新型治疗可能导致乙肝的功能控制

StephenW

Novel Treatment Could Lead to Functional Control of Hep B

Neil Osterweil
November 17, 2016

BOSTON — For treatment-naïve patients with e-antigen-negative hepatitis B, two nucleic acid polymers can markedly reduce viral DNA in the serum, according to preliminary trial results.

In patients who received the polymers, there was "a dramatic and rapid clearance of surface antigen," said Andrew Vaillant, PhD, chief scientific officer at Replicor, the maker of the two investigational polymers.

"Clearance of surface antigen is a critical first step in the functional control of hepatitis B infection," he explained. Clearance leads to the unmaking of the existing anti-surface antigen response, "which leads to a clearance of virions, both infectious and noninfectious."

"More important, it leads to the removal of immunosuppression, mediated by the surface antigen protein, which leads to seroconversion in antigen-positive patients, an enhanced immune response in the liver, measured with transaminase flares, and the establishment of functional control of treatment in some patients," he pointed out.

Dr Vaillant presented preliminary safety and efficacy data from a randomized controlled trial of the two nucleic acid polymers, used in combination with the nucleotide analog reverse transcriptase inhibitor tenofovir disoproxil fumarate (Viread, Gilead Sciences) and pegylated interferon alpha-2a (Pegasys, Genentech) (NCT02565719).

The experimental therapy delivers a one-two punch to the hepatitis B virus by blocking the expression of its surface antigen with a nucleic acid polymer and then hitting it with two commonly used antiviral agents, he told the audience here at The Liver Meeting 2016.

"In hepatitis B infection, most of the surface antigen is produced in the form of subviral particles, which are by far the most abundant circulating viral particles in the blood," said Dr Vaillant.

The nucleic acid polymers block the assembly and release of these subviral particles from hepatocytes, which "results in a mechanism that leads to the very efficient clearance of surface antigen from the blood," he explained.

The randomized open-label trial of 40 previously untreated patients was conducted at three sites in Chisinau, Republic of Moldova. All patients were free of hepatitis C, hepatitis D, and HIV coinfection, all had serum hepatitis B surface antigen levels above 1000 IU/mL, all had hepatitis B virus DNA above 7500 copies/mL, and all had mild to moderate fibrosis but no cirrhosis.

All patients received tenofovir 300 mg daily for 26 weeks as a lead-in. They were then randomized to one of two treatment groups for an additional 48 weeks. Patients in the polymer group received tenofovir and pegylated interferon alpha-2a plus one of the two nucleic acid polymers — either REP 2139-Mg or its derivative, REP 2165-Mg. Those in the control group received the two antiviral agents alone, but they could cross over and receive a polymer if they did not have a log reduction in surface antigen of at least 3 at week 49.

Dr Vaillant presented data on 29 patients who had been on therapy for more than 12 weeks after randomization.

In the polymer groups, many of the patients had serum antigen levels below the lower limit of quantification (0.05 IU/mL). It is expected that these patients will become surface antigen-negative in the near future, he reported.

All nine evaluable patients who received REP 2139 had a surface antigen response greater than 1 log, as did six of the nine who received the REP 2165.

Patients in the polymer groups experienced higher self-limiting transaminase flares than those in the control group.

"Liver function is normal during these transaminase flares," said Dr Vaillant. "We believe all these flares are therapeutic in nature and are a prognostic indicator of the eventual establishment of functional control."

Safety Data

So far, the administration of the nucleic acid polymers has proceeded without incident, except one patient developed infusion reactions after the twentieth weekly dose of REP 2165.

Thrombocytopenia and leucopenia were common after the introduction of pegylated interferon, but these adverse events were stable and manageable, and patients were largely asymptomatic.

To date, there have been three serious adverse events: one case of appendicitis and one case of community-acquired bronchopneumonia, both deemed to be unrelated to therapy, and one case of transient profound weakness, which was attributed to pegylated interferon.

"The Next Frontier"

"These are very exciting data," Anna Lok, MD, professor of hepatology at the University of Michigan Medical Center in Ann Arbor, who was not involved in the study, said after the presentation.

The ability to clear surface antigen "is the next frontier in hepatitis B," said session comoderator Ronald Sokol, MD, professor of pediatrics and head of the gastroenterology, hepatology, and nutrition section at the University of Colorado in Aurora.

"There's a movement now to try to cure hepatitis B, not to just treat it," he told Medscape Medical News.

"And to cure it we have to rid the body of the surface antigen as a marker for the presence of the virus. This study showed a remarkably high rate of patients who had a major drop in circulating hepatitis surface antigen, suggesting that a very difficult group of patients to treat — hepatitis B e-antigen-negative patients — seem to respond to that therapy."

The study was supported by Replicor. Dr Vaillant is an employee and shareholder in the company. Dr Lok reports receiving grant or research support from Gilead and BMS. Dr Sokol reports serving as an advisor or consultant for Yasoo Health, Roche, Ikaria, Otsuka American Pharmaceuticals, Alnylam, Retrophin, Alexion; and receiving grant or research support from Mead Johnson Nutritionals, Shire/Lumena, and FFF Enterprises.

The Liver Meeting 2016: American Association for the Study of Liver Diseases (AASLD): Abstract LB-7. Presented November 15, 2016.

StephenW

新型治疗可能导致乙肝的功能控制

尼尔Osterweil
2016年11月17日

BOSTON - 根据初步试验结果，对于无e抗原阴性乙型肝炎的初治患者，两种核酸聚合物可以显着减少血清中的病毒DNA。

在接受聚合物的患者中，“表面抗原的快速清除”，“两种研究聚合物制造商Replicor的首席科学官Andrew Vaillant博士说。

“清除表面抗原是乙型肝炎感染功能控制的关键第一步，”他解释说。清除导致现有的抗表面抗原反应的消失，这导致病毒体的清除，感染性和非感染性。

“更重要的是，它导致由表面抗原蛋白介导的免疫抑制的去除，其导致抗原阳性患者中的血清转化，肝脏中增强的免疫应答，用转氨酶耀斑测量，以及建立治疗的功能控制在一些患者中，“他指出。

Dr Vaillant介绍了来自两种核酸聚合物的随机对照试验的初步安全性和有效性数据，所述两种核酸聚合物与核苷酸类似物逆转录酶抑制剂替诺福韦酯富马酸盐（Viread，Gilead Sciences）和聚乙二醇化干扰素α-2a（Pegasys，Genentech） （NCT02565719）。

他在“肝脏会议2016”上告诉观众，实验性治疗通过用核酸聚合物阻断其表面抗原的表达，然后用两种常用的抗病毒剂治疗，向乙型肝炎病毒传递一两次冲击。

“在乙型肝炎感染中，大多数表面抗原以亚病毒颗粒的形式产生，这是迄今为止血液中最丰富的循环病毒颗粒，”Vaillant博士说。

核酸聚合物阻断这些亚病毒颗粒从肝细胞的装配和释放，其“导致导致非常有效地从血液中清除表面抗原的机制，”他解释说。

在40个先前未治疗的患者的随机开放标签试验在基希纳乌，摩尔多瓦共和国的三个地点进行。所有患者均无丙型肝炎，丁型肝炎和HIV合并感染，均有血清乙型肝炎表面抗原水平高于1000 IU / mL，乙型肝炎病毒DNA均高于7500拷贝/ mL，均有轻度至中度纤维化，肝硬化。

所有患者接受替诺福韦300mg每日26周作为引入。然后将它们随机分成两个治疗组之一再治疗48周。聚合物组中的患者接受替诺福韦和聚乙二醇化干扰素α-2a加上两种核酸聚合物之一 - REP 2139-Mg或其衍生物REP 2165-Mg。对照组中的那些仅接受两种抗病毒剂，但是如果它们在第49周时其表面抗原的对数减少为至少3，则它们可以交叉并接收聚合物。

Dr Vaillant博士提供了29名在随机化后已经治疗超过12周的患者的数据。

在聚合物组中，许多患者的血清抗原水平低于定量下限（0.05IU / mL）。据报道，预计这些患者在不久的将来将成为表面抗原阴性。

所有9名接受REP 2139的可评价患者的表面抗原反应大于1log，接受REP 2165的9名患者中有6名。

聚合物组中的患者经历了比对照组中的更高的自限性转氨酶闪烁。

“在这些转氨酶突发期间肝功能正常，”Vaillant博士说。 “我们相信所有这些耀斑本质上是治疗性的，并且是最终建立功能控制的预后指标。

安全数据

到目前为止，核酸聚合物的施用没有发生任何进展，除了一个患者在REP 2165的第二十周剂量后开发输注反应。

在引入聚乙二醇化干扰素后，血小板减少症和白细胞减少是常见的，但这些不良事件是稳定和可控的，并且患者基本上无症状。

到目前为止，已经发生了三个严重不良事件：一个阑尾炎病例和一个社区获得性支气管肺炎病例（均被认为与治疗无关）和一个短暂性深度虚弱病例（归因于聚乙二醇化干扰素）。

“下一个前沿”

“这些都是非常令人激动的数据，”安娜堡密歇根大学医学中心教授，没有参与这项研究的医学博士Anna Lok说。

清除表面抗原的能力是乙型肝炎的下一个前沿，“会议编辑Ronald Sokol博士说，他是科罗拉多大学奥罗拉大学儿科学教授，胃肠病学，肝脏病学和营养科主任。

“现在有一种运动试图治愈乙型肝炎，而不是仅仅治疗乙型肝炎，”他告诉Medscape医学新闻。

“为了治愈它，我们必须清除表面抗原的身体作为病毒存在的标志物，这项研究显示，循环肝炎表面抗原水平显着下降的患者的比例非常高，表明非常困难一组治疗的患者 - 乙型e抗原阴性患者 - 似乎对这种治疗有反应。

研究由Replicor支持。 Vaillant博士是公司的员工和股东。吕博士报告接受吉利德和BMS的资助或研究支持。 Sokol博士报告为Yasoo Health，Roche，Ikaria，Otsuka American Pharmaceuticals，Alnylam，Retrophin，Alexion的顾问或顾问;并接受Mead Johnson Nutritionals，Shire / Lumena和FFF Enterprises的资助或研究支持。

肝脏会议2016年：美国肝脏疾病研究协会（AASLD）：摘要LB-7。提交2016年11月15日。

厚德载物01

不知道rep公司的试验为什么总要放在第三世界进行？希望能有真进展。