和医药公司正竞相开发DAAs，最重要的目标就是要摆脱对干扰素的依赖。其中，研究进展最快的要数HCV蛋白酶抑制剂类药物，但这类药物并没能达到研究人员的预期。首先，这些抑制剂也需要与干扰素和利巴韦林联合使用。其次，这类药物也会产生许多不良副作用。不仅如此，它们也无法覆盖多种不同的HCV亚型，并且患者也会迅速对其产生耐药性。▲HCV的基因组结构和DAAs的作用靶点（图片来源：参考资料[4]）那时，索菲亚博士选择加入的生物技术公司正在开发的候选丙肝药物PSI-6130采取的是另一种治疗策略。PSI-6130是一种核苷类似物，靶向NS5B RNA聚合酶。这类药物可以作为DNA或RNA合成的替代物，被引入到新合成的DNA或RNA链中，从而干扰核酸的合成过程，阻止病毒的复制。索菲亚博士刚到公司就面临着一个棘手的问题。尽管PSI-6130在细胞实验中的表现非常突出——它耐受性良好，并且能显著抑制HCV RNA的合成，但该候选分子也有一个硬伤，它在口服时很难被吸收，还会产生一大堆没有活性的尿苷代谢物。为了解决这个问题，索菲亚博士带领团队尝试开发了PSI-6130的前药。简单地说，前药就好比是一种药物的“特洛伊木马”，它们通过对目标药物分子进行修饰，隐藏了目标药物的真实面目。这样一来，药物就能够通过一些原本无法通过的障碍（比如无法进入细胞），更容易被身体吸收。当前药进入体内后，外部的伪装会被解除，目标药物就能够显示出真正的功效。索菲亚博士团队开发的这款名为RG7128的前药的早期临床数据确实相当令人鼓舞。RG7128在单独给药或与干扰素+利巴韦林联合给药时都能抑制HCV的复制。尤其是在不使用干扰素的情况下，RG7128联用HCV蛋白酶抑制剂也能发挥作用，这让研究人员看到了开发出一款能够完全摆脱干扰素的丙肝疗法的希望。但这种前药依然存在局限性，丙肝患者需要每天多次服用以克为单位的药物才能看到临床效果，并且这种前药同样会产生大量无活性的尿苷代谢物。在这样的情况下，Pharmasset公司的一些工作人员认为，如果要开发出一款最终能够上市的丙肝疗法，他们可能需要找到一种更好的药物。索菲亚博士深以为然。救回“垃圾桶”里的药物分子，开启治愈丙肝的新时代索菲亚博士知道，自己所需要解决的问题很多，包括在保持药物良好特性（如HCV亚型覆盖广、不易耐药和具有高选择性）的同时，提高其药效并减少给药频率。此外，这种药物最好还能选择性地靶向HCV所在的肝脏。问题是，要如何找到这样一种药物呢？索菲亚博士的团队随后进行了大量药物结构改造的探索，但始终没能找到比最初发现的PSI-6130更好的候选分子。于是，他们决定重新以原本想要放弃开发的PSI-6130为突破口，继续开展研究。幸运的是，在他同事菲尔·弗曼（Phil Furman）及其团队的帮助下，索菲亚博士理出了一些继续开发的方向。通过研究PSI-6130的代谢过程和作用机制，他们发现PSI-6130的一种尿苷三磷酸（uridine triphosphate）代谢产物正好符合他们理想中的HCV聚合酶抑制剂的特性——它的半衰期更长，可能具有更好的效力并有望实现一天一次的给药频率。接下来的问题就在于，如何让这种活性代谢产物能特异性地在肝脏细胞中生成并发挥作用呢？索菲亚博士想到了肝脏的首过代谢。首过代谢是指，所有药物在消化道被吸收后，首先会通过门静脉系统直接输送到肝脏被代谢和清除。基于这个想法，索菲亚博士及其同事设计了一种磷酰胺前药，该药物是PSI-6130的衍生物，在进入肝细胞后会因首过代谢脱去药物中的磷酸基团，然后代谢为其单磷酸衍生物，并进一步代谢为他们找到的那种有效的HCV聚合酶抑制剂。为了从大量前药类似物中筛选出最佳候选药物，索菲亚博士团队还建立了全新的体外和体内筛选系统。经过一系列全面的筛选，他们最终选择了一种名为PSI-7851的分子作为临床候选药物。在1期临床试验中，这种疗法被证明是安全有效的，且每天只需服用一次。不过PSI-7851实际上是两种异构体分子的混合物，其中一种形式比另一种形式更有效。经过进一步的优化研究，索菲亚博士团队开发了一种新的化学合成方法来制造PSI-7851中疗效更佳的那种异构体，该单一分子被命名为PSI-7977，也就是后来的索非布韦。▲索非布韦的分子结构（图片来源：参考资料[4]）2012年初，吉利德科学公司（Gilead Sciences）收购了Pharmasset公司，并继续开发索非布韦。尽管此前索非布韦就在临床试验中展现了不俗的实力，但2013年1月公布的一项临床试验结果才最终奠定了其在丙肝治疗中的重要地位。在这项针对丙肝2型和3型患者的临床试验中，索非布韦联用利巴韦林在没有干扰素的情况下，只需给药12周，患者的治愈率为100%！这意味着，索非布韦是首款无需干扰素就能高效治愈丙肝的直接抗病毒药物，彻底变革了丙肝的治疗，让患者不再受干扰素副作用的困扰。2013年12月6日，美国FDA批准了索非布韦（Sovaldi）方案用于某些HCV类型患者的治疗。在它获批后，慢性HCV感染者开启了无干扰素治愈丙肝的新时代。而继索非布韦之后，国内外更多DAAs药物被研发上市，让全球丙肝患者看到了治愈的希望。后记在医学史上，只有屈指可数的慢性疾病能够被治愈，丙肝正是其中的一种。2016年，索菲亚博士因其在丙肝药物开发中做出的突出贡献与另外两位优秀科学家共同获得了拉斯克临床医学研究奖。▲2016拉斯克临床医学研究奖获得者（图片来源：拉斯克奖官网）对于索菲亚博士来说，获奖固然令人兴奋，但最令他感到开心的是，他实现了自己的理想，同时改变了许多丙肝患者的人生。在得知他即将获得拉斯克奖后，当年那位找他求药的小患者家属向他发来了祝贺，并告诉他，他们女儿的病已经治愈并过上了幸福的生活。对于一个基础科学家来说，没有什么是比这更好的奖励了。根据《内科学年鉴》上发表的一项新的研究，基于现有的筛查和治疗手段，到2036年，曾经在世界传染病中排名前列的丙肝将成为罕见病，世界卫生组织更是把2030年消灭丙肝作为目标。▲现有的丙肝疗法已能在短短2-3个月内，以90%以上的成功率治愈所有主要类型的丙肝！（图片来源：世界卫生组织）如今，与丙肝的斗争似乎已经进入了尾声，但科学家的努力还没有结束。期待有效的乙肝疫苗被开发出来那一天，人类能够正真消灭这种疾病。大家都在看▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料：[1] Hepatitis C replicon system and drug development. Retrieved March 30, 2024, from https://laskerfoundation.org/winners/hepatitis-c-replicon-system-and-drug-development/[2] Williams CL. Ralf Bartenschlager, Charles Rice, and Michael Sofia are honored with the 2016 Lasker~DeBakey Clinical Medical Research Award. J Clin Invest. 2016 Oct 3;126(10):3639-3644. doi: 10.1172/JCI90179. Epub 2016 Sep 13. PMID: 27620536; PMCID: PMC5096798.[3] Hepatitis C. Retrieved March 30, 2024, from https://www.who.int/en/news-room/fact-sheets/detail/hepatitis-c[4] Palese P. Profile of Charles M. Rice, Ralf F. W. Bartenschlager, and Michael J. Sofia, 2016 Lasker-DeBakey Clinical Medical Research Awardees. Proc Natl Acad Sci U S A. 2016 Dec 6;113(49):13934-13937. doi: 10.1073/pnas.1616592113. Epub 2016 Nov 18. PMID: 27864510; PMCID: PMC5150379.[5] Vilarinho S, Lifton RP. Pioneering a Global Cure for Chronic Hepatitis C Virus Infection. Cell. 2016 Sep 22;167(1):12-15. doi: 10.1016/j.cell.2016.08.038. Epub 2016 Sep 13. PMID: 27634325.[6] Sofia MJ. Enter Sofosbuvir: The Path to Curing HCV. Cell. 2016 Sep 22;167(1):25-29. doi: 10.1016/j.cell.2016.08.044. Epub 2016 Sep 13. PMID: 27634323.免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

上市批准疫苗

2009-07-07

·BioSpace

Pharmasset, Inc. Nominates PSI-938 as a New Nucleotide Analog Inhibitor of Hepatitis C for Preclinical Development

PRINCETON, N.J., July 7 /PRNewswire-FirstCall/ -- Pharmasset, Inc. announced today the nomination of PSI-352938 ("PSI-938") as a lead development candidate from two series of purine analogs for the treatment of chronic hepatitis C virus (HCV) infection. PSI-938 is a proprietary nucleotide analog polymerase inhibitor of HCV that is being advanced into studies required for submission of an Investigational New Drug (IND) application with the FDA or equivalent foreign regulatory application. "PSI-938 is particularly interesting to us since it differs from our pyrimidine analogs, R7128 and PSI-7851, because it has a complementary resistance pro is metabolized through a different phosphorylation pathway," stated Michael Otto, PhD, Pharmasset's Chief Scientific Officer. "These differences may prove to be particularly important as we explore combinations of nucleos(t)ides in clinical development in the future." Purine nucleos(t)ide analogs have many of the benefits of pyrimidine nucleos(t)ide analogs, like R7128 and PSI-7851, in that they have demonstrated in vitro activity across multiple genotypes, a higher barrier to resistance than other classes of HCV small molecules in development, and the potential to be combined with other direct acting antivirals targeting HCV. In addition, these purine analogs are also active against the S282T resistant variant selected in vitro by the pyrimidine analogs, and are metabolized to the active triphosphate form through a different phosphorylation pathway than the pyrimidines. Given these characteristics, purine and pyrimidine analogs have the potential to be combined as part of a future treatment regimen. About Pharmasset Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing, and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is on the development of oral therapeutics for the treatment of hepatitis C virus (HCV) and, secondarily, on the development of Racivir(R) for the treatment of human immunodeficiency virus (HIV). Our research and development efforts focus on nucleos(t)ide analogs, a class of compounds which act to inhibit the enzymes required for viral replication. We currently have three clinical-stage product candidates. R7128, a nucleoside analog for chronic HCV infections, is in a Phase 2b clinical trial in combination with Pegasys(R) plus Copegus(R) and is also in INFORM studies, the first series of studies designed to assess the potential of combinations of small molecules without Pegasys(R) and Copegus(R) to treat chronic HCV. These clinical studies are being conducted through a strategic collaboration with Roche. Our other clinical stage candidates are PSI-7851, an unpartnered, next generation HCV nucleotide analog which recently began Phase 1 clinical studies and Racivir, for the treatment of HIV, which has completed a Phase 2 clinical trial. Pegasys(R) and Copegus(R) are registered trademarks of Roche. Forward-Looking Statements Pharmasset "Safe Harbor" Statement under the Private Securities Litigation Reform Act of 1995: Statements in this press release regarding our business that are not historical facts are "forward-looking statements" that involve risks and uncertainties, including without limitation, the risk that adverse events could cause the cessation or delay of any of the ongoing or planned clinical trials and/or our development of our product candidates, the risk that the results of previously conducted studies involving our product candidates will not be repeated or observed in ongoing or future studies involving our product candidates, the risk that our collaboration with Roche will not continue or will not be successful and the risk that any one or more of our product candidates will not be successfully developed and commercialized. For a discussion of these risks and uncertainties, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section of our Annual Report on Form 10-K for the fiscal year ended September 30, 2008 and our Quarterly Report on Form 10-Q for the period ended March 31, 2009 filed with the Securities and Exchange Commission entitled "Risk Factors" and discussions of potential risks and uncertainties in our subsequent filings with the Securities and Exchange Commission. CONTACT: Richard E. T. Smith, Ph.D., VP, Investor Relations and Corporate Communications of Pharmasset, Inc., +1-609-613-4181, richard.smith@pharmasset.com Web site:

小分子药物合作

100 项与美立他滨相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10477	美立他滨	-	DB12045

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
代偿期肝硬化	临床2期	法国	Hoffmann-La Roche, Inc.	2012-04-01
代偿期肝硬化	临床2期	澳大利亚	Hoffmann-La Roche, Inc.	2012-04-01
代偿期肝硬化	临床2期	美国	Hoffmann-La Roche, Inc.	2012-04-01
慢性丙型肝炎基因型 1	临床2期	美国	Hoffmann-La Roche, Inc.	2011-02-01
慢性丙型肝炎基因型 1	临床2期	法国	Hoffmann-La Roche, Inc.	2011-02-01
慢性丙型肝炎基因型 1	临床2期	德国	Hoffmann-La Roche, Inc.	2011-02-01
慢性丙型肝炎基因型 1	临床2期	新西兰	Hoffmann-La Roche, Inc.	2011-02-01
慢性丙型肝炎	临床2期	新西兰	Pharmasset, Inc.	2006-10-01
慢性丙型肝炎	临床2期	美国	Pharmasset, Inc.	2006-10-01
慢性丙型肝炎	临床2期	波多黎各	Pharmasset, Inc.	2006-10-01

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临床结果

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01482390 \| NCT01482403 (DYNAMO 2； DYNAMO 2, Pubmed \| J Biol Chem) 人工标引	临床2期	慢性丙型肝炎	-	Peginterferon Alfa-2a+ribavirin+boceprevir+mericitabine	(簾製鏇餘範鏇鬱憲積廠) = 淵構齋糧顧遞夢餘憲範鹽簾膚鹹醖齋艱構糧憲 (淵構鹽選憲醖構襯網蓋 ) 更多	积极	2016-01-11
				Peginterferon Alfa-2a+ribavirin+telaprevir+mericitabine	(簾製鏇餘範鏇鬱憲積廠) = 壓艱鬱鬱選鹹構築蓋膚鹽簾膚鹹醖齋艱構糧憲 (淵構鹽選憲醖構襯網蓋 ) 更多