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慢性乙型肝炎（CHB）是全球范围内的重大公共卫生问题。传统抗病毒药物虽在一定程度上能够抑制病毒复制，但在实现功能性治愈方面仍显力不从心。在美国圣迭戈召开的2024年美国肝病研究学会年会（AASLD 2024）上，Barinthus Biotherapeutics公司公布了创新免疫疗法VTP-300的最新研究数据。VTP-300通过独特的作用机制治疗CHB，为患者提供新的治疗可能。《国际肝病》在现场邀请Barinthus Biotherapeutics公司首席科学官Nadege Pelletier围绕正在开展的VTP-300相关研究工作进行了交流。
01
《国际肝病》
请向我们的读者做个简单的自我介绍，并分享一下Barinthus Biotherapeutics公司的研究重点？
Nadege Pelletier：我叫Nadege Pelletier，是Barinthus Biotherapeutics公司的首席科学官。我们公司是一家临床阶段生物制药公司，致力于开发针对慢性传染病和自身免疫性疾病的免疫疗法。我们的主打产品为VTP-300，它正在被开发为CHB的免疫疗法。
Hepatology Digest: Thank you for joining us. Could you start by introducing yourself and sharing the focus of Barinthus Biotherapeutics?
Nadege Pelletier：Of course, thank you. My name is Nadege Pelletier. I am the Chief Scientific Officer at Barinthus Biotherapeutics. We are a clinical-stage company that is developing immunotherapeutics for chronic infectious diseases and autoimmunity. Our lead asset is called VTP-300, and it is being developed as an immunotherapy for chronic hepatitis B.
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《国际肝病》
在IM-PROVE Ⅱ研究中，VTP-300与Imdusiran联合使用取得了哪些初步成果？您如何看待这种联合疗法在未来CHB治疗中的潜力？
Nadege Pelletier：在讨论我们观察到的结果之前，首先需要了解CHB的治疗背景。目前普遍认为，CHB的有效治疗手段为联合治疗，仅靠一种药物治疗是行不通的。我们必须联合使用针对不同作用机制的药物。
实现CHB功能性治愈涉及三个关键要素。第一是抑制病毒复制，这可以通过核苷（酸）类似物，即当前的标准治疗方案来有效管理。第二是减少乙肝表面抗原（HBsAg），像Imdusiran这样的反义寡核苷酸或siRNA化合物便是针对这一机制的药物。第三个要素是刺激免疫系统，而VTP-300作为一种免疫治疗药物，正是通过这一机制发挥治疗作用。
迄今为止，在VTP-300的研究中，我们发现HBsAg水平较低的患者获益显著。无论是基线时HBsAg水平本身就低的患者（如HBV-003研究），还是通过siRNA将HBsAg水平降到较低水平的患者（如IM-PROVE II研究）。基于这种治疗模式，将上述三个关键要素结合起来似乎为实现CHB的功能性治愈带来了巨大希望。
本周，我们在美国肝病研究学会（AASLD）上公布了一项三臂临床研究的数据。该研究评估了先用siRNA进行导入期治疗，随后使用VTP-300联合PD-1单抗的治疗方案。在这一特定治疗组中，我们观察到23%的患者在治疗结束时实现了HBsAg清除。虽然目前还处于早期阶段，尚需进一步的随访和停药数据来确认功能性治愈，但这些初步结果令人鼓舞，我们对这种联合疗法的潜力保持乐观态度。
Hepatology Digest: What preliminary results have been achieved in the IM-PROVE II study with the combination of VTP-300 and Imdusiran? How do you see the potential of this combination therapy in the future treatment of chronic hepatitis B?
Nadege Pelletier: Before discussing the results we have observed, it's important to provide some context regarding the treatment of chronic hepatitis B. It is widely acknowledged that achieving effective treatment requires a combination approach. No single drug can fully address the complexities of this disease on its own. Instead, a combination of therapies targeting different mechanisms of action is essential.
Currently, three key components are considered crucial for successful treatment. The first involves inhibiting viral replication, which is effectively managed by nucleoside analogs—the current standard of care. The second component is reducing the HBs antigen burden. This is where compounds such as antisense oligos or siRNA, like Imdusiran, play a significant role. The third and final component is stimulating the immune system, and this is precisely where VTP-300 fits in as an immunotherapy.
In studies with VTP-300 so far, we have observed the greatest impact among patients with very low S-antigen levels. This applies whether these levels are naturally low at baseline, as seen in the HBV-003 study, or brought to these lower levels through siRNA, as demonstrated in the IM-PROVE II study. With this treatment paradigm in mind, combining these components seems to hold great promise for achieving a functional cure for chronic hepatitis B.
Now, regarding the results being presented this week at AASLD, the data come from the third arm of the study, which evaluates a lead-in phase with siRNA followed by VTP-300 in combination with an anti-PD-1. In this specific arm, we observed that 23% of patients achieved HBs antigen loss at the end of treatment. While it is still early days, with follow-up and discontinuation data pending to confirm functional cure, these results are very encouraging, and we remain optimistic about the potential of this combination therapy.
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《国际肝病》
目前VTP-300的临床试验进展如何？能否分享一些关键数据或里程碑事件，以展示其疗效和安全性？
Nadege Pelletier：我们目前正在进行两项关于VTP-300的临床试验。第一项是HBV-003，该研究评估了在基线时HBsAg水平较低的患者中联合使用VTP-300和PD-1单抗的疗效。第二项是IM-PROVE II，该研究先用siRNA降低HBsAg水平进行导入期治疗，再单独使用VTP-300或联合单抗PD-1进行治疗。
这两项试验仍在进行中，因此数据还在不断完善中。不过，我们目前看到的结果令人欣喜。例如，在HBV-003中，有8名患者实现了HBsAg清除，我们还观察到了几例功能性治愈以及部分患者实现了乙肝表面抗体（抗-HBs）阳性。此外，随着收集到的数据不断成熟，我们观察到的疗效也愈发显著。例如，我们去年在AASLD上公布了初步数据，今年早些时候在欧洲肝病研究学会（EASL）上公布了更成熟的数据，现在我们又在AASLD上公布了最新数据。这些结果不断显示了试验进展，并加强了我们对VTP-300疗效的信心。
值得一提的是，HBV-003研究已完成全部患者入组。这意味着到明年EASL时，我们将对治疗的疗效和安全性特征有更清晰的了解。到目前为止，研究结果看起来不错。在安全性方面，没有太多需要报告的，因为VTP-300的耐受性非常好，我们没有遇到任何令人担忧的不良事件。
Hepatology Digest: What is the current progress of VTP-300's clinical trials? Can you share some key data or milestone events to demonstrate its efficacy and safety?
Nadege Pelletier: We currently have two ongoing clinical trials with VTP-300. The first is HBV-003, which is evaluating VTP-300 in combination with an anti-PD-1 in patients who start with low S-antigen levels at baseline. The second is IM-PROVE II, which tests the approach of lowering HBs antigen with siRNA during a lead-in phase, followed by treatment with VTP-300, either alone or in combination with anti-PD-1.
Both trials are still ongoing, so the data are in the process of maturing. However, we are quite encouraged by the results we have seen so far. For instance, in HBV-003, eight patients have achieved HBs antigen loss, and we have observed a couple of functional cures along with some patients who have seroconverted to anti-HBs antibodies. Additionally, the more the data mature, the better the results have become. For example, we presented initial data last year at AASLD, followed by more mature data at EASL earlier this year, and now we are presenting again at AASLD. These results continue to demonstrate progress and reinforce our optimism regarding the efficacy of VTP-300.
It is worth noting that the HBV-003 study is now fully enrolled. This means that by EASL next year, we will have a much clearer picture of the treatment’s efficacy and safety profile. So far, things are looking good. On the safety side, there is not much to report, as VTP-300 has been very well tolerated. We have not encountered anything worrisome in terms of adverse events, which is very reassuring.
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《国际肝病》
VTP-300作为一种免疫疗法，其作用机制是什么？与市场上现有的其他乙型肝炎治疗药物相比，它有哪些独特之处？
Nadege Pelletier：就作用机制而言，目前市场上CHB的标准治疗方法主要依赖于核苷（酸）类似物和聚乙二醇干扰素等抗病毒药物。采用这些标准疗法，只有5%~7%的患者能实现功能性治愈。所以CHB的功能性治愈率相当低。因此，我们迫切需要更多治疗方法。
我们认为目前的标准疗法没有实现功能性治愈的原因是因为它们没有解决疾病的潜在机制。因为当患者长期暴露于乙型肝炎病毒及其产生的所有诱因（包括HBsAg）中时，免疫系统特别是T细胞会遭受很大压力。这种持续的压力会导致T细胞功能逐渐衰竭：它们首先开始丧失增殖能力，随后失去效应功能，在衰竭的后期，它们甚至会被清除，这意味着患者体内不再有能够对抗病毒的T细胞。
VTP-300的作用是重新构建一个非常健康且高效的HBV特异性T细胞库，这些T细胞可以被激活去攻击病毒。这就是VTP-300的作用机制。
Hepatology Digest: What is the mechanism of action of VTP-300 compared to other existing hepatitis B treatment drugs on the market, and what are its unique features?
Nadege Pelletier: So when it comes to the mechanism of action, the standard of care that is currently on the market for chronic hepatitis B is mostly antivirals like nucleoside analogs. With that type of treatment, and the other one—sorry—yeah, current treatment of care, we have the nucleoside analogs, and we also have a pegylated interferon. And with that standard of care, we only reach functional cure in like five, six, seven percent of the patients. So the rate of functional cure is rather low. So there's definitely a need to have more therapies for that.
The reason why we think the current standard of care is not addressing the real pathomechanism that is underlying the disease is that when you have chronic exposure to the virus—so hepatitis B—as well as all those decoys that it's producing, including HBs antigen, there is some pressure that is being exerted on the immune system and on T cells particularly. And those T cells become exhausted, and in reality, what's happening is first they start to lose their proliferative capacity, they lose their effector function, and in the later stage of exhaustion, they actually are getting deleted, which means that you don't have any T cells that are able to be there and fight the disease anymore.
What VTP-300 does is actually reconstitute a very, very healthy and highly efficacious pool of HBV-specific T cells that can then be licensed to actually go after the disease. So yeah, that's the mechanism of action of VTP-300.
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《国际肝病》
Barinthus Biotherapeutics对VTP-300的未来研发有何计划？是否会探索与其他药物的联合使用，以进一步提高治疗效果？
Nadege Pelletier：正如我前面提到的，研究仍在进行中，所以现在确定任何计划都为时过早。不过，随着试验的推进，数据正在不断完善，并且试验现已完成全部患者入组，我们只需等待进一步的研究结果。我们相信，到明年的EASL会议时，我们将对VTP-300的有效性和安全性有更清晰的了解。届时，我们有望确定开发计划。
目前，我们正在考虑针对HBsAg水平较低的患者，开展一项涉及VTP-300联合PD-1单抗的III期试验。至于这些患者的HBsAg水平是自然降低的还是通过siRNA或其他方法降低的，这将需要根据数据确定。也就是说，到明年的EASL时，我们将明确VTP-300开发的下一步方向。
Hepatology Digest: What are Barinthus Biotherapeutics' future plans for the development of VTP-300? Will you explore combination therapy with other drugs to further enhance treatment effectiveness?
Nadege Pelletier: As I mentioned earlier, the studies are still ongoing, so it is a bit early to finalize any plans. However, the data are maturing nicely, and with the trials now fully enrolled, it’s just a matter of waiting to see how the results continue to develop. We believe that by EASL next year, we will have a much clearer understanding of the efficacy and safety of VTP-300. At that point, we expect to finalize our development plan.
Currently, we are considering the possibility of a Phase 3 trial involving VTP-300, potentially in combination with PD-1 inhibitors, for patients with low S-antigen levels. Whether these levels are naturally low or reduced using siRNA or another approach is something that will need to be determined based on the data. That said, by EASL next year, we anticipate having a well-defined direction for the next steps in the development of VTP-300.