Hello, and welcome to the Vir Biotechnology's Investor Conference Call to discuss the results from the Phase II SOLSTICE trial. At this time, all participants are in a listen-only mode. An analyst Q&A session will follow the formal presentations. As a reminder, this call is being recorded and a replay will be made available on the company's website... 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 Rich 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 two 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, viral-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 four core scientific capabilities that are cutting-edge and set us apart in the industry. First, we have discovered and engineered unique novel monoclonal antibodies, which form 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 leverage leading machine learning and artificial intelligence capabilities to accelerate our drug discovery process and identify the most promising candidates. And finally, fourth, our core capability is 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 the United States and approximately 200,000 patients in Europe.
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 healthcare systems and society. The lack of approved therapies in the 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 five 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 one or 2x per month. Tobevibart, in addition to inhibiting viral entry, also neutralizes both HDV and HBV virions, preventing them from infecting new hepatocytes. 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 8th. 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 trial design. We will focus on three cohorts that will evaluate at least 96 weeks of treatment. First, the combination rollover cohorts consist of SIX total enrolled participants, four of which transitioned from a tobevibart monotherapy lead-in and two from elebsiran monotherapy lead-in after not meeting RME and ALP predefined criteria at week 12. All 6 participants in this cohort are not cirrhotics, and the dosing frequency is once every four weeks....
These six patients are the same participants that were reported on the last SLD liver meeting in 2023. Second, the novel combination cohort is receiving tobevibart and elebsiran with 32 enrolled participants and a dosing frequency of once every four weeks. Third, the tobevibart monotherapy cohort consists of 33 enrolled participants with a dosing frequency of once every two weeks. Both the de novo combination and monotherapy cohorts enroll participants with non-cirrhotic and compensated cirrhotic with Child-Pugh A. Across all regimens, the doses are tobevibart, 300 milligrams, and elebsiran, 200 milligrams, both administered through separately formulated subcutaneous injections. Now, I will summarize the CELSIUS trial endpoints and participant criteria. The primary endpoint of the study includes, 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 treatments evaluated using a combined endpoint of virologic response and ALT normalization at week 24. Virologic response is defined as achieving RNA less than the limit of detection, or at least a two log decrease from baseline, indicating a significant reduction in viral load. ALT normalization, defined as ALT levels below the upper limit 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 who achieved undetectable hepatitis delta virus RNA, measured as less than the limit of detection, or LOD, less than the lower limit of quantification, LLOQ, and whether participants achieve target not detected, or TND, which indicate there is no measurable presence of HDV RNA. This is a very important endpoint, target not detected, the Holy Grail.
To be eligible for the CELSIUS trial, participants had to meet specific criteria. Adults with chronic delta infections who were either non-cirrhotic or had compensated cirrhosis. Additionally, all participants were required to be on NEX therapy for hep B for at least 12 weeks prior to enrollment. I'd like now to briefly describe the participant dispositions for the novel combination and monotherapy cohorts as the May 2024 data cut. We have 32 participants who were randomized to the novel 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 cohorts to date.
In the monotherapy cohort, there were two treatment-related discontinuations and two participants who withdrew 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, a compensated cirrhosis. However, due to the timing in enrollment, the proportion of participants with compensated cirrhosis who have completed at least week 12 of treatment is lower as of the time of the data cut. In this slide, we summarize the extended follow-up of the six participants in the combination vollover cohort. At the time of analysis, all 6 participants remained on therapy. Five of the six had completed 48 weeks of combination therapy, and one participant had completed 40 weeks of combination therapy. At the time of analysis, all participants demonstrate sustained virological response.
6 of 6 achieve RNA below the lower limit of quantification, 5 of 6 achieve RNA below the limit of detection, and 5 of 6 achieve RNA target not detected, TND. 3 of the 6 participants achieved ALT normalization. There were no serious adverse events that have occurred to date, and the majority of adverse events were transient and grade one or two . Let's now look to the next slides, which highlights the high rates of virological suppression and ALT normalization rates observed with de novo tobevibart and elebsiran combination therapy. The graph on the left side demonstrates the rapid virological response achieved with this combination therapy. As you can see, a substantial proportion of participants experienced a steep decline in RNA level, with many achieving virological suppression below the lower limit of quantification as early as week 12.
Furthermore, by week 24, greater than 50% of participants had attained a virological endpoint called target not detected, TND. This means there were no detectable HDV RNA in these patients. This showed 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 with 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 demonstrate that a significant proportion of participants achieved ALT normalization by week 24, and the rate of normalization increases over time.
Moving to the table on the right, we can see the detailed virologic and biochemical response rates at week 12 and 24. At week 12, among the 27 participants, all 27 had a virologic response, and 14 achieved HDV RNA levels below the lower limit of quantification, 10 below the limit of detection, four target not detected. 12 achieved ALT normalization, and 12 achieved the combined endpoints. At week 24, among the 11 participants where data were available, all 11 achieved virologic response and achieved HDV RNA levels below the lower limit of quantification, 10 below the limit of detection, six target not detected, and seven ALT normalization, and seven achieved this combined. Let's now shift our focus with preliminary virologic suppression and ALT normalization rates observed with tobevibart monotherapy. You can see the graph on the left side with high rates of virologic response achieved with tobevibart monotherapy.
As you can see, a notable proportion of participants experienced a marked decline in HDV RNA levels, with many achieving virologic suppression below the lower limit of quantification by week 24. Although the virologic response rates are slightly lower compared to the combination therapy cohort, these findings, nonetheless, demonstrate the potent antiviral activity of tobevibart as a monotherapy. Moving to the graph in the center, you can see the ALT normalization rate in participants receiving tobevibart monotherapy. The data presented here show that the considerable proportions of participants achieve this ALT normalization by week 24, and this also increases over time. Moving to the table on your right, we can see the detailed virologic and biochemical response at week 12 and 24.
At week 12 among the 26 participants who reached this time point, 19 had a virologic response, 7 HDV RNA levels below the lower limit of quantification, five below the limit of detection, two achieved target not detected, 14 achieved ALT normalization, and 10 achieved the combined endpoint. At week 24, we have data for 11 participants. six had a virologic response, six HDV RNA below the lower limit of quantification, five below the limit of detection, two target not detected, and seven achieved ALT normalization, and six achieved the combined. It's important to note that these response rates are reported as ITT basis and include 4 participants who discontinued treatment, two due to adverse events and two who withdrew from the study.
Additionally, due to the limited number of compensated cirrhotic participants receiving tobevibart monotherapy through week 24 when this data cut, comparing non-cirrhotic and cirrhotics in this treatment is not meaningful at this time. We have to wait for the full data. 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 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 may indicate acute liver inflammation. Notably, there have been no treatment-related serious adverse events related to tobevibart alone or in combination with elebsiran observed in this study to date.
The majority of adverse events observed in the study were grade one and two 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, myalgia, and paralysis. 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 uncommon with immune modulatory therapies and suggest that these symptoms may be related to the initial immune response to the treatment. Furthermore, the study has high treatment continuation rates, with only two participants receiving tobevibart monotherapy having discontinued treatment due to an adverse event.
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 HBV 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 regimen. One of the key findings from the data to date is that de novo combination therapy achieved a substantial and rapid decline in viral 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 de novo combination cohorts. No treatment-related serious adverse events have been reported to date, and the majority of adverse events were transient and grade one and two of severity. Another important observation is the absence of ALT flares with tobevibart alone or in combination with elebsiran, regardless of baseline HBV surface antigen or hepatitis delta virus RNA levels. The SOLSTICE trial also demonstrated similar rates of virological suppression and ALT normalization in non-cirrhotic and compensated cirrhotic participants in the de novo combination treatment regimens in this initial data cut through week 24. Of course, we will have to wait the final data.
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 stages 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 ongoing trial. This will support our shared commitment to 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 this journey toward transforming the lives of those affected by this devastating disease. Thank you. Now I will turn the call to Tarik. Tarik, 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 HBV RNA virologic suppression was observed for participants who received tobevibart and elebsiran combination therapy in a 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 HBV RNA in the de novo combination cohort. Achieving TND 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 one or two 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 non-cirrhotic and those who have compensated cirrhosis in the de novo tobevibart and elebsiran combination 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 development of tobevibart and elebsiran. We recognize the 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 bulevirtide 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 the 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 their hepatitis B screening guidelines, will come more in line with WHO and EASL, where there is a strong trigger to screen everyone who has hepatitis 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 progressive to cirrhosis liver cancer. Without that reflex testing or that more universal testing of people with hepatitis B, you will not find the subset that's infected 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 wasn't necessarily presented in what we went over, but when you look at the dataset, the cirrhotic population is a younger population than people with hepatitis B mono infection.
We see that because these young individuals that were asymptomatic present with devastating decompensated cirrhosis or newly diagnosed liver cancer, and they are a 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 care utilization. I think, though, that when you have effective therapy, there's precedent that will change the entire care cascade and the paradigm. We saw that with hepatitis C, where although we had very effective treatments, they had toxicity and were not universally effective. And so when we had all oral treatment, that really led to a seismic shift in how we recommended for now near universal screening and application of a therapy.
So before we might have withheld treatment, now when you have a treatment that's efficacious, it really affected every point of the care cascade from identifying to offering treatment. I believe that same paradigm shift happened 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 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, you know, 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 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.
Our goal is to bring an innovative treatment to patients as quickly as possible, addressing the 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 those who need it most. Thank you for your continued support and belief 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. Thank you, Marianne. We will now start the Q&A section. Please limit questions to one to two per person, so that we can get to all of our covering analysts. I'll turn it over to you, Sarah.
Thank you, Rich. At this time, we will begin conducting our analyst Q&A session. For our analysts, please go ahead and raise your hand to indicate you would like to join the queue if you have not done so already. Once you hear the operator announce your name, you may unmute your line and ask your questions. Please hold for a moment while we pull for questions. Our first question comes from Gina Wang at Barclays.
Thank you. Can you hear my voice?
Yes.
Can you hear me? Okay, perfect.
Yes.
Well, thank you. Congrats on the data. So I have two questions. I think the 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, you know, 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 clinical and 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, you know, in the long term, will be continuous dosing, for the treatment?
Hey, thank you so much for that question, Gina. So maybe we will start with Dr. Asselah to give his perspective on your question.
Yes, thank you for your questions. So there's, you know, the monotherapy and the combination therapy. So the end, we are looking for, of, of course, viral efficacy with this virological decrease and target not detected. And we are looking for biochemical response, ALT normalization. So you raise the point that with monotherapy, we have many patients who achieve this ALT normalization, which is a good signal. And I think that today, there are still, we don't have the full data. So before to privilege the combination or the monotherapy, we will have to wait for the full data. But all these data are promising, encouraging, and as clinician, we like to have patient with normal transaminase, which is associated with less inflammation. But we will need long-term data and the full picture before making any decision.
Thank you. 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 person sitting in front of the patient. ALT normalization is a surrogate for inflammation and should result in decreased risk for complications and 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 two endpoints, and that there will be durable response.
Okay, and then maybe on the future pivotal study, Carey, could you maybe comment?
Yeah. Gina, your question was around whether we'd 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 the tobevibart and elebsiran in the SOLSTICE trial. So our current focus really is developing a safe and effective chronic suppressive therapy for patients. You know, obviously, hepatitis delta is complex and challenging. However, at this stage, you know, our priority is still to address this current urgent, unmet need, you know, for this kind of chronic suppression. And if, you know, there's further data that comes about in terms of looking for potential of a finite cure, then that could be explored in the future. But our focus right now is on a chronic suppressive therapy.
Thank you.
Thank you for the questions, Gina. The next question comes from Roanna Ruiz at Leerink.
Great, thanks, and hey, everybody. So I wanted to ask about the two 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.
Hi, Roanna. Yes, so those discontinuations were from the tobevibart monotherapy arm. So there were two participants who were discontinued due to adverse events, and these were the flu-like symptoms that they experienced. And then we had two other participants who withdrew from 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's why there can 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 who had 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 overinterpret the fact that some patients have not normal ALT; they can have a good immune response by clearing infected hepatocytes.
To support that, we, you know, as a person sitting there caring for 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 end 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.
Thank you.
Got it. Thanks.
Thank you for your questions. The next question comes from Phil Nadeau at Cowen.
Good morning. Congrats on the data. Thanks for taking our questions. So another one on ALT normalization versus viral reduction. 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, you know, the virologic response wasn't different between the cirrhotic and non-cirrhotic patients. Was there any difference in side effect profile between those two groups? Thanks.
Just to start and for just comprehension, you know, when you add RNA in the combo, you reduce S antigen production from the virus, and you may restore also immunity and clear hepatocytes. So it's why, in the beginning, you can have an increase in ALT with a reduction in viral load. So I think that it's very complex, and so I think that there's multi factors to understand, so it's why we have... I think we have also to remember that that's not the full picture, so we will have to interpret the data with all the patient data. But early on treatment, I think that transaminase not decrease is not very important because there's many explanation.
Yeah. 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, it's really sustained virologic suppression that we think will lend to best outcome, and that, 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 compensated cirrhotic population is really important.
Given the 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, non-cirrhotics, you see that efficacy is very similar. So efficacy remains very high in cirrhotic. We will need to have the full picture. So I think it's very important to see that this viral load efficacy is so strong.
Yeah. And yeah, Phil, this is Carey. Yeah, in terms of the safety profile between the cirrhotics and non-cirrhotics, you know, we haven't seen any difference to date or, you know, early on right now, so that's encouraging as well.
The cirrhotic population is relatively large. It's almost half of the patient population, so it's not like you have two token cirrhotics.
Yes, and just one thing that people don't always understand is that cirrhotic patient, even if they clear the virus, they can have baseline ALT above the limit of normal, and it's maintained. You know, ALT can be also higher the limit of normal with overweight, with other medications, with inflammations. So I think with alcohol. So I think that patient with cirrhosis, I think we should really look for the RNA undetectable.
Great. Thank you for the questions, Phil. The next question comes from Paul Choi at Goldman.
Thank you. Good morning. Can you hear me?
Yes.
Okay, great. I want to ask the KOLs just their thoughts on partial responders, you know, potentially changing to full responders on the aggregate endpoint, and just your thoughts on contextualizing that versus the historical boceprevir type data. My second question is just on safety. It seems like in the appendix, influenza or flu-like symptoms were 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 you know, 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 one year if the partial responders become responders, because for a long-term disease with chronic viral hepatitis, the most important is after one year to be maintained and durable with normal ALT. So if it's not reached at week 24 or earlier, but if it is reached after one year, it's a good result. So for partial responders, this is the predictor of good response in the long term. It's why also with the monoclonal antibody, we could have a good response. And the second question?
On safety of influenza symptoms.
All your-
On safety, when you start treatment, all these side effects about influenza-like symptoms arrives early in treatment, and they are transient, and they are grade one. It could be also factors associated with inflammation, immune response. We don't know the exact mechanism, but they are mild, and they arrived early, and they are transient. So for the patient in our hand, it was okay, it was favorable. We need for safety, of course, the full picture.
... Any comments on the partial refill?
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, you know, with a different mechanism. These, 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, it's okay. As a clinician, we're fine with that. We just need to have measurable endpoints and know when you have reached true utility, and I think right now, this data is too preliminary.
Yeah, and Paul, to your question around, you know, kind of the timing of the flu-like symptoms. You know, majority of these occurred, you know, after the first dose and then resolved within 48 hours. These were transient, you know, grade one or two, and then after subsequent doses, participants did not, you know, really have these symptoms. So I think that could be related to, you know, these participants having high baseline surface antigen levels. Patients that have delta have higher baseline surface antigen levels compared to just, uh, HBV mono-affected patients.
And so if you're giving, you know, the antibody and having immune complexes bind, sometimes that can give you that inflammatory, you know, type of a response, and then once you get that surface antigen down, you don't get those type of symptoms, and that's what we've observed so far to date in the trial.
As long as patients know what to expect, they're going to be able to tolerate therapy. So it's really just preparing them appropriately and about how long they would have these symptoms for them to be able to, to get through it.
And also injection site reactions are very hard. So I think it's interesting to notice that there was very few injection site reaction, just to mention it.
Right.
Thank you for the questions, Paul. The next question comes from Michael Ulz at Morgan Stanley.
Good morning, and thanks for taking the question. Maybe just to follow up on the phase III trial design, if you could give us maybe some updated thinking there, maybe in terms of patient numbers, you know, what's the thinking on duration? And it sounds like you're maybe considering including a monotherapy arm as well. Maybe you can just clarify that. Thanks.
Yeah, so, you know, we're going to have, you know, discussions with the regulatory authorities, you know, later this year, as we've said, to align on a development program. You know, we will, you know, be using the bulevirtide as a comparator, for the trial. According to the guidance, you know, they want to see 48-week data, both from a virologic and biochemical response in terms of ALT normalization. You know, obviously, you know, we feel this data is strong, and so we'll, we will have dialogue and, and get that alignment, hopefully, later this year. But, you know, I think it's too early to comment about, you know, specifics around the trial design and, and others until we have those, further discussions.
And the thought on a monotherapy or not, or is that still sort of in debate?
Yeah. So I think, yeah, so we will be, you know, looking at both the combination data and the monotherapy data as a whole and looking at, you know, efficacy, safety, as well as other potential factors to, to determine, you know, which, you know, which regimen we would potentially take forward. And, you know, that would also be with discussions with the regulatory authorities as well.
Got it. Helpful. Thank you.
Thank you, Mike. The next question is from Alec Stranahan at Bank of America.
Hey, guys. Thanks for taking our questions. Just a couple from us. I didn't see this in the presentation, but how has cohort four 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? Thanks.
Yes, thank you for your questions. So for the design of the study, you know, there was the first six patients who had a lead-in phase with monotherapy, and they all over to the combination. So it was one part, and then there was two de novo, one combination treatment and one monotherapy. So we present the results for these threee cohorts. We have no cohort number four, so sorry if I was not very clear. So this is the design of the study. And according to historical comparison, you know, it's very difficult because it's a rare disease. There's not so many cohorts available. There are fluctuation from one patient to another, so I think it will be very difficult to have historical cohorts to compare.
What we know is that we see this very impressive virologic efficacy, and we know that without treatment, there's no this virologic efficacy.
Great. Thanks.
Thank you, Alec. The next question comes from Joseph Stringer at Needham.
Hi, thanks for taking our questions. Question for the KOL physician. You'd mentioned that 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 change. 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 out?
Perfect. So I think there are two 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, if 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. There's precedent, happens with hepatitis C, but it is a little bit harder, and surface antigen testing is used differently than hep C antibody testing.
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 gonna 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.
I completely agree with Nancy, Reau. I think that medicine science is universal. I'm happy to see that we are aligned. We have the same ideas with Nancy in U.S. and us in Europe.
Thank you. That was very helpful. Thanks for taking our questions.
Thank you, Joey. The next question comes from Patrick Trucchio at H.C. Wainwright.
Thanks, 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 tobe monotherapy, can you discuss any learnings that emerged 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 achieve the virologic response would then also achieve ALT normalization?
And then separately, just wondering on the, you know, 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, you know, 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, maybe I will take the first part with what have we learned from the phase II study in the screening inclusion criteria, if I may. So for this, we learned that, you know, 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 a difficulty, because, as you know, one important is normalization of ALT. So many patients were not allowed to these studies, and I think we have to move for antiviral efficacy and to allow some patients with normal ALT. Then we cannot, I think, stratify too much according to HBsAg quantification, to cirrhosis, not cirrhosis, et cetera, because we are very few patients, and I think that for rare disease, we have to be more flexible, more open, with not so limited criteria.
I think the usual criteria are taking into account in the final statistical analysis, but it's one learning 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 Polaris database probably still has the most accurate estimate of how many individuals in the US are diagnosed, and there's a difference between diagnosed and undergoing treatment. So I think there's still probably about 60% of hepatitis B that is not diagnosed in the US, and of those that are diagnosed, only a tiny minority are actually treated, and that's a 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 it's in Asia, Europe, WHO or the US guidelines that are currently going.
As for hepatitis D, B patients on hep B therapy, that's gonna be really reflective of hep B replication. So if you don't have active hepatitis B and you are not cirrhotic, you may not be on hepatitis B therapy, and that may not be a limitation to treating your delta. That's gonna be one of the questions that is part of advisory boards and KOL discussion, that you have to have your hep B suppressed in order to undergo hep D treatment. There's precedent that that may not be true, but it might also vary by each regimen that we prescribe. As to of the D patients that are appropriate for therapy, so not every D patient, so some are antibody-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 DNA, 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 a delta patient that's active replication.
Nancy, you are a very important KOL, and everyone listens to you. And then, as all the guidelines, we listen to her. But two short comments. One is that I agree with you that all patients with D should be also allowed to include in the phase III studies, and we could start nucs at the same time of screening, for example. And we should maybe also include HIV co-infected patients. So I think that to be more open for all patients in need.
Great. Thank you so much.
Thank you, Patrick. The next question comes from Eric Joseph at J.P. Morgan.
Morning. Thanks for taking the questions. You may have actually touched on my question with your last answer, Nancy. But I'm curious about whether how strong is the understanding of which biomarkers are predictive of a reduction in liver outcomes in delta patients? And as these data mature, are there certain endpoints in addition to maintained viral reduction in ALT normalization that you are interested in tracking as perhaps a predictor of longer term benefit? And maybe with a potential input on the phase III trial design, are there certain endpoints that you might want to see incorporated to kind of help distinguish benefit on outcomes versus over time?
Yeah. I'll give my opinion and then open it up, I guess. So the first thing is that ALT suppression in DNA or RNA, you know, non-detectability are surrogates for clinical outcomes. And so I think that those are still gonna be the most important surrogates. If you don't get those, you're probably unlikely to get reductions in liver cancer rates and prevention of cirrhosis. But when you look at other markers, you know, you can look across the platform of all liver diseases. We would like to see an improvement in FibroScan or a reflection of fibrosis. These are not perfect in delta patients. We do not want histologic endpoints. You'd like those, you know, in theory, but we don't want to put our patient population through histologic endpoints.
We don't want to have that at all in any kind of clinical algorithm. So I think we're gonna be left with FibroScan or elastography for some of the other metrics that we use to gauge histology without histology. It has to be cost-effective enough that you're not putting someone through an MRE elastography or something like that.
Are there additional endpoints that you would consider? No, no, I agree with them, and since it is the usual endpoint for chronic viral hepatitis, so we look at transaminase RNA. But then after, there will be also, for real-world data to, to demonstrate that there's reduction in cancer, in carcinoma. There's no decompensation of cirrhosis. So I think that, more the study, the phase III has a long-term data with no clinical events, with safety measure, which will be important to, to implement.
Agreed. That's helpful. Thanks for taking the questions.
Thank you, Eric. 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. 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.