Vir Biotechnology, Inc.

call is being recorded. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question, you may press star followed by the number one on your telephone keypad. To withdraw your question, you may press star followed by the number one again. I will now turn the call over to Rich Lepke, Senior Director, Investor Relations. You may begin, Mr. Lapkin.

Thank you, and good afternoon. With me today are Dr. Marianne DeBacher, our Chief Executive Officer, Dr. Mark Eisner, our Chief Medical Officer, Jason O'Byrne, our Chief Financial Officer, and Dr. Mika Dering, our Executive Vice President of Oncology, who will be available during the Q&A session. Before we begin, I would like to remind everyone that some of the statements we are making today are forward-looking statements under the securities laws. These forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, future results, performance, or achievements to differ significantly from those expressed or implied by such forward-looking statements. These risks and uncertainties and risks associated with our business are described in the company's reports filed with the Securities and Exchange Commission, including Forbes 10-K, 10-Q, and 8-K. Please note that any cross-trial comparisons discussed today are not based on head-to-head studies and have inherent limitations, and caution should be exercised when interpreting such comparisons. With that, I'll now turn the call over to our CEO, Marianne DeBacher.

Thank you, Rich, and good afternoon, everyone. Thank you for joining us for our fourth quarter and full year 2024 earnings call. I'm truly excited to share our progress with you today. 2024 was nothing short of transformative for Vier Biotechnology. As I reflect on the past year, I'm incredibly proud of what we've accomplished. We've made significant strides in our oncology and infectious disease programs, positioning Vier Bio at the forefront of innovative therapies in these areas of critical unmet medical need. Our strategic focus on T-cell engagers and hepatitis has not only yielded promising results, but has also positioned us well for future growth and value creation. This focused approach allows us to allocate our resources efficiently and make meaningful progress across our pipeline. Now let me start with our infectious disease portfolio. We are moving full steam ahead with preparations for our Eclipse Phase III program in hepatitis delta, which we expect to initiate in the first half of the year. The regulatory designations we've received, US FDA breakthrough therapy and fast-track designations, as well as EMA prime designation and orphan drug status, underscore the potential impact of our combination regimen and the significant unmet medical need. We believe the market for hepatitis delta therapies shares characteristics with orphan diseases, including lack of efficacious treatment options, severe clinical outcomes, and the potential for value-based pricing that appropriately reflects the clinical benefit our therapy may offer. Current treatment options are limited, especially in the U.S., where there are no approved therapies. Hepatitis Delta virus requires hepatitis B surface antigen to complete its life cycle. Our combination therapy of Tobevibart and Elapseron offers a unique approach by reducing hepatitis B surface antigen through two distinct and complementary mechanisms. So Bevibart, an FC-engineered monoclonal antibody, is designed to block viral entry and neutralize virulence, while Elapseron, a small interfering RNA, aims to reduce hepatitis B surface antigen production by degrading HPV mRNA. This dual prompt strategy addresses both hepatitis delta and hepatitis B replication simultaneously, potentially offering comprehensive and durable viral suppression. We believe this approach has the potential to address the significant unmet need in chronic hepatitis delta and become a new standard of care. Now turning to our exciting progress in oncology. As many of you know, we held a successful T-cell engager investor event on January 8. The data we presented for VR5818, our HER2-targeted T-cell engager, was very promising. We saw promising early signs of clinical activity, particularly in colorectal cancer, with an encouraging safety profile. Our PSMA-targeted T-cell engager, VR5500, also showed strong early results in prostate cancer. with impressive PSA responses and a favorable safety profile. The activity we observed clinically is a clear indication that our dual mask construct is being cleaved and activated as intended. These results, now across two clinical programs, validate the potential of the ProX10 platform to address significant unmet needs in solid metastatic tumors. We are also making great progress with VR5525, our EGFR-targeted T-cell engager. We are on track to initiate the phase one study in the first half of this year. Importantly, we have secured worldwide rights to the ProX10 platform in both oncology and infectious diseases. This gives us a powerful foundation for future growth as the platform's universal plug and play masking technology can be applied to both existing as well as novel targets. This capability not only supports our current pipeline, but also provides us with significant flexibility to expand into additional high value indications in the future. In hepatitis B, we're looking forward to sharing functional cure data in the second quarter. It's important to note that we would take this program forward only with a commercialization and development partner. Our financial position remains strong with the cash runway expanding into mid-2027. This solid foundation is the result of our achievements since late 2023, where we significantly reduced our operating expenses and cash flow. We're maintaining a disciplined approach to capital allocation, focusing our resources on our most promising programs. At the same time, we're actively exploring partnership opportunities to maximize the value of our broader pipeline. As you'll hear in more detail shortly, our 2024 financial results reflect both our strategic investments and our commitment to fiscal responsibility. As we look to 2025, I'm confident that our strategy sets us up for long-term success and value creation. With that, I'll now turn the call over to Mark to provide an update on our clinical development program.

Thank you, Maryam. We've made significant progress in clinical stage programs, and I'm looking forward to sharing the details with you today. Let's start with our Hepatitis Delta program, which continues to be a key focus for us. We're making excellent progress towards initiating our Eclipse Phase 3 program in the first half of this year. These studies will form the basis of our marketing applications. Before we dive into the Eclipse program, let me briefly recap our solstice phase two data, which has given us confidence to move forward with our phase three program. We saw impressive virologic responses across multiple cohorts. To provide some context, when we refer to HDV RNA target not detected, or TND, we mean there is no measurable presence of the virus in the blood. This is the most stringent measure of viral suppression we can achieve with current testing methods. In our de novo combination therapy arm at 24 weeks, 41% of patients achieved HDV RNA levels below the target not detected threshold. Even more impressively, this increased to 64% of patients at week 36. In our rollover cohort, which provides our longest follow-up data, we saw even more encouraging results. At week 60, four out of five patients, or 80%, achieved target not detected levels. This suggests the potential for durable and deepening responses with our combination therapy over time. Importantly, we also observed significant declines in hepatitis B surface antigen levels. At week 24, approximately 90% of participants receiving the combination of tabivibart and lepsiran achieved surface antigen levels below 10 IU per ml. This is a crucial finding because reducing hepatitis B surface antigen is essential for controlling both hepatitis B and hepatitis D virus replication. Additionally, the combination of tabivibart and lepsiran demonstrated a favorable safety profile across all cohorts. Our approach has garnered significant regulatory support, which speaks to the potential impact of our therapy. We've received breakthrough therapy designation and fast track designation from the FDA. The EMA has granted us prime designation and orphan drug status. These designations could help accelerate our development and review process, potentially bringing this much needed therapy the patient sooner. Turning to our hepatitis B program, we are looking forward to sharing functional cure data in the second quarter of this year. This functional cure data will be a crucial milestone for this program. I want to reiterate that we would pursue the development of this program only with a partner. I'm very excited about the progress we've made in our infectious disease programs. We're on the cusp of potentially changing the treatment landscape for hepatitis delta, and we're looking forward to sharing our hepatitis B functional data. Now, let me shift gears to discuss our oncology portfolio to discuss the significant progress we've made with the ProExtend platform. As Marianna mentioned, we've shared compelling data at our investor event in January, and I'd like to dive deeper into those results. Before we get into the specifics of each program, let me briefly recap the ProExtend platform. This innovative technology allows us to create dual-masked T-cell engagers designed to be selectively activated in the tumor microenvironment. The key advantage is the potential for a wider therapeutic window allowing for higher dosing and improved efficacy with reduced systemic toxicity. The ProX10 masks are unstructured and hydrophilic, acting as a shield to prevent T-cell engagement in normal tissues expressing the target antigen. Importantly, their fluid nature also allows access to the cleavable linkers, enabling efficient activation when in the protease-rich tumor microenvironment. The ProX10 masks are universal and have been clinically validated, as seen in L2VO, and approved therapy for hemophilia. Ultuvio contains three protease cleavage sites that are quickly cleaved in a high protease microenvironment of a clot during the clotting cascade, demonstrating the ability of the ProXtend system to enable efficient and tightly regulated unmasking. We believe this approach could overcome many limitations seen with traditional unmasked T-cell engagers and the validated nature of the platform gives us confidence in its potential application across our oncology programs. Let's start with the VR5818, our HER2-targeted T-cell engager. We've seen encouraging efficacy signals across multiple HER2-positive tumors, particularly in colorectal cancer. At doses of 400 micrograms per kilogram and above, we observed a 33% confirmed partial response rate in colorectal cancer patients. It is important to note that these patients had exhausted all standard of care options and were heavily pretreated, with many having received multiple prior lines of therapy, including HER2-targeted treatments. Additionally, one of these three responses was observed in a patient on the every three-week dosing schedule. I'd also like to highlight a compelling case we presented at our recent investor event, which speaks to the potential for durable responses. A patient with HER2-positive colorectal cancer who progressed through six prior lines of therapy, including HER2-targeted agents, achieved a partial response. Remarkably, this response has been sustained for over 18 months, with the patient still on study as of our last data cutoff. Crucially, we've observed efficacy in microsatellite-stable or MSS colorectal cancer tumors, which typically are resistant to immunotherapies. This suggests FEAR-5818's ability to overcome the immunosuppressive tumor microenvironment in these hard-to-treat patients. To put these results in context, it's important to note that for patients who have exhausted multiple lines of treatment, Current regimens like Lonserf plus Befacizumab typically show objective response rates in the single digits. Our early results, therefore, are particularly encouraging in this heavily pretreated population. The safety profile of VR5818 has been favorable with no high-grade cytokine release syndrome or CRS and without mandatory prophylactic corticosteroids. We're continuing dose escalation on an every three-week schedule to optimize efficacy while maintaining this favorable safety profile. We're also exploring combination strategies, including with pembrolizumab. It's worth noting that VIR-5818 utilizes the pertuzumab binding epitope, which enables potential combination strategies with trastuzumab-based therapies in an earlier line setting. Turning to VIR5500, our PSMA-targeted T-cell engager for prostate cancer, we've seen impressive early results in our ongoing phase 1 dose escalation study. Among the 12 patients treated in the efficacious dose range, 100% experienced PSA declines, with 58% achieving a PSA50 response and 8% achieving a PSA90 response. This is particularly encouraging given the heavily pretreated nature of this population in the early stage of dose escalation. Like VERA5818, VERA5500 in early dose escalation has a favorable safety profile with minimal high-grade adverse events and no grade three or higher CRS. Notably, these results have been achieved without the use of prophylactic corticosteroids or anti-IL-6 therapies, which are often required with other T cell engagers, including masked T cell engagers. Importantly, we have not observed any cases of on-target, off-tumor toxicities, such as hearing loss, which have been reported with other PSMA-targeted therapies. We're continuing dose escalation, and based on our favorable safety profile, we believe there's significant room to potentially improve efficacy further. As we move to higher doses, we expect to see deeper and more durable responses, which could significantly improve outcomes for patients with prostate cancer. We're also actively exploring every three-week dosing, which could be a significant advantage, especially in earlier lines of therapy. This potential for less frequent dosing is supported by VERA 5500's pharmacokinetic profile which shows a half-life of 8 to 10 days. The potential for less frequent dosing, combined with the encouraging efficacy and safety profile we've observed, could offer meaningful benefit to patients across various stages of prostate cancer treatment. Importantly, these results have been achieved without the need for prophylactic corticosteroids or anti-IL-6 therapies. For VR5525, our EGFR-targeted T-cell engager, we're on track to initiate the Phase I study in the first half of this year. This program has potential to address multiple high-value indications, including non-small-cell lung cancer, colorectal cancer, and head and neck cancer. We're leveraging our learnings from VERA 5818 and VERA 5500 to optimize the study design and dosing strategies. Based on our experience with the ProExtend platform and the successes we've seen with our other T cell engagers, we're confident in our ability to achieve a broad therapeutic index with VR5525. Looking ahead, we anticipate sharing additional data from our ongoing dose escalation studies for VR5818 and VR5500. While the exact timing is still to be announced, we expect to present more mature data at higher doses for both programs. This will include results from both weekly and every three-week dosing schedules, which we believe will provide valuable insights into the optimal dosing regimens for these therapies. In conclusion, I'm very excited about the progress we're making across our oncology portfolio. The early data from our T-cell engager programs are further validating of the ProExtend platform, demonstrating both efficacy and the ability to dose higher than traditional unmasked approaches. We believe we're well positioned to redefine the treatment landscape for several challenging solid tumors. Our team remains focused on executing our clinical development plans and unlocking the full potential of these promising therapies. With that, I'll now hand the call over to Jason.

Thank you, Mark. I'm really pleased to share that our hard work on right-sizing the cost structure, improving efficiencies, and making thoughtful investment is paying off. Since late 2023, we've taken significant steps to streamline operations and focus on our most promising programs. We've implemented two restructurings, closed two sites, and deprioritized certain programs. Then in September, we executed the agreement with Santa Fe to license three dual-mask T-cell engagers, and the ProX10 technology. While this added modestly to our cost structure, including approximately 50 new team members from Sanofi, it significantly expanded our pipeline and brought in critical expertise in oncology, T-cell engager clinical development, and masking technology. This, combined with our existing expertise in protein engineering and immunology, positions us well for future growth and innovation. During our budget process last fall, we applied further financial discipline, culminating in our January 8th announcement to advance our HBV program only with a development and commercialization partner. Many of these actions have led to substantial improvements in our financial performance. Let me highlight a few key financial metrics for 2024 compared to 2023. R&D expenses for 2024 were $507 million, compared to $580 million in 2023. This decrease was achieved despite absorbing approximately $103 million in Santa Fe transaction expenses related to our licensing agreement. Excluding this one-time transaction-related expense, our R&D spending decreased by approximately $176 million, or about 30% year-over-year. reflecting our continued focus on cost management and program prioritization. G&A expenses decreased to $119 million in 2024 from $174 million in the prior year. This significant reduction, reflecting a 32% decrease year-over-year, was primarily achieved through multiple cost-saving initiatives implemented since late 2023. As a result, our net loss for 2024 was $522 million, compared to $615 million in 2023. Excluding the $103 million Santa Fe R&D transaction expense, our net loss for 2024 was $419 million, representing a decline of approximately 32% from the previous year. We ended 2024 with 408 employees compared to 587 at the end of 2023, representing about a 30% year-over-year reduction. It's important to note that the 408 includes approximately 50 employees who joined us from Sanofi as part of our licensing agreement. Now turning to cash. Our 2024 net cash consumption was roughly 532 million. Excluding approximately $179 million of Santa Fe transaction-related items, the decrease to cash and investments for 2024 was approximately $354 million. We're starting 2025 with a strong financial position of $1.1 billion in cash, cash equivalents, and investments. It's important to note that this 1.1 billion figure already excludes the 75 million pending EGFR milestone, which is currently in escrow and classified as restricted cash. Based on our current operating plan, we anticipate this will provide runway into mid-2027. As we look ahead to 2025, I want to emphasize that our capital deployment strategy remains focused on our most promising programs. Our priorities for the year are, first, We'll accelerate Eclipse clinical enrollment and initiate activities toward registration. Second, we'll invest in VIR 5500 to rapidly advance the program, capitalizing on the very encouraging PSMA data that was shared in January. Third, we'll continue enrolling patients in VIR 5818, potentially leveraging the promising early data we see in HER2-positive colorectal cancer. Fourth, we'll initiate the phase one study for VR5525 in patients with EGFR expressing solid tumors. And finally, for our Hepatitis B program, we continue to pursue a partnership strategy. We believe this approach will maximize the value of the asset while allowing us to focus our internal resources on our lead programs. In closing, I'm confident that our $1.1 billion in cash will fund these priorities into mid-2027 based on our current operating plan. This reflects our ongoing commitment to disciplined capital allocation, ensuring we have the resources to advance our key programs while maintaining financial flexibility. With that, I'll hand it back to Rich to initiate the Q&A session. Thank you, Jason.

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

time, we will begin conducting our analyst Q&A session. To ask a question, you may press star followed by the number one on your telephone keypad. To withdraw your question, you may press star followed by the number one again. For our analysts, please raise your hand to indicate you would like to join the queue if you have not done so already. Once you hear the operator announce your name, you can unmute your line and ask your question. We ask that you please limit your questions to two. Please hold for a moment while we call for questions. The first question comes from Jenna Wang from Barclays. Your line is open.

Hi, this is Hang Hu on behalf of Jenna Wang from Barclays. So we have two questions. First one is for TCO Engager. So you are using the cleavable linker. So can you elaborate the mechanism for the cleavage, and how efficient is the cleavage in the tumor microenvironment, for instance, for the single cleavage and for dual cleavage? And the second question is for HDV. So regarding the Eclipse, registrational studies start in the first half of the year. So what additional steps you need to start this trial And we understand this is event driven, but what is your estimated timing to complete the enrollment? Thanks.

Thank you very much for that question. I'll ask Mika to address the first one related to the mechanism of action related to cleavage of the leakers.

Yeah, thank you for that question. So we believe that we're getting efficiently cleavage for both masks and the reasons for this is that we've seen really nice activity in both the HER2 program as well as the PSMA program, both having the double mask and both having the same Pro Xtend masking technology, as well as both having the same Protease linkers on both sides of the linkers. In addition to that, seeing that activity that appears to be tumor-specific, as we've not seen any significant toxicity in the periphery, very minimal CRS, and the absence of prophylactic, widespread prophylactic corticosteroids. We're really seeing, you know, that tumor-specific cleavage. Besides that, the same exact Xtend masking technology is used in an approved drug, L-tuvia, as Mark had mentioned. This drug is a hemophilia drug. It has the same Xtend Max and it uses three thrombin cleavage sites. And it is efficiently cleaved, three sites, in the setting of a clot where you have efficient thrombin activation, efficient cleavage, and clotting as needed. as well as not having clotting in the state where there is no activated clotting cascade. So the efficiency of being able to cleave three sites, there's nothing about the Xtend Max in of itself that prevents access to the cleavage sites. Three sites versus two sites versus one site. Tumor microenvironment is known to have very high protease activity, so we don't think that the number of sites is really an issue in terms of efficiency of cleavage.

Thank you, Mika. So as to your second question related to additional steps before starting our Eclipse trial, I will ask Mark to address that.

Sure. Thank you for the question. So we are on track to initiate the Eclipse program in the first half of this year. The team is working with a high sense of urgency and excitement to get these trials up and running. We're confident that we will be able to initiate these trials in the near term and efficiently recruit patients because of the high on that need in HTV and our very compelling solstice phase 2 data. So we're working quickly to get these studies up and running, and we will provide some updated guidance at a future point.

The next question comes from Paul Choi from Goldman Sachs. Your line is open.

Hi. Thank you. Good afternoon, and thank you for taking our questions. My first question is on the 5525 EGFR TCE program. Can you maybe, you know, paint for us a picture of what sort of patients you're envisioning for your phase one study? Are you going to allow sort of met-experienced, met-treated-experienced patients or patients who have been treated with J&J's rib event by specific? be enrolled into your study. Any sort of color to understand what population you'll be there would be great. And my second question is on the HEP-B program. Realize that the March B data is coming up here next quarter fairly soon. But as you sort of think about, you know, sort of go, no-go criteria for the future, even though you plan to partner it, can you maybe just again, refresh your views on what you think is sort of clinically meaningful here and what you think would potentially be attractive to a theoretical development partner. Thank you.

Yes, thank you, Paul. On the hepatitis B program, our go, no-go criteria of Mark to address.

Sure. Thanks for the question, Paul. So, as you said, we will have our functional cure rate data second quarter of this year. In particular, this is going to be the functional tier data 24 weeks off treatment. You know, we had compelling results at the end of treatment at 48 weeks. In the surface antigen low patients, we had 39% S loss in the doublet with the bibigard and leptoran, and 46% S loss in the triplet, including pegylated interferon. In terms of go-no-go criteria, what we said before is we're looking for a 30% functional cure in the triplet, 20% in the doublet. Generally speaking, that's based on our care well interactions and what could be clinically meaningful. I think it's also maybe worth mentioning that GSK's Dr. Roberson had a 16% functional cure, and they're in phase three based on that. Their phase three program will weed out early next year, but that kind of gives you a little bit of context for what's been achieved so far. So we will be partnering this program and engaging with partners once we have the functional cure data, and I hope it gives you a little bit of context for what we're looking for.

So I can answer the EGFR question. So this is a pretty standard first in human phase one study. and in such that patients must have exhausted all current standard of care to be enrolled on study, which means that they must have exhausted standard approved drugs, but we will allow for patients who may have been on any prior experimental drugs as well. So we typically do get a smattering of different types of patients. We are enriching for patients who have EGFR as a target that's important, such as lung cancer, head and neck, pancreas, and colorectal cancer. But other than that, we're probably going to have patients with a variety of different prior treatments.

The next question comes from Mike Alls from Morgan Stanley. Your line is open.

Hey, it's Avi Novick on the line from Mike. Thank you for taking our questions. So I guess number one on 5525, given the strong safety profile you've seen in the Phase I studies of 5818 and 5500, do you see a read-through to 5525, and do you believe you can possibly more aggressively escalate doses in the upcoming Phase I study? And then my second question is, what are you thinking with respect to...

disclosing data for 5525 do you think you would maybe plan to do an initial data update as you did for 5818 and 5500 or wait for more mature data thanks yes thank you for that question as you know there have been significant learnings from the HER2 program that were translated to the 5500 program and you know the PSMA program could start at the higher dose and escalate more swiftly compared to the original 5818 program. So we expect that, you know, we will continue to learn across the clinical programs and that these learnings will benefit us also as we go into the 5525 program. Anything you want to add, Mark or Mika?

I mean, the only thing is that, you know, EGFR is broadly expressed in normal tissue, which makes it different from the PSMA program where, Of course, there is PSMA expressed outside the prostate. And then the HER2, there is HER2 expressed in lung and heart and other normal tissues. But UGFR is broadly expressed. So we're looking forward to this program because it will be a really vigorous test of our dual masking approach and the specificity for unmasking the tumor microenvironment, whether we can achieve an excellent therapeutic index. in EGFR-positive tumors, as Mika alluded to before. But to Mary Ann's point, yes, I mean, the learnings from the earlier two programs have and will continue to inform 5525 and further programs, so we do expect to be efficient in how we conduct that.

Yeah, and I might just also add in that, you know, from the HER2 program, again, EGFR molecules will use the same pro-extend technology, the same protease linkers, et cetera, With a HER2 program, you know, we've seen a prior naked T cell, HER2 T cell engager that had a grade four CRS at 0.5 micrograms per kg and IL-6 levels in the 10,000 picomole per mil range, suggesting that there's plenty of normal expression of HER2 enabling that significant CRS. But when you look at our 818 double mass molecule, Our start dose was one microgram per gig, so higher than this fully unmasked HER2 drug GBR1302 that was in the clinic many years ago. So we do believe with that very wide therapeutic index that we've seen for this HER2 double mask that that will give us confidence on the 5525.

The next question comes from Rowan Ruiz from Living Partners. Their line is open.

Hi, this is Mazie Ali-Mohamed on for Rowan Ruiz. Thanks for taking our questions. But first, so given the early clinical response signals in the heavily pretreated patients, what are your thoughts of potentially moving the cell engagers into earlier lines of therapy in future trials? And also, Could you elaborate on how machine learning and antibody engineering, your background in that, and those capabilities are being applied to optimize design and efficacy of your T-cell indicators?

Yes, thank you for that question. As to moving to earlier lines, maybe Mark, you can address that.

Sure. So, yes, you are correct that in both the HER2 and PSMA programs, You know, the basket trial for HER2, PSMA is all metastatic castration resistant prostate cancer, but they're heavily pretreated patient population, very heterogeneous in terms of their clinical features and prior treatment history. So that is where we are starting. For the PSMA program, of course, we are interested in getting into earlier lines of treatment. This is something that we will talk more about in a future time, but clearly that is of interest. In terms of your question about the DAISY machine learning and how to optimize the TCE platform, I mean, I think one of the beautiful parts about this deal bringing in the Ammunex platform and the people with it is that we can apply our antibody discovery platform in our DAISY AI abilities to optimize the next generation of T cell engagers. So we are using that to more rapidly identify and optimize the binders for the next generation of T cell engagers. So I think there's a real synergy there between, you know, our VIIRS antibody discovery and optimization platform that's AI driven, and the T-cell engager platform that we now have in-house.

Yeah, I would just add that, you know, our protein engineering platform is really such that, you know, we start with a starting point of a protein. It could be an antibody. It could be a bite or, you know, a single chain or whatever it might be. And then we deploy basically a compilation of different models to come up with molecules that have increased characteristics. you know, better potency, you know, increased developability and so on. And it's a combination of both internal models and external models, so large protein models and a lot of internal data that we have generated over the years that together gives us, you know, an output that we can quickly test in biological models and that sort of feeds back into the database.

The next question comes from Eric Joseph from JPMorgan. Your line is open.

Hi, this is Billy. I'm for Eric. Thanks for taking our questions. Quick one on the dosing frequency for the EGFR. You've pushed to go to two, three weeks with the other two. Is this something that you continue with the EGFR?

Yeah, so we are looking at both Q week and Q3 week for both the HER2 and the PSMA program, and we are planning to do the same for the EGFR. We're encouraged that the half-life so far for both of our clinical programs are very encouraging and that for the HER2 program appears to be safe and efficacious at both schedules.

Great. Thanks for taking our question.

The next question comes from Phil Nadeau from TD Cohen. Your line is open.

Good afternoon. Thanks for taking our questions. Two from us. The most common question we currently get on VEER is about the expectations for a dose response for 5500. I'm sure you get that same question. Can you talk a little bit more about What gives you confidence that higher doses will produce deeper, more durable PSA responses, given that there wasn't a clear dose response in the initial data? That's the first question. Second question, on the timing of the next updates for 5,500 and 5,818, we appreciate it's too early to give specific timing guidance, but could you speak to what you hope to have in the next update in terms of quality and quantity of data? Will you wait for some certain number of patients in the trials? Or do you want to wait for the phase two dose? Some sense of kind of what you hope to accomplish before giving us the next update would be helpful. Thank you.

Yeah, thank you, Phil. I mean, we are really trying to, as you mentioned, balance communication of data that is really meaningful with the need to draw important conclusions as to our next steps from And, you know, as you know, both programs are in dose escalation. We just discussed we're exploring two different, you know, dosing frequency models. We are exploring combination with PEMRO. So a lot of data that needs to read out of safety, efficacy, durability, and so on. So as that data develops, you know, we will, as soon as we have really meaningful updates, of course, share that with you all. As it relates to the dose response, yes, we do get that question quite often. So either Mark or Mika, do you want to address it?

Yeah, I think what we tried to emphasize in our investor event last January is that this is very early in the PSMA program in terms of dose escalation. And we believe we presented compelling early signs of efficacy in terms of PSMA, I'm sorry, PSA declines and excellent safety with minimal CRS and, you know, minimal toxicity. So we have a lot of room to move on the dose. So we've been escalating the dose both in Q week and Q3 weeks, and we are anticipating to see, you know, deeper and more sustained efficacy as we escalate the dose in that program. The other thing maybe to mention is that, you know, we have now shown good, compelling, early signs of efficacy and safety of both the HER2 and PSMA program. So we're really validated, we think, the platform and the dual-masked nature of the platform and the specificity of our ability to unmask these molecules in the tumor while maintaining a very high safety profile. Maybe just to mention one other thing, which is in that colorectal cancer patient we referred to today and that we presented you know, in our investor event in the HER2 program that when we escalate the dose from 60 to 600 micrograms per kilo in that patient, we start deepening, you know, anti-tumor responses. So that patient's an example of what can happen as we escalate the dose. Now, of course, the PSMA program's even earlier, and we are, you know, we're continuing to escalate the dose, but we anticipate with higher doses, we'll see better efficacy with acceptable safety.

The next question comes from Alex Chenahan from Bank of America. Your line is open.

Hey, guys. Thanks for taking our questions. Just two quick ones from us. First on 5525, apologies if this was already asked, but just on the need for steroid prophylaxis, do you think you'd approach this similarly to studies for for your other two assets or maybe a different approach just given the breadth of the EGFR expression. And secondly, appreciate the additional preclinical mass TC targets are undisclosed, but I guess as you're approaching maximizing the value of the ProExtend platform in oncology, is your development process driven more by de-risked targets or areas of high unmet need maybe with a novel target? Thank you.

Yeah, thank you, Alec. Maybe I'll address the second question. So since we announced the data on January 8, you know, it has been quite a bit of outreach as it relates to our platform. And so we have for ourselves defined a set of targets that we would believe would be highly valuable as next programs, but we also are, you know, getting educated on what some potential partners might be interested in. So, you know, we will certainly share going forward some more insight into how we are thinking about what next preclinical programs could be that really take advantage of the ProExtent platform because we do want to make sure we export that value out of the platform. And again, with promising data across two clinical programs, we think there's a high belief in the potential there. As it relates to the need for prophylactic corticosteroids, Just clarifying that we did not use any in our prior programs, and for 5525, the same is true.

I don't know, Mark, if you have anything to add. Yeah, so we've built quite a bit of confidence with this platform with the other two drugs. Again, not having to use prophylactic steroids with really minimal CRS, very minimal IL-6 levels. So, for the 5525, we are starting that study without any prophylactic steroids.

The next question comes from Joseph Stringer from . Your line is open.

Hi. Thanks for taking our questions. A financial one from us. Can you just remind us of the details of the collaboration agreement with Alnylam on the led saran component i believe it's a cost profit share but just want to make sure the details on the cost share uh i guess my question is around the financial impact of this does el nile have optionality coming up for that asset and is that potential decision built into some of your opex and cash burn assumptions over the next few years and then as a follow-up how does that current collaboration agreement impact your potential partnership negotiations for the HPV program? Thank you.

Yeah, thank you for that question. So our collaboration agreement with Alnylam starting from 2017 is a pure financial arrangement. So there's no operational role that Alnylam is playing in the development nor the commercialization. Alnylam does have an option to either, you know, step into the program and share 50% of the cost as it relates to the elapsed run component of the regiment. And then, of course, also share, you know, the commensurate percentage of the profit or opt out and have a typical type of milestone and royalty deal. So that is an option that Alnylam still needs to decide on. You know, the impact on any partnership related to HPV, you know, both are possible. I mean, again, because the nature of the deal with onilin is a pure financial one, it doesn't preclude from a large pharma partner to step in and take an operational role on the clinical development and commercialization. Obviously, it would be easier if there was sort of one partner for the program, but both are possible.

Could I just add on this? Further details will be in the 10-K on the El Nilem agreement. And just as you think about our runway, we have sort of assumed a worst case in the shorter term, which is that El Nilem opts out in the shorter term if they opt in and do a profit share, that would potentially be upside.

The next question comes from Patrick Trucchio from HDV Ride. Your line is open.

Thanks. Good afternoon. Just a couple of follow-ups from me on the HDV program. I'm wondering now as more time has passed and you've had more time to kind of digest the data from solstice, if there's been any further learning that could help inform the Eclipse program. And then separately, I was just curious if you could talk more about the relative importance of demonstrating that robust reduction in HB surface antigen in the hepatitis delta setting and how we should think about this reduction for combination treatment relative to the monotherapy antibody, particularly as we think about long-term outcomes in this chronic treatment setting with Delta.

Yeah, thanks for the question. So, in terms of solstice, just to recap for everyone, I mean, we did see at 24 weeks 41% of patients reaching complete viral suppression or target not detected at 24 weeks, 64% at 36 weeks, and in the 80% range, at 60 weeks in the rollover cohort. So I think we're really seeing, you know, unprecedented levels of viral suppression of the Delta virus. So we're very excited about that. And we're very keen to move into the Eclipse program. You know, obviously, we've learned a lot about Delta, both in terms of the data, but importantly, about the demographics of the disease, where the patients reside. And I think those learnings are really informed how we've approached site selection, investigator selection, and things of that nature. So, you know, we're not prepared to share more details about that today, but essentially, that's going to help us, I think, really optimize our Phase III program. In terms of your question about hepatitis B surface antigen reduction, yes. In the combination of tabivirgard and elapsorin, you know, we are seeing three log reduction hepatitis B surface antigen, which is much, much greater than our monotherapy with the antibody to Vivivar, which is a one-law reduction. We think this is really important because it shows the potency and the depth of antiviral effect of our combination therapy. It shows that we are as hepatitis B surface antigen is critical for a delta life cycle and forming nebureon, that this just really, you know, taken together with the very profound viral suppression data that, you know, we really think we have a very, very good chance of long-term viral suppression for patients. In terms of long-term outcomes, you know, I can speculate that, you know, because we can achieve such deep and durable suppression of Delta virus and HPV surface imaging that we hope that will translate into better outcomes for patients, less progression to cirrhosis, less progression to liver cancer and other poor outcomes. Of course, we have to demonstrate that, but the virus does drive those poor outcomes. So we do think that suppressing the virus as well as we can with our combination should lead to better outcomes for patients. We're very excited about the program, and we're moving with all haste to our Phase III initiation.

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

Thank you, operator. As we conclude, I'd like to emphasize the significant strides that we have made in 2024 and our exciting path forward. We've successfully transformed your biotechnology into now a dual platform company with promising advancements, as you have heard, in both infectious diseases and in oncology. Our hepatitis Delta program, as Mark just mentioned, is poised to enter phase three trials, while our innovative T-cell engagement platform has shown those really encouraging early results across multiple solid tumor types. A strong financial position with a runway extending into mid-2027 also provides us with the resources to advance our key programs through critical value interaction points. So we remain committed to our mission of harnessing the power of the immune system to transform patients' lives, and we are more confident than ever. and our ability to deliver on this promise. Thank you all for your continued support and for joining us today. We look forward to updating you on our programs in the coming months. Operator, you may end call.

Ladies and gentlemen, that concludes today's call. Thank you all for joining, and you may now disconnect.