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 two phase 2 clinical studies: the phase 2 SOLSTICE trial, which is evaluating the safety, tolerability, and efficacy of Tobevibart and elebsiran in 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 alfa in people living with chronic hepatitis B.
For this study, we will be sharing the interim on-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 Vir, 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 five 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 programs is a prime example of this progress. Second, we're 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, our 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 two advanced clinical programs in hepatitis. These 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're 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 three 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 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. The data we're 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. Importantly, no grade III 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 FDA to discuss our path forward, and based on the feedback received and our data, we're 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 poorly 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 five 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 three times the risk of liver-related death and liver cancer compared to those infected with hepatitis B virus alone. Additionally, the healthcare costs for managing hepatitis delta are approximately twice as high annually. These stark contrasts underscore why hepatitis delta is considered the most severe form of viral hepatitis. The accelerated disease progression, the heightened mortality risk, and substantial healthcare burden emphasize the urgent need for effective treatments. 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 delta affects a wide range of people from all walks of life, often in the prime of their lives. We've met young professionals whose careers have been interrupted, parents struggling to care for their families while managing their illness, and individuals from various cultural backgrounds grappling with a 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 a severe and potentially life-threatening condition, many patients and patient advocacy groups remain hopeful and determined. They're 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 the true purpose behind all of our efforts. Now, despite hepatitis delta severity, patients face several critical challenges that compound the difficulty of managing this disease. First and foremost, there are currently no approved treatments for hepatitis delta in the United States and limited options outside of the U.S. Second, we're facing a significant issue of underdiagnosis, 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 drive a significant financial burden. The complex nature of the disease, frequent hospitalizations, and the need for specialized care can lead to substantial healthcare 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 treatments, 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 affects. 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 populations. 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 transplants 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 focused strategy to address the key patient challenges we've outlined. Our approach is built on four 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're committed to ensuring the earliest possible access through payer engagement. We recognize the significant financial implications of hepatitis delta and will proactively work to address access and affordability issues for both patients and healthcare systems. Fourth and finally, we're dedicated to accelerating treatment rates through patient and provider education, where awareness and understanding is low. These priorities demonstrate our comprehensive approach to addressing hepatitis delta. We're 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 two 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, binding, and entry of both HBV and HDV virions into the hepatocytes.
By focusing on surface antigen, we're tackling a crucial step 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. One, it inhibits viral entry, preventing new infections of hepatocytes. Two, it neutralizes and clears both HDV and HBV virions. Three, 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 essential to the assembly and release of new HDV particles.
By combining these two mechanisms, the antibody-mediated action of Tobevibart and 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 three key cohorts. First, we have the Tobevibart monotherapy cohort. This group includes 33 participants receiving 300 milligrams of Tobevibart subcutaneously every two 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 four weeks.
The third cohort is our combination rollover group, comprising non-cirrhotic participants who transition 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 the limit of detection, or at least a two-log decrease in baseline, and ALT normalization at week 24, and safety, incidence of treatment-emergent adverse events. We're also tracking several key secondary endpoints, including the proportion of participants achieving undetectable HDV RNA 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 Tobevibart monotherapy group and 56% in the de novo combination group were 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 two-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 the 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, have 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 benefit 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 show 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 II 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 one and week 24 across both groups. By week 24, approximately 50% of participants in the combination cohort achieved ALT normalization.
While the ALT normalization rates differ between the two 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 virologic and ALT normalization. On the left, we see the protocol-defined endpoint: HDV RNA reduction of at least two 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 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% at 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 non-cirrhotic 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 our 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 two-log decrease in HDV RNA or levels below the limit of detection.
The rollover cohort maintains an impressive 100% response rate through week 60, with all five patients still in the study at that point showing this response. The right graph shows 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 a significant HDV RNA reduction and ALT normalization. At week 24, five out of nine patients met this endpoint.
While the absolute numbers decrease over time due to the smaller number of patients, we see a consistent proportion meeting this endpoint. 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 deep 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 bars 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 2 hepatitis delta data with bulevirtide's phase 3 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 bulevirtide 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 suggest the potential of our approach to advance hepatitis delta treatment options significantly.
Now, 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 three 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 Tobevibart and elebsiran achieved surface antigen values below 10 international units per mL. This suggests our combination therapy is not only suppressing HDV, but also significantly impacting HBV. In contrast, only about 22% of participants receiving Tobevibart monotherapy achieved surface antigen levels below 10 IU/mL at week 24. These results highlight a key advantage of our combination therapy. By targeting surface antigen 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 three cohorts.
The key takeaways of the safety profile across all three treatment groups are: one, most treatment-emergent adverse events were grade I or II, indicating that they were generally mild to moderate in severity. Two, the most common treatment-emergent adverse event was influenza-like illness. Importantly, these symptoms were generally mild to moderate and transient. While there were two discontinuations due to these symptoms in the monotherapy arm, there were no treatment-related discontinuations in the combination therapy cohort. Three, no ALT flares or greater than grade II elevations were observed in any of the treatment groups. These safety results are consistent with what we would hope to see for a chronic therapy. The absence 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 non-cirrhotic participants. From a safety perspective, we've observed that no grade II or higher ALT elevations have 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 3 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've designed three superiority trials, collectively known as the ECLIPSE program, each addressing different patient populations and treatment scenarios. ECLIPSE 1 is our phase 3 trial focusing on hepatitis delta patients in regions where Bulevirtide is not available or use is limited, including the United States. This study will enroll 120 participants randomized two-to-one to receive either our combination therapy or deferred treatment.
Two-thirds of participants will receive our combination therapy immediately, and one-third 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 and ALT normalization at week 48, compared to the deferred treatment group at the end of their deferred treatment period. ECLIPSE 2, also a phase 3 trial, will evaluate switching to our combination therapy in patients who have not adequately responded to bulevirtide. We will enroll 150 participants randomized two-to-one 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 2B trial comparing our combination to bulevirtide in bulevirtide naive patients. We'll enroll 120 patients randomized two-to-one 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 three studies will enroll both non-cirrhotic participants and those with CPT-A 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 that also have delta.
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 virologic replication, they tend to do much better. And so we're using that as a surrogate in hopes that suppressing virus, normalizing ALT will offer that 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 models 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, you know, 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 non-cirrhotic 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 a non-cirrhotic 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 to cirrhosis is going to 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 treatment at an earlier time point, 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 flares. We call those good flares or bad flares, 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 regimens, so we want patients to be adherent. You want something that's not going to be difficult to do.
Some of our therapies that look at daily injections are definitely going to be more problematic. Also, therapies where people can forget. Once-a-month dosing is really preferred because it's easy to remember. Patients are going to not get, you know, are going to be adherent with this. And I don't think that injections are an issue anymore, especially given the widespread use of 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 missed dosing. The last thing is really looking at the forefront of the 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 in 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 phase 2b 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 death. 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, Tobevibart and elebsiran, which you'll see in the MARCH phase 2B 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 a growing understanding in the field that 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 2 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 six months.
We divided these participants into three 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 endpoints for this study focus 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 at 24 weeks post-treatment. In the analysis we're presenting today, we have end-of-treatment data for all participants treated with Tobevibart alone and 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 study: hepatitis B surface antigen loss at the end of treatment. On the left side of the graph, we see the overall HBsAg loss across our three treatment arms in all comers. Here, we observed no HBsAg loss in the Tobevibart monotherapy group. However, in the doublet arm of Tobevibart plus elebsiran, we saw HBsAg loss in 8 out of 51 patients.
In the triplet arm, with the addition of pegylated interferon alpha, we observed S loss in six out of 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 seven out of 18 patients, or 39%, in the doublet arm, and five 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 at this data cut.
For patients with baseline surface antigen 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 milli-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 had the highest rate at 63%, 17 out of 27. The three 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 lines showing those who did achieve S loss. 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 HBV, 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. Two, a key finding is that all six participants in the triplet arm who achieved S loss also developed anti-HBs antibodies. This strong correlation between S loss and anti-HBs development in the triplet arm is particularly noteworthy and suggests a potentially important relationship between these two outcomes, and three, the presence of these antibodies may be important for 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 paying close attention to how these antibody levels correlate with the sustained surface antigen loss and other markers of functional cure. Now, this graph visually reinforces the strong relationship between surface antigen loss and 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 S loss. This also shows the relationship in the doublet arm, where half the patients who achieved S loss also developed 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 two 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 three components of the triplet therapy. It's important to note that both of these events improved without any lasting consequences. With this safety profile in mind, let's now turn to the preliminary overall conclusions. First, we've observed compelling hepatitis B surface antigen loss and anti-HBs development at the end of treatment with our combination therapies. In participants with baseline hepatitis B surface antigen levels below 1,000, we saw S loss in 39% of participants receiving the doublet regimen and 46% of participants receiving the triplet regimen. These rates of S loss in the low baseline group are compelling. Beyond seroclearance, 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 would 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, who 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 number one cause of liver cancer.
And so finding a therapy that has the ability to be finite and as well as decrease 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 outcomes, 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 B 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 going to have a higher rate of this than others. 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 marker, recognizing that worldwide, some places have used quantitative surface antigen more readily than others. We 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 when 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 cure as opposed to someone else who might want to achieve that but is 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're 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 immune-modulating 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 immune disease. It's definitely contraindicated in patients with more advanced cirrhosis. It is a predictable tool. And because of that, we know what to expect, what to monitor for, and how patients are going to do.
So if we take this and we loop back to the MARCH phase IIb trial, noting that in well-selected patients, those that have lower quantitative hepatitis B surface antigen, that you can achieve surface antigen loss in up to 45%, that's really instrumental, really points towards something that might offer a functional cure 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 Tobevibart and elebsiran has shown a promising efficacy and safety profile. This encouraging data has paved the 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's 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're 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 programs underscore our commitment to addressing significant unmet needs in liver disease, and as we look toward the future, I want to revisit our strategy for success in hepatitis delta. Our approach is multifaceted and built upon the priorities I outlined earlier. We're 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 underdiagnosis. A key part of our strategy is to drive awareness of testing in targeted ethnicities 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've shared today brings us closer to this objective. 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're 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 portfolios.
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. Please limit your questions to two per person so that we can get to all of our covering analysts. I'll turn it over to you, Operator. Thank you. At this time, we will begin conducting our analyst Q&A session. For our analysts, please raise your hand to indicate that you would like to join the queue if you have not done so already.
Once you hear the operator announce your name, you can unmute your line and ask your question. Please hold for a moment while we poll for questions. Your first question comes from the line of Paul Choi of Goldman Sachs. Your line is open. Hi. Thank you. Good morning, and thanks for taking our questions. My first question is for either Mark or Dr. Reau, and I was wondering if you could comment on the anti-HBs 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 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 all 50 patients in the triple treatment combination regimen? Thank you very much.
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 S antibody levels, right? So those we believe probably also represent an increased immune response from the patients and not just unmasking. But we really don't have good tools to disentangle the two possibilities, and they're not mutually exclusive.
But we do think in the case of some of the patients that get high titer surface antibody levels, that those probably represent a new immune response on top of whatever endogenous antibodies they may already have had. In terms of the end of treatment data for functional cure, we are going to have those in Q2 of next year. Thank you. Your next question comes from the line of Gina Wang of Barclays. Your line is open. Thank you for taking my questions. Congrats on the data. So I have two questions. The first one is regarding HBV. Getting impressed with curing from both double and triple in HBV patient with antigen less than 1,000 international units per mL, will you be only focusing on this patient population throughout the disease study? And my second question is regarding ECLIPSE II.
Any more color on bulevirtide , which regarding the baseline screening period, would this study design move Vir combo as a second-line therapy in regions where bulevirtide is available? Thank you for your question. So your first question is about the data and whether we intend to focus on surface antigen less than 1,000. As we presented, we do have the strongest data in HBV in terms of the end of treatment responses in the 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 it'll be a data-dependent decision as the data evolve. As you know, we'll note that in the triplet, by chance, we have no patients who have between 1,000 and 3,000 at baseline. So 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 and to provide more color. That is our bulevirtide switch study and bulevirtide experienced patients who have incomplete response and continue to be viremic. So those patients will be either randomized to continued bulevirtide for 24 weeks versus a switch to our regimen. And we will be comparing the target not detected in those two regimens in addition to other endpoints. Thank you. Your next question comes from the line of Roanna Ruiz of Leerink Partners. Your line is open. Hey, morning, everyone.
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 three 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 3, let's say if one of the ECLIPSE trials reads out ahead of another one? Yeah, 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 that bulevirtide is approved in Europe, but not in North America.
So in ECLIPSE I 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 packages we've mentioned, we believe that ECLIPSE I and ECLIPSE II should be adequate for filing. And in terms of the most stringent endpoint, 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 recently received E.U. 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 Mike Ulz of Morgan Stanley. Your line is open. Good morning. Thanks for taking the question.
Maybe just one on hepatitis B and with 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? Thanks. Yeah, 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. We're eagerly anticipating those data. I mean, it is notable that 100% of the triplet patients who cleared surface antigen developed surface antibody, whereas 50% of the doublet with Tobevibart and elebsiran without interferon developed surface antibody.
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, 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 the triple, I think that could be very attractive as well. So I think, again, it'll depend on the data and how they evolve. Dr. Reau, do you want to add anything? Yeah. 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 three and a patient's going to be able to tolerate that, you're certainly going to have that discussion. But some clinicians are going to be very interferon adverse, 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 J.P. Morgan. Your line is open. Hi.
Thanks for taking the questions. Maybe just for Dr. Reau, can you just elaborate on, in chronic hepatitis delta, the importance of ALT normalization as a predictor for liver outcomes, 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, well, 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 want me to take that 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 as a clinician that takes care of patients with viruses, you want to see that virus go away. And if you understand that 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 surrogate 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 a failed 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 show that that does truly reflect lower rates of cancer and lower rates of progression. Yeah, thank you, Dr. Reau.
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%, the majority reach target not detected or complete elimination of the virus. In terms of the composite that includes TND 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 and lower. Whether we're going to continue to see further declines in ALT after week 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 in the combination who have ALT above the 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. Thank you. Your next question comes from the line of Alec Stranahan of Bank of America. Your line is open. Hey, guys. This is Matthew on for Alec. Thanks for taking our question. 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 kinetics sort of what you would expect based on the mechanism of action?
Can we actually see this improve beyond week 60 as well? Then secondly, it looks like the percentage achieving target not detected in ALT normalization and 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. Yeah, thank you very much for your question. 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.
I think it does because the antibody to Tobevibart is blocking surface antigen. It's blocking entry of the virus into hepatocytes, and it's also increasing clearance of virions and subviral particles, whereas elebsiran as an siRNA is knocking down all of the HBV viral transcripts, including surface antigen. I think that we're seeing kind of a synergistic response between the two 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, the longer we go, the longer we're seeing the higher the proportion responses that we're getting. I think we'll just have to see how those data evolve. Then your question around the week 24 ALT plus TND at week 24 and the TND rate at week 24 versus the EASL update.
I mean, I think what we 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 ECLIPSE update. I think we're seeing relatively small numbers. I wouldn't say there's any actual drop that's significant. It's just within the small numbers. So we're seeing, for example, 41% TND 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. Your line is open. Good morning. Two questions from us.
First, in terms of the regimen in HDV, it does seem like maybe the siRNA is leading to somewhat elevated ALT levels over the long term versus what monotherapy has been producing. Would you consider looking at an induction regimen with the siRNA and then a maintenance regimen with the 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? Thanks. Yeah. 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 number one. Point number two is we are, as Dr.
Reau said, and as we've reemphasized, this is a viral disease. So knocking the Delta virus down to undetectable is really the most important goal. In terms of whether or not it's an siRNA, elebsiran drug effect, it is a possibility. I mean, certainly siRNAs have been associated with some ALT elevations in both the J&J REEF-D 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, yeah, 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 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 & Co. Your line is open. Thanks. Good morning and 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 II relative to ECLIPSE I? 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. And 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? Thanks. 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 or more difficult population. We really don't think so. I mean, first of all, the majority of patients at one year treated with bulevirtide, only 12% achieve 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 appear 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 II trial, which are, as you alluded to, bulevirtide incomplete 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 cure, 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, 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 have an option that is an easy-to-apply algorithm, that's going to be very successful. Yeah. Thank you. Thank you. Thank you. And your last question comes from the line of Joseph Stringer of Needham & Company. Your line is open. Hi. Thanks for taking our questions. 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?
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 that would be impactful over standard of care in terms of functional cure rates that would drive uptake among 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 tests go from a screening to a diagnostic. And sometimes that's hurdles. And it depends on if you run one sample in-house and you have to send the second sample out of house.
But these are just logistics 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 would do compared to not do? 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 Nuc.
But I think if you can offer surface antigen loss and a 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 Nuc 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 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 for participating in today's call. 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.