Aligos Therapeutics 提供 CAM 的 28 天安全性、疗效和药代动力学临

StephenW

Aligos Therapeutics 提供 CAM 的 28 天安全性、疗效和药代动力学临床数据...

    Aligos Therapeutics - (GLOBE NEWSWIRE) 20 小时前

  

- 在每天口服 ALG-000184 28 天后，在前四个给药慢性乙型肝炎 (CHB) 患者队列中，无论 HBeAg 状态如何，都观察到类似的乙型肝炎病毒 (HBV) DNA 和 HBV RNA 显着减少

-在我们 NASH 项目的第一次临床数据报告中，关于高脂血症受试者多次递增剂量 ALG-055009 的初步数据证明了良好的药代动力学、安全性和抗血脂活性

- 报告包括来自其他 2 个 CHB 项目的非临床数据

加利福尼亚州南旧金山，2022 年 6 月 22 日 (GLOBE NEWSWIRE) -- Aligos Therapeutics, Inc. (Nasdaq: ALGS) 是一家临床阶段的生物制药公司，专注于开发新的疗法来解决病毒和肝脏疾病中未满足的医疗需求。宣布该公司将在欧洲研究协会展示两张海报，展示其在 CHB 中的衣壳组装调节剂 (CAM) 计划及其在非酒精性脂肪性肝炎 (NASH) 中的甲状腺激素受体-β (THR-b) 激动剂的初步第一阶段数据肝脏数字国际肝脏大会™ 2022 (EASL ILC 2022)。 ILC 2022 将于 6 月 22 日至 26 日在英国伦敦的 ExCeL 伦敦展览中心举行。

该公司还展示了 Aligos CHB 产品组合中其他两种药物类别的非临床数据：小干扰 RNA (siRNA) 和小分子 PD-L1 抑制剂。这些海报将在 Aligos 网站 www.aligos.com 的“演示文稿”部分的“科学演示文稿和出版物”页面上提供。

“我们很高兴继续展示我们慢性乙型肝炎产品组合的进展，包括小分子衣壳组装调节剂、小干扰 RNA 分子和小分子 PD-L1 抑制剂。我们的团队也很自豪地宣布我们的 THR-b 激动剂在 NASH 中的第一个临床数据，”Aligos 董事长兼首席执行官 Lawrence Blatt 博士说。 “在慢性乙型肝炎的背景下，我们认为解决 HBV 病毒复制、HBsAg 降低和宿主 T 细胞衰竭的多部分方法可能会导致慢性乙型肝炎患者的功能性治愈或有效的慢性抑制。迄今为止，我们的 CAM 计划显示，在几个 CHB 患者队列中给药 28 天后，CHB 患者的病毒 DNA 和 RNA 显着减少，并且正在继续对其他队列进行给药。我们还计划很快启动一项长期研究，评估 ALG-000184 与核苷（酸）类似物治疗 HBeAg 阳性 CHB 的联合治疗。关于我们的 siRNA 项目 ALG-125755，一种潜在的同类最佳 HBV siRNA，我们仍有望在今年第四季度开始在健康志愿者中进行的 1 期研究中给药。同时，在 NASH 方面，我们对 ALG-055009 在高脂血症受试者中的初步临床数据感到鼓舞；这项试验的更多数据预计将在今年第三季度公布。”

Aligos 的 ILC 2022 演示文稿及其潜在影响总结如下。

慢性乙型肝炎 (CHB)

ALG-000184：衣壳组装调节剂 (CAM)

海报编号：SAT365

标题： II 类衣壳组装调节剂 ALG-000184 在慢性乙型肝炎患者中的安全性、药代动力学和抗病毒活性

主讲人：袁文峰教授，MBBS，M.D.，Ph.D.，DSc，香港大学，香港

摘要： ALG-000184 目前正在 ALG-000184-201 试验中进行评估，这是一项多部分、双盲、随机、安慰剂对照的 1 期研究 (NCT04536337)。第 3 部分正在进行并评估当前未治疗/初治 CHB 受试者的多个队列（N=10/队列；8 名活跃：2 名安慰剂），他们每天口服 ALG-000184 28 天，之后对其进行跟踪长达8周。

在这里，作者在第 3 部分报告了参加以下队列的 CHB 受试者的初步安全性、药代动力学和抗病毒数据：

    队列 1：HBeAg 阴性 CHB 中 100 mg 药物/安慰剂
    队列 2：HBeAg 阴性 CHB 中 50 mg 药物/安慰剂
    队列 3：HBeAg 阴性 CHB 中 10 mg 药物/安慰剂
    队列 4：HBeAg 阳性 CHB 中 100 mg 药物/安慰剂

主要调查结果如下：

    无论 HBeAg 状态如何，在所有剂量水平都观察到 HBV DNA 和 HBV RNA 的类似快速下降。
        在 HBeAg 阴性受试者中，观察到 DNA 和 RNA 降低到定量下限 (LLOQ) 以下的比率很高，在 10 mg 剂量水平下，100% 的受试者 DNA 和 RNA 均 < LLOQ。
        在 HBeAg 阳性受试者中观察到最大的 DNA (4.2 log10 IU/mL) 和 RNA (3.1 log10 拷贝/mL) 减少。
    ALG-000184 的所有剂量水平通常都具有良好的耐受性。
ALG-125755：siRNA

海报编号：SAT386

标题： HBV siRNA，ALG-125755，在 AAV-HBV 小鼠疗效模型中展示了良好的非临床特征和显着且持久的乙型肝炎表面抗原减少

主持人：Megan Fitzgerald，博士

摘要：在 AAV-HBV 小鼠中，使用 ALG-125755 观察到血浆 HBsAg 的剂量依赖性抑制。在最后一剂 ALG-125755 后，HBsAg 水平的降低持续至少 70 天。在大鼠和猴子中单次或重复给药后，ALG-125755 耐受性良好，分别高达 300 和 100 mg/kg/剂量，没有毒理学相关发现。

下一代 HBV siRNA

海报编号：SAT402

标题：新型 siRNA 化学物质的结合显着提高了 HBV siRNA 在 AAV-HBV 小鼠模型中的效力和耐久性

主讲人：金红，博士

摘要：作者将专有的 5' 磷酸模拟端帽和 2' 氟模拟核苷酸（这两种专有的核苷酸稳定化学物质）应用于旨在敲除乙型肝炎 S 抗原 (HBsAg) 的 siRNA 分子，目的是确定添加的部分对HBsAg 敲低的程度和持续时间。将两者结合到两个现有的 siRNA 分子中产生化合物 ALG-126081 和 ALG-126101，这表明 HBV 感染小鼠模型（AAV-HBV 小鼠）中 HBsAg 敲低的效力和持续时间显着改善。

PD-L1小分子抑制剂

海报编号：SAT401

标题：发现专门用于治疗慢性乙型肝炎的口服PDL1小分子抑制剂

演讲者：Francois Gonzalvez，博士和吴彤飞，博士

总结：在 CHB 中，乙型肝炎病毒 (HBV) 特异性 T 细胞上的 PD-1 和肝细胞上的 PD-L1 上调会导致 T 细胞耗竭，从而导致持续的 HBV 感染。抑制 PD-1/PD-L1 通路可能是 CHB 的有效治疗策略，但批准用于癌症的 PD-1/PD-L1 抗体受到全身免疫相关不良反应的限制。

    为了开发耐受性更好的治疗化合物，作者合理设计了两种口服、肝脏靶向的 PDL1 小分子抑制剂 ALG-093453 和 ALG-093578，它们表现出与 FDA 批准的抗体相似的效力和更高的肝脏特异性。
    这两种分子激活 HBV 特异性 T 细胞培养物的程度与已获批准的抗体 nivolumab 和 durvalumab 相似。

非酒精性脂肪性肝炎 (NASH)

ALG-055009：甲状腺激素受体 β (THR-b) 激动剂

海报编号：SAT145

标题：单次和多次递增口服剂量 ALG-055009（一种甲状腺激素受体 β 激动剂）在健康志愿者和高脂血症受试者中治疗非酒精性脂肪性肝炎 (NASH) 的安全性和药代动力学 (PK)

主讲人：Hakim Charfi，医学博士

摘要：设计用于治疗 NASH 的小分子 THR- 激动剂 ALG-055009 正在 ALG-055009-301 多部分、双盲、随机、安慰剂对照的首次人体试验中进行评估研究（NCT05090111）。在这里，作者报告了关于该研究已完成的第 1 部分（健康志愿者 (HV) 中化合物的单次递增剂量 (SAD)）和研究正在进行的部分的安全性、药代动力学 (PK) 和药效学 (PD) 的初步研究结果2（在患有轻度高脂血症的受试者中多次递增剂量（MAD）的化合物）。

    在 HV 中单次递增口服剂量 ALG-055009 至 4 mg 和在高脂血症受试者中连续 14 天多次剂量 0.3 mg 的耐受性良好。
        在 SAD 和 MAD 中，没有严重的不良事件、剂量限制性毒性或 ≥ 3 级治疗紧急 AE (TEAE)
        在 MAD 中，没有导致研究药物中止的 TEAE。
    ALG-055009 表现出良好的 PK 与剂量比例和线性血浆暴露、低变异性和多剂量后约 1.7 的累积比。
    观察到肝脏靶点参与和抗脂质活性的证据。对脂质的影响虽然变化很大，但在单次给药后通常呈剂量依赖性。

StephenW

Aligos Therapeutics Presents 28-Day Safety, Efficacy and Pharmacokinetic Clinical Data for CAM ...

    Aligos Therapeutics - (GLOBE NEWSWIRE) 20 hrs ago

  

- Similar significant reductions of hepatitis B virus (HBV) DNA and HBV RNA observed following 28 days of daily oral ALG-000184 dosing, regardless of HBeAg status, across first four dosing chronic hepatitis B (CHB) patient cohorts

-In the first clinical data presentation from our NASH program, preliminary data on multiple ascending doses ofALG-055009 in subjects with hyperlipidemia demonstrated favorable pharmacokinetics, safety, and anti-lipid activity

-Presentations include nonclinical data from 2 other CHB programs

SOUTH SAN FRANCISCO, Calif., June 22, 2022 (GLOBE NEWSWIRE) -- Aligos Therapeutics, Inc. (Nasdaq: ALGS), a clinical stage biopharmaceutical company focused on developing novel therapeutics to address unmet medical needs in viral and liver diseases, today announced that the company is presenting two posters showcasing preliminary Phase 1 data from its capsid assembly modulator (CAM) program in CHB and its thyroid hormone receptor-beta (THR-b) agonist in nonalcoholic steatohepatitis (NASH) at the European Association for the Study of the Liver Digital International Liver Congress™ 2022 (EASL ILC 2022). ILC 2022 is being held on June 22 - 26 at the ExCeL London Exhibition Centre in London, UK.

The company is also presenting nonclinical data from two other drug classes within Aligos’ CHB portfolio: small interfering RNA (siRNA) and a small molecule PD-L1 inhibitor. The posters will be available on the “Scientific Presentation and Publications” page in the “Presentations” section of Aligos’ website at www.aligos.com.

“We are pleased to continue demonstrating progress from across our chronic hepatitis B portfolio including small-molecule capsid assembly modulators, small interfering RNA molecules and small-molecule PD-L1 inhibitors. Our team is also proud to announce the first clinical data from our THR-b agonist in NASH,” said Lawrence Blatt, Ph.D., MBA, Chairman and CEO of Aligos. “In the context of CHB, we believe that a multi-part approach that addresses HBV viral replication, HBsAg reduction and host T cell exhaustion may lead to either functional cure or effective chronic suppression for CHB patients. To date, our CAM program has shown dramatic reductions in viral DNA and RNA in CHB patients following 28 days of dosing in several CHB patient cohorts and dosing in additional cohorts is ongoing. We also plan to soon initiate a longer-term study evaluating ALG-000184 in combination with nucleos(t)ide analog therapy in HBeAg positive CHB. With respect to our siRNA program, ALG-125755, a potential best-in-class HBV siRNA, we remain on track to begin dosing in a Phase 1 study in healthy volunteers in the fourth quarter of this year. Meanwhile, on the NASH front, we are encouraged by initial clinical data for ALG-055009 in subjects with hyperlipidemia; additional data from this trial are expected to be released in the third quarter of this year.”

Aligos’ ILC 2022 presentations, and their potential implications, are summarized below.

Chronic hepatitis B (CHB)

ALG-000184: Capsid assembly modulator (CAM)

Poster number: SAT365

Title: Safety, Pharmacokinetics, and Antiviral Activity of the Class II Capsid Assembly Modulator ALG-000184 in Subjects with Chronic Hepatitis B

Presenter: Professor Man-Fung Yuen, MBBS, M.D., Ph.D., DSc, University of Hong Kong, Hong Kong

Summary: ALG-000184 is currently being evaluated in the ALG-000184-201 trial, a multi-part, double blind, randomized, placebo-controlled Phase 1 study (NCT04536337). Part 3 is ongoing and evaluating multiple cohorts (N=10/cohort; 8 active: 2 placebo) of currently not treated/treatment-naïve CHB subjects, who receive daily oral doses of ALG-000184 for 28 days, after which they are followed up for 8 weeks.

Here, authors report preliminary safety, pharmacokinetic and antiviral data for CHB subjects enrolled in the following cohorts in Part 3:

    Cohort 1: 100 mg drug/placebo in HBeAg negative CHB
    Cohort 2: 50 mg drug/placebo in HBeAg-negative CHB
    Cohort 3: 10 mg drug/placebo in HBeAg-negative CHB
    Cohort 4: 100 mg drug/placebo in HBeAg-positive CHB

Key findings were as follows:

    Similar rapid declines in HBV DNA and HBV RNA were observed at all dose levels, regardless of HBeAg status.
        Among HBeAg-negative subjects, high rates of DNA and RNA reductions below the lower limit of quantification (LLOQ) were observed, with 100% of subjects <LLOQ for both DNA and RNA at the 10 mg dose level.
        The largest DNA (4.2 log10 IU/mL) and RNA (3.1 log10 copies/mL) reductions were observed in HBeAg-positive subjects.
    All dose levels of ALG-000184 were generally well tolerated.
ALG-125755: siRNA

Poster number: SAT386

Title: The HBV siRNA, ALG-125755, demonstrates a favourable nonclinical profile and significant and durable hepatitis B surface antigen reductions in the AAV-HBV mouse efficacy model

Presenter: Megan Fitzgerald, Ph.D.

Summary: In AAV-HBV mice, dose-dependent inhibition of plasma HBsAg was observed with ALG-125755. Reductions in HBsAg levels were sustained for at least 70 days following the final dose of ALG-125755. Following single or repeated doses in rats and monkeys, ALG-125755 was well tolerated with no toxicologically relevant findings up to 300 and 100 mg/kg/dose, respectively.

Next-Generation HBV siRNAs

Poster number: SAT402

Title: Incorporation of novel siRNA chemistries significantly improves the potency and durability of HBV siRNAs in the AAV-HBV mouse model

Presenter: Jin Hong, Ph.D.

Summary: Authors applied proprietary 5’ phosphate-mimetic end cap and 2’fluoro mimic nucleotides, both proprietary nucleotide stabilization chemistries, to siRNA molecules designed to knock down hepatitis B S antigen (HBsAg), with the objective of determining the added moieties’ effects on the extent and duration of HBsAg knockdown. Adding both in combination to two existing siRNA molecules yielded compounds ALG-126081 and ALG-126101, which demonstrated significant improvements in the potency and duration of HBsAg knockdown in mouse models of HBV infection (AAV-HBV mice).

PD-L1 small molecule inhibitors

Poster number: SAT401

Title: Discovery of oral PDL1 small molecule inhibitors specifically designed for the treatment of chronic hepatitis B

Presenters: Francois Gonzalvez, Ph.D. and Tongfei Wu, Ph.D.

Summary: In CHB, upregulation of both PD-1 on hepatitis B virus (HBV)-specific T cells and PD-L1 on liver cells causes T cell exhaustion and thus persistent HBV infection. Inhibiting the PD-1/PD-L1 pathway may be an effective therapeutic strategy in CHB, but the PD-1/PD-L1 antibodies approved in cancer are limited by systemic immune-related adverse effects.

    With the objective of developing better tolerated therapeutic compounds, authors rationally designed two oral, liver-targeted PDL1 small molecule inhibitors, ALG-093453 and ALG-093578, which demonstrated similar potency to FDA-approved antibodies and higher liver specificity.
    Both molecules activate HBV-specific T cell cultures to a similar extent as the approved antibodies nivolumab and durvalumab.

Nonalcoholic steatohepatitis (NASH)

ALG-055009: Thyroid hormone receptor beta (THR-b) agonist

Poster number: SAT145

Title: Safety and Pharmacokinetics (PK) of Single and Multiple Ascending Oral Doses of ALG-055009, a Thyroid Hormone Receptor Beta Agonist, for the Treatment of Non-Alcoholic Steatohepatitis (NASH), in Healthy Volunteers and Subjects with Hyperlipidaemia

Presenter: Hakim Charfi, M.D.

Summary: The small molecule THR- agonist ALG-055009, designed for the treatment of NASH, is being evaluated in the ALG-055009-301 multi-part, double-blind, randomized, placebo-controlled first-in-human Phase 1 study (NCT05090111). Here, authors report preliminary study results regarding the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the study’s completed Part 1 (single ascending doses (SAD) of the compound in healthy volunteers (HV)) and of the study’s ongoing Part 2 (multiple ascending doses (MAD) of the compound in subjects with mild hyperlipidemia).

    Single ascending oral doses of ALG-055009 up to 4 mg in HV and multiple doses of 0.3 mg for 14 days in subjects with hyperlipidemia were well tolerated.
        Across the SAD and MAD, there were no serious adverse events, dose-limiting toxicities, or Grade ≥ 3 treatment emergent AEs (TEAEs)
        In the MAD, there were no TEAEs leading to study drug discontinuation.
    ALG-055009 showed favorable PK with dose-proportional and linear plasma exposures, low variability, and a ~1.7 accumulation ratio after multiple doses.
    Evidence of liver target engagement and anti-lipid activity was observed. The effect on lipids, although highly variable, was generally dose-dependent after single doses.

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乙肝人1949

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