在早期测试中发出安全警告后，Enanta 放弃口服乙肝程序

StephenW

在早期测试中发出安全警告后，Enanta 放弃口服乙肝程序
本·亚当斯 | 2021 年 11 月 19 日上午 8:35

在第一阶段研究中出现严重的安全危险信号后，Enanta Pharmaceuticals 正在关闭其 EDP-721 口服乙型肝炎病毒 (HBV) 计划的工作。

EDP​​-721 是一种口服 HBV RNA，曾在一项针对健康志愿者的 1 期研究的单次递增剂量部分中进行，但在这些健康受试者服用该药物后发现了未公开的“安全信号”。

“患者安全是我们的首要任务，因此我们决定停止进一步开发这种化合物，”生物技术公司总裁兼首席执行官 Jay R. Luly 博士在周四的简短更新中说。

现在重点将转向 EDP-514，其 HBV 核心抑制剂目前处于 1 阶段，用于慢性 HBV 感染的病毒血症和 NUC 抑制患者。

“我们相信核心抑制剂将成为成功的联合方案的重要组成部分，我们将寻求通过内部发现工作、外部机会或两者的额外机制来推进我们的 HBV 项目，”Luly 补充道。

目前的 HBV 治疗可能会抑制病毒复制，但不能完全清除病毒；如果停止治疗，感染的共价闭合环状 DNA 或 cccDNA 可使 HBV 复制重新开始。

下一代治疗系列希望通过这一阶段进入治疗阶段，Gilead 和 Vir 等公司——这两家公司去年在乙肝中合作——已经朝着这个目标努力。但是，虽然是一个主要目标，但许多人已经落在了中线。

在给客户的一份报告中，加拿大皇家银行对 Enanta 表示，停产“确实显着降低了通过内部组合实现功能性治疗的任何竞争优势。”

相关：大会失败认为它从治疗转向慢性乙肝焦点

它还指出了该领域其他公司的失败，包括 Assembly Bio、Arbutus 和 Big Pharma Roche。

RBC 指出，EDP-721 靶向非经典 poly(A)-聚合酶 PAPD5 和 PAPD7，它们参与稳定 HBV RNA，可能是通过保护病毒 RNA 上的 poly(A) 尾部。

Arbutus 和罗氏也都针对 PAPD5/7，前者的资产 AB-452 根据临床前安全信号剔除，罗氏的药物在第一阶段停产。

“尽管 [Enanta] 没有报告临床前安全问题，但该类别的临床前和临床安全信号的出现表明 PAPD5/7 可能是一个固有的困难目标，”该公司在给客户的一份报告中沉思。

RBC 补充说，考虑到试验的早期阶段，该项目的成功总是“保守的”，但相信生物技术的未来更多地取决于其在 RSV 和 COVID 方面的其他工作。

此前，由于脂肪肝领域的失败和挫折越来越多，这家生物技术公司上个月削减了其两个 FXR 激动剂 NASH 项目的工作。这家生物技术公司到 2021 年年底将比开始时精简得多，但它希望未来能够提供一条管道。

StephenW

Enanta dumps oral hep B program after safety warnings in early test
by Ben Adams | Nov 19, 2021 8:35am

Enanta Pharmaceuticals is shutting down work on its oral hepatitis B virus (HBV) program for EDP-721 after serious safety red flags were raised in a phase 1 study.

EDP-721, an oral HBV RNA, had been in a single ascending dose part of a phase 1 study in healthy volunteers, but undisclosed “safety signals” were seen in those healthy subjects after being given the drug.

“Patient safety is our top priority, and we have therefore decided to discontinue further development of this compound,” said Jay R. Luly, Ph.D., president and CEO of the biotech, in a short update Thursday.

Focus will now turn to EDP-514, its HBV core inhibitor currently in a phase 1 for viremic and NUC-suppressed patients with chronic HBV infection.

“We believe core inhibitors will be an important component of a successful combination regimen, and we will look to advance our HBV program with additional mechanisms from internal discovery efforts, external opportunities, or both,” added Luly.  

Current HBV treatments may suppress viral replication, but they do not completely clear out the virus; the infection’s covalently closed circular DNA, or cccDNA, enables HBV replication to restart if treatment is stopped.

The next-gen series of treatments is hoping to move past this into a curative stage, with the likes of Gilead and Vir—both of which partnered up last year in hep B—already working toward that end. But, while a major goal, many have fallen at the halfway line.

In a note to clients, RBC said for Enanta, the discontinuation “does meaningfully reduce any competitive advantage on achieving a functional cure with an internal combo.”

RELATED: Assembly flop sees it pivot from curative to chronic hep B focus

It also notes the failure of others companies in the space including Assembly Bio, Arbutus and Big Pharma Roche.

RBC points out that EDP-721 targets the non-canonical poly(A)-polymerases PAPD5 and PAPD7, which are involved in stabilization of HBV RNAs, likely by protecting the poly(A) tail on viral RNA.

Both Arbutus and Roche have also targeted PAPD5/7, with the former’s asset, AB-452, culled on preclinical safety signals and Roche’s agent was discontinued in phase 1.

“Though [Enanta] reported no preclinical safety issues, the emergence of both preclinical and clinical safety signals for this class suggests PAPD5/7 may be an inherently difficult targets,” the firm mused in a note to clients.

RBC added that, given how early-stage the trial was, it was always “conservative” on the program’s success but believes the biotech’s future rests more heavily on its other work in RSV and COVID.

This also comes after the biotech last month axed work on its two FXR agonist NASH programs amid a growing pile of failures and setbacks in the fatty liver space. The biotech will end 2021 a lot leaner than it started, but, it hopes, with a pipeline that can deliver in the future.