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组合Tx与'进入抑制剂'治疗Hep D的最新希望  

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发表于 2019-4-13 15:55 |显示全部帖子

Combo Tx With 'Entry Inhibitor' Latest Hope in Treating Hep D
Myrcludex B and interferon shows promise in HBV/HDV co-infection

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    by Molly Walker, Staff Writer, MedPage Today
    April 12, 2019

    This article is a collaboration between MedPage Today® and: Medpage Today

VIENNA -- A first-in-class "entry inhibitor" for hepatitis D virus (HDV) infection suppressed viral RNA in most treated patients, phase II trial data reported here indicated, especially when combined with interferon.

Eight of 15 patients randomized to treatment with 2 mg of Myrcludex B (MyrB, also known as bulevirtide) in combination with pegylated interferon α 2a (PEG-IFNα) had undetectable HDV RNA, even 24 weeks after stopping treatment, reported Heiner Wedemeyer, MD, of Essen University Hospital in Germany.

At a press conference at the International Liver Conference, the annual meeting of the European Association for the Study of the Liver (EASL), moderator Markus Cornberg, MD, a member of the EASL Scientific Committee, and a researcher at Hannover Medical School in Germany, explained that HDV is a "neglected disease."

"We need to do something because we do not have good therapies for this besides interferon so far," he said.

Wedemeyer described HDV -- which only occurs simultaneously with hepatitis B -- as "the most severe form of chronic viral hepatitis." He further characterized various hepatitis infections to emphasize his point:

"[Hepatitis] E stands for emerging, C stands for 'mission completed' ... and D stands for devil," he said, adding that the virus is associated with a "higher likelihood to develop liver decompensation and also increase the likelihood of developing liver cancer."

There is no approved therapy for hepatitis D, but it is recognized by the FDA and European Medicines Agency (EMA) as an orphan disease, Wedemeyer noted.

MyrB blocks HBV and HDV viral entry into host cells, he said. Prior studies of the drug found that it induced HDV RNA declines and improved alanine aminotransferase (ALT) levels.

This study (MYR203) randomized 60 patients -- 15 to each of four regimens:

    PEG-IFNα only
    2 mg MyrB + PEG-IFNα
    5 mg MyrB + PEG-IFNα
    2 mg MyrB only

Patients were treated for 48 weeks, followed by a 24 week follow-up period. MyrB was given once daily, and PEG-IFNα once weekly, both as subcutaneous injections. The study's primary endpoint was undetectable serum HDV RNA at week 72.

Treatment arms experienced a "continuous linear decline" of hepatitis D RNA, but patients then experienced a rebound in HDV RNA at the end of therapy, Wedemeyer said. But the "big surprise" in this trial was the combination arm with 2 mg of MyrB, which experienced a much smaller rebound than even the 5 mg MyrB combination arm or the MyrB monotherapy arm.

"Not only was there an additive response, but a profound decline of HDV RNA, and many cases stayed HDV RNA negative 24 weeks after the end of therapy," Wedemeyer said.

Secondary endpoints included a normalization of ALT levels, which was achieved in seven of 15 patients in the 2-mg MyrB combination arm and five of 15 in the 5-mg combination arm at week 72. Another secondary endpoint was a reduction of hepatitis B surface antigen (HBsAg), and indeed, six patients in the 2-mg combination arm experienced >1 log decline in HBsAg, and four patients had undetectable HBsAg at week 72.

Examining safety, there were no serious adverse events related to the study drug during the treatment period, and two serious adverse events not related to the study drug occurred during the follow-up period (anal fistula and proctitis). Wedemeyer noted an increase in bile salts in MyrB and PEG-IFNα-treated patients, though patients did not report any symptoms related to an increase in bile salts, and when the drug was stopped, it was "completely reversible," he said.

The majority of adverse events came from PEG-IFNα treatment, the authors noted, though Wedemeyer defended the safety of interferon therapy.

"Interferon may cause side effects, but we've been using it for 15 years in hepatology and it's current practice, so it's not special," he told MedPage Today.

Wedemeyer said the plan would be for a longer-term phase III study with MyrB monotherapy for patients with more severe disease, and combination therapy for those that could tolerate interferon.

The study was funded by Myrcludex B's developer, MYR Pharmaceuticals. Wedemeyer disclosed support from Abbott, AbbVie, BMS, Boehringer Ingelheim, Eiger, Gilead, JJ/Janssen-Cilag, Merck/Schering-Plough, MYR, Novartis, Roche, Roche Diagnostics, and Siemens.

Cornberg disclosed support from AbbVie, Biogen, BMS, Gilead, Janssen-Cilag, Merck Sharp & Dohme, Roche, Spring Bank, and Falk.

    Primary Source
    European Association for the Study of the Liver
    Source Reference: Wedemeyer H, et al "Final results of a multicenter, open-label phase 2 clinical trial (MYR203) to assess safety and efficacy of myrcludex B with [sic] PEG-interferon alpha 2a in patients with chronic HBV/HDV co-infection" EASL 2019; Abstract GS-13.

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发表于 2019-4-13 15:56 |显示全部帖子
组合Tx与'进入抑制剂'治疗Hep D的最新希望
Myrcludex B和干扰素在HBV / HDV共感染中显示出前景

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    作者:Molly Walker,撰稿人,MedPage Today
    2019年4月12日

    本文是MedPageToday®与Medpage Today的合作

维也纳 - 一种针对丁型肝炎病毒(HDV)感染的一流“进入抑制剂”抑制了大多数接受治疗的患者的病毒RNA,这里报告的II期试验数据表明,特别是当与干扰素联合使用时。

15例随机接受2 mg Myrcludex B(MyrB,也称为bulevirtide)联合聚乙二醇化干扰素α2a(PEG-IFNα)治疗的患者中有8例在停止治疗后24周检测不到HDV RNA,Heiner Wedemeyer,MD报道,德国埃森大学医院。

在国际肝脏会议的新闻发布会上,欧洲肝脏研究协会(EASL)年会,主持人Markus Cornberg,医学博士,EASL科学委员会成员,以及德国汉诺威医学院研究员,解释说HDV是一种“被忽视的疾病”。

他说:“我们需要做一些事情,因为除了干扰素之外,我们还没有这方面的良好治疗方法。”

Wedemeyer将HDV描述为“最严重的慢性病毒性肝炎”,HDV仅与乙型肝炎同时发生。他进一步描述了各种肝炎感染,以强调他的观点:

“[Hepatitis] E代表新兴,C代表'任务完成'...... D代表魔鬼,”他说,并补充说这种病毒与“发生肝脏代偿失调的可能性更高,同时也增加了患上肝癌。“

Wedemeyer指出,目前没有针对丁型肝炎的批准疗法,但它被FDA和欧洲药品管理局(EMA)认可为孤儿疾病。

他说,MyrB阻断HBV和HDV病毒进入宿主细胞。该药物的先前研究发现它诱导HDV RNA下降并改善丙氨酸氨基转移酶(ALT)水平。

这项研究(MYR203)随机分配了60名患者 - 每种方案中有15名:

    仅PEG-IFNα
    2mg MyrB + PEG-IFNα
    5mg MyrB + PEG-IFNα
    仅2毫克MyrB

患者接受治疗48周,然后进行24周的随访。每天一次给予MyrB,每周一次给予PEG-IFNα,均作为皮下注射。该研究的主要终点是在第72周检测不到的血清HDV RNA。

Wedemeyer说,治疗组经历了肝炎D RNA的“连续线性下降”,但患者在治疗结束时经历了HDV RNA的反弹。但是这项试验中的“大惊喜”是含有2毫克MyrB的组合臂,其反弹甚至比5毫克MyrB组合臂或MyrB单药治疗组小得多。

Wedemeyer说:“不仅有加性反应,而且HDV RNA明显下降,许多病例在治疗结束后24周仍然维持HDV RNA阴性。”

次要终点包括ALT水平的正常化,其在2周MyrB组合组中的15名患者中的7名和在72周时在5mg组合组中15名患者中的5名中实现。另一个次要终点是乙型肝炎表面的减少。抗原(HBsAg),实际上,2-mg组合组中的6名患者HBsAg下降> 1 log,而第72周时有4名患者检测不到HBsAg。

检查安全性,在治疗期间没有与研究药物相关的严重不良事件,并且在随访期间发生了与研究药物无关的两个严重不良事件(肛瘘和直肠炎)。 Wedemeyer指出,MyrB和PEG-IFNα治疗的患者胆汁盐增加,但患者没有报告与胆盐增加有关的任何症状,当药物停止时,它“完全可逆”,他说。

作者指出,大多数不良事件来自PEG-IFNα治疗,尽管Wedemeyer为干扰素治疗的安全性辩护。

“干扰素可能引起副作用,但我们已经在肝病学中使用了15年,这是目前的做法,所以它并不特别,”他告诉MedPage Today。

Wedemeyer表示,该计划将用于长期III期研究,对于患有更严重疾病的患者进行MyrB单药治疗,对可耐受干扰素的患者进行联合治疗。

该研究由Myrcludex B的开发商MYR Pharmaceuticals资助。 Wedemeyer披露了Abbott,AbbVie,BMS,Boehringer Ingelheim,Eiger,Gilead,JJ / Janssen-Cilag,Merck / Schering-Plough,MYR,Novartis,Roche,Roche Diagnostics和Siemens的支持。

Cornberg披露了AbbVie,Biogen,BMS,Gilead,Janssen-Cilag,Merck Sharp&Dohme,Roche,Spring Bank和Falk的支持。

    主要资源
    欧洲肝脏研究协会
    来源参考文献:Wedemeyer H等,“多中心,开放标签2期临床试验(MYR203)的最终结果,以评估myrcludex B与[原文如此] PEG-int的安全性和有效性

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