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

Hello, and welcome to the Vir Biotechnology's investor conference call to discuss the results from the Phase II SOLSTICE. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the company's website at the conclusion of the event. I will now turn the call over to Richard Lepke, Senior Director of Investor Relations. You may begin, Mr. Lepke.

Thank you, Sarah, and hello, everyone. Welcome to Vir Biotechnology's investor conference call to discuss the preliminary results from the Phase II SOLSTICE trial in people living with chronic hepatitis delta. I'm Richard Lepke, Senior Director of Investor Relations at Vir Biotechnology. 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 law. 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. Joining me today from Vir Biotechnology are Dr. Marianne De Backer, our Chief Executive Officer; Dr. Carey Hwang, our Senior Vice President of Clinical Research. We are also honored to have 2 renowned hepatologists with us today, Dr. Tarik Asselah and Dr. Nancy Reau. Dr. Asselah is the lead investigator for the SOLSTICE trial. Marianne will begin the call with opening remarks. Dr. Asselah will then provide a summary of the interim Phase II SOLSTICE trial data and its implications for the treatment of chronic hepatitis delta. Following Dr. Asselah's presentation, Carey will discuss the conclusions and next steps for clinical development of tobevibart and elebsiran in hepatitis delta. Dr. Reau will then share her perspective on the unmet medical need in hepatitis delta and the potential impact of these findings on clinical practice in the United States. Finally, Marianne will provide closing remarks before we open the line for questions. I would like to now turn the call over to Marianne. Please go ahead.

Hello, everyone, and thank you for joining us today. I'm excited to share some of the remarkable progress we have made in pursuing our vision of powering the immune system to transform lives. And before we dive into the preliminary results from our SOLSTICE trial, which is evaluating the safety, tolerability and efficacy of tobevibart and elebsiran in people living with chronic hepatitis delta, I'd like to provide an overview of our core scientific capabilities and address the significance of the data we are sharing with you today. At Vir, we are committed to making our vision a reality by focusing on infectious diseases, bio-associated diseases and immune targeting in both infectious disease and oncology. Our approach is to leverage the immense potential of the immune system to develop innovative therapies that can significantly improve patient outcomes and address critical unmet medical needs. To achieve this, we have built a strong foundation based on 4 core scientific capabilities that are cutting-edge and set us apart in the industry. First, we have discovered an engineered unique novel monoclonal antibodies, which formed the foundation of our innovative therapies. Second, we have assembled a world-class team of experts in both immunology and virology who bring unparalleled knowledge and experience to our R&D efforts. Third, we leveraged leading machine learning and artificial intelligence capabilities to accelerate our drug discovery process and identify the most promising candidates. And finally, fourth, our core capabilities also our ability to rapidly advance pipeline candidates, furthering our mission to bring life-changing treatments to patients as quickly as we can. These core scientific capabilities have enabled us to make significant strides in the field of infectious disease, and we are now strategically expanding our focus beyond this area. We are applying our expertise to viral-associated diseases, recognizing the immense potential of our science to address these critical health challenges. Furthermore, we are venturing into immune targeting for both infectious disease and oncology, leveraging, again, our deep understanding of the immune system to develop novel therapies that can transform patient outcomes. A prime example of how we are applying our core scientific capabilities to address a critical unmet need is our work in chronic hepatitis delta, the most severe form of viral hepatitis. Hepatitis delta affects millions of people worldwide with at least 12 million people living with the virus globally. We estimate that there are approximately 100,000 patients in United States and approximately 200,000 patients in Europe. And despite the devastating impact of this disease, there is currently no approved therapy available in the United States, leaving patients with truly limited options and a dire need for effective treatments. Furthermore, the economic burden of hepatitis delta virus is substantially higher compared to hepatitis B, placing a significant strain on health care systems and society. The lack of approved therapies in United States further compounds this challenge, leaving patients and their families to bear the brunt of this devastating disease. Now, it is important to understand the unique biology of hepatitis delta and the severe clinical outcomes associated with this chronic infection. Specifically, the hepatitis B surface antigen is the key viral protein responsible for recognition, binding and entry of both hepatitis B virus and hepatitis delta virus particles into liver cells. As a result, hepatitis delta virus infection occurs as a co-infection with hepatitis B virus, leading to a more aggressive and rapidly progressing form of liver disease. Compared to chronic hepatitis B alone, people living with hepatitis delta face a significantly higher risk of irreversible liver damage and life-threatening complications. The clinical outcomes of chronic hepatitis delta are alarming with patients being twice as likely to die from the disease compared with those with chronic hepatitis B alone. In fact, more than 50% of hepatitis delta patients die within 10 years of diagnosis, truly highlighting the rapid progression and severity of this devastating illness. Moreover, a staggering 41% of hepatitis delta patients develop cirrhosis with an average progression time of only 5 years. Additionally, hepatitis delta patients have a 4x greater risk of developing hepatocellular carcinoma, with an average progression time of just 10 years from diagnosis. These statistics highlight the urgent need for effective treatments that can halt the progression of liver disease and improve patient outcomes. Our approach here at Vir to address this critical unmet need is through a multifaceted strategy, involving entry inhibition, neutralization of hepatitis delta and hepatitis B virions and a dual knockdown of hepatitis B surface antigen with tobevibart and elebsiran, potentially with a dosing regimen of just 1 or 2 times per month. Tobevibart, in addition to inhibiting viral entry, also neutralizes both HDV and HPV virions, preventing them from infecting new hepatocytes. And by targeting hepatitis B surface antigen and the entry mechanism, we aim to achieve a truly transformative level of viral suppression. Simultaneously, elebsiran works to reduce the production of hepatitis B surface antigen, which is essential for the assembly and release of new HDV particles. By targeting different aspects of the viral life cycle, tobevibart and elebsiran have the potential to work together to suppress the hepatitis delta virus. Additionally, tobevibart, our antibody, has been engineered to potentially enhance T cell activation by delivering hepatitis B surface antigen to antigen presenting cells, which may enhance the immune system's ability to recognize and eliminate infected hepatocytes. Our goal is to offer patients a safe and highly efficacious therapy that can significantly improve their quality of life and long-term outcomes and establish market leadership in the treatment of hepatitis delta. The data that we are presenting today represent a significant milestone in our journey to address this deadly disease and bring hope to those affected by it. Our unwavering commitment to scientific excellence, coupled with our core scientific capabilities, has brought us to this pivotal moment, and we are excited to share the details of progress with you. To provide further insights into the preliminary Phase II SOLSTICE trial data, I would like to introduce Dr. Tarik Asselah, a renowned expert in the field of hepatology and viral hepatitis. Dr. Asselah will expand on the preliminary trial results and their significance. He will also be presenting this data in more detail at an oral presentation at the EASL Congress on Saturday, June 8. Dr. Asselah, the floor is yours.

Thank you, Marianne. It's a pleasure to be here today, and I'm excited to summarize the impressive preliminary results from this Phase II SOLSTICE trial. The Phase II SOLSTICE trial is evaluating the efficacy and safety of tobevibart alone or in combination with elebsiran in participants with chronic hepatitis delta virus infection, including both non-cirrhotic and compensated cirrhotic individuals. Let's take a closer look at the SOLSTICE study design. We will focus on 3 courts that will evaluate at least 96 weeks of treatment. First, the combination rollover cohort consists of 6 total overall participants, 4 of which transitioned from tobevibart monotherapy lead-in and 2 from elebsiran monotherapy leg after not meeting RNA and ALT classified criteria at week 12. While 6 participants in these cohorts are non-cirrhotic and the dosing frequency is once every 4 weeks. These 6 patients are the same participants that were reported on the last EASL Liver meeting in 2023. Second, de novo combination cohort is receiving tobevibart and elebsiran with 32 enrolled participants and a dosing frequency of once every 4 weeks. Third, the tobevibart monotherapy cohort consists of 33 enrolled participants with a dosing frequency of once and every 2 weeks. Both the de novo combination and monotherapy cohorts and all participants with non-cirrhotic and compensated cirrhotic with Child-Pugh A. Across all regimens, the dose of tobevibart 300 milligrams and elebsiran 200 milligrams, both administered through separately formulated subcutaneous injections. Now I will summarize the SOLSTICE trial endpoints and participant criteria. The partnering endpoint of the said include: first, the safety of tobevibart and elebsiran as assessed by the proportion of participants experiencing treatment-emergent adverse events and serious adverse events. Second, the efficacy of the treatment evaluated using a combined endpoints of virological response and ALT normalization at week 24. Virologic response is defined as achieving RNA less than the limit of detection or at least a 2 log decrease from baseline, indicating a significant reduction in viral LOD. ALT normalization, defined as ALT levels below the pyramid of normal is a biochemical marker associated with improved liver function. In addition to the primary endpoints, the trial also includes key selected endpoints, such as the proportion of participants to achieve undetectable hepatitis delta virus RNA, measured as less than the limit of the detection, or LOD, less than the lower limit of quantification, LLOQ, and whether participants achieve target not detect, or TND, which indicate there is no measure or presence of HDV currently. This is a very important endpoint, target not detected. To be eligible for the SOLSTICE trial, participants had to meet specific criteria, adults with chronic delta infections, who were either not cirrhotic or have composite cirrhosis. Additionally, all participants were required to be on next therapy for heading for at least 12 weeks earlier to [indiscernible]. I'd like now to briefly describe the participant dispositions for de novo combination and monotherapy cohorts as the May 2024 direct. We have 32 participants who are in the match of de novo combination cohorts and 33 randomized to the monotherapy cohort. On the slide, you can see, the participant numbers for those who had completed 12 and 24 weeks of therapy, which is also broken out for cirrhotic patients. There have not been any treatment-related discontinuations in the de novo combination cohort to date. In the monotherapy cohort, there were 2 treatment-related discontinuation and 2 participants who withdraw consent to participate in the trial, which were not treatment related. Demographics and baseline characteristics are generally well balanced across these cohorts. Of note, around half of participants in the monotherapy and de novo combination cohorts have Child-Pugh A cirrhosis, the compensated cirrhosis. However, to the timing in enrollment, the proportion of participants with compensated cirrhosis were completed at least week 12 of treatment is over as of the time of the [indiscernible]. In this slide, we summarize the extended follow-up of the 6 participants in the combination rollover. At the time of analysis, all the 6 participants remain on therapy, 5 of the 6 had completed 48 weeks of combination therapy, and 1 participant had completed 40 weeks of combination therapy. At the time of the analysis, all participants demonstrate sustained biological response, 6 of 6 achieved RNA below the lower limit of quantification, 5 of 6 achieved RNA below the limit of detection, and 5 of 6 achieved RNA target not detected, TND. 3 of the 6 participants achieved anti-normalization. There was no serious adverse events have occurred to date and the majority of adverse events were transient and Grade I or II. Let's now look to the next slide, which highlights the high rates of virological suppression and ALT normalization rates observed with de novo, tobevibart and elebsiran combination throughout. The graph on the left side, demonstrate the rapid biological response achieved with this combination drug. As you can see, a substantial proportion of participants experienced a swift decline in RNA level, with men achieving biological separation below the lower limit of quantification as early as week 12. Furthermore, by week 24, greater than 50% of participants had attended virological endpoint called target not detected. This means there were no detectable HDV RNA in these patients. This shows the potent antiviral activity of this combination. Notably, while small numbers at this time point, the virological suppression was similar in participants with and without cirrhosis in de novo combination therapy cohort. This early signal suggests that the viral suppression of this combination therapy may be maintained across different stage of liver disease, which is particularly encouraging for patients in more advanced hepatitis delta. Moving to the graph in the center of the slide, we can observe the ALT normalization rates. In participants receiving de novo, tobevibart and elebsiran combination therapy, the data presented here demonstrated a significant proportion of participants achieved an organization by week 24, and the rate of normalization increases over time. Moving to the table on the right, we can see the detailed virological and biochemical response rate at week 12 and 24. At week 12, among the 27 participants, all 27 had a virological response and 14 HDV RNA levels below the lower limit of quantification, 10 below the limit of detection, 4 target not detected, 12 achieved ALT normalization and 12 achieved the combined endpoints. At week 24, among the 11 participants where data was available, only they can achieve virological response and achieved HDV RNA levels, below the lower limit of quantification, 10 below the limit of detection, 6 target not detected and 7 ALT normalization and 7 achieved these combined endpoint. Let's now treat our focus with preliminary virological suppression and ALT normalization rates observed with tobevibart monotherapy. You can see the graph on the left side, with high rates of virological response achieved with tobevibart monotherapy. As you can see, a notable proportion of participants experienced a marked decline in HDV RNA levels, with mainly achieving virologic suppression below the lower limit of quantification by week 24. Although the virological response rates are slightly lower compared to the combination therapy cohort, these findings nonetheless demonstrate antiviral activity of tobevibart as monotherapy. Moving to the graph in the center, you can see the ALT normalization rate in participants receiving tobevibart monotherapy, the data presented here shows that they consider our proportions of participants achieved this ALT normalization by week 24 and this also increased over time. Moving to the table on your right, we can see the dictates, virological and biochemical response at week 12 and 24. At week 12, among the 26 participants who reached this time, 19 had a virological response, 7 HDV RNA levels below the lower limit of quantification, 5 below the limit of detection, 2 achieved target not detected, 14 achieved ALT normalization and 10 achieve the combined endpoint. At week 24, we had data for 11 participants, 6 had a virological response, 6 HDV RNA below the lower limit of quantification, 5 below the limit of detection, 2 target not detect, and 7 achieved ALT normalization and 6 achieved the combined endpoint. It's important to note that these response rates are reported as ITT basis and include 4 participants for discontinued treatment, 2 due to adverse events, and 2 [indiscernible]. Additionally, due to the limited number of compensated cirrhotic participants receiving tobevibart monotherapy through week 24, we did that comparing non-cirrhotic and cirrhotics in this treatment time is not meaningful at this time. So we have to wait for the full level. Now let's turn our attention to the preliminary safety and tolerability summary from the SOLSTICE trial, which is summarized on this slide. I'm pleased to report that there were no ALT flares were observed in participants receiving tobevibart alone, or in combination with elebsiran. This finding is particularly encouraging as ALT flares can be a concern with some therapies for viral hepatitis and mainly get acute liver intervention. Notably, there was no treatment related serious adverse events related to tobevibart alone or in combination with elebsiran have been observed in this study to date. The majority of adverse events observed in the study were Grade I and II in severity and transient in nature with a low incidence of injection site reactions. The most common adverse events reported were influenza-like illness, chills, arthralgia, myalgias and pyrexia. These symptoms were typically reported within 24 hours of the first dose, and usually resolved within 48 hours. This pattern of adverse event is not in common with immune modulatory therapies and [indiscernible] that these symptoms may be related to the initial immune response to the treatment. Furthermore, the study has high treatment continuation rates, with only 2 participants receiving tobevibart monotherapy having discontinued treatment due to the numbers. In conclusion, ladies and gentlemen, the preliminary results from this Phase II SOLSTICE trial provide highly encouraging evidence for the tolerability and antiviral activity of both tobevibart monotherapy and tobevibart and elebsiran combination therapy in participants with chronic hepatitis delta, including those with compensated cirrhosis. Durable HDV RNA virologic suppression was observed for participants who received tobevibart and elebsiran combination therapy in the rollover cohort suggesting the potential for sustained antiviral activity with this reason. One of the key findings from the data to date is that de novo combination therapy achieved a substantial and rapid decline in virus RNA. This level of viral suppression suggests the potential of this combination approach to improve treatment outcomes for chronic hepatitis delta. Importantly, rates of ALT normalization increased from week 12 to 24, with more than 50% of participants achieving normalization at week 24 in both the tobevibart monotherapy and do novo combination cohorts. No treatment-related serious adverse events have been reported to date and the majority of adverse events were transient in Grade I and II of severity. Another important observation is the excess of ALT flares with tobevibart alone or in combination with elebsiran regardless of basilar HBV surface antigen for hepatitis delta virus, RNA. The SOLSTICE trial, also demonstrates similar rates of virological suppression and ALT normalization in non-cirrhotic and compensated cirrhotic participants in de novo combination treatment regimens in this initial data to week 24. Of course, we will have to wait that final level. In summary, these preliminary results from the Phase II SOLSTICE trial represent a very important milestone in the development of potential effective therapies for chronic hepatitis delta. The antiviral activity, tolerability profile and high rates of virological suppression across different stage of liver disease observed with tobevibart and elebsiran therapy, bring us closer to addressing this urgent unmet need in this patient population. The data is gathered and analyzed from this trial. This will support our shared commitment by advancing the scientific understanding of chronic hepatitis delta and translating these findings into meaningful improvement in patient care. The future of chronic hepatitis delta treatment looks promising, and I'm very excited to be part of the journey toward transforming the lives of those affected by this devastating disease. Thank you. And now I will turn to Carey. Carey, please?

Thank you, Dr. Asselah for that comprehensive overview of the preliminary results from the Phase II SOLSTICE trial. I would like to take a moment to discuss Vir's perspective on these findings and our plans for the future development of tobevibart and elebsiran. First and foremost, we are incredibly excited and encouraged by the data presented today. The results strongly suggest that either tobevibart and elebsiran in combination or tobevibart as monotherapy has the potential to become an important treatment option for the many patients in need of effective therapies for chronic hepatitis delta. I would like to quickly highlight a few key takeaways from the preliminary data that we find particularly compelling. First, sustained HDV RNA virologic suppression was observed for participants who received tobevibart and elebsiran combination therapy in the rollover cohort, suggesting the potential for durable antiviral activity with this regimen. Second, high rates of virologic suppression were achieved in participants receiving tobevibart alone or in combination with elebsiran with more than 50% achieving target not detected HDV RNA in the de novo combination cohort. Achieving TMD is a particularly impressive virologic milestone and underscores the potent antiviral activity of these investigational agents. Third, rates of ALT normalization increased from week 12 to 24, with more than 50% of participants achieving normalization at week 24 in both the tobevibart monotherapy and de novo combination cohorts. Fourth, no treatment-related serious adverse events or ALT flares have occurred to date regardless of baseline hepatitis B surface antigen or hepatitis delta virus RNA levels, and the majority of adverse events were transient in Grade I or II in severity, which is encouraging. Finally, while in small numbers, similar rates of virologic suppression and ALT normalization at week 24 were observed in participants who are noncirrhotic and those who have compensated cirrhosis in the de novo tobevibart and elebsiran cohort. This consistency seen in this interim data cut across different stages of liver disease is promising and suggests the potential applicability of this combination in a broader patient population. Moving forward, we are working with a great sense of urgency to continue making progress in advancing the [indiscernible] of tobevibart and elebsiran. We recognized a critical unmet need in hepatitis delta and are fully committed to seeking an expedited drug development process to bring much needed treatments to patients as quickly as possible. We are eager to engage with regulatory authorities in the third quarter of this year to discuss the next steps for the development program. We anticipate that the next trial will use the liver titer as a comparator, and we look forward to aligning the clinical development plan with health authorities. Additionally, we will explore all available acceleration pathways such as fast track, prime, orphan drug and breakthrough therapy designations, and we are acting with great urgency to prepare and move forward as rapidly as possible. In the fourth quarter of this year, we are excited to share complete data for approximately 30 participants per regimen at the 24-week time point. This additional data will provide further insights into the efficacy and safety profile of tobevibart and elebsiran and inform our future development plans. Overall, we have a strong conviction that tobevibart and elebsiran represent a potentially transformative future treatment option for the millions of patients in need. With that, I would like to hand the call over to Dr. Nancy Reau, who will provide her valuable perspective on the unmet need in hepatitis delta and the potential impact of these findings on clinical practice in the United States. Dr. Reau, over to you.

Thank you so much, Carey, and thank you for allowing me to offer my perspective to this really powerful story. For context, I am a clinician in the United States, but specifically in Chicago, Illinois, and Illinois is a hotspot for delta. There's no map that you can pull up where Illinois is not a bright spot. So that gives me significant first-hand experience into the unmet need for delta. First, the unmet need is multifactorial. First, we do not have adequate screening guidelines. So we do hope that the United States, and as they revamp the hepatitis B screening guidelines become more in line with WHO and EASL, where there is a strong trigger to screen everyone who has hep B surface antigen for delta, although it is uncommon. It is a devastating disease, as Marianne already pointed out, and our patients do have very rapidly progressed to cirrhosis, liver cancer. And without that reflex testing or that more universal testing of people with hepatitis B, we're not buying the subset that's impacted with delta also. My own personal experience is very much in line with the data that was given. Most of the patients with compensated cirrhosis are young. That was necessarily presented in what we went over, but when you look at the data set, this cirrhotic population is a younger population than people with hepatitis B viral infection. And we see that because these young individuals that were asymptomatic, present with devastating decompensated cirrhosis or newly diagnosed liver cancer, and they are young population that's working, have families, and so this is incredibly impactful, not on just that patient, but the family and the society and the health care utilization. I think though that when you have effective therapy, there's precedent that will change the entire care cascade in the paradigm. We saw that hepatitis C where, although we had very effective treatments, they have toxicity and were not universally effective. And so when we had no oral treatment that really led to a seismic shift in how we recommended for now near universal screening and application of therapy. So before we might have withheld treatment, now we will have treatment that's efficacious, it really affected every point on the care cascade from identifying to offering treatment. I believe that same paradigm shift happen in hepatitis B and delta when you have an effective treatment because applying that treatment at an earlier time point will really potentially save these individuals from a significant consequence and that will shift the entire paradigm. I think that the data that was just presented is a window into this shift. We definitely look forward to the full data set to longer, not just preliminary results, but this presented data is very, very encouraging. And I think gives all of us, from a clinical side and a patient perspective, a window into incredible enthusiasm because this really gives an opportunity for us to see a curative path, a suppressive path to this very high risk patient population. I look forward to answering your questions as we go forward, but we'll turn it back over to Marianne.

Thank you so much, Nancy. Those are really valuable insights and truly appreciate your perspective on the unmet need in chronic hepatitis delta and then the potential impact of our investigational treatments. So the data presented today mark a significant milestone in our journey to address this devastating disease. The preliminary results from our Phase II SOLSTICE trial, as summarized here on this slide, underscore the potential of tobevibart and elebsiran to become a truly transformative treatment option for people living with this disease. We have observed impressive early efficacy signals across treatment regimens and patient populations. And these results are a testament also to really the dedication and the expertise of our team here at Vir. Looking ahead, we are committed to expediting the drug development process and engaging with regulatory authorities to discuss the next steps of our program. And our goal is to bring an innovative treatment to patients as quickly as possible, addressing a significant unmet need in hepatitis delta. I do want to express my gratitude to the participants in our clinical trials, the clinical trial investigators and our dedicated employees who have made all this progress possible. Together, we stand at the forefront of a potential breakthrough in the fight against hepatitis delta, and we will not rest until we have delivered a safe and efficacious therapy to dose who need it most. Thank you for your continued support and believe in our mission. We look forward to keeping you updated on our progress as we work tirelessly to transform the lives of patients worldwide. I will now turn the call back to Rich.

[Operator Instructions]. I'll turn it over to you, Sarah.

[Operator Instructions] So our first question comes from Gena Wang at Barclays.

Can you hear my voice? Can you hear me?

Yes.

Perfect. Congrats on the data. So I have 2 questions. I think first, regarding actually surprisingly for the monotherapy, when we look at the combined endpoint, it did show encouraging 55% response rate at the 24 weeks. So wondering could that be also a potential choice and more for the doctors, like what kind of clinical profiles you will be looking for in order to be clinically meaningful? And then second question is for the companies regarding, say, future pivotal study design. Will you be aiming for fixed treatment duration? Or will you be looking for in the long term will be continuous dosing for the treatment?

Thank you so much for that question, Gena. So maybe we will start with Dr. Asselah to give his perspective on your question.

Yes. Thank you for your questions. So as you know, the monotherapy and the combination therapy, so the end we are looking for, of course, viral efficacy with this virological decrease and target not detected. And we are looking for biochemical response, ALT normalization. So you raised the point that with monotherapy, we have many patients to achieve this ALT normalization, which is a good signal. And I think that, today, still, we don't have the full data. So before to privilege the combination of the monotherapy, we will have to wait for the full data. But all this data optimizing encouraging and as clinicians, we like to have patients with normal transaminase, which is associated with less inflammation, which will need long-term data and the full picture before taking any decision.

I absolutely agree. I think when you're a clinician, you want to have something measurable and measuring a virus that goes away is very encouraging for both the patient and the persons who have been in front of the patient. And ALT normalization is a surrogate for inflammation and should result in decreased risk for complications of liver cancer rates. But I think that ultimately, you need the full data set. You need to show that the majority of the patients will achieve these 2 endpoints and that there will be durable response.

Okay. And then maybe on the future bi-frontal study, Carey, could you may be come on?

Yes, Gena, your question was around whether we have a fixed timing for dosing or we would be going chronic treatment. And so I mean, we're really encouraged by the high virologic rates of suppression that we're seeing with both tobevibart and elebsiran in the SOLSTICE trial. So our current focus really is developing a safe and effective chronic suppressive therapy for patients. Obviously, hepatitis delta is complex and challenging. However, at this stage, our priority is still to address this current urgent unmet need for this kind of chronic suppression. And if there's further data that comes about in terms of looking for potential of [indiscernible], then that could be explored in the future, but our focus right now is on a chronic suppressive therapy.

The next question comes from Roanna Ruiz at Leerink.

So I wanted to ask about the 2 patients who discontinued. I think you mentioned that it was not drug related, but could you just clarify what arms those discontinuations happened in? And what were the specific reasons behind discontinuation?

Yes. Thank you, Roanna.

Yes. So those discontinuations were from the tobevibart monotherapy arm. So there are 2 participants who are discontinued due to adverse events, and these were the flu-like symptoms that they experienced. And then we had 2 other participants who withdrew the study just from withdrawing consent, but not due to adverse events.

Okay. Helpful. And also, we've heard from KOLs that there can be somewhat of a lag for ALT normalization happening after you start to see viral RNA approaching undetectable levels. I was curious maybe a little bit for the KOLs as well, how much more time do you think is needed to possibly maximize the number of patients achieving ALT normalization with the combo regimen?

I think that when you start the treatment, early on treatments and you decrease viral load, you can have associated an immune response with clearance of hepatocyte. So that -- why -- that could be a disconnection between RNA decrease and still not normalization of ALT. So I think normalization of ALT is more a long-term benefit that would be interesting. I think in the beginning, it's very difficult to interpret patients with not normal ALT with a decrease in RNA. So I think we will also have to have the full picture of all the data, but I think we should not over interpret the fact that some patients have not normal ALT, they can have a good immune response by giving infected hepatocytes.

To support that, we -- as a person sitting there caring the patients, you want to see the virus go away. And if the ALT lags, that's okay. And I think that one of the most important things is you did not have ALT flares. So those are sometimes good or sometimes bad, but they're always scary for the clinician and the patient. And if you ended up with great virologic endpoints without any risk of flare, which is what this has shown so far, I think that we will tolerate a lag in ALT normalization because we know it will come eventually.

The next question comes from Phil Nadeau at Cowen.

So another one on ALT normalization versus viral reduction. It does seem like there's a greater reduction for the combo regimens, but ALT normalization seems similar between the combo and monotherapy. We're curious to hear if the company or the KOLs have any thoughts as to why that would be. And then second, the virologic response wasn't different between the cirrhotic and non-cirrhotic patients. Is there any difference in side effect profile between those 2 groups?

Just to start and for just comprehension, when you add snRNA in the combo, you reduce S-antigen production from the virus, and you may restore the unity and get hepatocyte. So it's why in the beginning, you can have an increase in ALT with the reduction in viral load. So I think that it's very complex, and so I think that there are multi-factors to understand, so it's why we have. I think we have also to remember that it's not the full picture. So we will have to interpret the data with all the patients treated. But definitely on treatment, I think that transaminase not decrease is not very important because there's many explanation.

I also think it's important. These numbers are still small. We'd love to see trends. But when you have maybe 200 patients in each arm, you will have a more solid understanding of whether combination therapy has a lag in ALT normalization versus monotherapy. But ultimately, it's really sustained virological suppression that we think will then to best outcome, and that's what I would concentrate on. Now you don't want to have dangerous side effects or flares and you don't have that with this. So I think everything looks very encouraging. To also emphasize the fact that you do not see an increase in adverse events and you see equal efficacy in a competitive cirrhotic population, is really important. Given delta milieu, most of these individuals that come into studies are going to have more advanced disease, and so it's really important to have efficacy and safety in these more advanced patients.

I think another comment is just when you see the decrease in viral load for cirrhotic and non-cirrhotics, you see that efficacy is very similar. So efficacity remains very high in cirrhotic. We will need to have the full picture. So I think it's very important to see that this virological efficacy is so strong.

And yes, Phil, this is Carey. Yes, in terms of the safety profile between the cirrhotics and non-cirrhotics, we haven't seen any difference to date early on right now. So that's encouraging as well.

And the cirrhotic population is relatively large. It's almost half of the patient population. So it's not like you have 2 token cirrhotics.

Yes. And just one thing that people don't always understand is that cirrhotic patients, even if they kick the virus, they can have baseline ALT per the limit of normal, and it's maintained. ALT can be also higher the permit of normal with overweight with other medications with the inflammations. So I think with alcohol. So I think that patient with cirrhosis, I think we should really look for the RNA and detectability.

The next question comes from Paul Choi at Goldman.

Can you hear me?

Yes.

Okay. Great. I want to ask the KOLs, just their thoughts on partial responders, potentially changing to full responders on the aggregate endpoint. And just your thoughts on contextualizing that versus the historical bloveratide data? And my second question is just on safety. It seems like in the appendix, influenza or flu-like symptoms for the primary or most common adverse event. Could you maybe just talk a little bit to the severity and whether this is an on mechanism result? And just how quickly does it resolve? Thank you very much.

Yes, so for the partial responders, I think what is most important is to wait for 1 year if the partial responders become responders. Because for a long-term disease like chronic viral hepatitis, the most important is after 1 year to be maintained and durable with normal. So if it's not reached at week 24 or earlier, but it's if it is rich after 1 year, it's a good result. So for partial responders, this is the predictor of good response in the long term. It's 1 year or so with the monoclonal antibody, we could have a good response. And the second question?

On safety and testing.

So when you start treatment, all these side effects about the influenza-like symptoms, early in treatment, and they are transient and they are Grade I. And it could be also factors associated with inflammation, immune response. We don't know the exact mechanism, but they're in mind and they arrived early and they're transient. So for the patient in our hands, it was okay. It was favorable. We need for safety, of course, the full picture.

Any comments on the partial?

I mean, I think that you get nervous when you see ongoing replication in the face of treatment, but that's because our paradigm was with a different mechanism. The mechanism of action is not going to be something where we worry about resistance. And so if it takes a little time for you to have full virologic suppression, especially in patients that have compensated cirrhosis or even potentially more decompensated cirrhosis, it's okay. As a clinician, we're fine with that. We just need to have measurable endpoints and now when you have reached true utility and I think right now, this data is too preliminary.

Yes. And Paul, to your question around kind of the timing of the flu-like symptoms, majority of these occurred after the first dose and then resolved within 48 hours. These were transient Grade I or II. And then after subsequent doses, participants did not really have these symptoms. So I think that could be related to these participants having high baseline surface antigen levels. Patients that have delta have higher baseline surface antigen levels compared to just HBV mono-affected patients. And so if you're giving the antibody and having immune complexes buying, sometimes that can give you that inflammatory type of a response. And then once you get that surface antigen down, you don't get that -- get those types of symptoms, and that's what we've observed so far to date in the trial.

And as long as patients know what to expect, they're going to be able to tolerate therapy. And so it's really just preparing them appropriately and -- about how long they would have these symptoms for them to be able to get through it.

And also injection site reactions are really hard. So I think it's interesting to notice that there were very few injection site reactions, just to mention.

The next question comes from Mike Ulz at Morgan Stanley.

Maybe just a follow-up on the Phase III trial design. If you can give us maybe some updated thinking there may be, in terms of patient numbers, what's the thinking on duration? And it sounds like you may be considering including a monotherapy arm as well. Maybe you can just clarify that?

Yes. So we're going to have discussions with the regulatory authorities later this year, as we've said, to align on a development program. We will be using the liver tide as a comparator for the trial. According to the guidance, they want to see 48-week data, both from a virologic and biochemical response in terms of ALT normalization. Obviously, we feel this data is strong, and so we will have dialogue and get that alignment, hopefully, later this year. But I think it's too early to comment about specifics around the trial design and others until we have those further discussions.

And the thought on the monotherapy or not? Or is that still sort of in debate?

Yes. So I think -- yes, so we will be looking at both the combination data and the monotherapy data as a whole and looking at efficacy, safety as well as other potential factors to determine, which regimen we would potentially take forward. And that would also be with discussions with the regulatory authorities as well.

The next question is from Alec Stranahan at Bank of America.

Just a couple from us. I didn't see this in the presentation, but how has cohort 4 from the study performed to date prior to crossover? Anything to share here? Or will this come more maybe in the 4Q or the fuller update? And as a follow-up to that, is there any historical control study you expect may form the basis for FDA's review or part of the discussion, or you think might be an appropriate comparator to SOLSTICE just to put the data in context?

Yes. Thank you for your questions. So for the design of the study, there was the first 6 patients who had the leading phase with monotherapy and the rollover to the combination. So it was 1 part. And there was 2 de novo, 1 combination treatment and 1 monotherapy. So we present the results for these reports, we have no cohorts number 4. So sorry, if I was not directed. So this is the design of the study. And according to historical comparison, it's very difficult because it's a rare disease. There's not so many cohorts available. There's fluctuation from one patient to another. So I think it will be very difficult to have historical cohorts to compare. But what we know is that we see this very impressive biological efficacy. And we know that with that treatment, there's this no virological efficacy.

The next question comes from Joey Stringer at Needham.

Question for the KOL position. You mentioned there's no adequate screening guidelines in the U.S. and you also mentioned that the emergence of an effective therapy could be a catalyst for chain. So wondering if you could maybe elaborate more on that. What specifically needs to change? And maybe walk us through the process in terms of how soon you think guidelines could change if there was a new effective therapy out there? How do you see this playing now?

Perfect. So I think there are 2 things that are necessary from a guideline perspective. The first is universal screening in a hepatitis B surface antigen population. So that's the lowest hanging fruit, which means that every person who is identified as having hep B should be screened for delta. Ideally, you'd like to see that as a reflex test so that when you get the hepatitis B surface antigen and it's positive, it was done as a screening study and it was positive, the lab would just automatically then go to delta testing. So that's a little bit harder, whereas precedent, happens with hepatitis C, but it is a little bit harder and surface antigen testing is used differently than hep C antibody testing. And so at the regulatory and lab levels that one might be a little bit more difficult of a task, but there is precedent. As to how soon it can be, it's not going to be fully dependent on a treatment. I think just the suggestion that we have therapies is enough to impact guideline authors, and the AASLD guidelines are currently under review, they're being developed. They could be as early as late 2024, but more likely 2025. And if you look at the European guidelines and the WHO guidelines, we already have guidelines out there that you could use in the U.S. knowing that our 2018 hep B guidelines are a bit archaic.

Typically a key beginning rule. I think that medicine allowance is universal. I'm happy to see that we are aligned. We had the same ideas with Nancy in U.S. and us in Europe.

The next question comes from Patrick Trucchio at H.C. Wainwright.

And congrats on the data. A couple of questions. The first is just -- in the patients across this program, the SOLSTICE program, including those in the combo rollover, de novo combo and tobevibart monotherapy, can you discuss any learnings that emerge regarding patient baseline characteristics in those patients who achieved the combination endpoint. For instance, was there some level of baseline hepatitis B surface antigen? Or was this more dependent on length of infection or other variables? And in this way, would you have an opportunity to perhaps enrich the Phase III program? Or is it just a matter of time before all the patients, who achieved the virologic response, would then also achieve ALT normalization? And then separately, just wondering on the HDV patients in the U.S. I'm wondering how many are currently on suppressive treatment for HDV? And what proportion of patients with HDV remain to be discovered? And as well, based on this data that's been generated so far, what proportion of the HDV patients would appear to be appropriate for treatment with the de novo combination?

Maybe I will take the first part with what have we learned from the Phase II study in the screening including criteria, if I may. So for this, we learned that delta is a rare disease, so we don't have to be too strict for inclusion criteria. I think what we learned is that to exclude patients with normal ALT was also difficulties because, as you know, one part is normalization of ALT. So many patients not -- were not allowed to the studies. And I think they have to move to antiviral efficacy to allow something should be normal contaminant. Then we cannot, I think, stratify too much according to edge-based quantification [indiscernible] because there are very few patients and they think that for our disease, we have to be more flexible, more open with not so limited criteria. I think the usual criteria taking into account in the final statistical analysis, but it's one not need from the study.

I will try to cover the many components of your second question. So the first I think is hepatitis B prevalence in the United States. I think that the prevalence database probably still has the most accurate estimate of how many individuals in the U.S. are diagnosed. And there's a difference between diagnose and undergoing treatment. So I think there's still probably about 60% of hepatitis B that is not diagnosed in the U.S. And of those that are diagnosed, only a tiny minority are actually treated, and that's the limitation of our current treatment guidelines. The hope is that those guidelines will shift and allow treatment to be more permissive and not just one guideline, but all guidelines, and that's the movement across our guideline production, whether that's in Asia, in Europe, WHO or the U.S. guidelines that are currently going. As for hepatitis D, hepatitis B patients on hep B therapy, that's going to be really reflective of hep B replication. So if you don't have active hepatitis B and you are not cirrhotic, it may not be on hepatitis B therapy. And that may not be a limitation to treating your delta. And that's going to be one of the questions that is part of advisory boards and KOL discussion that you have to have hep B suppressed in order to undergo hep D treatment. There's precedent that may not be true, but it might also vary with each regimen that we prescribed. As to of the D patients that are appropriate for therapy, so not every D patient, so some are antibiotic positive, RNA negative, and you would not treat someone that doesn't have evidence of replication. But for a delta patient because there is no sign that there's safe delta replication and the disease is so aggressive for both liver cancer rates as well as progression to cirrhosis, if you have active D RNA, you should be appropriate for therapy. Now, I am not the guideline writer, so sometimes guidelines come out with recommendations that we may not all universally agree on, but I cannot see reserving treatment for delta patient, that's active replication.

Nancy, you have a very important Q1 and everyone listened to you. There are certainly guidelines we listen to. Patrick, two short comments. One is that I clearly do that, all patients with B should be also allowed to include in the Phase III studies and they could start this and the said diagnosed screening, for example. And we should maybe also include [indiscernible] for infected patients. So I think that to be more open for all patients in need.

And the next question comes from Eric Joseph of JPMorgan.

You have actually touched on my question with your last answer, Nancy. But I'm curious about whether -- how strong is the understanding of the -- of which biomarkers are predictive of a reduction in liver outcomes in delta patients? And as these data mature, are there certain end points in addition to viral -- maintained viral reduction and ALT normalization that you are interested in tracking as perhaps a predictor of longer-term benefit? And maybe with potential input on the Phase III trial baseline, are there certain endpoints that you might want to see incorporated to kind of help distinguish benefit on outcomes versus builder time?

Yes. I won't give my opinion and then open it up, I guess. So the first thing is that ALT suppression and DNA or RNA non-detectability are surrogates for clinical outcomes. And so I think that those are still going to be the most important surrogates. If you don't get those, you're probably unlikely to get reductions in liver cancer rates and reduction in stabilization of prevention of cirrhosis. But when you look at other markers, you can look across the platform with all liver diseases. We would like to see an improvement in FibroScan or reflection of fibrosis. These are not perfect in delta patients. We do not want histologic endpoints. You'd like those in theory, but we don't want to put our patients population through histologic endpoints. We don't want to have that at all, in any kind of clinical algorithm. So I think we're going to be left with FibroScan or elastography for some of the other metrics that we use to gauge histology without histology, and it has to be cost effective enough that you're not putting someone through an MR elastography or something like that.

Are there additional endpoints that you would consider?

No, no, I agree with Nancy. This is usual endpoint for chronic viral hepatitis so we look for snRNA. But thereafter, there will be also for enroll data to demonstrate a reduction in cancer, in hepatocarcinoma, there's no decompensation of cirrhosis. So I think that more of the study the Phase III has a long-term data with no clinical events with safety measure, which will be brought into increment.

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

Thank you, everyone, for your insightful questions and for taking the time to join us today. We are incredibly excited about the potential of tobevibart and elebsiran to transform the lives of patients living with chronic hepatitis delta. And we look forward to sharing further updates on our progress in the coming months. With that, operator, you can conclude the call.

Thank you, everyone. This concludes today's call. You may go ahead and disconnect your line.