Vir Biotechnology, Inc. (VIR) Q2 2025 Earnings Report, Transcript and Summary

Hello. Welcome to Vir Biotechnology's Second Quarter 2025 Financial Results and Corporate Update Call. As a reminder, this conference call is being recorded. [Operator Instructions] I will now turn the call over to Rich Lepke, Senior Director, Investor Relations. You may begin Mr. Lepke.

Thank you, and good afternoon. With me today are Dr. Marianne De Backer, our Chief Executive Officer; Dr. Mark Eisner, our Chief Medical Officer; Jason O'Byrne, our Chief Financial Officer; and Dr. Mika Derynck, our Executive Vice President of Oncology, who will be available during the Q&A session. Before we begin, I would like to remind everyone that some of the statements we are making today are forward-looking statements under the securities laws. These forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, future results, performance or achievements to differ significantly from those expressed or implied by such forward-looking statements. These risks and uncertainties and risks associated with our business are described in the company's reports filed with the Securities and Exchange Commission including Forms 10-K, 10-Q and 8-K. I will now turn the call over to our CEO, Marianne De Backer. Please go ahead.

Good afternoon, everyone, and thank you for joining us for Vir Biotechnology's Second Quarter 2025 Earnings Call. I'm excited to share our progress with you today as we've achieved several important milestones across our pipeline this quarter. The past few months have been remarkably productive with significant advances in both our hepatitis delta and oncology program. These achievements reflect our team's commitment to our mission of powering the immune system to transform patients' lives and I'm grateful for both their dedication and your continued interest in our journey. Our key accomplishments this quarter demonstrate our continued momentum across our pipeline. First, we've made significant progress in our ECLIPSE registrational program for hepatitis delta. Following our first quarter milestone of enrolling the first patient in ECLIPSE 1, we have now recently enrolled the first patients in both ECLIPSE 2 and ECLIPSE 3 and all 3 registrational studies are now actively recruiting patients globally. Second, we've successfully initiated our Phase I study for VIR-5525, our EGFR-targeted T cell engager, marking our third clinical stage T cell engager program. And third, we've continued to make progress in our existing T cell engager programs with both VIR-5818 and VIR-5500 advancing in their respective Phase I studies. We also received IND clearance to evaluate VIR-5500 in earlier lines of prostate cancer treatment in combination with androgen receptor pathway inhibitors. Let me now elaborate on our chronic hepatitis delta program, which represents a significant near-term commercial opportunity for Vir Bio. The ECLIPSE registrational program is designed to address different patient populations across the treatment continuum, from treatment-naive patients to those who have not adequately responded to existing therapies. This comprehensive approach builds on our compelling SOLSTICE Phase II data, which demonstrated impressive virological responses with our combination therapy of tobevibart plus elebsiran. The hepatitis delta opportunity is particularly compelling from a commercial perspective for several reasons. Our comprehensive market analysis indicates approximately 7 million active viremic HDV RNA-positive patients globally, including approximately 61,000 patients in the United States and 113,000 patients in the EU member countries plus the U.K. The patient population is geographically concentrated, particularly in the United States, where delta patients are predominantly clustered in major urban centers like New York, Chicago, Los Angeles and San Francisco. This concentration would allow for an efficient commercial approach with a targeted specialty sales force focused on hepatologists and infectious disease specialists. This disease has severe clinical outcomes, including accelerated progression to cirrhosis and a more than 50%, 5-0, mortality rate within 10 years, creating a compelling case for effective intervention. The EMA orphan disease designation and the lack of FDA- approved treatments in the U.S. support a value-based pricing model similar to other rare disease therapies. Additionally, the high economic burden of untreated disease progression provides a strong economic rationale for effective treatment, while the regulatory designations we've received may help accelerate our development time line. As we advance our hepatitis delta program towards potential commercialization, our strategy includes pursuing commercialization partnerships in Europe and other key international markets. Turning to our oncology portfolio. As mentioned, I'm very excited about VIR-5525, our dual-masked EGFR targeted T cell engager. This program addresses a significant unmet need across multiple solid tumor types where EGFR is expressed. Despite years of development of EGFR-targeted therapies, including tyrosine kinase inhibitors and monoclonal antibodies, these approaches have limitations. TKIs are primarily effective only in the subset of patients with specific EGFR mutations, while antibodies like cetuximab and panitumumab face resistance mechanisms and significant toxicities that limit their use. For example, these therapies are not used in tumors with KRAS or BRAF mutations in colorectal cancer and head and neck squamous cell carcinoma, as they typically derive minimal or no benefit from current EGFR-targeted treatments, leaving a substantial unmet need. The PRO-XTEN approach fundamentally changes this paradigm. By redirecting T cells to kill tumor cells expressing EGFR, VIR-5525 has the potential to work across a much broader patient population regardless of their mutational status, including those with KRAS mutations. Because VIR-5525 harnesses the patient's own immune system to target EGFR-expressing tumors, we believe the likelihood of developing resistance to treatment that often occurs in these diseases is low. Mark will provide more details on the clinical development plan, but I want to emphasize that VIR-5525 exemplifies how we're leveraging our platform to potentially address major limitations of existing therapies. For VIR-5818, our dual-masked HER2-targeted T cell engager, we have completed the monotherapy dose escalation portion of our study and are now analyzing that data as we continue dose escalation in combination with pembrolizumab. For VIR-5500, our dual-masked PSMA-targeted T cell engager, we continue our dose escalation study and recently obtained U.S. IND clearance to evaluate the program in earlier lines of prostate cancer. This expansion into first-line metastatic castration-resistant prostate cancer and hormone-sensitive disease in combination with ARPi represents an important step in exploring VIR-5500's full potential across the prostate cancer treatment continuum. The PRO-XTEN universal masking approach continues to demonstrate potential advantages in terms of safety profile and dosing flexibility across our T cell engager portfolio. This platform technology allows us to apply an identical masking approach across multiple targets, accelerating our development time lines for future programs. Beyond our clinical stage programs, we continue to advance multiple preclinical T cell engager candidates targeting various tumor- associated antigens. For these preclinical candidates, we're taking a strategic approach to development, advancing some internally while exploring potential partnerships for others, where combining our platform with complementary expertise could maximize value and accelerate development time lines. Our financial position remains strong with approximately $892 million in cash, cash equivalents and investments at the end of the second quarter. This provides us with a cash runway extending into mid-2027, giving us resources to advance our key programs through critical value inflection points. Looking ahead, we're focused on several key priorities: driving enrollment across all 3 ECLIPSE studies to advance our chronic hepatitis delta program towards registration; advancing our clinical stage T cell engager programs, including exploring VIR-5500's potential in earlier lines of prostate cancer treatment; and executing on our business development strategies to maximize the value of our assets. With that, I'll now turn the call over to Mark to provide a more detailed update on our clinical development program.

Thank you, Marianne. We've made significant progress across both our infectious disease and oncology portfolios during the second quarter, and I'll walk you through the key developments. I'm excited to report substantial progress in our ECLIPSE registrational program for hepatitis delta. Building on our first quarter milestone of enrolling the first patient in ECLIPSE 1, we have now just recently enrolled the first patients in both ECLIPSE 2 and ECLIPSE 3, and all 3 studies are now actively recruiting patients globally. We remain on track with our overall development time line with primary completion for ECLIPSE 1 expected by December 2026. Let me now provide details on each study. ECLIPSE 1 is designed to evaluate our combination therapy in regions where bulevirtide is not available or has limited use, including the United States. The study will enroll 120 participants randomized 2:1 to receive either our combination therapy or deferred treatment. The primary endpoint is a composite endpoint of HDV RNA target not detected and ALT normalization at week 48. ECLIPSE II will enroll approximately 150 patients randomized 2:1 and evaluate switching to our combination therapy in patients who have not adequately responded to bulevirtide. This study addresses an important unmet need for patients who have limited options after bulevirtide treatment. ECLIPSE 2 has a 24-week primary endpoint of HDV RNA target not detected, which could potentially provide a readout at a similar time point as ECLIPSE 1. ECLIPSE 3 is our Phase IIb study that will enroll approximately 100 patients comparing our combination therapy to bulevirtide and bulevirtide-naive patients. This head-to-head comparison will provide important data to support access and reimbursement discussions. Together, ECLIPSE 1 and 2 are designed to form the backbone of our regulatory submissions in the U.S. and Europe. This comprehensive approach addresses different patient populations and treatment scenarios, providing a robust evidence package for regulatory review and approval. The regulatory designations we've received, including Breakthrough Therapy and Fast Track in the U.S. plus PRIME and Orphan Drug in the EU continue to facilitate productive interactions with regulatory authorities. These designations reflect the significant unmet need in hepatitis delta and the compelling data from our SOLSTICE Phase II study where our combination regimen demonstrated impressive virologic responses. I'd now like to turn to our oncology portfolio where we've also made important advances this quarter across our T cell engager programs. As Marianne mentioned earlier, I'm pleased to report that we've successfully dosed our first patient in our Phase I study for VIR-5525, our EGFR-targeted T cell engager, which has the potential to address several critical limitations of current EGFR-targeted therapies. EGFR has been a validated oncology target for many years with multiple approved therapies demonstrating clinical benefit in specific patient populations. However, current approaches face significant challenges First, TKIs like osimertinib are primarily effective only in the subset of patients with specific EGFR mutations, leaving the majority of EGFR-expressing tumors unaddressed. Second, in colorectal cancer, monoclonal antibodies like cetuximab and panitumumab are ineffective in patients with KRAS mutations which represent approximately 30% to 45% of cases. Similarly, in non-small cell lung cancer, where 25% to 30% of non-squamous tumors harbor KRAS mutations, current EGFR-targeted therapies have limited efficacy in this population. Third, KRAS inhibitors have been important advances in lung and colorectal cancer, but redundancy of the pathway and other resistance mechanisms result in eventual progression. Our VIR-5525 program takes a fundamentally different approach of redirecting the patient's own immune system to eradicate EGFR- expressing tumors. The Universal PRO-XTEN dual mask design allows for selective activation in the tumor microenvironment where proteases can unmask VIR-5525 to unleash a potent T cell engager against EGFR-expressing tumors. In normal tissues where EGFR expression may occur, the masks remain intact and prevent any T cell activation. Preclinically, VIR-5525 has demonstrated potent protease-dependent tumor killing in xenograft models to a similar extent as the unmasked version. Importantly, no cell killing was observed in normal cells even at very high concentrations in vitro. In safety studies with nonhuman primates, VIR-5525 showed an approximate 250-fold safety margin compared to the unmasked version with only minimal cytokine release syndrome and IL6 elevation, substantially less than seen with the unmasked T cell engager in these models. What's particularly encouraging is that VIR-5525 uses the same masking technology as our other 2 clinical programs, both of which have demonstrated promising safety profile so far. This consistent performance across multiple targets gives us confidence that VIR-5525 will show a similar safety profile. In contrast to traditional oncology therapies that inhibit signaling through wild-type or mutated EGFR, VIR-5525 is designed to be unmasked specifically in the tumor microenvironment where the unmasked TCE can effectively redirect T cells to kill EGFR-expressing tumors. Through this tumor-specific unmasking mechanism, VIR-5525 has the potential to treat a wide spectrum of tumors regardless of their underlying mutational status or resistance mechanisms, while sparing normal tissues that express EGFR. With this broad potential in mind, our Phase I study is designed to address significant unmet needs across a focused group of tumor types with high EGFR expression. In non-small cell lung cancer, VIR-5525 may benefit patients regardless of their tumor-specific driver mutations, whether they have EGFR mutations, KRAS mutations, BRAF mutations or others. Our approach is potentially applicable to both major histological subsets, squamous and non-squamous. This includes tumors with high PD-L1 expression, where we can leverage the existing T cell infiltration to enhance tumor killing. We will also be exploring combinations with pembrolizumab in this Phase I study. For colorectal cancer, approximately 80% of tumors express EGFR, yet current antibody therapies like cetuximab and panitumumab are not effective for the 30% to 45% of patients with KRAS mutations. Our experience with VIR-5818 has shown promising activity in colorectal cancer, demonstrating that T cell engagers using our PRO-XTEN platform can be effective in this disease. In head and neck squamous cell carcinoma, over 90% of HPV-negative tumors significantly express EGFR and these HPV-negative cases represent the majority of this cancer type. Despite cetuximab's approval, response rates remain low and resistance develops quickly. The overall prognosis and quality of life for these patients remains poor. Introducing a T cell redirecting therapy like VIR-5525, potentially in combination with pembrolizumab, could offer a major advance by potentially avoiding the resistance mechanisms that limit current chemotherapy and targeted treatments. In metastatic cutaneous squamous cell carcinoma, approximately 80% of the tumors express EGFR and advanced disease has limited treatment options beyond checkpoint inhibitors to which nearly half of patients don't respond. Collectively, these indications represent hundreds of thousands of patients diagnosed annually with EGFR-expressing tumors who face significant treatment challenges. Our PRO-XTEN approach is designed to address these limitations through its unique dual masking technology and T cell engaging mechanism. The Phase I study design for 5525 has been optimized to efficiently assess proof-of-concept and incorporates extensive learnings from our VIR-5818 and VIR-5500 programs, potentially allowing for accelerated dose escalation and more efficient decision-making while prioritizing patient safety. We've designed a focused approach that includes both monotherapy and combination approaches with pembrolizumab. We believe the combination with pembrolizumab represents a particularly promising approach. Pembrolizumab is already approved as first-line therapy in non-small cell lung cancer and head and neck cancer, providing a strong foundation for combination and a potential path to earlier lines. T cell engagers like VIR-5525 can potentially convert cold tumors to hot tumors by recruiting T cells to the tumor microenvironment, potentially enhancing the efficacy of checkpoint inhibitors. With this strong scientific rationale, we've designed a robust yet focused clinical development program for VIR-5525 that is now recruiting at multiple sites. Having discussed our newest clinical program, I'd now like to provide updates on our other T cell engager programs For VIR-5818, our HER2-targeted T cell engager. we've recently completed the monotherapy dose escalation portion of our study and are now analyzing that data as we continue dose escalation in combination with pembrolizumab. We're taking a comprehensive approach to determine the optimal dose and schedule for advancing this program. We are encouraged by the responses we've seen in HER2- positive colorectal cancer patients, which are particularly noteworthy as these patients typically have limited options after progressing on these standard therapies. This activity in microsatellite stable patients who have traditionally immunotherapy-resistant tumors underscores the potential of our PRO-XTEN platform approach. Among these responses, we've observed 1 colorectal cancer patient who has maintained a durable response for over 18 months as of our January update, further supporting the promise of this approach. For VIR-5500, our PSMA-targeted T cell engager, we continue to dose escalate on a q-week and q-3-week dosing schedule. The program is progressing with no maximum tolerated dose reached yet. The half-life of 8 to 10 days supports our q-3-week dosing evaluation, which could offer significant convenience advantages for patients. We're excited about the recent U.S. IND clearance to evaluate VIR-5500 in combination with ARPis in first-line metastatic castration- resistant prostate cancer patients and patients with hormone-sensitive prostate cancer. This expansion into earlier lines of therapy and combination settings represents an important step in exploring the full potential of VIR-5500 across the prostate cancer treatment continuum. We look forward to generating a more comprehensive dataset as we continue to advance this program and remain committed to sharing meaningful updates as our programs progress. As we look to the future, our PRO-XTEN platform's clinical validation across 3 distinct targets is demonstrating its versatility and provides a strong foundation for our pipeline of preclinical candidates. This validation enables us to advance additional T cell engager candidates more efficiently and with greater predictability, whether independently or through strategic partnerships. In conclusion, I'm very pleased with the progress we're making across our entire portfolio. We remain focused on executing our clinical development plans with scientific rigor and operational excellence. With that, I'll now hand the call over to Jason. Jason O’Byrne: Thank you, Mark. I'm pleased to share our second quarter financial performance and overall financial position. R&D expenses for the second quarter of 2025 were $97.5 million, which included $6.9 million of noncash stock-based compensation expense. This compares to $105.1 million for the same period in 2024, which included $13.1 million of stock-based compensation expense. The decrease was primarily driven by cost savings from previously announced restructuring initiatives, partially offset by clinical expenses from the initiation of our ECLIPSE registrational program, expenses associated with the progression of our oncology programs, and expenses incurred due to an increase in the fair value of potential future hepatitis delta milestone payments. SG&A expenses for the second quarter of 2025 were $22.3 million, which included $5.5 million of stock-based compensation expense compared to $30.3 million for the same period in 2024, which included $9.1 million of stock-based compensation expense. The decrease was largely due to ongoing cost savings realized through headcount reductions and other restructuring initiatives. Our second quarter 2025 operating expenses totaled $119.6 million, representing a $42.1 million decrease from the same period in 2024. This year-over-year reduction reflects the changes I just noted in R&D and SG&A expenses, plus the absence of $26.3 million in restructuring and impairment charges that were incurred in the second quarter of 2024. Net loss for the second quarter of 2025 was $111 million compared to a net loss of $138.4 million for the same period in 2024. Turning to cash. Our net cash consumed in the second quarter was approximately $127.7 million, which includes $50.5 million in milestone payments related to the first patient dosed in ECLIPSE 1. These amounts were previously expensed in prior quarters. These milestone payments were anticipated and are described in our SEC filings, including the 2024 10-K. Excluding these milestone payments, our quarterly net cash consumed was approximately $77.2 million. We ended the second quarter with approximately $892 million in cash, cash equivalents and investments. Based on our current operating plan, we continue to project our cash runway extending into mid-2027. Our capital deployment strategy remains focused on our most promising programs. First, advancing our hepatitis delta ECLIPSE registrational program with all 3 registrational studies. ECLIPSE 1, 2 and 3, now actively enrolling patients globally following the recent enrollment of the first patients in ECLIPSE 2 and ECLIPSE 3. Second, advancing our T cell engager programs in clinical development, including VIR-5500, VIR-5818 and the recently initiated VIR-5525. We maintain strict financial discipline while focusing our resources on programs that can both create shareholder value and address significant unmet patient need. With that, I'll hand it back to Rich to initiate the Q&A session.

Thank you, Jason. This concludes our prepared remarks, and we will now start the Q&A session. Please limit your questions to 2 per person so that we can get to all of our covering analysts. I'll turn it over to you, operator.

[Operator Instructions] Our first question comes from the line of Mike Ulz from Morgan Stanley.

It's Avi Novick on the line for Mike. Yes. So I guess just on HDV, could you perhaps give us a little bit of an enrollment update on the ECLIPSE programs, particularly for ECLIPSE 1? And then this might be a little bit premature, but I guess, as we think about the TAM in HDV, can you tell us about any sort of prep work or thoughts on how to further identify the prevalent patient population?

Thank you, Avi. I'll ask Mark to comment on that.

Yes. Thanks for the question. So yes, we're really excited that we now have all 3 ECLIPSE registrational studies up and running with enrolling patients. Enrollment in ECLIPSE 1 is going very well. We're not in a position yet to provide more specific updates, but we have said before, we anticipate completing enrollment by the end of this year with a completion date for the primary endpoint at the end of '26. ECLIPSE 2 and ECLIPSE 3, we've just gotten up and running, so a little premature to make statements about how enrollment is going. But so far, we're working really hard, executing really well, really excited about the investigator excitement and responsiveness for these programs. In terms of the work on prevalent HDV, I mean, I think what you're alluding to is it is a challenge estimating the epidemiology of HDV because, particularly in the U.S., because there's no approved therapy, there's no reflex testing, which is automatic testing in HDV-positive patients for delta. So it's a little bit unclear right now how many patients there may be. We're estimating about 61,000 who are viremic in the U.S. right now. We suspect that's probably an underestimate. Once we get to the finish line and launch our therapy, which would be very attractive for patients, that there'll be more education, screening and effort to find patients.

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

I have 2. One is for ECLIPSE and the other is for 5525. So regarding ECLIPSE, if I hear correctly, you said that December 2026 primary completion for ECLIPSE 1. Is it fair to say that you've already enrolled majority of the 120 patients since the study is of 48 weeks? My second question is regarding 5525. I saw your starting dose is only 3 micrograms per kilogram. Since you expect similar safety profile for 5525 versus the other 2 targets, why not start at the higher dose? Also, will you test both like once-weekly dosing and once every [Technical Difficulty] dosing?

Thank you, Gena. It was a little bit difficult to hear you, so please correct us if we haven't fully understood the question. On ECLIPSE 1, you were referring to our primary data completion of December 2026 and enrollment. So maybe, Mark, you can comment on that.

Yes. I would say we're not providing specific updates on enrollment, but recall that enrollment in trials always starts off slower and then ramps up as sites are activated, enrolling patients. All I can say is we're really pleased with how we're doing, and we'll provide an update in the future, so stay tuned for that.

Okay. And then as it's related to your question on our EGFR T cell engagers, 5525. So if I understood you correctly, you were asking why not start at a higher dose given what we have learned from our prior programs. Mika, do you want to comment on that?

Sure, sure. Yes. No, thanks for the question. So we are basically starting at a dose that is standard by regulatory authorities for T cell engagers, which is using the label dose. And so each molecule has --they're in the same range, but they have their own estimated label dose. And we just have to do our start dose from there. But we do have a lot of confidence that we have the potential for a wide therapeutic index for 5525 in that this is a universal platform in that the masks are identical for 5500 and 5818 and as are the protease linkers. And so in terms of if you look at the preclinical data for 5500 and 5818, both of those programs have shown really robust potential for a wide therapeutic margin and safety profile. And similar, when we make those comparisons preclinically with 5525, again, we see this very encouraging and promising potential for a wide therapeutic margin looking at safety studies, toxicology studies in animals and so forth. So we do believe that there is this wide potential for this molecule, and we'll be able to accelerate this program much faster given the learnings that we've had from both the 2 previous HER2 and PSMA programs. And as far as testing other dosing regimens, just as standard for the IND studies, we are required to study this initially weekly, but we are certainly -- again, the preclinical data does suggest that we would have a potentially good half-life to be able to dose less frequently q-3-week and potentially later.

Our next question comes from the line of Paul Choi from Goldman Sachs.

This is [ Daniel ] on for Paul. We're wondering if there are going to be additional data cuts from the Phase II SOLSTICE study for the HDV program. And we're also wondering for the next data cut for VIR-5500 for PSMA. Are you going to share PFS data or radiology-based measurements in addition to PSA biomarkers?

So thanks for the question. We do plan to provide an update on the SOLSTICE study, the complete 48-week data by the end of the year. So stay tuned for that. For 5500 next data cut, we haven't provided guidance about exactly when that will be. We do want it to be a very meaningful update. We're currently escalating in Q1, q-3-weeks, and it's going very, very well. In terms of what specific data we'll present, also we haven't provided guidance there. But we will try to provide clear evidence of dose response, depth and durability, the PSA responses, and other biomarkers and other measures. So we'll provide more detail on what to expect at a later date.

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

This is [ Matthew ] on for Alec. Maybe first one from us on ECLIPSE. Can you just remind us whether both ECLIPSE 1 and 2 data is needed for registration in the U.S.? And then maybe on the TCE program, would you expect the next updates for 5818 and 5500 to be sort of the go/no-go point for these studies? And would we expect a final decision on dosing frequency for those programs as well?

So thank you for those questions. The first question is around whether we expect or need both ECLIPSE 1 and ECLIPSE 2 for the first registrational filing. That is our base case. That said, we have other scenarios that we could consider. If, for example, ECLIPSE 1 completed much ahead of ECLIPSE 2, we could consider following that along with SOLSTICE for an initial approval in the U.S. That would have to depend on the strength of the data, discussions with regulators, including FDA, having breakthrough therapy designation status in the U.S. and PRIME in Europe does allow us to have those conversations, but it's going to depend on the relative speed of enrollment of the trials. And as a reminder, ECLIPSE 2, although it started a little bit later, it's a 24 as opposed to 48-week program point, so it could complete around the same time as ECLIPSE 1, but it's a little early to say for sure. I think your next question was around data updates for the 5818 and 5500 and what to expect there. We haven't made a final decision about exactly what those updates will look like, whether they'll be together or whether they'll be separate. For 5818, we have said that we are --we've completed monotherapy dose escalation, but we're continuing with escalation with pembrolizumab, and we're currently analyzing all of the data, PK/PD, efficacy, looking at dose and schedule and making --we'll be making decisions about next steps of development. So we would expect to provide that at an upcoming time. And for 5500, again, it's a little early to be definitive about what we'll provide. But as I was saying before, we want to be able to provide a meaningful update where you get a strong sense of depth, durability, dose response, other key pieces of information.

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

Congrats on the progress. First one on ECLIPSE 2. I believe that you are defining the enrollment criteria for that of patients who are on Hepcludex who don't achieve HDV RNA less than 500 international units per ml. Can you talk about how you're identifying those patients and how easy you expect it to be to recruit that trial? That's the first question. And then second, just in terms of updated data for 5518 in particular, it sounds like the monotherapy dose escalation is completed. Are there any thoughts to releasing that monotherapy data once you're done analyzing it, or will you hold that data to have the combo data as well?

Sure. So thanks for your questions. On the first question for ECLIPSE 2, correct. These are patients who have been on bulevirtide for at least 6 months, are still viremic and they are then eligible, if they meet other criteria as well, for enrollment. Actually identification of these patients is relatively straightforward because the investigators all know which of their patients are on bulevirtide. So they can then test them to see what their level of viremia is, and then if they're eligible, they can be enrolled. So identifying those patients is relatively straightforward. And then I think we randomized them, of course, to switch to tobevibart and elebsiran versus continued bulevirtide with the 24-week primary endpoint of HDV target-not-detected virologic endpoint. I think it's a very appealing trial because patients who are still viremic on bulevirtide, then we'll have the opportunity to test it on our regimen where we've been able to show approximately 2/3 of patients are achieving complete viral suppression. For your question, about 5518, what's the next data release look like, is it going to be monotherapy, or are we going to hold for combination. Yes, we really haven't decided. We're looking at the totality of the data now. We're escalating in combination with pembrolizumab. That's going very well. So we'll just have to make a decision about what would be the most appropriate update and what would be the most appropriate setting for that update.

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

Yes. This is Mazi for Roanna. Just one on the hepatitis space from us. So how do you view the evolving competitive landscape in the chronic hepatitis delta space? And then what advantages do you see for your combination approach in terms of market positioning?

Sure. So in terms of the competitive landscape, a couple of comments. One is Gilead apparently has or is refiling bulevirtide, Hepcludex, for the U.S. And we don't know about the timing specifically. But assuming that they would get approved sometime in 2026, we actually think that would be a big positive for us because having Gilead going out and starting that education of physicians and health care providers and promoting testing for HDV would help prepare the way for Vir and our launch. So we would welcome that opportunity. And particularly since we have a drug regimen with our combo of tobevibart and elebsiran, we're achieving high levels of target not detected at week 48, and we've shown we expect to have above 60%. All told, that compares to 12% with bulevirtide. So we think we have a very compelling clinical case to make there. In terms of the combo approach, I think we're very excited about it because we're suppressing the virus to undetectable in the majority of patients. It's clearly better than our monotherapy with tobevibart, our antibody. So we think we can beat other monoclonal antibodies as well in terms of viral suppression. We also can suppress hepatitis B surface antigen by 3 logs, which is multiple logs greater than a monoclonal antibody alone. And recall that you need the HBV surface antigen for the delta virus to replicate itself. So we're starving the delta virus of what it needs for its viral life cycle. So I think all in all, we feel like we have a best-in-disease, best-in- class approach, and we're executing the trials well, and we're looking forward to helping as many patients as possible.

Thank you, Mark. I would just add that, as Mark mentioned, we have a profile that really has the potential to set a new standard of care. And obviously, with more entrants entering to the market, it's also really a testament to the unmet need that we are seeing in hepatitis delta and obviously, the commercial opportunity that it represents.

Yes, that's great, Marianne, really great comment. And the other point would be that with the monthly administration, we feel we're going to have a very, very superior convenience to bulevirtide, which is daily and other competitors are more likely going to be weekly with an antibody. So we think from a convenience and adherence point of view, we're feeling very good about where we're landing there.

Our next question comes from the line of Sean McCutcheon from Raymond James.

Just a couple on 5500 for us. Can you speak to the patients you've been enrolling since the payer update for 5500? Obviously, a lot of focus on the post-PSMA radioligand setting. Are you prioritizing this patient population? And should we anticipate a meaningful look at activity in that patient population at the next update? And then additionally, can you provide your view on the relative importance of less frequent dosing for 5500 and maybe perhaps speak to the biologic rationale for less frequent dosing or dosing holiday as it relates to T cell exhaustion for T cell engagers?

Yes. So thank you for that question. So the types of patients that we are currently enrolling is sort of a standard first-in-human Phase I where they must have exhausted all standard of care. Now having said that, where we are currently open right now is in Australia and in Europe. And in those settings, there aren't as many -- there are some, but there aren't as many patients who've had prior radioligands. So we don't have quite yet a lot of data in that patient setting. But we do plan on opening in the U.S., and we do plan on trying to generate that data in late-line setting. But we're also excited about going into the early line setting as well. We've recently, as Mark had mentioned, opened --have IND clearance to combine with androgen receptor pathway inhibitors in the frontline setting in a very early metastatic hormone-sensitive prostate cancer setting as well as a biochemical recurrence setting. And so that early line setting, I think, will be quite meaningful for something like this with our current toxicity profile. And then that also relates to the less frequent dosing. So we have demonstrated with the HER2 program that we can dose less frequently at q-3-week and see a similar safety and efficacy profile thus far. We are currently encouraged with what we're seeing. We're now dosing at q-3-week in the 5500 program as well. And what we've learned from the HER2 program, at least is that we don't see resensitization during that week holiday. So I think this is an important factor in T cell engager space is that most people have to step up dosing, everybody has to step up dose. And reason to get that is to desensitize so that you can get to much higher doses. But then once you get up there, what's really next important is to have a reasonable half-life that allows you to then do less frequent dosing and then you don't have that resensitization. And that's been proven out with the HER2 program. And similarly, efficacy, we've seen at the same doses, either q- week or q-3-week efficacy in the HER2 program. So we think that this bodes well for the 5500 program. It has a slightly longer half-life than the HER2 program. And then this is going to be so important in the early line setting where that [indiscernible] where dosing strategies are often for months, if not years, and to have a much less frequent dosing is going to be a key differentiator for our program.

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

Just a couple of follow-ups from us. Just a clarification question on whether the U.S. regulatory filing could proceed based on ECLIPSE 1 and SOLSTICE or is the base case still for both ECLIPSE 1 and 2? And then just with ECLIPSE 3, this is the head-to- head comparison versus bulevirtide. Can you talk about what you would need to see in that program? And is that primarily for the European or ex-U.S. reimbursement? And what would you need to see to give confidence in that you can get reimbursement in that program internationally? And then just separately on the PRO-XTEN, I'm just wondering, given this unique opportunity in KRAS- mutant tumors, particularly in CRC and lung, how are you designing the 5525 program to ensure you capture that population?

Okay. So a couple of quick questions on delta. The first one has to do with the U.S. regulatory filing and what we expect we need. You're right. We do expect ECLIPSE 1 and 2 to be the base case for filing. I do think that they're -- if they finish in the similar time frame, which we expect, that would be ideal, and we would use both of those as the core part of the filing for the U.S. If for some reason ECLIPSE 1 were to finish substantially ahead, we could talk to FDA about whether ECLIPSE 1 and SOLSTICE could comprise the initial filing package and leverage our breakthrough therapy designation in the U.S. and by our PRIME designation in Europe to have those discussions. So those do remain potential options down the road. For ECLIPSE 3, yes, remind everyone it's a head-to-head study of tobevibart and elebsiran versus bulevirtide and bulevirtide-naive patients. And we are looking at virologic endpoint target not detected at week 48 compared to bulevirtide. Bulevirtide is expected to be about 12%, and we expect to be north of 60% for our combination. So we are looking for superiority based on the virologic endpoint. The primary driver for the study, rationale for the study is to enable European payer HTA negotiations around price and access. It will comprise data that will be useful for all of our filings globally on the safety data side and also head-to-head data are always helpful. But primarily, we are looking at that as a payer and access-oriented study.

Yes. So I can take on the PRO-XTEN question. So our 5525 Phase I study as standard -- again, we have to enroll patients who must have exhausted all standard-of-care. And that includes any KRAS inhibitors that are approved in either lung cancer or any other space. And so we do anticipate that we will be able to enroll these patients. But I think a really very important point is that the T cell engager, our masked T cell engager is a different mechanism of action altogether. It is redirecting your immune cells to kill any tumor cells expressing EGFR. And by doing so, it uses it as an address. And so it's regardless of the downstream mutations that are there. So it should work in tumor types that are driven by KRAS as well as any other mutation, even EGFR mutation as well as a multitude of other mutations that happen in lung cancer. So I think this is a unique modality that could either go anywhere in the journey of a patient with lung cancer. It potentially could combine with a KRAS inhibitor, again, because of that differential mechanism of action.

Our final question comes from the line of Joseph Stringer from Needham & Company.

The ECLIPSE 1 trial has a 12-week deferred treatment period versus 24 weeks for a Phase III competitor. So can you remind us the rationale for the 12 weeks here? And what's the potential impact on trial success or potential differentiation?

Yes. So good question. So ECLIPSE 1 randomizes us to our regimen of tobevibart and elebsiran versus a 12-week deferred treatment period. And the primary endpoint is actually 48 weeks for our combination versus 12 weeks in the deferred treatment arm. The rationale for that is that delta virus without any treatment, we expect essentially 0 patients to spontaneously clear the delta virus. So a 12-week deferred treatment arm is really acceptable because it's going to predict almost perfectly what's going to happen in week 48. We have agreement from FDA and EMA on that point. 12 weeks is, in our mind, better than 24 weeks operationally because it's a more appealing design for patients because they don't have a long time to wait if they get randomized to the deferred treatment arm to cross over to the active treatment arm. So we think it's a very patient-friendly design from that standpoint. From a probability of success, I would say 12 versus 24 weeks is essentially the same because in neither time period do we expect spontaneous delta conversions to complete suppression in either setting. So I think it's 12 weeks is very patient friendly. I think in terms of probability of success, it's also very attractive.

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

Thank you, operator. Thank you all for your continued support and for joining us today. We look forward to updating you on our progress in the coming months. Operator, you may end the call.