Editor's note: Chronic hepatitis B (CHB) is a major public health problem worldwide. Although traditional antiviral drugs can inhibit viral replication to some extent, they are still inadequate in achieving functional cure. At the 2024 American Association for the Study of Liver Diseases (AASLD) Annual Meeting in San Diego, USA, Barinthus Biotherapeutics announced the latest research data on its innovative immunotherapy VTP-300. VTP-300 treats CHB through a unique mechanism of action, providing patients with new treatment possibilities. Hepatology Digest invited Nadege Pelletier, Chief Scientific Officer of Barinthus Biotherapeutics, to discuss the ongoing research work related to VTP-300.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.
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.
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.
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.
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. Thank you.
