AASLD132 |的临床前表征 新型高效小号 分子乙型和丁型肝炎病

StephenW

132 |的临床前表征
新型高效小号
分子乙型和丁型肝炎病毒进入
抑制剂
海蒂·康特雷拉斯1、迪娜拉·阿齐莫娃1、约瑟夫·谭1、
Nuruddin Unchwaniwala1, Lida Guo1, Michael Shen1,
Jiaxin Yu1、Marc P. Windisch1、Xiang Xu1、Michel
Perron1,2，迈克尔沃克 1，威廉德莱尼 3 和
Min Zhong1, (1)Assembly Biosciences, (2)Discovery
生物学，装配生物科学，（3）装配
生物科学公司
背景：慢性 HBV 感染 (cHBV) 和 HDV
感染 (cHDV) 影响大约 2.96 和 1200 万人
世界各地的患者，分别。 HDV是一种卫星病毒
这需要HBV包膜感染肝细胞。
cHDV 患者具有最严重的病毒形式
与肝炎相比，疾病进展更快
单独感染 cHBV 的患者。 Bulevirtide (BLV)，一种肽
干扰牛磺胆酸钠共转运
多肽 (NTCP) 是 HBV 和 HDV 的受体，
2020 年在欧洲有条件地批准用于治疗
cHDV 患者的治疗。虽然 BLV 已显示出安全性和
在临床试验中的疗效，它需要每天注射。这里
我们描述了一类新型的临床前概况
口服有效抑制HBV的小分子
和 HDV 条目。方法：EC50 用于细胞外 HBeAg
在感染的 HepG2-NTCP 细胞中也进行了测量
通过 ELISA 作为原代人肝细胞 (PHH)。蛋白质
在受感染的 HepG2 中测定了调整后的 EC 50 秒-
在人血清白蛋白和 α 中培养的 NTCP 细胞
酸性糖蛋白。对依赖 NTCP 的胆汁的影响
在 HEK293 细胞中测定酸摄取量
荧光标记的胆汁酸摄取。代谢稳定
ity 在人和啮齿动物的肝微粒体中进行了评估
(LM) 和 PHH。药代动力学（PK）研究是
中进行。结果：我们从结构上选择了三个
用于分析的差异化化合物以收集 bench-
标记数据。在 HepG2 中有效抑制的所有化合物
NTCP 单元 (EC50 2.3 – 8.2 nM) 和 PHH (EC50 9.8 – 163
纳米）。抗病毒效力降低（约 10-
倍）在功能性血清转移测定中观察到。这
化合物抑制 NTCP 依赖的胆汁酸摄取
(NTCP IC50 20 – 30 nM)。测试的化合物显示
啮齿动物 LMs (mLM) 的中度至高度代谢稳定性
CLint 16 - 77 mL/min/kg 和 rLM CLint 19 - 23 mL/min/
kg) 和人类 LMs (CLint 8 – 28 mL/min/kg) 以及
PHHs (CLint 5 – 16 mL/min/kg)。良好的生物利用度
观察到（F = 19 – 105% 在小鼠和 32 – 186% 在
大鼠）在小鼠中的终末半衰期为 1-5 小时，
大鼠 1-2 小时。结论：我们已经确定了一个
新型高效、口服生物可利用的 HBV 和
具有药物样特性的 HDV 进入抑制剂。铅选
这一系列化合物的mization正在进行中
专注于提名研究开发可以-
用于评估 cHBV 和 cHDV 治疗的日期。
披露：
Heidi Contreras – 装配生物科学：就业；
Dinara Azimova – 装配：就业；
Nuruddin Unchwaniwala – 组装生物科学：
就业；装配生物科学：库存
股东;
Marc P. Windisch – 装配生物科学：就业；
Michel Perron – 装配生物科学：就业；
Michael Walker – 装配生物科学：就业；
Assembly Biosciences：股东；
钟敏 – 装配生物科学：就业；
披露信息在发布时不可用
阳离子：Joseph Tan, Lida Guo, Michael Shen, Jiaxin Yu,
向旭，威廉·德莱尼

StephenW

132 | PRECLINICAL CHARACTERIZATION OF
A NOVEL CLASS OF HIGHLY POTENT SMALL
MOLECULE HEPATITIS B AND D VIRUS ENTRY
INHIBITORS
Heidi Contreras1, Dinara Azimova1, Joseph Tan1,
Nuruddin Unchwaniwala1, Lida Guo1, Michael Shen1,
Jiaxin Yu1, Marc P. Windisch1, Xiang Xu1, Michel
Perron1,2, Michael Walker 1, William Delaney 3 and
Min Zhong1, (1)Assembly Biosciences, (2)Discovery
Biology, Assembly Biosciences, (3)Assembly
Biosciences, Inc.
Background: Chronic HBV infection (cHBV) and HDV
infection (cHDV) affect approximately 296 and 12 million
patients worldwide, respectively. HDV is a satellite virus
that requires the HBV envelope to infect hepatocytes.
Patients with cHDV have the most severe form of viral
hepatitis and faster disease progression compared to
patients with cHBV alone. Bulevirtide (BLV), a peptide
that interferes with sodium taurocholate co-transporting
polypeptide (NTCP), the receptor for HBV and HDV, was
conditionally approved in Europe in 2020 for the treat-
ment of cHDV patients. While BLV has shown safety and
efficacy in clinical trials, it requires daily injections. Here
we describe the preclinical profile of a novel class of
orally available, small molecules that potently inhibit HBV
and HDV entry. Methods: EC50 s for extracellular HBeAg
were measured in infected HepG2-NTCP cells as well
as primary human hepatocytes (PHH) by ELISA. Protein
adjusted EC 50 s were determined in infected HepG2-
NTCP cells cultured in human serum albumin and alpha
acidic glycoprotein. The impact on NTCP-dependent bile
acid uptake was determined in HEK293 cells measuring
fluorescence labelled bile acid uptake. Metabolic stabil-
ity was evaluated in human and rodent liver microsomes
(LMs) and PHHs. Pharmacokinetic (PK) studies were
performed in . Results: We selected three structurally
differentiated compounds for profiling to collect bench-
mark data. All compounds potently inhibited in HepG2-
NTCP cells (EC50 2.3 – 8.2 nM) and PHH (EC50 9.8 – 163
nM). A reduction of antiviral potency (approximately 10-
fold) was observed in a functional serum shift assay. The
compounds inhibited NTCP-dependent bile acid uptake
(NTCP IC50 20 – 30 nM). The tested compounds showed
moderate to high metabolic stability in rodent LMs (mLM
CLint 16 - 77 mL/min/kg and rLM CLint 19 – 23 mL/min/
kg) and human LMs (CLint 8 – 28 mL/min/kg) as well as
in PHHs (CLint 5 – 16 mL/min/kg). Good bioavailability
was observed (F = 19 – 105% in mice and 32 – 186% in
rats) with terminal half-lives of 1 – 5 hours in mice and
1 – 2 hours in rats. Conclusion: We have identified a
novel class of highly potent, orally bioavailable HBV and
HDV entry inhibitors with drug-like properties. Lead opti-
mization of this series of compounds is in progress with a
focus on nominating an investigational development can-
didate for evaluation for treatment of cHBV and cHDV.
Disclosures:
Heidi Contreras – Assembly Biosciences: Employment;
Dinara Azimova – Assembly: Employment;
Nuruddin Unchwaniwala – Assembly Biosciences:
Employment; Assembly Biosciences: Stock
Shareholder;
Marc P. Windisch – Assembly Biosciences: Employment;
Michel Perron – Assembly Biosciences: Employment;
Michael Walker – Assembly Biosciences: Employment;
Assembly Biosciences: Stock Shareholder;
Min Zhong – Assembly Biosciences: Employment;
Disclosure information not available at the time of publi-
cation: Joseph Tan, Lida Guo, Michael Shen, Jiaxin Yu,
Xiang Xu, William Delaney