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

Hello, and welcome to Vir Biotechnology's T-Cell Engagers Investor Conference 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, operator, and hello, everyone. Welcome to Vir Biotechnology's PRO-XTEN Masked T-cell Engager Investor Event Conference Call. Before we begin, I'd like to remind everyone that some of the statements we are making today are forward-looking statements under applicable securities laws. These forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, future results, performance or achievements to differ significantly from those expressed or implied by such forward-looking statements. These risks and uncertainties and risks associated with our business are described in the company's reports filed with the Securities and Exchange Commission, including Forms 10-K, 10-Q and 8-K. Joining me on today's call from Vir Biotechnology are Dr. Marianne De Backer, our Chief Executive Officer; Dr. Mark Eisner, our Chief Medical Officer; Dr. Mika Derynck, our Executive Vice President of Oncology; and Jason O'Byrne, our Chief Financial Officer. We are also honored to be joined today by two renowned key opinion leaders in the field of oncology, doctors Josep Tabernero and Johann de Bono. Let me briefly outline today's agenda. Marianne will start with opening remarks on Vir's cancer modalities and the PRO-XTEN platform. Mika will then provide an update on the Phase I data for VIR-5818, a dual mass T cell engager targeting a variety of HER2 expressing solid tumors. We're pleased to then have Dr. Josep Tabernero join us to offer his perspective on the data and potential of this modality in HER2-expressing cancers. Mika will then return to present the Phase I data for VIR-5500, a dual mass T-cell engager targeting PSMA in metastatic castration-resistant prostate cancer. Dr. Johann de Bono will then offer his perspective on the data and the activity seen to date in these patients. Finally, Marianne will provide closing remarks before we open the call for questions. Please note that due to scheduling constraints, Dr. Tabernero will not be available for the Q&A portion of today's call. However, Dr. de Bono will remain with us to address any questions related to the clinical data and prospective shared during the presentation. With that, I'll now turn the call over to our CEO, Marianne. Please go ahead.

Thank you, Rich, and good early morning, everyone. We appreciate your participation in today's call, which marks an exciting milestone for Vir Biotechnology. We are driven by bold vision, harnessing the power of the immune system to transform patients' lives. Today, I'm thrilled to share with you the progress we've made in bringing this vision to life, specifically in our oncology program. The data we'll present today represents a significant step forward in our mission to develop innovative immune powered therapies for people living with cancer. Our in-licensed PRO-XTEN masked T-cell engager platform is driving our oncology strategy. Let me highlight our most advanced assets and their potential to redefine cancer immunotherapy. 5818 is the only marked HER2 targeted T-cell engager in development, and has shown broad activity and a promising safety profile across HER2 expressing tumors. At early efficacious doses, we're seeing tumor shrinkage in 50% of the patients, with responses deepening as we increase the dose, and we have observed a low incidence of Grade 3 or higher treatment-related adverse events. We've observed minimal CRS, only grade 1 and 2 with no grade 3. Our second clinical stage asset, VIR-5500, is the only dual masked PSMA targeted T-cell engager in development. We believe it has the potential to be the best-in-cost treatment due to its therapeutic index, all patients have shown PSA declines, with 58% achieving PSA50 response, and we have significant room to further escalate the dose. Importantly, unlike VIR-5818, we have seen no Grade 3 CRS and very low levels of grade 3 or higher treatment-related adverse events. We also believe the long half-life of VIR-5500 will enable every 3-week dosing, which could significantly improve patient convenience, particularly in earlier lines of prostate cancer therapy. Looking ahead, we are excited about VIR-5525, our EGFR-targeted T-cell engager, which represents an opportunity to pursue multiple high-value indications. We plan to initiate Phase I studies in the first half of 2025. A key advantage of our platform is that our masks are universal. We can apply them to new targets without the need to titrate and tailor each mask, accelerating our pipeline expansion. Moreover, the learnings from our initial clinical study allow for more rapid dose escalation in future programs. Underpinning all of this is our robust estimated cash and investment position of approximately $1.1 billion as of January 1, which allows us to pursue our programs with the urgency they deserve, while maintaining financial discipline. Next, we'll explore how our oncology programs are translating this innovative approach into reality. I'd like to take a moment to place our oncology programs in the broader context of our portfolio. Vir Biotechnology is uniquely positioned to harness the power of the immune system in both infectious diseases and oncology, two fields with immense potential for transforming patient care. In our infectious disease portfolio, we're working to rapidly advance to our hepatitis delta registrational ECLIPSE program in the first half of 2025. I also want to briefly mention our hepatitis B program, where we are pursuing a functional cure. It's important to note that further development will only proceed with a partner. Alnylam has the right to opt in on elebsiran, with that decision to be confirmed. I'll expand on our capital deployment priorities later in the presentation. Turning to oncology. The landscape, despite numerous advances, still presents substantial challenges. Many patients with metastatic solid tumors face limited treatment options, drug resistance and debilitating side effects. It's these persistent unmet needs that drive our ambition to take on cancer. To address these challenges, we are advancing a portfolio of masked T-cell engagers, leveraging the innovative PRO-XTEN platform. In time, we aim to build on this foundation, leveraging our in-house capabilities in antibody discovery and protein engineering to further expand our T-cell engager pipeline with new and novel targets. It's important to understand both the promise and the challenges of this technology. T-cell engagers have shown compelling activity and the potential for long-term responses in cancer treatment. As you can see on the left, T-cell engagers work by facilitating T-cell engagement and tumor cell killing. They act as a bridge, forming an immunological sign-ups between T-cells and tumor cells, expressing a specific tumor-associated antigen. This interaction triggers a powerful cascade of events. It activates T-cells leading to tumor cell killing, while stimulating a robust cytokine release. This cytokine response further activates and recruits additional T-cells to the tumor site. The mechanism allows for potent T-cell activation against cancer cells, which can potentially lead to deep and durable tumor control, the key promise of T-cell engager technologies. However, unmasked T-cell engagers face a significant challenge, as illustrated on the right side of the slide. They don't differentiate between tumor cells and normal cells that may also express the target antigens. This lack of selectivity can lead to systemic toxicity, such as cytokine release syndrome, and can lead to the destruction of healthy cells expressing the tumor antigens, limiting both the safety profile and the therapeutic index of these drugs. This challenge has been a major hurdle in the development of T-cell engagers for solid tumors, leading to a narrow therapeutic window and inability to dose these agents high enough to drive deep tumor responses. This is where the PRO-XTEN technology comes in. Our approach is designed to preferentially unmask and activate T-cell engagers in the tumor microenvironment, addressing this fundamental limitation. On the right, you can see how our dual masking strategy works in healthy tissue. By masking both a tumor binding and the T-cell binding domains, we significantly reduced interactions with normal cells. This dual masking limits binding and reduces T-cell-mediated cytotoxicity in healthy tissues, dramatically improving tolerability. The critical activation happens though, in the tumor microenvironment, as illustrated on the left. Here, tumor-associated proteases selectively cleaved the masks, activating our T-cell engager. Once unmasked, it combined both tumor cells and T-cells, promoting targeted cancer cell killing. Importantly, any unmasked molecule that doesn't immediately blind is rapidly eliminated, further minimizing off-tumor toxicity. This selective activation is the key to the PRO-XTEN's platform's promise. Building on this foundation, our goal is ambitious yet focused, achieving long-term durable responses across a broad spectrum of solid tumors. The powerful PRO-XTEN technology offers this potential and allows us to differentiate our T-cell engagers in several critical ways. First, our approach involves masking both the tumor-associated antigen and the CD3 binding domain. This dual masking strategy is designed to maximize the therapeutic index. Second, we anticipate lower toxicity compared to both unlocked and single masked T-cell engagers. Third, our data demonstrate a longer half-life, supporting the potential for every 3-week dosing. Fourth, it's important to note that our masking technology has been clinically validated. This isn't just a theoretical advantage. We are seeing real-world evidence of its benefits in our clinical trial. And lastly, our universal dual-masking platform has the potential to accelerate clinical development into new targets. We believe our unique dual-masked assets could enable us to redefine the standard of care in multiple solid tumor indications across lines of therapy. By potentially offering improved safety, convenience and efficacy, we aim to make a significant impact on patient outcomes in areas of high unmet medical need. I would now like to turn the presentation over to Dr. Mika Derynck, our Executive Vice President and Head of Oncology. Mika will dive deeper into our clinical data, starting with VIR-5818. Mika, over to you.

Thank you, Marianne. I'm excited to share with you today some compelling data on VIR-5818, which we believe demonstrates the significant potential of the PRO-XTEN platform. I'd like to start with a case study that illustrates the transformative potential of VIR-5818. This slide shows a remarkable journey of a HER2-positive breast cancer patient who had exhausted multiple lines of therapy, including in HER2. At baseline, this patient presented with extensive ulcerated chest wall lesions that invaded throughout her skin and back. Having undergone 9 prior lines of therapy, this case underscores the treatment-resistant nature of her disease. After the very first dose on day 1, within 1 to 3 days, the patient noticed increased redness and induration along with tumor pain, indicating an intense initial inflammatory response to the drug. By the end of cycle 1, the pain resolved, and just after 3 weeks of treatment, we observed significant regression of tumor lesions on her chest and back. Her tumor alterations also started scabbing over and healing. Over the next few cycles, the patient continued to have a dramatic response. By week 12, cycle 4, she had a transformative result, leading to a near complete normalization of her chest well and back. She also showed a 52% tumor shrinkage of our target lesions. This level of response is rarely observed in such a late-line setting and is quite impressive. It demonstrates the potential power of immune-directed treatments when they are well tolerated. It's also a unique opportunity to visually see the drug in action and observe the initial pro-inflammatory nature of the drug's activity, which eventually resulted in the near complete eradication of her tumors. The patient tolerated the treatment well, experiencing only the initial tumor pain. Notably, there was no evidence of elevated cytokines. This case provides an excellent visual example of proof of mechanism for VIR-5818, and showcases its potential to deliver significant clinical benefit that can make a real difference in patients' lives. Now let's dive into the details of our Phase I study for VIR-5818. Our dose escalation strategy has been deliberately conservative, aligning with health authority expectations given the safety concerns observed with our unmasked T-cell engagers. This cautious approach was particularly important given that VIR-5818 was the first PRO-XTEN masked T-cell engager to enter the clinic. We started at an extremely low dose of 1 microgram per kg and have gradually escalated at 200 micrograms per kg, followed by step-up dosing cohorts. We're now evaluating a top dose of 1,000 micrograms per kg and 800 micrograms per kg Q3 week. Of note, a historic unmasked HER2 T-cell engager has shown great Grade 4 CRS at just 0.5 micrograms per kg, and could not escalate the doses to show any evidence of antitumor activity or radiological responses. This showcases how masking can dramatically extend the therapeutic index. In parallel, we're also exploring Q3-week dosing, which may offer greater convenience for patients, in particular, in earlier lines of treatment. It's important to note the breadth of our patient population. We've enrolled 79 patients to date across multiple indications. These patients have HER2 IHC 2 to 3 positive, HER2 amplification or HER2 mutant tumors. Now let's examine VIR-5818 pharmacokinetics. The left graph illustrates pharmacokinetics during step-up dosing. The mass drug exhibits dose-dependent linear pharmacokinetics. At higher doses, we have observed small amounts of the unmasked molecule in circulation. This low level of the unmasked drug was predicted by our preclinical models, demonstrating minimal peripheral and unmasking, and is consistent with the minimal cytokine release syndrome that we have observed. On the right, we see linear and dose proportional PK with an overall half-life of 5 to 6 days, which supports a dosing frequency of 3 weeks or more. This is a major advantage as we develop this drug for patients in earlier lines of treatment, where convenience and quality of life considerations become increasingly important. This observed profile could significantly improve patient experience compliance, especially in long-term treatment settings. Now let's examine the patient population enrolled in this study. It's a diverse and heavily pretreated group of patients who have exhausted all available standard of care treatments. Approximately 62% of our patients have received over 3 lines of therapy and about 25% have undergone more than 5 lines. Many have had prior HER2-targeted therapy, representing the most resistant type of tumors with a very high unmet need. Our study includes a wide variety of tumor types, including patients with liver metastases. Liver metastases are often resistant to immunotherapies. Overall, this heterogeneous patient population represents some of the most challenging cases in oncology and resistance of treatment. Now let's turn to VIR-5818 safety profile, which is impressive, particularly regarding CRS. Only 16.5% of patients experienced grade 3 or higher treatment-related adverse events, which is impressively low compared to other T-cell engagers. Crucially, we observed an overall low rate of CRS, primarily Grade 1, which is just fever managed with antipruritics and no Grade 3 or higher CRS events even without mandatory pretreatment steroids. Regarding pneumonitis, most of the cases were Grade 1, asymptomatic and often not requiring intervention. Grade 2 cases were generally reversible and manageable with steroids, allowing for [ the ] challenge without any sequela. The majority of cases occur in patients with lung metastases, suggesting tumor flare may play a role. This profile differs significantly from ADC induced lung injury, which is often irreversible and requires discontinuation. There were only two Grade 3 pneumonitis cases, one successfully managed with corticosteroids, and a second patient with extensive lung metastases, who are rapidly progressing disease throughout the lung in the first weeks of dosing, confounding the picture. Importantly, we observed no other Grade 3 or higher safety signals, including cardiotoxicity, liver toxicity or colitis. Dose escalation continues as we haven't yet reached the maximum tolerated dose. The graph on the right demonstrates the benefit of our masking technology. Even at doses up to 1,000 micrograms per kg, we're seeing very low levels of IL-6. This is all consistent with the minimal CRS overall and no high-grade CRS. This contrast sharply with unmatched HER2 T-cell engagers, [ GBR 1302 ], where severe CRS has been observed at doses as low as 0.5 micrograms per kg with Grade 4 CRS and sky high IL-6 up to 10,000 picograms per ml, as seen with the red dotted line. In the coming slides, you'll see enriched responses and tumor shrinkage at doses of 400 micrograms per kg and higher. This favorable safety profile, particularly the minimal CRS without widespread steroid use, suggest VIR-5818 has the potential for a very wide therapeutic index, not afforded by unmasked T-cell engagers. With this in mind, let's now turn our attention to the efficacy data we've observed with VIR-5818, which are very encouraging, especially considering the heavy pretreated nature of our patient populations. This waterfall plot shows the best change in some of the longest diameters from baseline for patients treated at doses of 400 micrograms per kg and above. What's striking is that 50% are having some tumor shrinkage across multiple indications, and we have a disease control rate of 65%, which is impressive, given that this is a very late line population that often shows progression with the first tumor assessment. We've observed recess defined responses in 4 out of these 20 patients, with dose escalation still ongoing. We've also seen additional responses at lower doses, which aren't reflected in this waterfall. We are also seeing a dose response relationship with more and deeper responses at higher doses. This is particularly exciting as we continue dose escalation in both weekly and Q3 week regimens. Remarkably, we're observing responses in patients who have received up to 9 prior lines of therapy, including the breast cancer patient I highlighted earlier. This speaks to the potential of VIR-5818 to provide benefit even in patients who have exhausted all treatment options. As we continue to escalate the dose and gather more data, we're optimistic about the possibility for even deeper responses in characterizing this in a more homogeneous patient population. Now I'd like to focus on a particularly exciting subset of our data, the results we're seeing in HER2-positive colorectal cancer patients. This group represents an area of significant unmet need, and our findings here are especially encouraging. At doses of 400 micrograms per kg and above, we're observing compelling results. A confirmed partial response rate of 33%, 2 out of 6 patients. One of those patients have been on study for greater than 2 years, with a duration of response of greater than 18 months. CEA is a tumor biomarker reflecting tumor burden. And here, we're seeing a 100% response rate for patients who had a CEA biomarker. We are also seeing an impressive disease control rate of 83%. Notably, we've seen an additional colorectal cancer patient with a 40% tumor shrinkage at a dose of 200 micrograms per kg. Importantly, all of these patients had microsatellite stable tumors, a population historically resistant to immunotherapy. Approximately 6% of metastatic colorectal patients are HER2 positive, which is typically a poor prognostic and resistant tumor type. These results, while early, are particularly encouraging given the challenging nature of this patient population and the possibility for accelerated development. In addition to the clinical responses we've observed, we're also gathering compelling molecular evidence that supports VIR-5818's antitumor activity. Let's turn our attention to the circulating tumor DNA, or ctDNA, which can provide a more sensitive measure of treatment effect. This waterfall plot shows the percentage change in ctDNA from baseline for patients treated with our step-up dosing regimen. Each bar represents an individual patient with the dose levels indicated below. There are several points that I'd like to highlight. One, we're seeing a 54% molecular response rate defined as greater than 50% decline in overall ctDNA levels and an impressive 31% with a 100% molecular response. Two, these responses are observed across various dose levels and in both HER2-positive and HER2 low patients, suggesting broad applicability. Three, ctDNA analysis may provide complementary information to imaging-based assessments, potentially offering additional insights into treatment effects and changes in tumor burden. This is particularly valuable in cases where tumor inflammation might mask early signs of efficacy in imaging studies. And finally, there's emerging evidence that ctDNA can be a biomarker for monotherapy immunotherapy activity in numerous cancer types, and in some cases, ctDNA responses can be associated with overall survival and be a better predictor than tumor shrinkage. Moving forward, we're now collecting ctDNA in all patients. This will provide us with an even more comprehensive picture of VIR-5818's activity over time, and they help guide our dosing and treatment strategies. As we conclude our discussion for VIR-5818, I'd like to highlight how this program is validating the PRO-XTEN platform and informing our broader strategy. We recognize that HER2 is a highly competitive field, yet we believe our dual-mask technology offers a differentiated approach to this disease. The data we've presented is very encouraging. At efficacious doses, we're seeing a wide therapeutic index in a heavy pretreated population. We've observed a 33% response rate in heavily pretreated colorectal cancer patients, which could possibly open an accelerated regulatory pathway. Our ctDNA and tumor biomarker data provides additional insights complementing our recent findings. VIR-5818 has provided convincing proof of concept of our platform. We're seeing evidence of unmasking with antitumor activity, coupled with unprecedented tolerability, no Grade 3 or higher CRS, and only 16% Grade 3 or higher treatment-related adverse events overall. This safety profile is particularly striking when compared to unmasked T-cell engagers or current standard of care therapies, which often see much higher rates of severe adverse events. The universal nature of our masking technology means that these learnings apply across our entire platform. This has allowed us to more rapidly dose escalate in our VIR-5500 PSMA-targeted program and will inform the development of future targets. To that end, we're continuing dose escalation both weekly and every 3-week regimens, pushing the boundaries of what's possible with T-cell engagers in solid tumors. Additionally, we're exploring combination therapy with PD-1 inhibitors with enrollment ongoing. The potential that we're seeing with VIR-5818 is truly exciting. To provide an external perspective, I'm pleased to introduce Dr. Josep Tabernero, a key opinion leader, Director of the Vall d'Hebron Institute of Oncology and an investigator on this study. Dr. Tabernero will discuss the new patient case study and share his thoughts on the VIR-5818 data. Dr. Tabernero, the floor is yours.

Thank you, Mika. I'm pleased to share my perspective on VIR-5818, an exponential impact compared to targeted therapies across various cancers. Let me start with a compelling case study. A 57-year-old male with HER2 IHC 3+ colorectal cancer to have progress through [indiscernible] lines of therapy, including HER2-targeted agents. HER2-positive colorectal cancer represents a high unmet need because patients develop resistance to HER2 targeted therapies, and this heavily [indiscernible] would typically be particularly resistant to additional therapies. Starting at relatively low dose cohort of 60 micrograms per kg, this show a dramatic 90% CEA tumor marker response in the first cycle. He continued with [indiscernible] stable disease. And as he was able to dose escalate per protocol, we observed initial tumor shrinkage. But when he escalated to 600 milligrams per kg, he achieved a partial confirmed response, about a year after starting the treatment. This response has been sustained for over 18 months, which is quite extraordinary for this indication on treatment [indiscernible]. As of the last data cutoff, he continues on the study, with response maintained and importantly, his tumor [indiscernible] stable, which typically resist in new therapies. What is [indiscernible] impressive is the [ relaxed tolerability ]. The patient has experienced minimal adverse events over 2 years of treatment. And what we have heard, he has been able to go back to work, get married and have an absolute quality of life for an otherwise end-stage terminal illness. Moving to the overall data set. This is a heavily [indiscernible] population. The safety profile is [indiscernible]. Previous attempts at developing HER2 measures without masks were [indiscernible] toxic, with Grade 3/4 CRS, even with prophylactic [indiscernible]. In contrast, VIR-5818 has shown minimal CRS, mostly grade 1, without [indiscernible] use. This double-mask approach represents a significant advance for T-cell directed therapies. We have observed pneumonitis, but it's primarily low grade. The majority of cases were grade 1, which means it's symptomatic and found incidental on CT scans. Many of these patients did not require additional treatment and could continue on the study. The few grade 2 cases were manageable and reversible with historic treatment, and most grade 1, 2 cases, [indiscernible] patient rechallenge without major issues. Many of the grade 2 events have been associated with [indiscernible] and lung metastasis, possibly indicating a strong inflammatory response to the tumor. And unlike ADCs induce IOD, which tends to be more serious and irreversible, these profiles is very manageable. There were 2 Grade 3 [indiscernible] related adverse events which were manageable or had rapid progression of the disease in the lung. Other related to adverse events such as tumor flare are expected, given the mechanism of action. And in some patients, this flare has later resolved into more shrinkage. The aggregate data suggests that much of the tumor flare has now been mitigated with a step-up dosing. Importantly, there were no reported adverse events for liver or cardiac toxicities nor were their original sign-offs for colitis, which are typically concerns with HER2 and or other [ immune agents ]. Efficacy rate shows responses and a dual response across multiple tumor types, which is impressive, given that this is a highly treated population, later line population that has exhausted all standard of care. This has the potential to address an unmet need in particular tumors, including colorectal cancer, endometrial and pancreatic cancers, a major advance for solid tumor T-cell engagers. Monotherapy T-cell engagers can cause [ severe ] progression, where tumor shrinkage may not be the only indicator of antitumor activity. I am very encouraged to see biomarker responses and in particular, ctDNA responses in the liquid biopsies, even in patients that have progressive disease as a rare response, which may indeed be progression due to tumor inflammation, which we have seen on this study. This indicates to me that radiographic tumor size decrease may underestimate the totality of the clinical benefit seen with this drug. I look forward to seeing how these signals evolve in more homogeneous expansion cohorts at higher doses. The activity in colorectal cancer is particularly exciting. The activity seen in the [indiscernible] stable patients is very encouraging and could potentially lead to an accelerated approval. Overall, I see clinical validation of the masking platform, and also look forward to the other PRO-XTEN pipeline candidates such as EGFR. In conclusion, while these data are early data, I'm very encouraged with what I have seen with VIR-5818. The combination of durable responses, manageable safety profile and potential for use both as a monotherapy and in combination across multiple lines of therapy suggests that this could be a significant advancement in HER2-positive cancer treatment. Thank you very much, and I'll now hand it back to Mika for further discussion.

Thank you, Dr. Tabernero, for those insightful comments. Your perspective on the unique case study and the broader implications of our VIR-5818 data is invaluable as we continue to advance this program. Now I'm excited to shift our focus to another promising asset in our pipeline, VIR-5500, our PSMA-targeted dual mass T-cell engager for prostate cancer. Let's dive into our Phase I study for VIR-5500. This study design was built on the learnings from our VIR-5818 program, allowing us to move more rapidly and efficiently in our dose escalations. On the left, you'll see our weekly dosing regimen. We're currently at step-up dosing of 300, 600 and 1,000 micrograms per kg. This is a significant acceleration of dose escalation, reflecting our confidence in the safety of our PRO-XTEN programs. On the right, you can see that we're also exploring a Q3-week dosing schedule. This could potentially offer greater convenience for patients while maintaining efficacy. We're currently evaluating doses stepping up from 500 to 2,000 micrograms per kg in this regimen. Now let's take a closer look at the patient population. As you can see, we've enrolled a heavily pretreated group of patients that are both resistant to hormonal and chemotherapies. The median age is 69. On average, these patients have undergone 4 prior lines of therapy. 94% of patients have received prior chemotherapy. 22% of our patients have previously received PSMA radioligand therapy. We have one patient who has previously been treated with a C1 T-cell engager. In terms of disease burden, all of our patients have significant metastatic disease. 100% of participants have bone metastases. Over 50% also have lymph node metastases. This is a population with high unmet need. Traditional therapies often fall short here and prognosis are very poor. That's why any activity we see in this group is particularly meaningful. Now let's look at VIR-5500 pharmacokinetics. The left graph illustrates the pharmacokinetics in a single patient who showed any measurable fully unmasked T-cell engager or TCE. It's important to note that in 13 out of 14 evaluable participants, no unmasked TCE was detectable above the assay's lower limit of quantification. In this one patient, the unmasked TCE only becomes detectable after 2 cycles, demonstrating a nominal level of unmasking in the periphery. The right graph shows first dose pharmacokinetics across all dose levels. We observed a linear dose proportional relationship with a half-life of 8 to 10 days, potentially enabling Q3-week dosing or less frequent dosing. This potential for extended dosing intervals is particularly advantageous as we consider moving to earlier lines of treatment. Prostate cancer in earlier stages is often managed as a chronic disease, with patients requiring treatment for months to years. So coming to the clinic less often is really important for patients. Looking at the left side of this slide, we're seeing a very well-tolerated profile overall. Importantly, we've observed no dose-limiting toxicities to date. The majority of treatment-related adverse events have been low grade, with only a single grade 3 adverse event of the laboratory elevation of AST, without a Grade 3 ALT increase, indicating that this is unlikely specific to liver toxicity or related to CRF. Notably, we see no adverse events of ICANs or hearing loss, suggesting superior protection of our double mask compared to other PSMA-targeted therapies. Moving to the right side, we see data on CRS. What's immediately striking is the low overall incidence of CRS, with only a small percentage of patients experiencing grade 1 or 2 events, and we've observed no Grade 3 or higher CRS events at any dose level. Even more impressively, at our highest dose level, we see no CRS events at all. This is an unprecedented CRS profile, in particular without the use of prophylactic steroids or anti-IL-6 medications. And as you'll see in subsequent slides, this is at early but efficacious doses. As we continue to dose escalate, we'll monitor closely these safety parameters. However, the data we've seen so far gives us confidence in the potential of VIR-5500 to offer best-in-class therapeutic index among PSMA-targeted therapies and other T-cell engagers. Now I'm excited to share with you our efficacy data for VIR-5500, which we believe demonstrates significant promise in treating metastatic castration-resistant prostate cancer. While early, these results are truly remarkable. Every single patient, 100% of the cohort reflected here, experienced a PSA decline. Looking closer at the magnitude of responses, 58% of patients or 7 out of 12, achieved a PSA 50 response, meaning their PSA levels decreased by 50% or more. We've also observed a PSA90 response in one patient. These are promising early response signals, especially considering the heavily pretreated nature of our patient population and at very low doses. Notably, there's no correlation between antitumor activity and CRS. The graph only shows 3 participants experiencing low-grade CRS with no relationship with PSA response. Moreover, we observed no IL-6 elevations, which are a hallmark of severe CRS. The fact that we're seeing these responses with such a favorable safety profile suggests that we have significant headroom to continue dose escalations, which could lead to even more deeper and more durable responses. As we move forward, we'll be closely monitoring not just PSA responses, but also radiographic responses and crucially, the durability of these responses. Now let's examine this graph showing the longitudinal PSA responses. This chart illustrates PSA changes from baseline over time for patients across different dose levels. As mentioned, we're seeing confirmed PSA50 responses in 7 out of 12 patients or 58% of the cohort. We're also observing a trend towards increased durability for certain patients. Additionally, we see a PSA 90 response in one patient, which is particularly encouraging at this early stage of dose escalation. Note the call out for patients who paused treatment due to an unrelated infection resulting in a nondurable response. These data suggest a large therapeutic index for VIR-5500 with early efficacy, with minimal CRS and toxicity, without the need for prophylactic steroids. We have a lot of room to increase dosing to achieve deeper or more durable responses. We already have hints that we are on the low end of the therapeutic window, with the case of a patient with deep radiographic and PSA response that Dr. de Bono will highlight. Let's contextualize our VIR-5500 data within the landscape of other PSMA-targeted T-cell engagers in development for prostate cancer. We do not have head-to-head data, and cross-trial comparisons are inherently limited and may suggest similarities or differences in outcomes that may not be reflected in the actual results of any head-to-head studies due to differences in study design, patient population, subject characteristics and other factors. However, we believe cross-trial comparison can provide valuable insights into the potential differentiation of our approach. Looking at the far right of the graph, you'll see VIR-5500 safety profile of our dual masked approach. Only 25% of patients experienced grade 1 or 2 CRS. Importantly, we've seen no Grade 3 or higher CRS events. Grade 3 or higher treatment-related adverse events were observed in just 10% of patients, which is just one patient with an asymptomatic laboratory event. Notably, we achieved a safety profile without prophylactic corticosteroids. This contrast with other T-cell engager programs, both unmasked and single mask, which often require steroid premedication to manage CRS and other toxicities. The unmasked and single mask T-cell engager programs represented here show significantly higher rates of CRS, and treatment-related Grade 3 or higher adverse events with some reporting CRS rates over 90% and meaningful percentages of high-grade CRS. We believe our differentiated safety profile is a direct result of our dual-masking approach. What's particularly exciting is that we're seeing this favorable safety profile while also observing promising efficacy signals. This suggests that we have significant room for further dose escalation, with the goal of achieving a best-in-class therapeutic index. Now let's consider our efficacy in the context of evolving PSMA-targeted therapies. Our current Phase I data shows a PSA50 response rate of 58% and a PSA90 rate of 8%, encouraging results, especially given that we're still in the early dose escalation stages. And again, while we do not have head-to-head data, we believe we have a lot of room to move with our current safety profile relative to other levels of CRS and the use of prophylactic steroids in competitive programs. We believe that there is significant opportunity for further optimization in both our weekly and Q3 week dosing schedules. As favorable safety profile with no high-grade CRS and no need for prophylactic steroids gives us confidence to explore higher doses and potentially establish a best-in-class therapeutic index. As we continue to dose escalate, we're keenly focused on accelerating VIR-5500 development to get this important modality to patients as quickly as possible. As we conclude our discussion of VIR-5500, let's consider its potential positioning across different stages of prostate cancer, highlighting how our dual mass approach is driving its differentiated profile. In the late-line metastatic castration resistance setting, we've already shown clear initial activity in heavily pretreated patients. For early line treatment, three factors stand out: one, VIR-5500s long half-life supports every 3-week dosing, which is crucially important for patients in that early line setting. Two, the safety profile without prophylactic medications. Corticosteroids can be very problematic in this early setting, where patients have more options and less tolerance for side effects. Three, the dual-masking approach may allow us to reach higher doses, with a much wider therapeutic index which could translate to improved efficacy, with better tolerability, compared to single mask or unmasked T-cell engagers. Looking ahead, we see opportunities in non-metastatic and hormone-sensitive prostate cancer. Our dual-masking approach may provide a competitive edge here, enabling both monotherapy and combination strategies. Overall, VIR-5500 shows broad promise across the prostate cancer landscape. We believe its promising efficacy and safety profile position it as a potential best-in-class therapy from late to early line treatment. Now to provide further insights into our findings, I'd like to introduce Dr. Johann de Bono, who will present one of his patients on the study and offer his expert perspective on the data we've discussed. Johann, over to you.

Hello. My name is Professor de Bono. I am Professor of Cancer Medicine at the Royal Marsden and the Institute of Cancer Research in London. And I want to thank you for the opportunity to discuss these really exciting early results with this double-mask by specific tumor-targeting antibody, targeting PSMA and CD3. The double masking here is really key since we are seeing significant anti-tumor activity in the absence of any major concerns regarding cytokine release or CRS, which is of huge importance to this class of novel drugs. Let me start, first of all, by sharing a case from my own experience, giving this agent to my patients in my trials unit. I really believe illustrates the huge potential of this novel [ IMP ]. Can I please see the next slide of my case. This is a 73-year-old man who had exhausted most available standard therapies, including [ darolutamide ], the RRP, and 2 chemotherapies, including [ docetaxel ] and [indiscernible]. He had high burden disease with a large number of [indiscernible], more than 20. And a high-PSA that was roughly rising and almost 1,000. His PSA was [ 9 5 9 ] at baseline. He then went on to this IMP Phase I trial and received step-up doses of 200, 300 and then 400 micrograms per kilogram and [indiscernible] very well without requiring any steroids or anti-IL-6 pretreatment to manage any CRS. He really had minimal toxicity. And in fact, we also saw impressive and significant rapid PSA fall of more than 90%, now sustained for multiple months of follow-up. And importantly, on whole-body magnetic residence imaging, which I would argue, based on our publications, is actually the best way to monitor tumor response in bone, we have seen significant antitumor activity, with essentially liquefication of his hypercellular cancer and the eradication of tumor with a major increase in the ADC, what I would call the apparent diffusion coefficient, which basically measures water movement in the cancer, showing a major increase in water movement from the back cellular limited water movement, pretherapy, the hypercellular tumor, to a lot of water movement in the cancer indicating tumor liquefication and tumor kill after therapy. And in my experience, this really means major tumor response, keeping with the more than 90% PSA fall. So this drug in this gentleman has had impressive antitumor activity. Now critically, with this dual mask bite from a safety perspective, this gentleman has experienced only grade 1 mild minimal, really hypotension. But importantly, what we're seeing, and this gentleman had this, was a significant flare up of lower back pain, grade 1 and management with analgesics. But this, to me, indicates that this agent is having a significant impact on the immune T-cell response against his cancer and is probably, in my opinion, an on-target effect. Importantly, we are collecting quality of life data in this trial. And then the gentlemen, we have now seen a major reduction in pain symptoms in keeping with the observed antitumor activity we have seen with this dual masked bite. I know this is a single case, but it really demonstrates the potential of this IMP for 5500 to elicit deep biochemical and clinical responses in patients with really advanced high burden -- tumor burden in prostate cancer with this major PSA decline, imaging changes on whole body MRI and symptomatic improvements. When you look at the overall trial data set, not just my patient, but overall, I'm really impressed by several [indiscernible] of this new IMP, VIR-5500. Particularly, one, the safety profile is hugely encouraging. I'll develop multiple similar drugs, and the slow rate of CRS that we're seeing is very important because it will allow higher dose intensification with this agent, which will maximize antitumor activity and partly avoiding the use of steroids or anti-IL-6 therapy. And in particular, steroids really [ worry me ] because these can really fuel tumor growth as well as cause side effects. Importantly, we are seeing PSA decreases in multiple patients. So that is really supportive of the fact this drug has significant tumor activity. And also with some of these other agents, we have seen other toxicities such as hearing loss or hypoacusis xerostomia, liver toxicity due to PSMA binding of the agent away from the tumor, and this actually is a major issue for other bites that are not double mask like this [ bite ]. Now because this is not being seen to date, although it's early days, I guess, we'll have to get more data with higher doses, it would indicate really principal that this drug is primarily being activated and unmasked at the tumor site. I do believe there is considerable room for further dose escalation. And I am confident we're going to continue to see a dose response by increasing dose of this novel agent. But if as we are seeing this dual masking approach continues to pay dividends in terms of safety with little to no evidence of peripheral and masking, I think we'll have a broad therapeutic index with more antitumor activity. Even in this heavily true population of patients who have exhausted all other therapy options. So that's really all the durability of response that we're seeing so far is encouraging, but we need more data for sure. But really, the trends we're seeing so far with increasing doses make me hopeful indeed confident that this agent, with its longer half-life of 8 to 10 days, that will support [indiscernible] dosing is very promising for this population of patients. So thank you for your attention. I think I've covered most of the bases. And with that, I would like to now hand over to Marianne. Thank you.

Thank you, Dr. Tabernero and Dr. de Bono, for sharing your valuable insights with us today. We truly value your expert contributions to this discussion. As we conclude, I'd like to highlight the key takeaways from today's presentation. First and foremost, is clinically validated to universal dual masking PRO-XTEN platform. Our data indicates a potentially best-in-class therapeutic index, with minimal CRS and few grade 3 or higher treatment-related [indiscernible] events across programs. We are seeing clear efficacy signals in both our HER2 and PSMA program even in heavily pretreated patients. Importantly, we believe we have significant headroom for further dose escalation, which could lead to even stronger efficacy. Our T-cell engagers demonstrate differentiated pharmacokinetic profile with the possibility for every 3-week dosing. And finally, the universal nature of our market approach enables rapid development of new targets as evidenced by our upcoming EGFR program. These achievements highlight the PRO-XTEN's platform's potential to redefine solid tumor treatment with our masked T-cell engager approach. Looking ahead, we have several key catalysts on the horizon. For hepatitis delta, we are initiating our Eclipse registration program in the first half of 2025. For our oncology portfolio, we'll start first in patient dosing with our EGFR dual masked [indiscernible] in the first half of 2025. In chronic hepatitis B, we'll share 24-week functional cure data from our March Part B study in the second quarter. These milestones underscore the potential of our pipeline across both infectious diseases and oncology. All our efforts are underscored by a strong financial position, with an estimated $1.1 billion in cash and investments as of January 1, 2025. Over the past year or more, we have taken numerous steps to rightsize our cost structure. After applying strict financial discipline and portfolio prioritization during our 2025 planning process, we are pleased to share that we have secured a cash runway extending into mid-2027. Our capital allocation priorities are clear and strategic. We are accelerating investment in two main areas: First, our hepatitis delta program. Following the compelling data we presented at AASLD 2024, we're moving forward with our registrational Phase III ECLIPSE studies. Second, our masked T-cell engager programs. We are prioritizing dose escalation for VIR-5500 and VIR-5818, an [indiscernible] of the Phase I study for VIR-5525. For our chronic hepatitis B program, we look forward to sharing functional cure data from our March Part B study in the second quarter of 2025. As mentioned, future advancement of this program will be contingent on securing a worldwide development and commercialization partner. We will not proceed in HBV alone. We are evaluating the best path forward to maximize the value of this important asset. Through a focused approach to capital allocation and strategic partnerships, we believe we can drive significant value creation while extending our cash run rate. As we wrap up today, I want to emphasize how far Vir has come. We resolved from a company that developed a life-saving therapeutic antibody for COVID-19 to one that's now working to address high unmet needs in both hepatitis and cancer. This evolution leverages our unique antibody identification and AI-powered engineering capabilities, both across infectious diseases and oncology. By applying our core strength to these areas, we're building a broader, more robust pipeline while staying true to our mission of harnessing the immune system to transform patient care. Our dual mask T-cell engager technology isn't just another incremental step. It's a fundamental rethinking of how we can possibly make immunotherapies safer and more effective. The early data we've shared today, particularly the encouraging efficacy signals that early doses suggest we're on the right track. But what really excites me is the potential impact from patients. Whether it's someone battling hepatitis delta or cancer patients who have exhausted standard of care, our goal is to offer new hope and better outcomes. We're not there yet. We have a lot of work ahead. But with five clinical programs now underway and a robust pipeline behind them, we are positioned to make a real difference in areas of significant unmet need. In closing, I want to express my sincere gratitude to our study participants, investigators, team members and investors. Your contributions drive our mission to transform patient care. With that, I'll turn the call back over to Rich to begin the Q&A session.

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

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

Happy New Year, everyone, and congratulations on the data. It looks like the licensing deal with Sanofi has the potential to pay off nicely here. My first question is on 5818. And I was wondering if you could comment on if you're seeing any responses in patients who are RAS mutants? That's historically a limitation of HER2 therapy, particularly in colorectal cancer, but just I was wondering if you've seen any responses in patients who are RAS mutant? And just does that give you any clarity on what tumor type you want to focus on initially as your lead indication there? And second, for 5500, can you maybe comment on your development plans in earlier lines, maybe potentially the [ pre-taxane ] setting, just thought on what the timing and strategy there might be?

Thank you, Paul, for your questions. I will ask Dr. Derynck to address them.

Yes. Thank you for the question. So the 5818, in terms of RAS mutants, we have not yet done the analysis to see which patients are RAS mutants. But I think it's important to note that the mechanism of action of T-cell engagers is they use HER2 as an [indiscernible] in order to cause that T-cell killing. So regardless of the -- regardless of what's driving the tumor in terms of oncogenic mutations, these things should work regardless of that status. As long as there's HER2 expression, and it's really the major question that you're talking about. It is true, though, that for EGFR inhibitors, there is a higher rate of HER2 expression that occurs. And so for patients who've been pretreated with EGFR inhibitors, there might be an enrichment for HER2 positivity. And of course, EGFR inhibitors tend to not be used in the HER2 mutant patient population. In terms of your 5500 question, in terms of going into earlier lines of treatment, particularly in [ pretaxane ] patients, we think that there is a significant opportunity and differentiation with our drug, in that we have a superior safety profile, which we think is a result of the double masking. We only have a 25% CRS rate, grade 1 and 2. And also, we do not use, at least for now, we're not using pretreatment corticosteroids. Corticosteroids is actually very problematic for patients if you have to give it routinely, and so that is a significant advantage that we don't need to use that. In terms of also scheduling, we are evaluating a Q3-week dosing. Our half-life is 8 to 10 days, which really affords that less frequent dosing. This is so crucially important for patients in that early line setting where prostate cancer is more of a chronic disease. And so having to not go to the clinic every week is particularly advantageous. So overall, we think that the opportunity in the early line setting is there. We are currently, in our current protocol, have the opportunity to combine with other agents, such as androgen receptor pathway inhibitors as well as other standard of care options that will get us into the earlier line setting. We're also allowing, with a new amendment that's been approved, to have patients with earlier lines of setting, definitely in the pretaxane space. And we believe that the drug actually will work better in the early line setting given that the immune systems tend to be much more robust in that early line setting.

The next question comes from Roanna Ruiz with Leerink Partners.

Just adding on to the prior question. I was curious if you could give more granularity on the subsequent dose escalation plans that you have across your PSMA and HER2 programs? And secondly, I was particularly curious, which specific doses and schedules you might want to test? And how much Q3-week data do you have at this point?

Thank you, Roanna. Mika, please go ahead.

Yes. In terms of more granularity of our HER2 and PSMA plans, for HER2, we're focusing more on the Q3 week dosing at this point, and we're currently at 800 micrograms per kg. We are not -- we do believe that we have some room to move with that drug, but we haven't reached the MTD. And so it's unclear yet what that ceiling would be for the HER2 space. For PSMA, we are very -- we believe that we're very early in our dose escalation stage with just really very minimal toxicities. And as I mentioned in the presentation, we only have one grade 3 event -- related event, and that's a laboratory finding. And so there's really very little toxicity. And again, we're not using prophylactic steroids, and we have a very low-grade CRS rate. So we believe that we're still in the early stages for dose escalation for the PSMA drug. And then in particular, regarding to which doses we want to test at the Q3 week dosing schedule. For HER2, we are -- again, as I mentioned, we're focusing really on the Q3 week dosing primarily. We do believe that the Q3 week is significant advantageous. Our early data suggests that it is similarly well tolerated. There's no -- there doesn't appear to be any resensitization with that extra holiday that you have between the 3 weeks. And as well, we've seen responses at the Q3 week with the HER2 agent. And so we do believe that it's still early, but we do believe it's similarly efficacious, but much more convenient in dosing. And there might be an advantage of giving the immune system a holiday between those 3 weeks because weekly intense T-cell activation may not be necessarily good for your immune system. So overall, the focus has been on the Q3 week. We just started for the PSMA drug, the Q3 weeks dosing, and we don't yet have data on that, but we're also very encouraged because of that superior half-life of 8 to 10 days, really affords that Q3-week dosing with the possibility of even less frequent dosing, which would be really advantageous in the earlier line setting.

The next question comes from Gena Wang with Barclays.

Congrats on great data. I have 2 questions, one more technical, one is clinical data. So the technical question is regarding your dual masking component, the [ XPAT ] proteins, can you give a little bit more color regarding the molecular weight? And are these 2 components, the molecular weight, identical, and also for the 2 candidates? And then second, clinical data questions, maybe Slide 30. When we look at the 300, 600, 1,000 microgram per kg QW versus 200, 300, 400 microgram per kg, we did not see too much dose response. I know it is small patient numbers, and it's still early, so maybe any thoughts there? And a follow-up, Mika, will you just comment, would that be the similar dose you will carry forward with Q3 week dosing?

So regarding the technical question on the dual masking, so I'm not quite sure if you mean on both sides of the mask or between the 2 molecules. But on both sides of the molecules, it's slightly longer on the CD3 binding side and versus what's on the tumor antigen binding side, and that's true for both molecules, both the PSMA and the HER2. And the molecular weight overall, don't have the exact molecular weight. It's slightly smaller than an antibody, but it is around 150 or so kilodaltons is my belief, but I would need to go back and check the actual molecular weight. With regards to the clinical data of looking at those different dose levels for 5500, the 400 microgram per kg top dose versus the 1,000 microgram per kg top dose, I think you're right in terms of the data is still pretty small. We only have a few patients per cohort at this point. And so we're -- it's really likely that we're going to get more robust understanding of a dose response when we get to higher doses, which we do believe we have a lot of room to move on that dose escalation. And as well, we do think that we're looking at 2,000 micrograms per kg at the Q3 week dose level right now. And so we still need to generate that data. And we'll continue to dose escalate even beyond 2,000, which we think we have the room to do. So -- but I also would like to ask Dr. de Bono, whether he wants to talk about dose response and the experience with T-cell engagers in general. I mean ours is really early, but perhaps he can give us some of his experience with other T-cell engagers.