Vir Biotechnology, Inc. (VIR) Earnings Call Transcript & Summary

Thank you, operator, and hello, everyone. Welcome to Beer Biotechnologies Hepatitis Investor Event Conference Call. Before we begin, I would like to remind everyone that some of the statements we are making today are forward-looking statements under applicable securities laws. These forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, future results, performance, or achievements to differ significantly from those expressed or implied by such forward-looking statements. These risks and uncertainties and risks associated with our business are described in the company's reports filed with the Securities and Exchange Commission, including Forms 10-K, 10-Q and 8-K. Today, we will discuss results from 2 Phase II clinical studies. The Phase II SOLSTICE trial, which is evaluating the safety, tolerability and efficacy of tobevibart and elebsiran and people living with chronic hepatitis delta. And Part B of the MARCH study, evaluating the safety, tolerability and efficacy of tobevibart and elebsiran with and without pegylated interferon alpha and people living with chronic hepatitis B. For this study, we will be sharing the interim end of treatment results. Joining me on today's call from Vir Biotechnology are Dr. Marianne De Backer, our Chief Executive Officer; Dr. Mark Eisner, our Chief Medical Officer; and Jason O Byrne, our Chief Financial Officer. We are also honored to be joined today by a renowned hepatologist and key opinion leader in the field, Dr. Nancy Reau. Before we begin, I'd like to briefly outline the agenda for today's call. Marianne will start with opening remarks and address the significant unmet medical needs in hepatitis delta and chronic hepatitis B. Mark will then provide an update on the Phase II SOLSTICE data presented at AASLD and discuss next steps for clinical development. We're pleased to then have Dr. Nancy Reau join us to offer her perspective on the hepatitis delta data and unmet medical needs. Mark will then return to present the Phase II MARCH Part B data update from AASLD followed by Dr. Reau's insights on the hepatitis B data. Finally, Marianne will provide closing remarks before we open the line for questions. With that, I'll now turn the call over to our CEO, Marianne. Please go ahead.

Thank you, Rich. Good morning, everyone, and thank you for joining us today. At here, we have a bold vision powering the immune system to transform the lives of patients. I'm excited to share some of the remarkable progress we are making towards achieving our vision. First, we currently have 5 clinical stage assets in our portfolio, spanning both infectious diseases and oncology. These programs are advancing rapidly with several near-term catalysts. The data we're presenting today from our hepatitis program is a prime example of this progress. Second, we are strategically focusing our investments in areas of high unmet medical need. By doing so, we aim to create transformative solutions for patients, who desperately need new treatment options, while simultaneously driving growth and creating value for our investors. Third, I want to emphasize our industry-leading expertise in differentiated AI-driven antibody discovery, protein engineering and marketing technology. These synergistic core capabilities will continue to be a driver of our success. These strategic pillars are robust pipeline, strategic focus and technical expertise form the foundation of our path forward. We are excited about the progress we've already made and the potential impact of our work. Now building on this foundation, let me give you a more detailed picture of where VIR stands today. As you can see, we're advancing our mission with immune targeted therapies across both infectious diseases and oncology. In infectious disease, we have 2 advanced clinical programs in hepatitis. This will be the primary focus of today's call. Our Phase II program in hepatitis delta is aimed at developing a chronic suppressive treatment while our Phase II program in chronic hepatitis B is pursuing a functional cure. We are also continuing to build on our infectious disease pipeline with preclinical programs in HIV cure and RSV. We've recently broadened the focus of our portfolio into oncology, specifically targeting solid tumors. We now have 3 clinical stage dual masked T-cell engager programs targeting HER2, PSMA and EGFR. These programs are in Phase I or initiating Phase I studies, and they target a range of solid tumor indications. T cell engagers are bispecific molecules with binding domains for both tumor-associated antigens and T cells for which our expertise in antibody discovery and protein engineering is key for developing a future masked molecules. Our unique combination of skills positions us for success in developing therapies across both infectious diseases and cancer. Now let's delve deeper into our hepatitis programs. Today that we are presenting today underscore the significant potential of our hepatitis programs, starting with our transformational results in hepatitis delta. In our SOLSTICE trial, the combination therapy of tobevibart and elebsiran has yielded impressive results. A large proportion of patients achieved undetectable HDV RNA below the lower limit of quantification and target not detected meaning there was no measurable presence of the virus in the blood. We also observed decreasing ALT levels for the majority of patients. In a separate small rollover cohort, responses were maintained up to week 60, suggesting the potential for a sustained and durable response. And importantly, no grade 3 or higher treatment-related adverse events were observed. These encouraging outcomes have paved the way for our next steps. We've held a Type C meeting with the FDA to discuss our path forward and based on the feedback received and our data we are advancing to our registrational ECLIPSE program with study initiation expected in the first half of 2025. Turning to chronic hepatitis B. We also have exciting news from Part B of our Phase II MARCH study. The top line results show very promising hepatitis B surface antigen loss at the end of treatment or seroclearance in patients with low baseline surface antigen levels. We also found that surface antigen loss at the end of treatment was associated with the development of anti-HBs antibodies. Looking ahead, we anticipate sharing our 24-week off-treatment functional cure data in the second quarter of 2025. This data will be critical in our understanding of the durability of response and the potential for achieving functional cure in chronic hepatitis B patients. These results across both our hepatitis delta and our hepatitis B programs highlight the significant progress we're making in addressing areas of high unmet medical need. The potential impact both for patients and for Vir as a company is substantial. In the next few slides, I'd like to focus our attention on hepatitis delta, our most advanced clinical program. This often overlooked form of viral hepatitis leads to particularly severe outcomes for patients, yet it remains fully understood by many. It's crucial to understand the profound impact of hepatitis delta, a disease that occurs exclusively in patients also infected with hepatitis B virus. Hepatitis delta dramatically increases the risk of severe liver complications, including cirrhosis and cancer, which can lead to premature death. The statistics from the hepatitis delta population are sobering. More than 50% of patients with hepatitis delta face liver-related death within just 10 years of diagnosis. The progression to cirrhosis and liver failure is alarmingly rapid, taking an average of only 5 years. Globally, we estimate the patient population to be approximately 12 million with up to 300,000 of these patients in the United States and Europe. To put this into perspective, individuals with hepatitis delta face 3x the risk of liver-related death and liver cancer compared to those infected with hepatitis B virus alone. Additionally, the health care costs for managing hepatitis delta are approximately twice high annually. These STAR contracts underscore why hepatitis delta is considered the most severe form of viral hepatitis. The accelerated disease progression, a heightened mortality risk and substantial health care burden emphasized the urgent need for effective treatment. But let's remember, these aren't just statistics. They represent real people facing a critical need. People for whom our work could make a life-changing difference. To truly understand the impact of hepatitis delta, we need to look beyond the numbers and consider the human stories behind them. This slide serves as a powerful reminder of the diverse lives affected by this disease. Hepatitis does affect a wide range of people from all walks of life, often in the prime of their lives reason that young professionals whose careers have been interrupted, parent struggling to care for their families, while managing their illness and individuals from various cultural backgrounds grappling with the diagnosis that carries significant stigma in their communities. For many, especially those from disadvantaged backgrounds, the financial burden of the disease compounds their already difficult situations. What strikes us most is the resilience of the hepatitis delta community despite facing severe and potentially life-threatening condition, many patients and patient advocacy groups remain hopeful and determined they are actively seeking information, advocating for better care and supporting others in their community. This is why our work at Vir Biotechnology is so critical. When we develop new therapies, we're not just aiming to improve clinical outcomes. We are working to transform the lives of real people to give them hope for a future where hepatitis delta doesn't define or limit their potential. As we continue our discussion and present our data, I encourage us all to keep these real patients in mind. They represent true purpose behind all of our efforts. Now despite hepatitis delta severity, patients face several critical challenges that compounds the difficulties of managing this disease. First and foremost, there are currently no approved treatments for hepatitis delta in United States and limited options outside of the U.S. Second, we are facing a significant issue of under diagnosis, exacerbated by low physician awareness and the lack of reflex testing in the AASLD guidelines. Reflex testing would lead to automatic testing for hepatitis delta in patients, who test positive for hepatitis B. Without this, many cases of hepatitis delta go undetected delaying crucial interventions. Third, the severe clinical outcomes associated with hepatitis delta drives a significant financial burden. The complex nature of the disease, frequent hospitalizations and need for specialized care can lead to substantial health care costs. Finally, hepatitis delta patients face limited physician and public awareness of the disease. This lack of understanding can lead to delayed diagnosis and missed opportunities for early intervention. Even in countries like the United States without approved treatment, it delays crucial disease management strategies, including monitoring, lifestyle modifications, transmission prevention and potential clinical trial participation. These challenges collectively create a perfect storm that hinders effective management of hepatitis delta as a disease. They underscore the urgent need not just for new treatments, but for a comprehensive approach that includes improved diagnostics, increased awareness and support for patients navigating this complex disease. To effectively address these challenges and [ develop ] targeted solutions, we must first understand who hepatitis delta effect? So let's take a closer look at the demographics of this patient population. Our strategy includes identifying who is most at risk and where they are located so that we can better tailor our approach to diagnosis, treatment and support. In the U.S., hepatitis delta is predominantly found in urban centers with diverse international communities. For instance, we see that Chicago accounts for about 37% of the total diagnosed population, New York City for 16% and Los Angeles for 11%. This concentration has important implications. First, it shows that the disease is primarily concentrated in distinct urban centers with international population. Second, there are relatively few hepatitis delta specialists often centered in these urban areas. Third, this concentration presents an opportunity for targeted awareness and testing drives in these high prevalence areas in a very resource-efficient manner. From a patient perspective, hepatitis delta can have life-altering impacts. This disease can remain undiagnosed for years silently progressing. Once present, hepatitis delta can lead to rapid and severe progression of liver disease. And in some cases, patients may require major medical interventions like liver transplant at a young age. So we're using this demographic information to inform our approach and shape our priorities for developing and eventually delivering treatments for hepatitis delta. Now let me share how we're translating this understanding into action. We've developed a focus strategy to address the key patient challenges we've outlined. Our approach is built on 4 key priorities: first, we aim to stimulate diagnosis by creating a transformative efficacious treatment. We believe an effective therapy will motivate increased testing and enable earlier interventions. Second, we're focused on understanding who and where Delta patients are to bridge the gap between testing and treatment. Third, we are committed to ensuring the earliest possible excess to pair our engagement. We recognize the significant financial implications of hepatitis delta and will proactively work to address access and affordability issues for both patients and health care systems. Fourth, and finally, we're dedicated to accelerating treatment rates through patients and provider education, where awareness and understanding is low. These priorities demonstrate our comprehensive approach to addressing hepatitis delta. We are not just developing a treatment. We're working to transform the entire landscape of care from diagnosis to treatment access and education. With that, I'll now hand over to Mark, who will provide an update on our Phase II SOLSTICE data presented at AASLD and discuss our next steps for clinical development.

Thank you, Marianne. I'm excited to share with you today the latest data from our SOLSTICE study, which we believe represents a potentially transformative treatment for chronic hepatitis delta. Let me walk you through our approach and the promising results we've seen. Our ambition in addressing hepatitis delta is to achieve chronic viral suppression with a convenient monthly dosing regimen. To understand how we aim to accomplish this, let's look at the mechanism of action of our 2 key investigational compounds, tobevibart and elebsiran. At the core of our strategy is targeting hepatitis B surface antigen. This is the key viral protein responsible for recognizing, finding and entry of both HBV and HDV virions into the hepatocytes by focusing on surface antigen, we're tackling a crucial stop of the viral life cycle for both viruses. Tobevibart is an Fc-engineered monoclonal antibody designed to bind to hepatitis B surface antigen on virions. It works in multiple ways: 1, it inhibits viral entry preventing new infections of hepatocytes; 2, it neutralizes and clears both HDV and HBV virions; 3, it's engineered to potentially enhance T cell activation by delivering hepatitis B surface antigen to antigen presenting cells, which may boost the immune response against infected cells. Elebsiran is a small interfering RNA or siRNA. It is designed to degrade HBV RNA transcripts, thereby limiting the production of surface antigen. This reduction is crucial because hepatitis B surface antigen is a central, the assembly and the release of new HGV particles. By combining these 2 mechanisms, the antibody mediated action of tobevibart in the RNA interference of elebsiran, we're targeting different aspects of the viral life cycle. We believe this multifaceted approach has the potential to achieve robust levels of viral suppression. Now let's touch on the design of our SOLSTICE trial, which is evaluating the safety and efficacy of tobevibart and elebsiran in chronic hepatitis delta patients. The study consists of 3 key cohorts. First, we have the tabevobart monotherapy cohort. This group includes 33 participants receiving 300 milligrams of tobevibart subcutaneously every 2 weeks. Second, we have the de novo combination cohort. This group consists of 32 participants receiving both 300 milligrams of tobevibart and 200 milligrams of elebsiran subcutaneously every 4 weeks. The third cohort is our combination rollover group comprising non-cirrhotic participants, who transitioned from monotherapy to combination treatment after not having met specific criteria at week 12 of monotherapy. The primary endpoints of the SOLSTICE trial are twofold: efficacy proportion of participants achieving both virologic response, defined as HDV RNA less than a limit of detection or at least a 2 log decrease in baseline and ALT normalization at week 24. Safety incidence of treatment-emergent adverse events. We're also tracking several key secondary endpoints, including the proportion of participants achieving undetectable HDV RNA and as measured as below the limit of quantification, target not detected. This slide shows well-balanced demographics and baseline characteristics across treatment groups. Notably about 46% of participants in the tobivibart montherapy group and 56% in the de novo combination group where cirrhotic allowing us to assess safety and efficacy in this important subpopulation. This slide shows the impressive virologic responses we're seeing in our SOLSTICE trial. Let's break it down. On the left, we see the proportion of patients achieving either a 2-log decrease in HDV RNA or levels below the limit of detection, the combination therapy achieved and maintained a 100% response rate at both week 24 and 36 compared to 82% and 78% for tobevibart monotherapy. It's important to note that not all patients have reached a 36-week time point in the study. The right graph shows an even more stringent and clinically meaningful measure, HDV RNA target not detected, which means undetectable viral RNA. Here, we see a striking increase in the combination therapy group from 41% at week 24 to 64% at week 36. The monotherapy group maintained a 30% response rate. I want to emphasize that these are some of the strongest data we've seen to date in hepatitis delta treatment. The high rates of undetectable HDV RNA, particularly with our combination therapy has shown its ability to suppress this challenging virus. From our perspective, these results are truly exceptional in the field of hepatitis delta research. This level of viral suppression, if maintained, has the potential to deliver transformative benefits for patients with hepatitis Delta, a disease that has long been considered one of the most difficult-to-treat forms of viral hepatitis. Now let's look at the ALT responses. On the left, we see ALT normalization rates. The tobevibart monotherapy group showed high rates of 76% and 74% at weeks 24 and 36, respectively. The combination therapy group demonstrated ALT normalization in 47% of patients at week 24, increasing slightly to 50% by week 36. The line graphs on the right give us a more detailed view of individual patient responses. Both groups showed significant ALT reductions from baseline to week 24. In the monotherapy group, we see deep and sustained ALT normalizations across most patients. The combination therapy group also shows substantial ALT reductions in the majority of patients. While we do observe some variability in responses in the combination group, particularly among patients, who started with lower baseline levels, these ALT changes were generally mild. Importantly, there were no grade 2 or higher ALT elevations observed in either group. Even for those patients who experienced some ALT increase, we have not seen any associated clinical symptoms or safety concerns. Overall, ALT decreased in most participants between day 1 and week 24 across both groups. By week 24, approximately 50% of participants in a combination cohort achieves ALT normalization. While the ALT normalization rates differ between the 2 groups, it's crucial to interpret these results in the context of our overall efficacy data, including the impressive HDV RNA target not detected results we saw in the previous slide. This slide presents our combined endpoint responses, which considers both biologic and ALT normalization. On the left, we see the protocol-defined end point HDV RNA reduction of at least 2 logs or below the limit of detection, combined with ALT normalization. The tobevibart monotherapy group maintained a 70% response rate at both week 24 and 36. The combination therapy group showed a slight increase from 47% at week 24 to 50% at week 36. The right graph shows the more stringent combined endpoint, HDV RNA target not detected plus the ALT normalization. We're particularly focused on the target not detected endpoint because it represents the most complete suppression of viral replication that can be measured. Here, we see encouraging trends in both groups. The monotherapy group increased from 21% at week 24 to 26% at week 36 while the combination therapy group showed a slightly more pronounced improvement rising from 19% in week 24 to 27% at week 36. Importantly, the rates of this stringent combined endpoint increased over time for both treatment groups. This suggests that the therapeutic benefits may continue to accrue with longer treatment duration. This slide presents a crucial finding from our SOLSTICE trial. The efficacy of our treatments appears to be consistent across both cirrhotic and non-cirrhotic patients. The graph on the left shows the mean HDV RNA levels over time for both treatment groups separated by cirrhosis status. What's striking is the similarity in their trajectories. We see consistent downward trends across all subgroups with the combination therapy showing slightly lower levels overall. The bar graphs to the right reinforce this observation. They compare the rates of HDV RNA target not detected and ALT normalization between cirrhotic and noncirrhotic patients at weeks 24 and 36. Again, we see comparable responses across these subgroups. This is a significant finding as a high proportion of patients with hepatitis delta are cirrhotic and these patients often have more challenging treatment outcomes. This slide provides an extended view of our HDV RNA responses, now including data from a rollover cohort. This cohort is insightful as it gives us our longest follow-up for the combination therapy. On the left, we see the proportion of patients achieving either a 2-log decrease in HDV RNA or levels below the limit of detection. The rollover cohort maintains an impressive 100% response rate through week 16 with all 5 patients still in the study at that point, showing this response. The right graph is our more stringent measure of HDV RNA target not detected. In the rollover cohort, we see a strong and sustained response over time. By week 36, 75% of patients achieved this stringent endpoint, and this high level of response is maintained through week 60 with 80% of patients showing target not detected at this late time point. These results from the rollover cohort are encouraging as they demonstrate the durability of the virologic response to our combination therapy. This slide presents our combined endpoint responses for the rollover cohort, on the left, we see the proportion of patients achieving both significant HDV RNA reduction and ALT normalization. At week 24, 5 out of 9 patients met this endpoint. While that absolute numbers decrease over time due to the smaller number of patients, we see a consistent proportion meeting this point. The right graph shows our more stringent combined endpoint HDV RNA target not detected plus ALT normalization. Once again, the rates of HDV target not detected combined with ALT normalization generally increased over time. This graph provides a visual reinforcement of the robust virologic suppression we've been discussing. The graph shows the mean HDV RNA levels over time for both our rollover and de novo combination cohorts. As you can see, both the rollover and de novo combination cohorts show a rapid and substantial decline in HDV RNA levels. This steep downward trajectory starts immediately and continues over time with levels falling below the lower limit of quantification and approaching the target not detected line. Not only do we see similar patterns between the rollover and de novo cohorts, but the tight error of ours indicate a consistent response across patients within each group. Importantly, these results demonstrate that the decrease in HDV RNA levels were maintained over time. This slide compares our Phase II hepatitis delta data with bulevirtide's Phase III results, the current standard of care in Europe. Our combination therapy shows a 41% HDV RNA target not detected at 24 weeks, increasing to 64% in a subset with longer follow-up at 36 weeks. This compares to 12% for bolevretide at 48 weeks with comparable ALT normalization rates. While cross-trial comparisons have limitations, especially given the different trial phases, patient populations and endpoints, these results adjust the potential of our approach to advance hepatitis delta treatment options significantly. Now so let's shift our focus to the impact of our treatments on hepatitis B surface antigen levels. This is a critical marker as surface antigen is essential for HDV replication and persistence. The line graph on the left shows the mean surface antigen levels over time for all 3 cohorts. What's striking here is the significant difference between the combination therapy groups and the monotherapy group. Both the de novo and rollover combination cohorts show a dramatic decrease in surface antigen levels, which is sustained through the study period. In contrast, the monotherapy group shows a more modest reduction. The stacked bar chart on the right gives us a more detailed view of hepatitis B surface antigen levels at week 24. This is a crucial measurement in the context of hepatitis delta because reduction of surface antigen will decrease HDV replication and persistence. Moreover, reduction of antigen below this level may lead to improved immune control of both HBV and HDV viruses. The results here are remarkable. Approximately 90% of participants receiving the combination of the tobevibart and elebsiran achieved surface antigen values below 10 international units per mil. This suggest our combination therapy is not only suppressing HDV, but also significantly impacting HBV. In contrast, only about 22% of participants receiving to tobevibart monotherapy achieve surface antigen levels below 10 IU per ml at week 24. These results highlight a key advantage of our combination therapy. By targeting surface engine through multiple mechanisms we're able to achieve and maintain very low levels of this crucial viral protein that is necessary for both HBV and HDV replication. Now let's review the safety profile of our treatments through week 24. The table on this slide summarizes the adverse events across all 3 cohorts. The key takeaways of the safety profile across all 3 treatment groups are: 1, most treatment-emergent adverse events were grade 1 or 2, indicating that they were generally mild to moderate in severity. 2, the most common treatment-emergent adverse event was influenza-like illness. Importantly, these symptoms were generally mild to moderate and transient. While there were 2 discontinuations due to these symptoms in the monotherapy arm, there were no treatment-related discontinuations in the combination therapy cohort. 3, no ALT flares or greater than grade 2 elevations were observed in any of the treatment groups. These safety results are consistent with what we hope to see for a chronic therapy. The options of treatment-related severe adverse events or ALT flares, combined with the transient nature of the most common side effects suggests that our treatments are generally well tolerated. I'll now summarize the key takeaways from our SOLSTICE trial data. First and foremost, the combination of tobevibart and elebsiran has shown great promise as a novel investigational treatment regimen for chronic hepatitis delta. We've observed that the combination rapidly reduces HDV RNA leading to high rates of undetectable HDV RNA or target not detected. Impressively, in a subset of patients with data through 36 weeks in the de novo combination cohort 64% achieved HDV RNA target not detected. This level of viral suppression is crucial for potentially halting disease progression. We've also observed decreasing ALT levels in the majority of patients in the de novo combination cohort. A key finding is that we saw similar virologic responses and ALT normalization in both cirrhotic and noncirrhotic participants. From a safety perspective, we have observed no grade 2 or higher ALT elevations occurred to date, showing our combination therapy appears generally well tolerated. Finally, the combination therapy showed significant reductions in surface antigen levels. This dual impact on both HDV and HBV markers is a unique and valuable aspect of our approach. Given these encouraging results, I'm excited to announce that we plan to initiate Phase III clinical trials evaluating tobevibart in combination with elebsiran for chronic hepatitis delta patients in 2025. Here, you can see our clinical development plan for tobevibart and elebsiran in chronic hepatitis delta. Building on the SOLSTICE results presented today, we have designed 3 superiority trials collectively known as The ECLIPSE program, each addressing different patient populations and treatment scenarios. ECLIPSE 1 is our Phase III trial focusing on hepatitis delta patients in regions, where bulevirtide is not available or use is limited, including in the United States. This study will enroll 120 participants randomized 2:1 to receive either our combination therapy or deferred treatment. 2/3 of participants will receive our combination therapy immediately and 1/3 will have a deferred treatment period during which they will receive only NRTIs. After this delay, they will then switch to the combination therapy. The primary endpoint is HDV RNA target not detected in ALT normalization at week 48 compared to the deferred treatment group at the end of their deferred treatment period. ECLIPSE 2, also a Phase III trial will evaluate switching to our combination therapy in patients who have not adequately responded to bulevirtide. We will enroll 150 participants randomized 2:1 to either switch to our combination therapy or continue on bulevirtide. The primary endpoint is HDV RNA target not detected at week 24 after randomization. We believe that ECLIPSE 1 and 2 taken together as our pivotal trials will be sufficient to support the initial marketing applications of our combination in the United States and Europe. These trials are designed to provide the comprehensive efficacy and safety data needed for regulatory submission. ECLIPSE 3 is expected to be a Phase IIb trial comparing our combination to bulevirtide in bulevirtide-naive patients. We will enroll 120 patients, randomized 2:1 with a primary endpoint of HDV RNA target not detected at week 48. We believe ECLIPSE 3 will provide important supportive data, particularly in Europe, which can also help us to establish appropriate pricing and reimbursement in key markets. Additionally, this study may support future label expansion. Importantly, all 3 studies will enroll both noncirrhotic participants in those with CPTA cirrhosis allowing us to evaluate the efficacy and safety across the spectrum of disease severity. All trials include virologic response, specifically HDV RNA target not detected as the key measure of efficacy. This approach will allow us to thoroughly evaluate our combination therapy across different patient populations and in comparison to both deferred treatment and the current standard of care, where it's available. I believe it's crucial to understand how these impressive data could translate to real-world patient care. To provide that valuable context, I'm honored to introduce Dr. Nancy Reau, a renowned hepatologist and key opinion leader in the field of viral hepatitis. Dr. Reau, thank you for joining us today. Could you please share your perspective on the SOLSTICE data and its implications for hepatitis delta treatment?

Thank you so much, Mark. So I think it's really important before discussing the data to understand the context that we actually are looking at our Delta patients in. We recognize that it's only a minority of our patients with hepatitis B surface antigen also have delta. And finding these individuals is going to be really important because they are much more likely to have progressive disease to cirrhosis and liver cancer at much earlier ages. This is reflected in all of our data sets that the individuals tend to be about a decade earlier and they tend to have very advanced disease. We are using surrogates right now to estimate outcome. So ultimately, we're trying to prevent cirrhosis, decompensation, liver cancer. And in natural history studies, if you have someone who's delta antibody positive that has no urologic replication, they tend to do much better. And so we're using that as a surrogate and hope that suppressing virus normalizing ALT will offer the same outcome to the patient population that we're treating. And right now, treatment is really maintenance for Delta. You would love to have a finite therapy, but most of our treatment strategies are in a way that we're going to use suppressive therapy without necessarily the hope of discontinuing treatment in the near future. This really is important because the context of the SOLSTICE trial shows that this combination therapy works incredibly well on normalizing liver enzymes and decreasing viral replication to a point, where it is target not detected. And I think that if you're looking at a virus and if you're using other virologic model of like hepatitis B or hepatitis C, it's not good enough to just decrease the virus. You really want to aim for no detectable replication. And we assume that, that's going to be the best outcome to decrease cancer rates and progression. We would love to see hepatitis B surface antigen reduction, and that's something that we're going to be very interested in when we're looking at these treatment strategies. And ultimately, that probably offers even better prognosis for our patients and might hint towards finite therapy. But low-hanging fruit first, ALT normalization and reduction with preferably no replication of hepatitis D RNA. I think it's also very important when you're looking at cirrhotic and noncirrhotic data because given that about half of the patients that are in our clinical treatment programs, for Delta have cirrhosis. It is not going to be adequate to have a therapy that only works in the noncirrhotic population. And the SOLSTICE trial really shows that cirrhosis patients do just as well as non-cirrhotic patients. Now we know that their outcome might be different because a person who has already progressed cirrhosis have a higher rate for liver cancer and poor outcome. And so ultimately, again, screening is important. We want to identify these individuals and get them into the treatment at their earlier time points, but you still want to offer a benefit to the patients with more advanced disease. And this program has definitely impacted that. It has also been shown to be very safe. We always worry about ALT players. We -- all those good players or bad players. But I think it's important to have outcome with no flare and that has definitely been shown in this data. One of the other things is looking at dosing regimen. So we want patients to be adherent. You want something that's not going to be difficult to do and some of our therapies that look at daily injections are definitely going to be more problematic. Also, therapies where people can forget. So once a month dosing is really preferred because it's easy to remember. Patients are going to not -- are going to be adherent with this. And I don't think the injections are issue anymore, especially given the widespread use in GLP-1s, I think patients are very accepting of an injectable therapy. You just want to make sure that it's in a way that is not going to be forgotten or lift dosing. The last thing is really looking at the forefront of ECLIPSE clinical development program. I think it's really important to recognize that patients have been worldwide exposed to other things like bulevirtide. And looking at longer-term outcome and larger groups as well as individuals, who had suboptimal response to what might be available for them is going to be really important. And I think this sets the stage for us to learn more about delta -- the gaps and how this is going to work as a therapy that's going to eliminate these things.

Thank you, Dr. Reau for your invaluable insights. Your perspective helps put our SOLSTICE data into context and underscores the potential impact of our work on patients living with hepatitis delta. Now I'd like to shift our focus to another critical area of our clinical development, chronic hepatitis B. Before we delve into our March Part B data, let's briefly review the context of chronic hepatitis B and why our work in this area is so crucial. Chronic hepatitis B is a global health challenge affecting an estimated 254 million people worldwide. This includes approximately 1.6 million people in the United States and 2.8 million in Europe. The impact of this disease extends far beyond the numbers, profoundly affecting individuals' lives and health systems. Chronic HBV infection is associated with severe long-term liver complications, including cirrhosis, liver cancer and liver failure. In some cases, it can lead to the need for liver transplantation or result in liver related debt. Beyond these physical health impacts, patients often face stigma and discrimination, which can significantly reduce their quality of life. Despite advances in treatment there remains a substantial unmet medical need. Current therapies can suppress the virus, but rarely lead to a functional cure defined as sustained off-treatment loss of hepatitis B surface antigen. Achieving this functional cure could dramatically improve long-term outcomes for patients. Our approach with our investigational agents to bulevirtide and elebsiran, which you'll see in the March Part B data aims to address this critical need. As we transition to our hepatitis B program, you'll notice that this slide looks familiar. Indeed, we're leveraging the same combination of tobevibart and elebsiran that we discussed in our hepatitis delta program. However, our ambition here is distinct and particularly challenging to achieve a functional cure following a finite treatment regimen in chronic hepatitis B. This goal would represent a significant advancement over current therapies, which typically require lifelong administration to suppress the virus. Our approach aims not just to suppress the virus but to allow the immune system to regain control potentially leading to sustained viral suppression even after treatment is stopped. The mechanism of action we discussed earlier tobevibart's role in inhibiting viral entry and neutralizing virions and elebsiran's ability to reduce surface antigen production are just as relevant in HBV as they are in hepatitis delta. This approach aligns with the growing understanding in the field the combining antiviral and immunomodulatory therapies may be key to achieving functional cure in chronic hepatitis B infection. Let's now look at the design of our Phase II March Part B study, which is evaluating our approach to functional cure in chronic hepatitis B. This study enrolled a total of 121 participants, all of whom met specific criteria listed on the slide, which include being on NRTIs for at least 6 months. We divided these participants into 3 treatment arms: 20 received tobevibart monotherapy, 51 received the doublet of tobevibart plus elebsiran and 50 received the triplet of tobevibart, elebsiran and pegylated interferon alpha. Our primary end points for this study focused on both safety and efficacy. We're assessing the proportion of participants experiencing treatment-related adverse events and serious treatment-related adverse events. For efficacy, we're looking at hepatitis B surface antigen loss, or S loss, both at the end of treatment and the '24 weeks post treatment. In the analysis we're presenting today, we're having the treatment data for all participants treated with tobevibart alone and to tobevibart plus elebsiran. For the triplet arm, we have data for 27 out of the 50 participants at this time. Now here, you can see participant demographics and baseline characteristics of our study population. These characteristics were generally balanced across all treatment groups. However, it is important to note a specific aspect of the baseline hepatitis B surface antigen levels. In the doublet arm, we had 14 out of 51 participants with baseline hepatitis B surface antigen levels between 1,000 and 3,000 IU per ml. However, in the triplet arm, we had no participants in this range of the 27 we have data for at this time point. Now let's turn our attention to one of the key findings from our March Part B study, hepatitis B surface antigen loss at the end of treatment. On the left side of the graph, we see the overall SLOS across our 3 treatment arms in the [ locums ]. Here, we observed no SLOS in the tobevibart monotherapy group. However, in the doublet arm of tobevibart plus elebsiran, we saw S loss in 8 out of 51 patients. And in the triplet arm with the addition of pegylated interferon alpha, we observed SLOS in 6 of the 27 patients. But perhaps the more compelling data is shown in the center and on the right side of the graph, where we stratified the results by baseline surface antigen levels. This analysis reveals an interesting finding in patients with baseline surface antigen levels below 1,000. In this subgroup, we observed surface antigen loss in 7 out of 18 patients or 39% in the Dublin arm and 5 out of 11 patients or 46% in the triplet arm. It's important to note that the response rates were much lower in patients with higher baseline surface antigen levels. In the 1,000 to 3,000 range, we saw only one responder out of 14 in the doublet arm and no patients from the triplet arm fell into this category of this data cut. For patients with baseline surfacing the June above 3,000 we observed one responder in the triplet arm. These results suggest that our combination therapy, both with and without pegylated interferon alpha, shows particular promise in patients with lower baseline surface antigen levels. Let's now look at the development of antibodies against hepatitis B surface antigen or anti-HBS at the end of treatment, which is an important marker of immune response to our therapies. The bar graph on the left shows the percentage of participants, who developed anti-HBS levels of 10 ml IU per ml or higher at the end of treatment. Interestingly, we saw anti-HBS development across all treatment arms. In the monotherapy group, 40% of patients, 8 out of 20 developed these antibodies. In the doublet arm, we saw a slightly higher rate of 45%, 23 out of 51. The triplet arm with the highest rate at 63%, 17 out of 27. The 3 line graphs on the right give us a more detailed view of the anti-HBS antibody kinetics for each treatment arm. Each line represents an individual patient with gray lines indicating participants who did not achieve surface antigen loss at the end of treatment and green line showing those who did achieve SLOS. What's particularly noteworthy is that the combination of tobevibart, elebsiran and pegylated interferon alpha was associated with the highest antibody levels. This suggests that the triplet regimen may be particularly effective at stimulating the immune response against HBV. These results are encouraging for several reasons. One, they demonstrate that our treatments may be capable of stimulating an immune response against HPV even in cases where we don't see complete surface antigen loss. This is an area that requires further investigation to fully understand the mechanism. 2, the key finding is that all 6 participants in the triplet arm who achieved SLOS also developed anti-HBS antibodies. This strong correlation between SLOS and anti-HBS development in the triplet arm is particularly noteworthy and suggests a potentially important relationship between these 2 outcomes. And 3, the presence of these antibodies may be important maintaining viral suppression after treatment, which is crucial for achieving a functional cure. As we continue to analyze this data and await the post-treatment follow-up results, we'll be playing close attention to how these antibody levels correlate with the sustained surface engine loss and other markers of functional cure. Now this graph visually reinforces the strong relationship between surface antigen loss, anti-HBS antibody development that we just discussed. As mentioned, we see a particularly strong correlation in the triplet arm for all participants who achieved SLOS. This also shows the relationship in the doublet arm, where half the patients who achieved SLOS also develop protective antibody levels. Now let's review the safety profile of the treatments in our study. Overall, the safety data from our study appears generally well tolerated. The most common adverse events related to tobevibart or elebsiran were headache and influenza-like illness. Importantly, these were generally mild to moderate in severity and transient in nature. For the triplet arm that included pegylated interferon alpha, the adverse events related to this component were consistent with its established safety and tolerability profile. We did observe treatment-related serious adverse events in 2 participants in the triplet arm, one case of leukopenia, which was related to pegylated interferon alpha and one case of hepatitis, which was considered related to all 3 components of the triplet therapy. It's important to note that both of these events improved without any lasting consequences. With this safety profile of mine, let's now turn to the preliminary overall conclusions. First, we've observed compelling hepatitis B surface antigen loss in anti-HBS development at the end of treatment with our combination therapies. And participants with baseline hepatitis B surface antigen levels below 1,000, we saw SLOS in 39% of participants receiving the doublet regimen and 46% participants receiving a triple regimen. These rates of SLOS in the low baseline group are compelling. Beyond CR clearance, we've also observed encouraging anti-HBS antibody development in both regimens. Our end of treatment data is highly encouraging. Its true significance will depend on whether it translates to functional cure and the key test lies in the sustained response after treatment cessation. If these initial results lead to durable functional cures that will be transformational for hepatitis B patients with low baseline surface antigen. With that in mind, we're eagerly anticipating our functional cure data, which we expect to have in the second quarter of 2025. Now I'd like to turn it back over to Dr. Nancy Reau, will provide her expert perspective on these findings and their potential implications for chronic hepatitis B treatment. Dr. Reau, the floor is yours.

Thank you so very much. So the hepatitis B landscape is huge. We recognize that worldwide hepatitis B drives huge amounts of cirrhosis and is the #1 cause of liver cancer. And so finding a therapy that has the ability to be finite and as well as decreased cancer rates and progression to cirrhosis is imperative, especially while we recognize that this is a vaccine preventable disease, our vaccination rates have been very limited, and we are going to be dealing with hepatitis B for decades. When we look at long-term outcome, every single guideline has demonstrated that hepatitis B surface antigen loss is paramount, this seems to be the strongest marker of decreasing liver-related events. And this has been shown both with natural history studies as well as hepatitis B surface antigen loss with our NUCs and hepatitis surface antigen loss with pegylated interferon. If we have suppression of virus, but not surface antigen loss, liver cancer rates are lower, but outcomes are not as ideal as you have with actual surface antigen loss. When we look now towards applying a therapy that is going to achieve this quintessential outcome across the landscape of hepatitis B, we know that there are -- certain patients are going to have a higher rate of this than others. And here is where we start to pull in the importance of quantitative hepatitis B surface antigen. I think in the U.S., we still are a little naive in this market, recognizing that worldwide, some places have used quantitative surface antigen more readily than others. We'd also recognize that patients who are e antigen positive have higher rates of quantitative surface antigen as opposed to those that are e antigen negative, but we're starting to shift the paradigm to push clinicians to think about their patients and what therapy might be appropriate, we're going to have to start to talk about the role of quantitative surface antigen because this is going to be very important when you're identifying a patient that might have an opportunity for a finite therapy that's going to lead towards functional care as opposed to someone else, who might want to achieve that, but it's going to have less outcome with our current tools. So when we look at implications for patient selection, quantitative surface antigen is going to be really important. And when we're looking at some of the groups like e antigen negative patients, which are really important because this group is often identified as someone who needs lifelong therapy. They often will have a lower quantitative surface antigen, and they might be a candidate for some of the other clinical paths such as what we are looking at here with the MARCH Part B trial. That takes us really to other ways of pushing patients towards functional cure. And what you might need is an immunomodulating effect. So knowing that most of our strategies are going to be a bit personalized and you're going to need direct acting antivirals across multiple different locations in the hepatitis B replication cycle. And then you're probably also going to need something that helps that immunologic push because although some of our strategies have shown to improve the innate immune response to hepatitis B maybe not enough to actually get functional cure. And then when we look at our tools for that, pegylated interferon isn't perfect, but it is a very well-known partner. We've been using PEG for decades in hepatitis B as well as hepatitis C. And although we recognize that it has limitations, you cannot use it easily in patients who have the immune disease. It's definitely contraindicating patients with more advanced cirrhosis, it is a predictable tool. And because of that, we know what to expect, what's monitor for and how patients are going to do. So if we take this and we look back to the MARCH Part B trial, noting that in well-selected patients, those that have lower quantitative hepatitis B surface antigen that you can achieve surface antigen loss and up to 45% and that's really instrumental. It really points towards something that might offer a functional care for these individuals, although we definitely look forward to the second quarter data next year, which will hopefully confirm that. I'm going to turn it back over to Marianne now.

Dr. Reau, thank you for lending your expertise to our discussion here today. Your insights not only validate the potential of our approach, but also underscore the transformative impact we could have on patient care. Now building on Dr. Reau's expert perspective, I'd like to share some closing thoughts. As we conclude our presentation, I'm filled with a sense of excitement and purpose. The data we've shared today represents more than just scientific progress. It embodies hope for millions of patients living with hepatitis delta and chronic hepatitis B. Let me summarize the key takeaways. In hepatitis delta, our combination of the bulevirtide and elebsiran has shown a promising efficacy and safety profile. This encouraging data has paved a way for our pivotal ECLIPSE Phase III program, which we expect to initiate in the first half of 2025. The potential of this treatment has been recognized through Fast Track designation by the FDA. Additionally, we've just recently announced that we received a positive opinion on orphan drug designation for the combination in chronic hepatitis delta from the European Medicines Agency. This latest recognition further highlights the growing acknowledgment of our treatment potential. In chronic hepatitis B, we've observed encouraging rates of surface antigen loss in patients with low baseline hepatitis B surface antigen levels. This is a critical step towards functional cure for these patients. We are eagerly anticipating our functional cure data, which we expect to have in the second quarter of 2025. These advancements in both our hepatitis delta and hepatitis B program underscore our commitment to addressing significant unmet needs in liver disease. And as we look towards the future, I want to revisit our strategy success in hepatitis delta. Our approach is multifaceted and built upon the priorities I outlined earlier. We are committed to driving the continued evolution of hepatitis delta guidelines, ensuring they reflect the latest advancements in treatment. Simultaneously, we're working to enable and encourage testing and diagnosis for both HBV and HDV addressing the critical issue of under diagnosis. A key part of our strategy is to drive awareness of testing in targeted initiatives and populations most affected by hepatitis delta. Our ultimate goal is to establish tobevibart and elebsiran as the standard of care in HDV. The promising data we shared today brings us closer to these objectives. Finally, we aim to leverage our leadership position in hepatitis delta to bring value to the broader HBV population. And while we focus on hepatitis today, our development pipeline is robust with many programs representing multiple opportunities to create value in the near and midterm. Looking ahead, I'm excited to highlight some key near-term catalysts for VIR. First and foremost, we are on track to initiate our ECLIPSE registrational program for hepatitis delta in the first half of 2025. Additionally, we now expect to share initial monotherapy data for both our HER2 and PSMA T cell engagers in the first quarter of 2025. These catalysts represent important milestones in both our infectious disease and oncology portfolio. They underscore the potential of our pipeline to deliver meaningful advancements in multiple therapeutic areas. In closing, I want to express my sincere gratitude to our study participants investigators, team members and investors. Your contributions drive our mission to transform patient care. With that, I'll turn the call back over to Rich to begin the Q&A session.

Thank you, Marianne. This concludes our prepared remarks, and we will now start the Q&A section. [Operator Instructions] I'll turn it over to you, operator.

[Operator Instructions] Your first question comes from the line of Paul Choi of Goldman Sachs.

My first question is for either Mark or Dr. Reau. And I was wondering if you could comment on the antibody -- [ anti-HV ] antibody levels. And my question here is, do you think that the treatment is actually raising the antibody levels? Or is it merely unmasking existing antibodies that had previously been bound up due to the infection? And then my second question for the company is, can you comment on when you would expect to have the full end of treatment data for the all 50 patients in the triple treatment a combination regimen?

Thanks, Paul. This is Mark. Appreciate your question. Your first question about development of anti-HBS antibodies, it's an important one. We believe that both could be going on. So in other words, when tobevibart is administered to the patients, I do think that we can get some unmasking of previously existing endogenous surface antibody that the patient may have already generated because we're binding the surface antigen up and the assay can now detect endogenous surface antibody the patient already may have. But as you'll note, especially in the triple therapy data, we're seeing some very high titer antibody levels, right? So those, we believe probably also represent an increased immune response from the patients and not just on unmasking. But we really don't have good tools to disentangle those 2 possibilities, and they're not mutually exclusive. But we do think in the case of some of the patients get high titer surface antibody levels that those probably represent a new immune response on top of whatever endogenous antibodies they already have had. We -- in terms of the end of treatment data for functional cure, we are going to have those in Q2 of next year.

Your next question comes from the line of Gena Wang of Barclays.

Congrats on the data. So I have 2 questions. The first one is regarding HDV, giving impressive curing from both double and triple in HDV patients with engaging less then 1,000 international units per ML. Will you be only focusing on visitation population for a Phase III study? And then my second question is regarding ECLIPSE 2, any more color on the bulevirtide, which regarding the baseline screening period with this study design with Vir combo as a second-line therapy in [indiscernible] bulevirtide is available?

Thank you for your questions. So your first question is about the data and whether we intend to focus on surface antigen less than 1,000. As you -- we presented, we do have the strongest data in HBV in terms of the end of treatment response as in surface antigen under 1,000. But we need to see the data continue to emerge before we will be making any final decisions about the study population. So we will -- it will be a data-dependent decision as the data evolve. As you know, we'll note that in the triplet, there -- by chance, we're not any patients who had between 1,000 and 3,000 at baseline. So we -- that's a data gap right now. We will have some patients in the subsequent approximately 20 patients on the triplet that were enrolled a little bit later. We will have some additional data in that range of surface antigen. So that's another point that will be helpful. You asked about ECLIPSE 2 and to provide more color, that is our bulevirtide switch study and bulevirtide experienced patients who have incomplete response and are continue to be viremic. So those patients will be either randomized to continued bulevirtide for 24 weeks versus switch to our regimen, and we will be comparing the target not detected in those 2 regimens in addition to other end points.

Your next question comes from the line of Roanna Ruiz of Leerink Partners.

So first question for me on the delta virus program. I was curious if you could elaborate on how long it might take to complete the ECLIPSE registrational trials and whether in FDA discussions, the FDA encouraged you to do 3 separate trials and the more stringent endpoint? And the second question is also on the delta virus program, would it be possible for you to file in the U.S. based on a single Phase III, let's say, if one of the ECLIPSE trial reads out ahead of another one?

Yes. But those are really good questions. In terms of -- first of all, we had a very collaborative and productive discussion with the FDA. And we've designed the program really to address the unmet medical need as it exists across the world, recognizing the bulevirtide is approved in Europe, but not in North America. So in -- ECLIPSE 1 really will address the population that in the U.S. and North America that doesn't have access to bulevirtide or in other countries where access is a challenge. In terms of the actual registrational package as we've mentioned, we believe that ECLIPSE 1 and ECLIPSE 2 should be adequate for filing. And in terms of the most stringent end point, we've chosen the target not detected endpoint because it is the most robust virologic endpoint. It represents inability to amplify any RNA on the PCR. So there's no virus detectable at all. We believe that, as Dr. Reau mentioned in her remarks, will be most valuable in terms of protecting the patients from long-term outcomes such as cirrhosis and liver cancer. In terms of your question about filing on a single study, I think that's just something that we would have to consider once we have data from the trials, I think it's premature to comment in any detail there. But just to reassure you, we are going to pursue any and all opportunities to get this to patients as quickly as possible because of the high unmet medical need. And we've announced, for example, we've recently received EU orphan designation, which I think reflects not only the rarity of the disease, but the fact that it is a high unmet medical need and patients need better treatments for it.

Your next question comes from the line of Michael Ulz of Morgan Stanley.

Maybe just one on hepatitis B and at the end of treatment data now. Do you think you have a better chance of reaching a functional cure with the triplet versus the doublet. And then secondly, do you have a preference for one or the other? Or is this more of a situation where maybe one gets used in a certain subset of patients and the other in a different subset?

Yes. Really good questions. The short answer is we don't know. I mean we'll have to see the functional cure data in Q2 next year, and we're eagerly anticipating those data. I mean it is notable that 100% of the triplet patients who cleared surface antigen develop surface antibody whereas 50% of the doublet with tobevibart and elebsiran without interferon develop surface antibodies. So that does signal more of an immune response in the triplet versus the doublet, which isn't really surprising given the administration of an immunomodulator. But at the end of the day, we really have to see the data as they emerge in terms of functional cure next year in Q2 and then make a decision there. In terms of preference, there's -- clearly, our KOLs are very interested in having new better treatments for hepatitis B. I think, obviously, an interferon-free regimen is easier for patients. But if the cure rates are high enough then with triple, I think that could be very attractive as well. So I think, again, it will depend on the data and how they evolve. Dr. Reau, do you want to add anything?

Yes. I mean, I think that like it was expressed, it's just a little premature. But clinicians are absolutely going to look at a patient individually. If you have someone who's likely to have intolerance to interferon and still have a good outcome with the doublet, then you would offer that alternative even if it might have less rates of long-term efficacy because you have an opportunity for that patient that, that patient may not have had. And if you have better outcome with all 3 and a patient is going to be able to tolerate that, you're certainly going to have that discussion that some clinicians are going to be very interferon-averse and some patients are not going to be good candidates, which is why it's really nice to have options, but we really need the long-term data before we can understand those options.

Your next question comes from the line of Eric Joseph of JPMorgan.

Maybe just for Dr. Reau. Can you just sort of elaborate on in chronic hepatitis delta, the importance of ALT normalization as it predicted for liver outcomes, maybe perhaps relative to achieving target not detected. And then for the company, just if you're looking at your ALT normalization signal, I'm wondering, if you're seeing any events of normalization beyond 24 weeks so far? It looks like the numerators really don't change that much. Do you expect -- or really, where do you expect to sort of be on the level of overall ALT normalization at 48 weeks of follow-up?

So if you may take at first, we like metrics that are measurable. And so it's nice to have an ALT that normalizes because you can reassure the patient that this is a good outcome. But you -- as a clinician that takes care of patients with viruses, you want to see that virus go away. And if you understand the mechanism of action includes an increase in your ALT, you're going to tolerate that. Many of our drugs have minor increases. And it's a composite endpoint. But you are going to go with the surgate that you think has the best association with good long-term outcome. So I would much rather see not an increase in my ALT, but it fails normalization with a strong response in the virus knowing that, that's probably going to be a better long-term opportunity until we actually have the real data that showed that, that does truly reflect lower rates of cancer and lower rates of progression.

Thank you, Dr. Your other question around ALT after 24 weeks, I think the first thing we would emphasize is over time with the combination regimen, we're clearly seeing increasing levels of complete viral suppression. So in the rollover cohort at week 60, we're seeing 80% of the majority reach target not detected or complete elimination of the virus. In terms of the composite that includes T&D plus ALT normalization, those proportions continue to increase. For example, in the rollover cohort, at week 48, we're seeing 50% achieve that. So we're driving the virus lower and lower, lower. Whether we're going to continue to see further declines in ALT after week 28 -- 24, sorry, we will need to see those data as they continue to evolve. But I think it's important to note that in the majority of patients, we are dropping ALT. In the patients who -- in the combination we have ALT above upper limit of normal, a lot of those are just very, very minimally elevated and they kind of oscillate around the upper limit of normal. So they're not probably very clinically meaningful, particularly in the context of the profound virologic suppression and target not detected that we are seeing.

Your next question comes from the line of Alec Stranahan of Bank of America.

This is Matthew on for Alex. Two for us on HDV. First, when you look at the progressive improvement in target not detected from 41% at week 24 all the way up to 80% at week 60. Are these cannot expect -- what you'd expect based on the mechanism of action? And could we actually see this improve beyond week 60 as well? And then secondly, it looks like the percentage of achieving target not detected in ALT normalization in the de novo group at week 24 actually declined a little bit from the last update. Curious if there's anything patient demographic wise, in the larger 32 patient population that could be driving this difference?

Your first question is around the increasing proportion of target not detected from 41% at week 24 to 80% in the rollover cohort at week 60 and whether or not that reflects the mechanism of action of the combination. And I think it does because the antibody tobevibart is blocking surface antigen, it's blocking entry to virus into hepatocytes and it's also increasing clearance of virions and subviral particles, whereas electron is an sRNA is knocking down all of the HBV viral transcripts, including surface antigen. So I think that we're seeing kind of a synergistic response between the 2 mechanisms of action biologically. Whether we'll continue to see further reductions after week 60 is an unknown. I mean, we don't have those data speculating, I mean, we continue -- the longer we go, the longer we're seeing the higher the proportion responses that we're getting. So I think we'll just tough to see how those data evolve. And then your question around the week 24 ALT plus T&D at week 24 and the T&D rate at week 24 versus the EASL update, I mean I think what you have to recognize is we're now seeing a complete data set at week 24 compared to 11 patients in each group approximately at the EASL update. I think what we're seeing relatively small numbers. I wouldn't say there's any actual drop. It's significant. It's just within the small numbers. So we're seeing, for example, 41% T&D at week 24, we had previously reported 55%. But then as we go out, we're seeing 64% at week 36, 80% at week 60. So we really believe we're going to suppress virus undetectable in the vast majority of patients over time.

Your next question comes from the line of Phil Nadeau of TD Cowen.

2 questions from us. First, in terms of the regimen in HDV. It does seem like maybe sRNA is leading to use somewhat elevated ALT levels over the long term versus what monotherapy would has been producing. Would you consider looking at an induction regimen with siRNA and then a maintenance therapy with a maintenance regimen with monotherapy in order to perhaps keep viral levels low, but allow the ALTs to normalize? That's the first question. And then second question, appreciating it's early days. Do you have any estimate on how long it would take for the pivotal program to enroll and complete when could we see an FDA or EMA filing in HDV?

Yes. So your first question about ALT. So first thing I'd emphasize is we are seeing reductions in the majority of patients in the combination treatment. So that's point #1. Point #2 is we are -- as Dr. Reau said, and as we've reemphasized this is a viral disease, so whom -- we're knocking the delta virus undetectable is really the most important goal. In terms of these -- whether or not it's a sRNA/elebsiran drug effect, it is a possibility. I mean certainly, siRNAs have been associated with some LT elevations in both in the J&J read study and so forth. But we haven't seen any flares of ALT in combination with tobevibart. And generally speaking, the ALT elevations that we've seen or lack of total declines have been very, very mild. In terms of an induction and maintenance, I think the problem there is that we won't get the profound sustained viral suppression that we're really needing to see in order to, we hope, predict better long-term outcomes for patients. So I think we're committed to using the combination approach because we really think that the virus is causing the disease, and that gives us the best chance of suppressing the virus. In terms of your question about how long the pivotal trials will take, we haven't really provided that guidance yet. We have said that we'll start the Eclipse Phase III registrational program in the first half of next year, and we'll look forward to providing that guidance at the earliest opportunity.

Your next question comes from the line of Patrick Trucchio of H.C. Wainwright.

Congrats on the data. I have a question on the HDV program and on the HBV program. So the first on HDV, can you tell us whether or not we should think about the bulevirtide patients who do not achieve HDV-target not detected as being more difficult to treat? And how, if at all, that could impact the outcome from ECLIPSE 2 relative to ECLIPSE 1? And then on the HBV program, I think in the past, you've discussed targeting functional cure rates of 20% without interferon or 30% with interferon. I'm wondering as we look ahead to a Phase III program, can you tell us what rate of a functional cure we would need to see to support FDA or EMA approval in an all-comers population? And if separately, we could anticipate the 20% without interferon or 30% with interferon target as being a fair expectation for that under 1,000 cohort.

Really, really good question. So your first question about hepatitis delta is whether or not patients, who do not -- or remain viremic on bulevirtide, whether they represent kind of a more refractory population, a more difficult population. We really don't think so. I mean, first of all, the majority of patients at 1 year treated with bulevirtide, the only 12% achieved target not detected. So the majority are still viremic. So it's about 90% or so. The second thing is we have patients in our SOLSTICE trial, who've been on bulevirtide in the past, and discontinued before the study started, and they appeared to perform similarly to the patients, who have never been on bulevirtide. So we don't believe that, that's going to enrich the population for a more difficult population at all. So in our ECLIPSE 2 trial, which are, as you alluded to, bulevirtide in complete responders, we think those should behave similarly, when we switch to our regimen of the combination of tobevibart and elebsiran, we expect to achieve high rates of target not detected in that population. In terms of the hepatitis B program and the functional cure targets, and we have talked about 30% for the triplet, 20% in the doublet as before, I don't think the FDA has specific requirements for those -- for that. I mean I think right now, functional -- there's no drug approved really that has functional cure in the label right now. And I think anything would be a meaningful advance. And in terms of whether or not all comers versus low surface antigen would be required. Again, I don't think that there's a specific regulatory requirement around that, and we would expect to be able to study a range of populations and potentially have approval based on data in low surface antigen or a different population. But Dr. Reau, maybe I should ask you, what's your thought about what expectations might be from regulators on the surface antigen levels?

I would say that it has to do with predictability. I wouldn't look at an all-comer. I would really look at can you identify easily a population that has a high chance for a good outcome? And so although it's a little disappointing to have to limit your strategy to a subset of the entire population, if limitations to that subset have really good predictability, and really good outcome, that's key. And it allows you to optimize your agent. And I think the regulators are going to look at that, knowing that there is really nothing right now that offers a finite functional cure. If you can -- you have an option that isn't easy to apply algorithm that's going to be very successful.

And your last question comes from the line of Joseph Stringer of Needham & Company.

Two for Dr. Reau for HDV. Just curious in terms of the barriers -- get your thoughts on the barriers to changing the AASLD guidelines to include potentially reflex testing and increasing that HDV diagnosis. How likely is it that we could see changes to the guidelines in the near future? And I guess as a follow-up to the last question, just again on HBV functional cure rates. I wanted to get your updated thoughts on what you would consider in your practice, it would be impactful over standard of care in terms of functional cure rates that would drive uptake amongst the majority of your patients?

Excellent. So the first question is the easiest. The AASLD guidelines for hepatitis B are currently under revision. So they will 100% be different when they come out. Now will they include reflex testing, I think that that's more challenging. I'm just remembering what we had to do in order to get hepatitis C reflex testing. In the U.S., reflex test go from a screening to a diagnostic and sometimes that's hurdles, and it depends on if you run one sample in-house then we have to send in the second sample outhouse, but these are just logistic things. If the guidelines say that reflex testing is preferred, then that gives an open door to the diagnostic companies to make that a possibility. And so I would say we just have to wait for the guidelines, but they will be different. The second question is probably a little bit harder. You're asking me, is there a line in the sand, where I would think that offering a finite therapy that has functional cure to a patient is something I wouldn't do compared to not do? Like if I can offer you a cure at 29%, is that significantly different than 33%? And I mean I think that's where you'd bring the personalization to the patient. Some patients may not want any -- may want to know that there's no chance for failure and want to stay on something like a nuke. But I think if you can offer surface antigen loss on the finite therapy to a patient, most patients are willing to try that, knowing that your salvage is still going to capture, right? If I fail a finite therapy, and I only had a 20% chance of getting that goal, but I can then just start a nuke and wait for the next treatment option that might come down the pipeline. I'm fine as a patient, especially if I'm a young patient. So I think that this is where engaging patients in these discussions is going to be very helpful because they're not -- these decisions aren't always predictable, but I think you're not burning a bridge by having a low outcome as long as the patient understands the expectations.

This concludes the Q&A session of the call. Thank you for participating, and I'll turn the call back over to Rich.

Thank you all for your interest in Vir and participating in today's call. We continue -- we appreciate your continued support and look forward to providing further updates on our progress in the near future. Operator, this concludes the call. Thank you.

This concludes today's conference call. You may now disconnect.