乙型肝炎：葛兰素史克的贝匹罗韦森能提供功能性治愈吗？

StephenW

乙型肝炎：葛兰素史克的贝匹罗韦森能提供功能性治愈吗？

GSK 的反义寡核苷酸正在寻求通过 III 期试验进一步证明其在破坏病毒复制方面的价值。

作者：Urtė Fultinavičiūtė

上个月，葛兰素史克（GSK）提供了对乙型肝炎领域兴奋的积极 IIb 期数据的早期研究。结果表明，贝匹罗韦森可能会导致功能性治愈，这意味着候选药物将乙型肝炎表面抗原 (HBsAg) 降低到无法检测到的水平。

米兰大学胃肠病学教授 Pietro Lampertico 博士说，IIb 期数据是一个“重大突破”。 Lampertico 解释说，这是十年来第一次新的候选药物在治疗数周后能够将 HBsAg 降低到检测不到的水平。

随着葛兰素史克（GSK）准备在 2023 年上半年启动贝匹罗韦森 III 期试验，这是在此阶段首次研究反义寡核苷酸候选物。多伦多综合医院研究所高级科学家 Jordan Feld 博士指出，在第三阶段研究一种新的乙型肝炎药物也已经有好几年了。

因此，所有的目光都集中在葛兰素史克将如何设计其即将进行的研究，以及该资产的功效概况是否能在下一个开发阶段持续。

虽然有初步的积极 IIb 期数据，但需要这项研究的更多结果。专家表示，对于候选人的持久疗效潜力以及对肝脏炎症的担忧仍然存在疑问。也有人怀疑贝匹罗韦森本身是否会为许多人提供功能性治愈。
IIb 期乙型肝炎数据有警告

葛兰素史克（前身为葛兰素史克）在今年的 EASL 肝脏大会上提交了来自 IIb B 期清除试验（NCT04449029）的积极中期分析，该试验调查了贝匹罗韦森在初治患者和已经服用核苷酸类似物（NA）的患者中的作用。在试验的次要终点中，28% 的 NA 患者 (n=68) 和 29% 的初治参与者 (n=70) 在 24 天结束时使用 300mg 贝匹罗韦森降低了 HBsAg 和乙型肝炎病毒 (HBV) 水平-周治疗。 NAs 将 HBV 抑制到无法检测到的水平，但必须长期服用，如果不是无限期的话。

最终的 B-clear 数据预计将在今年晚些时候发布。 IIb 期研究人员 Man-Fung Yuen 博士指出，该资产在首次给药后 48 周的持久疗效潜力（该试验的主要终点）将成为关键疗效指标。
香港大学肝病学教授、B-clear 试验首席研究员袁文峰博士

同样是香港大学肝病学教授的 Yuen 指出，在停止治疗后，贝匹罗韦森可能会产生一些挥之不去的疗效影响。 “我可以放心地说，在停止治疗后，持续的效果将持续至少六个月，”他说。

在 IIa 期试验 (NCT03020745) 中，下降的 HBsAg 水平在两周后反弹，但参与者接受的剂量低于 IIb 期。就耐久性而言，表现最好的 IIa 期队列每周给予一次 120mg 的药物，持续 12 周。在 IIb 期，阳性数据来自于 24 周时每周给予 300mg 剂量的患者。

香港大学临床医学院临床教授 Way-Kay Seto 博士说，即使 B-clear 耐用性数据是积极的，现在得出疗效结论还为时过早。他补充说，IIb 期数据太小了。虽然 IIb 期有 457 名患者，但它有多个研究不同剂量的手臂。

还有一些副作用问题需要解决。 IIb 期数据显示丙氨酸氨基转移酶 (ALT) 升高，这是肝脏炎症的标志物。 Yuen 解释说，由于药物引起的损伤或免疫系统攻击肝脏中的病毒，可能会发生 ALT 耀斑。他补充说，在后者中，HBsAg 下降幅度越大，发生 ALT 耀斑的可能性就越大。他指出，无论是什么原因导致发作，肝损伤仍然是一个风险，因此患者需要进行广泛的监测。

葛兰素史克的一位发言人说，在 IIb 期中，在不到 1% 的接受 NA 的患者和 1% 的初治患者中观察到了与治疗相关的严重不良事件 (AEs)，治疗组之间的 AEs 没有具有临床意义的差异。

StephenW

Hepatitis B: can GSK’s bepirovirsen deliver functional cure?

GSK’s antisense oligonucleotide is looking to further prove its value in disrupting viral replication via a Phase III test.

By Urtė Fultinavičiūtė

Last month, GSK provided an early look at positive Phase IIb data that got the hepatitis B field excited. Results show that bepirovirsen could potentially lead to functional cure, which means that the candidate lowered hepatitis B surface antigen (HBsAg) to undetectable levels.  

The Phase IIb data is a “major breakthrough,” says Dr Pietro Lampertico, professor of gastroenterology at the University of Milan. This is the first time in a decade whereby a new candidate was able to show lowered HBsAg to undetectable levels after weeks of treatment, Lampertico explains.

With GSK gearing to initiate a Phase III bepirovirsen trial in the first half of 2023, this is the first time an antisense oligonucleotide candidate would be investigated at this stage. It’s also been years since a new hepatitis B agent would be studied at Phase III, notes Dr Jordan Feld, senior scientist at Toronto General Hospital Research Institute.

As such, all eyes are on GSK on how it will design its forthcoming study, and if the asset’s efficacy profile sustains in the next development stage.

While there is initial positive Phase IIb data, more results from this study are needed. Experts say there are still questions about the candidate’s potential for durable efficacy, as well as concerns around liver inflammation. There are also doubts if bepirovirsen, by itself, would deliver functional cure for many.
Phase IIb hepatitis B data has caveats

GSK, formerly GlaxoSmithKline, presented positive interim analysis at this year’s EASL Liver Congress from the Phase IIb B-clear trial (NCT04449029) investigating bepirovirsen in treatment-naïve patients and ones already taking nucleotide analogues (NA). In the trial’s secondary endpoint, 28% of patients on NA (n=68) and 29% of treatment-naïve participants (n=70) experienced lowered HBsAg and hepatitis B virus (HBV) levels with 300mg bepirovirsen at the end of the 24-week treatment. NAs suppress HBV to undetectable levels but must be taken long term, if not indefinitely.

Final B-clear data is expected later this year. Phase IIb investigator Dr Man-Fung Yuen notes the asset’s potential for durable efficacy at 48 weeks after the first dose, which is the trial’s primary endpoint, will be a key efficacy indicator.
Dr Man-Fung Yuen, hepatology professor at the University of Hong Kong and B-clear trial principal investigator

Bepirovirsen is likely to have some lingering efficacy impact after the therapy is stopped, notes Yuen, who is also a hepatology professor at the University of Hong Kong. “I would be comfortable to say that the sustained effects would last for at least six months after stopping the therapy,” he says.

In a Phase IIa trial (NCT03020745), declined HBsAg levels rebounded after two weeks but participants received a lower dose than in the Phase IIb. The best performing Phase IIa cohort in terms of durability was given the drug once weekly at 120mg for 12 weeks. In Phase IIb, the positive data was from patients given a 300mg weekly dose at 24 weeks.

Even if B-clear durability data is positive, it would still be too early for efficacy conclusions, says Dr Way-Kay Seto, clinical professor, School of Clinical Medicine, at the University of Hong Kong. The Phase IIb data is too small, he adds. While the Phase IIb had 457 patients, it had multiple arms investigating different doses.

There are also side-effect questions that need to be addressed. Phase IIb data shows an increase in alanine aminotransferase (ALT), which is a marker for liver inflammation. ALT flares can occur due to drug-induced injury or the immune system attacking the virus in the liver, Yuen explains. In the latter, the larger the HBsAg drop, the higher chance of an ALT flare, he adds. Regardless of what causes the flare, liver damage is still a risk, and thus patients need extensive monitoring, he notes.

A GSK spokesperson says, in the Phase IIb, treatment-related serious adverse events (AEs) were observed in less than 1% of patients receiving NA and 1% of treatment-naïve patients, with no clinically meaningful differences in AEs across treatment arms.

StephenW

https://www.clinicaltrialsarena. ... en-functional-cure/

newchinabok

我60岁之前能看到一，二个新药上市也无怨无悔了。

乙肝人1949

同意

sky8989

下降的 HBsAg 水平在停药后会反弹，那三期不反弹也很难啊。另外这副作用没干扰素大吧

lancas

回复 newchinabok 的帖子

同意+1

tim889

前期试验中具体副作用的分析，感觉耐受性还好。300mg 出现ALT升高，但如原文所说并不确定是否是药物导致的肝损伤还是免疫激活导致的： https://www.nature.com/articles/s41591-021-01513-4/tables/2

300mg出现CRP升高，大部分是头几次注射，后面就消退了，健康人也会有，所以应该是和药物有关。CRP elevations were dose-related in patients and were consistent with those observed in healthy volunteers

tim889

Safety and tolerability
The most common treatment-emergent adverse events (TEAEs) were local injection site reactions (Table 2). Injection site reactions were reported in zero, three (50%) and three (25%) treatment-naïve patients in the placebo, bepirovirsen 150 mg and bepirovirsen 300 mg arms, respectively, and in zero and two (40%) on-NA patients in the placebo and bepirovirsen 300 mg arms, respectively. Pyrexia was commonly reported in treatment-naïve patients (one patient (16.7%) each in the placebo and bepirovirsen 150 mg arms; three patients (25%) in the bepirovirsen 300 mg arm).

TEAEs were mostly mild (division of acquired immune deficiency syndrome (DAIDS) grade 1: 52 of 69 events); the remainder were moderate (DAIDS grade 2: 16 of 69 events), except for one treatment-naïve patient in the bepirovirsen 300 mg treatment group who experienced a serious adverse event (DAIDS grade 4) of alanine aminotransferase (ALT) increase (described in the ‘ALT increase’ section).

Treatment-related TEAEs were reported in four (66.7%), six (50.0%) and one (16.7%) treatment-naïve patients in the bepirovirsen 150 mg, bepirovirsen 300 mg and placebo groups, respectively. The most common treatment-related TEAEs in treatment-naïve patients were injection site pruritus (bepirovirsen 150 mg, n = 2 (33%); bepirovirsen 300 mg, n = 1 (8.3%)), injection site erythema (bepirovirsen 150 mg, n = 0 (0%); bepirovirsen 300 mg, n = 3 (25%)) and nausea (bepirovirsen 150 mg, n = 1 (16.7%); bepirovirsen 300 mg, n = 2 (16.7%)). Injection site swelling, ALT increase and myalgia were each considered treatment-related in two patients (16.7%) in the bepirovirsen 300 mg arm. In on-NA patients, injection site bruising, injection site swelling, injection site erythema and pyrexia were each reported in one patient (20.0%) in the bepirovirsen 300 mg arm.

An increase in C-reactive protein (CRP) levels following the first dose of bepirovirsen was observed in patients with CHB. In most patients, levels increased on day 2 with peak levels observed pre-dose on day 4 (see example patient in Supplementary Fig. 3a). Levels were substantially recovered by day 8, suggesting the day 4 dose did not lead to further CRP increases. There were generally no CRP spikes at later time points, and no symptoms were consistently associated with CRP elevations. CRP elevations were dose-related in patients and were consistent with those observed in healthy volunteers (Supplementary Fig. 3b and unpublished data).

Aside from ALT, aspartate aminotransferase (AST; described below) and CRP effects, there were no clinically significant changes in laboratory tests related to bepirovirsen treatment. Transient prolongations in activated partial thromboplastin time were observed 3–5 h after administration of both bepirovirsen doses on day 1 and day 22. The magnitudes of these prolongations were not clinically relevant, with a maximum observed value of 43.9 s (~1.21× upper limit of normal (ULN); ULN = 36.5 s) in two participants in the bepirovirsen 300 mg treatment group. There were no bleeding or bruising events associated with the elevations and little or no coincidental prolongation of prothrombin time.

There were no observations of complement activation related to bepirovirsen dosing and no clinically significant findings in other safety assessments (for example, electrocardiogram, physical examination, concomitant medication usage).

newchinabok

tim889 发表于 2022-7-30 00:34
前期试验中具体副作用的分析，感觉耐受性还好。300mg 出现ALT升高，但如原文所说并不确定是否是药物导致的 ...

反义药物毒副作用也有问题