Vir Biotechnology, Inc. Q4 FY2025 Earnings Call

Good afternoon, and welcome to Vir Biotechnology's conference call to discuss the company's VIR-5500 Strategic Collaboration with Astellas, the Positive Phase I Data, and the 2025 financial results. This conference call is being recorded. I will now turn the call over to Kiki Patel, Head of Investor Relations. You may begin, Kiki.

Thank you, operator, and welcome, everyone. Earlier today, we issued 3 press releases, including a joint release with Astellas, announcing a strategic collaboration with our PSMA-targeted T-cell engager, VIR-5500, a second release reporting the Phase I VIR-5500 data that will be presented at ASCO-GU, and a third release reporting our fourth quarter and year-end earnings. Before we begin, I would like to remind everyone that some of the statements we are making today are forward-looking statements under applicable securities laws. These forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, collaboration outcomes, future results, performance or achievements to differ significantly from those expressed or implied in such forward-looking statements. Forward-looking statements include, but are not limited to, statements regarding the potential benefits of our collaboration with Astellas, that the closing of the Astellas collaboration is subject to the expiration or termination of the applicable waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976, the therapeutic potential of VIR-5500, our PRO-XTEN platform, our development plans and time lines, financial terms and milestone payments, and our cash runway and capital allocation priorities. These risks and uncertainties associated with our business are described in the company's reports filed with the Securities and Exchange Commission, including our 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; and Jason O'Byrne, our Chief Financial Officer. Additionally, Dr. Johann de Bono from the Institute of Cancer Research in the U.K. is joining us for our prepared remarks to provide a clinical and investigator perspective. Let me briefly outline today's agenda. Marianne will start by sharing the high-level overview of the strategic collaboration with Astellas and discuss how VIR-5500 has the potential to be a best-in-class T cell engager to address the significant unmet need in metastatic castration-resistant prostate cancer or mCRPC. Mark will then review the Phase I clinical data for VIR-5500, and he'll invite Dr. de Bono to walk through illustrative case examples. Mark will then summarize the broader data set and outline next steps for the program. Jason will cover the financial terms of the collaboration and provide an update on our 2025 financial results. And finally, Marianne will close the call, and we'll open the line for Q&A. With that, I'll now turn the call over to Marianne.

Thank you, Kiki. Good afternoon, everyone. Today marks a pivotal moment for Vir Biotechnology as we announced a landmark strategic collaboration with Astellas to advance the global development and commercialization of VIR-5500, our PRO-XTEN, dual masked PSMA-targeting T cell engager for prostate cancer. VIR-5500 is our most advanced immuno-oncology asset. And today, we are sharing new Phase I data that will be further presented by Dr. de Bono at ASCO-GU this Thursday, February 26. Together, we believe these milestones position VIR-5500 for rapid advancement and allow us to move forward with both urgency and discipline. The collaboration we've announced with Astellas combines their deep global experience in prostate cancer with our differentiated T cell engager powered by the PRO-XTEN masking technology. Structurally, the collaboration is designed to accelerate the development of VIR-5500 across both earlier and later lines of prostate cancer, unlocking a significant market opportunity while meaningfully derisking our pipeline of cancer immunotherapies more broadly. Importantly, the new Phase I data that we are sharing today show a compelling emerging safety and efficacy profile. While still early, these data increase our confidence that VIR-5500 has the potential to be a best-in-class T cell engager for the treatment of prostate cancer. And finally, today's update is also an important validation for the broader PRO-XTEN platform approach, which we believe can unlock opportunities to develop next-generation T-cell engagers in solid tumors. To understand the significance of this opportunity, it's important to consider the current landscape in prostate cancer. Prostate cancer remains a significant global health burden, representing the most common diagnosed cancer among men, with 1 in 8 men being diagnosed in their lifetime. Despite significant progress in treatment, the 5-year survival for patients with mCRPC is only 30% with an estimated 100,000 mCRPC patients in the U.S. and Europe. Across the prostate cancer continuum, there is a substantial and growing unmet need for novel solutions, capable of improving long-term disease control as well as quality of life. T-cell engagers, which activate the human body's own immune cells in situ to fight cancer have transformed outcomes in several hematologic malignancies, and there are multiple products on the market today. In solid tumors, however, use has been limited by toxicity challenges, including tumor activation and cytokine release syndrome. We believe VIR-5500 powered by the PRO-XTEN technology has the potential to address these challenges. The PRO-XTEN platform leverages a universal dual masking approach, which consists of a T-cell engager that simultaneously targets both the tumor antigen and CD3 on T cells, with the PRO-XTEN masks shielding the T-cell engager through a unique steric hindrance mechanism. As you can see, the large hydrophilic polypeptide XTEN masks surround and sterically hinder the CD3 and tumor-associated antigen binding sites. Upon reaching the tumor microenvironment, proteases cleave the linkers, unmasking the active molecule precisely where it's needed. And once unmasked, the molecule combines both tumor cells and T cells, promoting targeted cancer cell killing. In healthy tissue, the XTEN masks remain intact, dramatically reducing interactions with normal cells and minimizing systemic T-cell activation and subsequent cytokine release. The dual masking approach is designed to reduce toxicity, enabling higher dosing and a wider therapeutic window. Additionally, the XTEN masks themselves provide an extended half-life of the molecule supporting optimization of dosing schedules for patients. And as you'll see later in this call, this hypothesis is translated directly into our VIR-5500 Phase I clinical study results. In the trial, VIR-5500 affirmed early signals of a favorable safety and efficacy profile. Treatment with VIR-5500 also showed a dose-dependent antitumor activity as measured by PSA declines, radiographic RECIST responses as well as PSMA-PET responses. Now let me turn to the collaboration with Astellas and why we believe they are the partner of choice for VIR-5500. First, Astellas is the market leader in prostate cancer. XTANDI remains the #1 therapy globally in this space, having treated more than 1.5 million men worldwide. This commercial success demonstrates the deep experience in bringing important prostate cancer therapies to patients at scale. Second, Astellas has repeatedly proven its abilities to successfully co-develop blockbuster medicines with biotech partners. The examples on this slide highlight Astellas' ability to work collaboratively and successfully to translate innovation into market-leading therapies. Third, Astellas brings strong internal global clinical development and life cycle management capabilities, operating across roughly 70 countries. XTANDI has benefited from robust life cycle management, enabling multiple label expansions into earlier lines of prostate cancer. This ability to continually generate data, expand indications and maximize long-term asset value is a key differentiator and an important capability as we think about the future development opportunities. Here is a snapshot of the deal terms that we announced with Astellas today, whereby Vir Bio and Astellas will co-develop and co-commercialize VIR-5500 for the treatment of prostate cancer. The financial impact of these terms is substantial. The total potential in combined upfront and milestone payments is $1.7 billion. In addition, in the U.S., commercial profits will be split 50-50 between the parties, with Vir Bio having the option to co-promote alongside Astellas. And outside of the U.S., Astellas obtains exclusive commercial rights for VIR-5500, while Vir Bio is entitled to receive sales milestones and tiered double-digit royalties on ex-U.S. net sales. Global development costs will be shared between the parties with Vir Bio contributing 40% and Astellas 60%. Overall, this deal provides immediate capital and significantly reduces our near-term development spend while preserving substantial long-term economic upside. The collaboration can maximize the potential of VIR-5500 through accelerated clinical development and global reach, thereby creating value and benefiting more patients. I'll now turn to Mark to walk you through the compelling VIR-5500 Phase I data that forms the foundation of this collaboration.

Thank you, Marianne, and good afternoon, everyone. I'm pleased to walk you through the latest Phase I data for VIR-5500, which have been accepted for an oral presentation at the ASCO-GU conference taking place later this week. This is the only dual mask T-cell engager under evaluation in prostate cancer, and the emerging signals we are seeing reflect the potential of the PRO-XTEN masking platform to unlock the promise of TCEs for the treatment of solid tumors. As of the January 9, 2026, cutoff, we enrolled 58 patients with advanced metastatic castration-resistant prostate cancer in weekly and every 3-week monotherapy dosing regimens. Importantly, all dose escalation cohorts have cleared the dose-limiting toxicity period. Our dose escalation strategy leveraged insights from our broader TCE platform, enabling us to advance efficiently from very low initial flat doses to step-up dosing with the highest Q3 week maintenance dose of 4,000 micrograms per kilogram. Throughout this escalation, prophylactic steroids or IL-6 blockade were not required and was only explored in 3 patients at the highest 4,000-microgram cohort. Based on the emerging data for VIR-5500, our development focus is now centered on doses at or above 3,000 micrograms per kilogram given once every 3 weeks. These dose levels are where we are seeing the clearest clinical signals. Here, we see the baseline characteristics for patients enrolled in the study. Participants were heavily pretreated with a median of 4 prior lines of therapy and some receiving up to 7. 95% had received prior taxane chemotherapy. These are patients with extensive disease burden, 93% presented with bone metastases, 45% had visceral involvement and 18% had liver metastases. Liver metastases are associated with rapid disease progression and poor response to existing treatment modalities. Approximately half of the study population was RECIST evaluable at baseline, enabling assessment of radiographic responses alongside PSA and biomarker responses. This slide summarizes the emerging compelling efficacy and safety signals across the study. Overall, the VIR-5500 data show a favorable safety and tolerability profile with no observed dose-limiting toxicities. Cytokine release syndrome events were limited and predominantly low grade, representing fever only. Importantly, we did not observe Grade 3 CRS events at the dose levels of 3,000 micrograms per kilogram and above, reinforcing the potential of the PRO-XTEN dual masking platform to widen the therapeutic index of our T-cell engagers. We observed a clear dose response relationship for efficacy. At Q3 week doses at or above 3,000 micrograms per kilogram, the data showed deep and consistent PSA declines. In 11 RECIST evaluable patients at these dose levels, 5 experienced objective responses, 4 of these responders achieved confirmed responses with 1 pending follow-up confirmation. We're also seeing emerging evidence of durability with several patients maintaining PSA and radiographic responses with continued therapy up to 27 weeks, though many in the higher dose cohorts remain early in their treatment course. Finally, the depth of PSA declines is particularly encouraging. 82% of patients achieved PSA50, more than half achieved PSA90, and nearly 1/3 reached PSA99. These are meaningful results for late-line metastatic castration-resistant prostate cancer patients, especially patients with visceral disease and liver metastases who represent the poorest prognosis population. To bring these data to life at the individual patient level, I'd now like to invite Dr. Johann de Bono to share his clinical perspective and discuss the real-world implications that illustrate the depth of responses we're seeing.

Thank you, Mark. The 5 case studies I'm going to share with you, many of whom are my patients, demonstrate multiple, impressive, biochemical and radiology responses to this dual masked T cell engager, VIR-5500, in sufferers from metastatic and heavily pretreated prostate cancer. I serve these men in my clinics and have witnessed their experiences and symptomatic improvements on this agent. In advanced metastatic prostate cancer, many subjects experienced significant pain, especially bone pain. VIR-5500 resulted in pain disappearing following treatment in many patients as their disease regressed. Reduction in such pain is incredibly important to these men that we serve. Critically, I believe that the data from this trial show that the dual masking approach works at minimizing cytokine release syndrome, also known as CRS. We are reporting multiple amazing responses with little clinically significant CRS. In fact, circulating interleukin-6 levels remain low and relatively unchanged following treatment with VIR-5500 across these patients, with usually only grade 1 fever being observed, which is really quite remarkable and different from many other T-cell engagers we have studied that have resulted in cytokine release syndrome with hemodynamic instability requiring patient admission, vasopressors and treatment with oxygen, etc. for respiratory compromise. In addition to this absence of requirement for prophylactic steroids or tocilizumab in this trial, very few subjects have required treatment with steroids after receiving this drug, VIR-5500. And this is really quite important since steroids are immunosuppressive and can limit immunotherapy with T cell engagers antitumor activity. So this dual masking by limiting CRS has major advantages. Now let's go through these 5 cases in turn. Case study 1 demonstrates complete resolution of multiple approximately 14 liver metastases after 9 weeks of therapy with a 99% PSA fall, really very impressive. This was a 63-year-old man who had received most standards of care treatments, including taxanes, olaparib, the PARP inhibitor and abiraterone. This man had a substantial disease burden, many liver metastases, diffuse bone disease, and poor prognosis disease seen on the PSMA PETs imaging as shown on the left side of the slide. This gentleman received VIR-5500 at 800, 1,500 and 3,000 micrograms per kilogram, step dosing regimen dosed every 3 weeks. And he had a stunning response with complete resolution of all the liver lesions and near complete resolution of the bone disease, as you can see in these images. The patient achieved a partial radiographic response with a 62% reduction in the sum of the longest diameters and the 99%, as I said, PSA decline and importantly, marked improvement in his tumor pain. Now what's really noteworthy here is that liver metastases are often resistant to therapy associated with poor prognosis, including resistant to hormonal therapies and often other therapies, too. And in my practice, these patients are very hard to treat and seeing such remarkable responses in late-stage heavily treated prostate cancer is really quite amazing, really unprecedented maybe even. In the next slide, case study 2, we see here another significant RECIST response in multiple large liver metastases again in a 75-year-old man with large bulky disease in the liver. As seen on the CT imaging on the left, with 3 courses of treatment with VIR-5500 monotherapy, resulting in major shrinkage of liver lesions by 50% measurements being shown here on the slide. This patient had a 94% PSA fall as well as partial response radiologically and remains on treatment after 10 courses. Again, such responses in liver lesions is particularly impressive with a single-agent T cell engager and underscores the broad potential of this agent monotherapy to really impact outcomes from this challenging disease. Let's move now to the next case, case study 3. This 70-year-old man had a durable RECIST, PSMA PET and PSA90 response lasting more than 8 months. He had peritoneal and abdominal wall lesions, as can be seen on the scan and essentially had complete resolution of these lesions on PSMA PET scan with a complete metabolic response. And as I said, a PSA fall of more than 90%, maintaining an excellent quality of life while on therapy. Let's now turn to the fourth case. This is a gentleman who is a farmer, who had been off work because of his symptoms. What's been amazing is that he had a resolution of his pain and he was able to go back to work. That's very powerful. The 63-year-old man with diffuse lesions in the bone and lymph nodes with prior exposure to multiple prior lines of therapy, including an actinium-based PSMA radiopharmaceutical, had a complete radiographic response by week 9, accompanied by a 99% PSA fall, as you can see on the right in the slide here, with PSA resolution to nearly undetectable levels, as you can see down to 0.05 ng/mL. Now let's turn to the matched tumor biopsy data from the same patient on the left, which we believe is compelling evidence for VIR-5500's mechanism of action and potential. The Duplex PSMA/CD3 IHC for these biopsies at baseline on the left and post-treatment on the right show what this drug induces. You see on the left extremely dense PSMA-positive tumor architecture and no meaningful T cell infiltration. At week 5, you now start seeing a major increase in T cell abundance and a significant eradication of PSMA-positive tumor cells. This overall illustrates the ability of PRO-XTEN masked T cell engagers to engage the immune system to drive an antitumor immune response. Let's now turn to the last subject. Here, we see a complete response with 3 weekly 1,000 microgram per kilogram with approximately 12 months of durability in response. This is a 77-year-old man with more than 20 bone lesions and lymph node involvement, who actually received a lower dose of VIR-5500 with step dosing of 300, 600 and 1,000 micrograms per kilogram, given every 3 weeks after the step dosing. This patient, as I said, had a complete radiographic response by week 9 with resolution, as you can see on the scans of his bone lesions and his PSA becoming undetectable. He experienced clinical benefit with diminished pain and actually, in fact, is regularly going to the gym while on drug. And here, we start seeing durability really even with lower doses of drug. So overall, I've shown you 5 very impressive case studies from the trial overall, showing the potential for impressive and durable disease control in many patients with this dual masked T cell engager. I will now pass back to Mark to review the results of the trial overall. Thank you so much for your attention.

Thank you, Dr. de Bono. Your clinical perspective on these patients treated with VIR-5500 is invaluable as we continue to advance this program. Turning back to the full study population, the safety profile of VIR-5500 remains favorable. The table on the left displays treatment-emergent adverse events for all patients treated with weekly and every Q3-week dosing. The emerging safety profile supports a wide therapeutic index. We've seen no dose-limiting toxicities to date with grade 3 or higher treatment-related adverse events in only 12% of patients. Most of these are laboratory abnormalities. We had only 2 patients discontinue treatment due to an adverse event. The first patient experienced spinal cord compression that was due to his underlying disease and not attributable to VIR-5500, and the second patient due to treatment-related blurred vision. The bottom half of the table on the left displays treatment-related adverse events at the highest doses of more than 3,000 micrograms per kilogram Q3 week. As you can see, the AEs were mostly grade 1 and 2. The grade 3 and higher events are listed at the bottom, but primarily consist of neutropenia and tumor flare, which are indicative of immune-mediated engagement. We observed 2 events of treatment-related blurred vision with unclear pathophysiology and nonspecific MRI findings that improved toward baseline visual acuity. Overall, limited CRS was observed in high-dose cohorts of 3,000 micrograms per kilogram and higher. The bar graph on the right shows cases of CRS by dosing cohort. As you can see, all cases were low grade, either Grade 1 or 2 with no Grade 3 CRS. The Grade 1 events were only fever, treatable with antipyretics. We did not require prophylactic steroids or anti-IL-6 therapy overall. In the highest dose cohort of 4,000 micrograms per kilogram, we did evaluate pre-dose steroids in cycle 1. This slide highlights the strength of the dose response relationship across the doses tested. The waterfall plot illustrates all patients who had an evaluable PSA. Each bar represents an individual patient with the dose cohorts indicated at the bottom and CRS shown by the green and white colored markers. Across the entire dose range, increasing doses generated deeper and more consistent PSA declines. At doses of 3,000 micrograms per kilogram and above, PSA responses were rapid, pronounced and durable with responses confirming at subsequent time points. CRS severity remained low grade at the higher doses with no Grade 3 CRS observed. This slide presents PSA data for patients treated at or above 3,000 micrograms per kilogram in the Q3-weekly regimen. Responses were observed early with some patients demonstrating deep declines as rapidly as cycle 1, day 8. What's striking here is the depth and consistency of the PSA responses displayed in the table on the right. Additionally, radiographic RECIST responses were concordant with PSA responses in evaluable patients. In other words, patients with the deepest PSA responses, PSA90 and PSA99 often had confirmed RECIST responses, supporting clinically relevant antitumor activity. This is an exploratory analysis evaluating the concordance of PSMA PET total tumor volume as assessed by RECIP criteria with PSA declines and RECIST responses. RECIP is an imaging-based response framework developed specifically for PSMA PET scans in prostate cancer. RECIP can detect treatment effects earlier because it tracks PSMA-avid tumor volume, not just anatomical size changes. This is especially useful in prostate cancer where PSMA levels reflect tumor activity. Higher doses of VIR-5500 significantly reduced PSMA-avid tumor volume. These reductions correlated with both PSA responses and RECIST responses, providing further evidence of the drug's targeted activity against PSMA expressing tumors. This slide presents radiographic response data for the 11 RECIST evaluable patients treated at our highest Q3 week dose cohorts of 3,000 micrograms per kilogram or above, showing best changes from baseline in some of the longest diameters. We're seeing a 45% objective response rate or ORR, which includes 4 patients with confirmed responses and 1 patient who is awaiting a confirmatory scan. We are seeing a 64% disease control rate. Patients with partial RECIST responses are also showing deep PSA declines with PSA90s. It's worth noting that we're seeing these deep RECIST responses in patients with challenging disease characteristics, including those with liver metastases. What you're looking at on this slide is a spider plot illustrating the change of RECIST SLD or sum of the longest diameters over time at the 3,000 microgram per kilogram or higher Q3 week dosing level. We're starting to observe RECIST responses that persist over time and are concordant with deep and sustained PSA responses. The higher dose cohorts are continuing to mature. This swimmer plot gives us a longitudinal view of durability. Here, we're also looking at patients treated at 3,000 micrograms per kilogram or higher Q3 week. In this graphic, you'll see markers indicating PSA50 and PSA90 responders, RECIST responses, and grade 1 or 2 CRS events. Each bar represents 1 individual patient. And importantly, we have multiple patients staying on treatment for at least 6 months. Patients achieving deeper responses, both PSA and RECIST, are also the ones remaining on therapy longer. As shown, CRS is largely limited to Grade 1 and 2 early cycles, after which it falls off, allowing patients to continue on therapy with good tolerability. This slide presents VIR-5500's early clinical profile with other clinical stage T cell engagers currently in development for the treatment of prostate cancer. While cross-trial comparisons have inherent limitations and are not head-to-head studies, in the table, we compared VIR-5500 against each program's recommended or go-forward dose. Based on the early numbers, VIR-5500 is exhibiting a highly active profile with deep PSA responses and markedly lower rates of high-grade CRS and treatment-related AEs despite the majority of patients not receiving prophylactic steroids. Importantly, our every 3-week dosing schedule for VIR-5500 may enable administration in the outpatient setting, representing a potential advantage in treatment convenience and broader clinical adoption. Overall, the combination of potent antitumor activity and favorable safety profile underscores VIR-5500's potential as a best-in-class T cell engager for the treatment of prostate cancer. The totality of the data we've shown you today has enabled us to select a preliminary dose to take forward in the late-line mCRPC expansion cohorts. Importantly, we do not plan to use prophylactic steroids or anti-IL-6 agents with this dose. With Q-week and Q3-week dose escalation complete, our program is now positioned to transition into expansion cohorts. Our initial focus areas include late-line mCRPC monotherapy, first-line mCRPC in combination and metastatic hormone-sensitive prostate cancer in combination. We expect to initiate these dose expansion cohorts in the second quarter of 2026. We plan to continue dose optimization in parallel to address the goals set out by the FDA Oncology Center of Excellence's Project Optimus and support advancement into Phase III development in 2027. These next steps reflect our confidence in VIR-5500's clinical profile and the strength of the collaboration with Astellas, which enables broad and accelerated development across all disease stages. Now I will turn the call over to Jason.

Thank you, Mark. Let me first summarize the economic structure of the Astellas collaboration. In the U.S., we will co-develop and co-commercialize VIR-5500 under a 50-50 profit-sharing arrangement, with Vir Bio retaining the option to co-promote alongside Astellas. Outside the U.S., Astellas will hold exclusive commercial rights, and Vir Bio will receive milestones and tiered double-digit royalties on net sales. Global clinical development costs are shared 40% by Vir Bio and 60% by Astellas. Expenses related to U.S. specific studies will be shared by Vir Bio and Astellas 50-50, while Astellas will cover 100% of any expenses related to ex U.S. specific studies. We will receive combined upfront and near-term payments of $335 million, excluding certain payments to third parties. That amount includes a $315 million upfront, comprised of $240 million in cash and $75 million as an equity investment. The $75 million equity investment is priced at $10.36 per share, a 50% premium to Vir Bio's 30-day volume-weighted average price as of February 17, 2026. Further, we are entitled to a $20 million manufacturing tech transfer milestone expected by mid-2027. The collaboration includes up to an additional $1.37 billion in development, regulatory and ex-U.S. commercial milestones. The total potential in combined upfront and milestone payments, excluding certain payments due to third parties, is $1.7 billion. The closing of the Astellas collaboration is subject to the expiration or termination of the applicable Hart-Scott-Rodino Act waiting period. We are pleased with the terms of the agreement and see Astellas as the partner of choice in prostate cancer. The agreement offers a capital-efficient structure that derisks our development spend while potentially expanding the number of patients who may have access to VIR-5500. Moving now to our year-end results. We are pleased to report that our multiyear focus on financial discipline and prioritization has led to continued improvements in performance. Let me highlight a few key financial metrics for 2025 compared to 2024. R&D expenses for 2025 were $456 million compared to $507 million in 2024, a $51 million or 10% reduction. SG&A expenses decreased to $92 million in 2025 from $119 million in the prior year. This represents a 23% decrease in SG&A spend compared to 2024. This net reduction was primarily achieved through previously announced cost-saving initiatives. Our net loss for 2025 was $438 million compared to $522 million in 2024. Turning to cash, our 2025 net change in cash and investments was approximately $314 million. This amount includes a $64.3 million initial cost reimbursement payment received from Norgine in December. We're starting 2026 with a strong financial position of approximately $782 million in cash, cash equivalents and investments, not including the upfront cash and equity we will receive through the Astellas collaboration. Based on our current operating plan and including the net effects of the Norgine and Astellas agreements, we anticipate cash runway extending into the second quarter of 2028, enabling multiple value-creating milestones across our pipeline. I will now turn the call back to Marianne to provide the closing remarks.

Thank you, Jason. Today's announcements mark major progress towards our goal of building a world-class cancer immunotherapy program, the vision we set out for our company just 18 months ago. We believe the data we have shared today for VIR-5500 validates the potential of the PRO-XTEN platform, enabling more rapid advancement of our pipeline of differentiated T cell engagers and positioning Vir Bio to be a leader in immuno-oncology. We have a lot to look forward to across our pipeline. Our HER2 and EGFR programs use the same dual masking architecture and benefit from shared learnings. We plan to share Phase I dose escalation data from our HER2 program in the second half of this year. The PRO-XTEN's platform plug-and-play design also lets us rapidly engineer new masked T-cell engagers for high-value solid tumor targets, creating a sustainable pipeline of differentiated therapies. We have thus far developed 7 preclinical programs and will progress to development candidate selection by early 2027. As we conclude today's presentation, I want to return to what fuels everything we do at Vir Bio: transforming patients' lives, especially people living with devastating diseases who are vastly underserved by current treatment options. The partnership with Astellas will not only allow for swift advancement of VIR-5500, but also positions us well for more rapid pipeline expansion. All this gives us further flexibility to consider how we develop our pipeline assets and continue to unlock earlier value for patients and our shareholders alike. And importantly, by combining Vir Bio's potential best-in-class T cell engager with Astellas' global capabilities, we will bring complementary strengths to one of the biggest unmet needs in oncology. Together, we can move faster and maximize the potential impact of VIR-5500 for people living with prostate cancer. I would like to close by sincerely thanking the patients, their families and the investigators who have supported the development of this program. With that, I'll turn the call back over to Kiki to begin the Q&A session.

Thank you, Marianne. This concludes our prepared remarks, and we will now start the Q&A section. Joining me for the Q&A are Marianne, Mark, and Jason. Please limit questions to 2 per person so we can get through all of our covering analysts. I'll now turn it over to you, operator.

Your first question comes from the line of Paul Choi with Goldman Sachs.

Congratulations on the data as well as the deal. Two questions for us, please. First, either for Marianne or Mark. Can you maybe comment on the range of PSA responses you've seen by prior line of therapies, particularly with regard to prior radiotherapy? Any details there would be helpful, both on the PSA50s and PSA90s. And my second question is, how do you think your data today potentially reflects on the probability of success for your other T-cell engager programs? And just what is your level of confidence that we can make a reasonable inference of higher probabilities of success for your other programs?

Thank you, Paul. Really appreciate it. I'll start with answering your second question and then turn it over to Mark. So we really believe that the data we have showed you today validates our dual masking steric hindrance approach, so really the PRO-XTEN masking. You've seen that the lower systemic immune activation is reflected in limited CRS toxicity, very low incidence of high-grade treatment-related AEs and very limited number of PSMA target-related AEs, again, all very low grade. Also, you saw that we can reach now a wider therapeutic window. So we are able because of the mask to dose higher and less frequently. So we have actually selected a preference for every 3-week dosing. And then thirdly, you have seen that there's great concordance between PSA responses, RECIST responses, PSMA PET responses, which all show great on-tumor engagement. So we think this all bodes really well for our other programs. Of course, every program is unique, but we have, I think, really here shown a validation for the technology. As to your question of range of PSA responses, especially with patients that have been exposed to prior radioligand therapy, Mark, can you...

Sure. That's a great question, Paul. To start, our population is heavily pretreated, with a median of four prior lines of therapy, and the majority of patients have received taxanes. We believe we are seeing very strong PSA responses, especially at doses of 3,000 micrograms per kilogram and higher. For instance, I'd point you to Case # 4 presented by Dr. de Bono. This patient had been treated with a radioligand, specifically an actinium conjugated PSMA-targeted agent, and demonstrated a PSA99 response along with a complete response in the target lesions. Moreover, five weeks after treatment, there was a notable decline in PSMA expression and T cell abundance in the lymph node. While we do not yet have extensive data in the post-RLT setting, the results from this individual patient are extremely promising. Regarding the effects of other prior lines of therapy, it is challenging to determine specific impacts since patients are generally heavily pretreated. Nonetheless, PSA responses appear robust across all patients, particularly at higher doses.

Yes. I mean the only thing I would add is we have 2 patients that were exposed prior to the steep TCE, so we have annotated those on the slides if you would want to go and have a look.

Your next question comes from the line of Cory Kasimov with Evercore ISI.

This is Josh Chazaro on for Cory. Congrats on all the progress. And clearly, you guys have been busy executing here. And question here is, can you give us a little bit more color on what the next steps are before you and Astellas move to Phase III? And are there plans for you and Astellas to explore additional dosing schemes beyond the Q3 week?

Yes. Thank you for that question. Is it Josh? Yes, Josh, thank you for the question. Mark, do you want to take that?

Absolutely. We are very excited about our partnership with Astellas and the upcoming steps in the program. We have selected a dose to proceed with and plan to enter expansion cohorts in the second quarter of this year. We will focus on late-line mCRPC as a monotherapy and also have a combination with enzalutamide for the early line taxane-naive setting. In parallel, we will optimize doses to meet the goals of Project Optimus to fulfill FDA requirements. Additionally, we will explore combinations for metastatic hormone-sensitive prostate cancer in our expansion cohort. With these expansion cohorts and dose optimization efforts, we anticipate entering Phase III by 2027 and feel well positioned moving forward.

Yes. This was exactly why we were so excited about entering into the partnership with Astellas. It allows us to accelerate the clinical development and also really broaden the potential and expand the trials to reach more patients.

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

So 2 questions from me. On the Astellas collaboration, I'm just curious, how are you thinking about unlocking resources for investing into the broader PRO-XTEN platform and thinking about other solid tumor indications? And what sort of calculus will you do in terms of thinking about prioritizing certain programs over accelerating others? And my second question with the larger cohort of patients evaluated on VIR-5500, how does this evolve your thinking about where VIR-5500 could be positioned within the sort of treatment paradigm in terms of line of therapy, combination versus monotherapy and thinking of the future?

Yes. Thank you, Roanna. Yes, as it relates to resourcing, obviously, teaming up with a world-class player in the prostate cancer field and Astellas has entirely internal development capabilities, that will help us tremendously in again, accelerating the VIR-5500 program. From a finance perspective, also it allows us to divert certain expenses to other programs and potentially accelerate those as well. So we think that the collaboration certainly has a lot of benefits beyond just for VIR-5500 alone. As to where to position VIR-5500, do you want to...

Sure, absolutely. So yes, we are very excited about the progress we've made so far and the data that we've presented to you today. And we plan to really be able to address a broad range of patients with metastatic prostate cancer, including late-line mCRPC as a monotherapy. These are the data we presented to you today, a more early line mCRPC in combination. And as you recall, we've been dose escalating in combination with enzalutamide in the frontline taxane-naive setting already, and that's going well. And then in addition, in metastatic hormone-sensitive prostate cancer in combination. So we really are very excited to continue to progress the program. And these are certainly 3 high unmet need populations within the metastatic prostate cancer setting that we think we can address.

Your next question comes from the line of Mike Ulz with Morgan Stanley.

Congratulations on the data and the deal as well. Maybe just one on VIR-5500 and durability. I guess, maybe just talk about your level of confidence there that some of this very strong early data that you're seeing can be sustained over a longer term.

Yes, absolutely. So we are very encouraged by the RECIST responses that we've seen, particularly those that have occurred up to 27 weeks, and the fact that we're able to confirm RECIST responses in patients. We're also seeing a concordance of RECIST responses with PSMA PET responses and deep PSA responses, which we also think is further evidence of the efficacy we can achieve. Also, the case studies that Dr. de Bono presented illustrate patients with up to 1 year of durability, which represents the potential, I think, of VIR-5500. So taken together, we're really pleased with the emerging evidence of durability in the program.

Yes. Makes sense. And maybe just one more question for me. Obviously, you're presenting the data at ASCO-GU later this week. Just curious if the data you shared with us today is the same that will be presented at the meeting? Or are there any additional updates or data points we should be looking out for?

Yes. The oral presentation at ASCO-GU this Thursday by Dr. de Bono, I mean, these oral presentations are rather short. So there won't be additional data, but it will be a subset of this data.

Your next question comes from the line of Phil Nadeau with TD Cowen.

Congratulations on the data and the Astellas collaboration. Two from us. First, in terms of the go-forward dose, could you give us more information on what that dose is? And I guess, in particular, was there a dose response in those doses above 3,000 microgram per kilogram Q3W? Or how did you identify that go-forward dose? And then second, just a clarifying question. It sounds like there's no Grade 3 CRS in doses above 3,000. Was there any below? It didn't seem to be from one of the slides, but we just want to make sure we saw that correctly.

Thank you for the question. We have conducted extensive work on the go-forward dose, taking into account safety, efficacy, PSA, PSMA PET, RECIST responses, and more. We have chosen a go-forward dose. With our new partner Astellas, we will not be disclosing the exact dose today, as it is a collaborative decision. However, I can share that it will be in the range of 3,000 to 3,500 for the maintenance dose. Regarding the dose response above 3,000, we have presented data showing clear PSA response across all tested doses, indicating a strong dose response. While there is still a dose response above 3,000, we are primarily in a range that demonstrates very strong efficacy and a favorable therapeutic index. We are confident that we have pinpointed a go-forward dose that optimizes therapeutic effectiveness. Concerning Grade 3 CRS in the go-forward dose above 3,000 mg per kilo, we have not observed any. There was one instance of Grade 3 CRS in a lower dose cohort involving a patient who experienced intra-patient dose escalation; however, this episode resolved quickly, and the patient recovered well.

Your next question comes from the line of Etzer Darout with Barclays.

Congrats on this data set. Really nice to see. Just one question I had on the go-forward dose. Just wondering if in the combination study that you've initiated if new patients would be enrolled at these effective doses of greater than 300 micrograms per kilogram. And then also, is there an opportunity with this data in hand to maybe convert to a flat dose versus a weight-based dose in these patients and whether you see this as a potential opportunity moving forward for the molecule?

Yes, thank you for the question. Regarding the ongoing dose in combination with enzalutamide, we expect that the dose will be consistent across both populations. We are nearing completion of the dose escalation in combination with enzalutamide for frontline mCRPC to ensure there are no issues, and we believe it should be very similar or identical. As for a flat dose, we currently do not have plans for that. While it is theoretically possible, we are still utilizing the microgram per kilogram dosing.

Your next question comes from the line of Joseph Stringer with Needham & Company.

Just a follow-up on the deal with Astellas for VIR-5500. What might this mean for the rest of the oncology pipeline? Is there an opportunity for some of these programs to be stand-alone for Vir? Or do you see the long-term strategy here to seek partners or to partner these programs? And then a question for Dr. de Bono, just based on these updated data, what are the read-throughs in your outlook? And where do you see potential for VIR-5500 in earlier lines of mCRPC therapy?

Thank you, Joey. The Astellas deal was a strategic decision driven by the significant unmet need in prostate cancer and the rapidly evolving landscape. We prioritized time to market and sought a global partner with the necessary scale and aligned incentives to help us accelerate the program. Our collaboration with Astellas allows us to expand our reach and enhance the value we provide to a wider range of patients, while still retaining a considerable share of the value through the 50-50 profit split, milestones, and ex U.S. royalties. Moving forward, we will approach the rest of our pipeline with similar strategic consideration, guided by the competitive landscape, the size of the commercial opportunity, and the financial requirements needed to advance these indications. We will make deliberate choices regarding partnerships and what to keep fully in-house. Additionally, we have seven preclinical masked T cell engagers, and it’s clear that we cannot progress these preclinical programs alone; we will definitely seek partners in those areas. The plug-and-play nature of our platform enables us to move swiftly in preclinical research, so expect to see us looking for partners in some of these domains. Regarding your second question about read-throughs, Dr. de Bono is not available for the Q&A, but Mark, would you like to address that?

Sure. So your question was about the potential in earlier lines of metastatic prostate cancer. So yes, we definitely believe there is potential there. We are planning first-line taxane naive metastatic castration-resistant prostate cancer as an expansion cohort in addition to metastatic hormone-sensitive prostate cancer. So we are really looking across the metastatic prostate cancer landscape to help these patients who really need better treatments.

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

Congrats on the data and the deal. I guess just a follow-up on the Astellas deal with Vir having an option in the U.S. to co-promote, what would that look like? And at what point in the development process would you be able to exercise that option?

Okay. Thank you, Patrick. Yes, so we have an option to co-promote alongside Astellas in the U.S. And up to a year before the start of our pivotal trials, we will be able to make that decision.

Great. And then if I could, just a follow-up question for Dr. de Bono. I'm just wondering, just based on the data that you've seen so far, how confident are you that this treatment could potentially move into frontline? And what would you need to see in order to give you that confidence?

Thank you, Patrick. Unfortunately, Dr. de Bono is not available for this Q&A as he will be at the ASCO-GU this Thursday. But Mark, do you want to...

Yes. So yes, I encourage everybody who can to attend this talk or to understand his perspective there. But for sure, we see potential across the metastatic prostate cancer landscape. We have generated, we think, compelling early data in the late-line mCRPC setting. We're currently enrolling patients in dose escalation in the frontline taxane naive mCRPC setting. We would anticipate based on what we've seen to date that we should have an effective drug in that population potentially. They do have lower disease burden overall, and we think our mass TCE approach should work, and we will be generating those data. And as I mentioned before, we are also going to be looking at the metastatic hormone-sensitive prostate cancer setting as well. So that gives you kind of an idea of where we're heading.

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

Congrats on the strong data. A couple from us. Given the seeming lack of strong dose response on CRS and lack of DLTs, how are you thinking about the limit on the higher end of the range of dose escalation, whether that's saturating on enzymatic activity or otherwise? And second question, how are you guys thinking about the partnership with Astellas and optionality for combining VIR-5500 with other ARPIs beyond enzalutamide?

Thank you, Sean. I'll address your second question. In collaboration with Astellas, we will be defining our future combination strategy, which could potentially extend beyond just the ARPIs. However, we will provide you with updates on that at a later date. Regarding your first question, which concerns the dose...

Yes. So you're asking about dose response for CRS and efficacy and what's the limit of the dose on the high end. So a couple of points there. I mean our whole goal has been to maximize and optimize the therapeutic window to get the best possible safety with the minimum possible adverse events and CRS. So we've taken a careful look across the data set on all the efficacy parameters and safety parameters, including PSA, including RECIST, PSMA PET, all the safety events, CRS, et cetera. And we think we've gotten to a range in the 3,000 to 3,500 maintenance dose, and we have a specific dose there, which we can communicated in combination with our partner at a later date where we think we really optimize the therapeutic index and can move forward into expansion cohorts in Q2 of this year.

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

Congratulations on the clear update. I would like to follow up on an earlier question about durability. Can you share your thoughts on how we might connect PSA declines with PFS, particularly as a potential leading indicator? When do you expect to have data to update the market on this? Additionally, regarding the six patients with evaluable PSA but not RECIST, can you explain why those results weren't available at baseline and what your expectations might have been for their response, considering many showed significant PSA declines? What can you tell us about the disease control rate or related outcomes?

Your first question relates to the relationship between durability and how PSA declines will align with PFS. Generally, deeper PSA declines, especially PSA90s and PSA99s, indicate more durable responses, and we are pleased to observe significant PSA declines in these categories. Regarding radiographic PFS, you are correct that we did not share that data in this update because it is still developing, particularly for the high-dose cohorts, and we need more time for the patients to mature. Therefore, that data isn’t ready yet. As for when we will present further data, we will provide guidance on that at a later date. Could you please clarify your second question? I wasn't entirely certain about what you were asking regarding the patients who were not PSA evaluable.

There were 6 patients with a PSA like out of the 17, and 6 were not evaluable for RECIST. Was the issue that you couldn't obtain the baseline scans? Also, what do you expect in terms of progression-free survival for those patients?

Yes, thank you for clarifying. I appreciate it. In the cohort of 3,000 or more, we had 22 patients. Among those, 17 were PSA evaluable. Two of the patients had early data at the time of the clinical cutoff, so we will receive their subsequent PSA values, but they weren’t included in the dataset. Out of five patients, two are early and three discontinued early, meaning they won't provide PSA data. This is quite common in late-line prostate cancer trials, as these patients typically have significant disease burden. We have 11 patients who can be evaluated by RECIST criteria, and among them, we had five responses: four confirmed and one pending confirmation, which we expect to receive between week 9 and week 18.

This concludes the call. Thank you for participating.