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Mark Eisner

Thank you, Marianne. I'm pleased to provide an update on our clinical development programs. We've made significant progress across both our infectious disease and oncology portfolios during the first quarter, and I'll walk you through the key developments. Let me start with our hepatitis delta program, where we've achieved an important milestone with the initiation of our registrational ECLIPSE Phase III program. I'm pleased to report that we enrolled the first patient in ECLIPSE-1 during the first quarter, keeping us on track with our development time line.
ECLIPSE-1 is designed to evaluate our combination therapy in regions where bulevirtide is not available or has limited use, including the United States. The study will enroll 120 participants randomized 2-to-1 to receive either our combination therapy or deferred treatment. The primary endpoint is a composite endpoint of HDV RNA target not detected, meaning that there was no measurable presence of the virus in the blood and ALT normalization at week 48. The key secondary endpoint is HDV RNA target not detected. We're also preparing for the initiation of ECLIPSE-2, which will evaluate switching to our combination therapy in patients who have not adequately responded to bulevirtide.
ECLIPSE-2 will have a 24-week primary endpoint of HDV target not detected. Together, ECLIPSE 1 and 2 are designed to form the backbone of our regulatory submissions in the United States and Europe. This comprehensive approach addresses different patient populations and treatment scenarios, providing a robust evidence package for regulatory review. These studies will include both non-cirrhotic participants and those with compensated cirrhosis. This broad eligibility is important as it reflects the real-world patient population and will provide valuable insights into the treatment effects across different stages of disease.
The regulatory designations we've received, breakthrough therapy and Fast Track in the United States and prime and orphan drug in the EU, reflect the significant unmet need and the potential of our approach to address it. These designations may help accelerate our development and review time lines, potentially bringing this important therapy to patients sooner. At the upcoming EASL Congress, we'll be presenting a poster showcasing data from a 24-week subgroup analysis of our SOLSTICE trial, examining the impact of baseline viral parameters and cirrhosis status on responses to our combination therapy. For our hepatitis B program, we'll be presenting 24-week post-treatment follow-up data from our MARCH Phase II study at EASL on May 9. This presentation will provide insights into functional cure after treatment discontinuation.
As a reminder, advancement of this program into further clinical development is contingent on securing a partner. Now I'd like to turn to our oncology portfolio, where we continue to make progress with the PRO-XTEN masked T-cell engager programs. Our dual masked approach is designed to selectively activate T-cell engagers in the tumor microenvironment, potentially providing a wider therapeutic window than traditional unmasked approaches. Our PRO-XTEN masked TCEs achieved this through the addition of long hydrophilic polypeptide XTEN masks that shield both the CD3 and tumor-associated antigen binding domains by a steric hindrance. Importantly, these universal masks are cleaved by proteases found within the tumor microenvironment, enabling selective activation where it's needed most.
This technology allows for higher dosing with reduced systemic toxicity, which we believe could translate to improved efficacy and safety profiles. The selective activation in the tumor microenvironment is key to minimizing off-target effects while maximizing antitumor activity. For VIR-5818, our HER2-targeted T-cell engager, we're continuing dose escalation in both monotherapy and in combination with pembrolizumab. As a reminder, our data presented in January showed a 33% confirmed partial response rate in HER2-positive colorectal cancer at doses of 400 micrograms per kilogram and above with response lasting over 18 months. This durability is particularly encouraging in this heavily pretreated population.
Importantly, as Marianne mentioned, the responses we observed in microsatellite stable colorectal cancer are noteworthy from a mechanistic perspective. These tumors typically have low tumor mutational burden and limited T-cell infiltration, creating significant challenges for immunotherapy approaches. Our data suggests that VIR-5818's ability to redirect T-cells to HER2-expressing tumor cells may provide a way to overcome these immunological barriers. The durability of response we've seen further supports the potential of this approach in a setting where patients typically experience rapid progression after exhausting standard treatment options. We remain focused on evaluating the potential of this program across multiple HER2-expressing tumor types as we believe our approach could address significant unmet needs in various solid tumors where HER2 expression plays a role.
For VIR-5500, our PSMA-targeted T-cell engager, we're advancing our dose escalation strategy in both weekly and Q3-week dosing regimens. Our January data showed that 100% of patients at doses above 120 micrograms per kilogram experienced PSA declines with 58% achieving a PSA50 response, all without prophylactic steroids and with minimal cytokine release syndrome. This favorable safety profile differentiates our approach from other PSMA-targeted therapies in development. The program continues to evaluate the potential of our PRO-XTEN dual masked approach in metastatic castration-resistant prostate cancer, a setting with significant unmet need despite recent therapeutic advances. We are particularly encouraged by the potential for Q3-week dosing.
With a half-life of 8 to 10 days for VIR-5500, we believe we can offer a much more convenient dosing schedule. This would be especially important for patients in earlier lines of treatment where quality of life considerations become increasingly significant. We've successfully evaluated multiple dose levels since the data we shared in our January 8 event and are continuing with dose escalation. This ongoing dose optimization is critical to identifying a regimen that provides the optimal balance of efficacy and safety. We believe VIR-5500 has the potential to be a best-in-class treatment option in this area of significant unmet medical need, offering a combination of efficacy, safety and convenience that could meaningfully improve outcomes for patients with prostate cancer.
Building on our progress with our first 2 TCE programs, we're now expanding our portfolio with our third clinical candidate. We're on track to initiate our Phase I study for VIR-5525, our EGFR-targeted T-cell engager during this quarter. This program has the potential to address multiple high unmet need and high-value indications with EGFR expression, including non-small cell lung cancer, colorectal cancer, head and neck squamous cell carcinoma and other EGFR-expressing tumors. The unmet need in these indications remain substantial despite recent advances with hundreds of thousands of patients diagnosed annually with EGFR-expressing tumors across these indications. VIR-5525 has the potential to address a substantial unmet need through a novel modality that harnesses the patient's T-cells to kill EGFR-expressing cancer cells.
Our PRO-XTEN dual masked approach could offer a differentiated safety profile, potentially allowing for more aggressive targeting of EGFR-expressing tumors compared to traditional approaches. The universal nature of the PRO-XTEN platform enables us to leverage our learnings from our earlier T-cell engager programs to optimize study design and dose escalation for VIR-5525. In conclusion, I'm very pleased with the progress we're making across our entire portfolio. The initiation of our ECLIPSE Phase III program and continued advancement of our T-cell engager programs demonstrates our commitment to addressing significant unmet medical needs. We remain focused on executing our clinical development plans with scientific rigor and operational excellence, always keeping in mind the patients who could benefit from these potential therapies.
With that, I'll now hand over the call to Jason.

Jason O'Byrne

Thank you, Mark. I'm pleased to share our first quarter financial performance and overall financial position. We continue to maintain a strong financial foundation while advancing our key programs, and I'll start with several key financial metrics for this past quarter. R&D expenses for the first quarter of 2025 were $118.6 million, which included $7 million of noncash stock-based compensation expense compared to $100.1 million for the same period in 2024, which included $13.6 million of stock-based compensation expense. The increase in R&D expenses was primarily driven by a $30 million payment to Alnylam and expenses related to the initiation of the ECLIPSE registrational program.
These increases were partially offset by lower R&D expenses associated with past headcount reductions, deprioritized programs and the closing of our St. Louis, Missouri and Portland, Oregon sites. SG&A expenses for the first quarter of 2025 were $23.9 million, which included $7.1 million of stock-based compensation expense. compared to $36.3 million for the same period in 2024, which included $10.2 million of stock-based compensation expense. The decrease was largely due to ongoing cost savings realized through headcount reductions and other initiatives.
Combined, our first quarter operating expense of $142.6 million increased modestly by approximately $6 million year-over-year. Net loss for the first quarter of 2025 was $121 million compared to a net loss of $65.3 million for the same period in 2024. The higher net loss was largely driven by $52 million of revenue in the first quarter of 2024 compared to approximately $3 million of revenue in the first quarter of 2025. Turning to cash. Our net cash consumed in the first quarter was $75.6 million, which is in line with our expectations.
We ended the quarter with approximately $1 billion in cash, cash equivalents and investments. Based on our current operating plan, we continue to project our cash runway extending into mid-2027. This provides us with the resources to advance key programs through planned value inflection points. As Marianne mentioned earlier, Alnylam has elected not to opt into the profit-sharing arrangement for elebsiran. As a result, we recognized $3 million as R&D expense in the first quarter, which was paid in cash to Alnylam in April of this year.
This payment reduced potential future development and regulatory milestones that were described in our most recent 10-K from $175 million to $145 million. The amended terms are further described in our first quarter 10-Q. The agreement with Alnylam remains a milestone and royalty-based arrangement. This was our base case outcome and was assumed in our current runway guidance. Our capital deployment strategy remains focused on our most promising programs, advancing our hepatitis delta ECLIPSE registrational studies with ECLIPSE-1 continuing to enroll and preparations underway for ECLIPSE-2 and ECLIPSE-3; continuing dose escalation for our T-cell engager programs, VIR-5818 and VIR-5500; and finally, initiating and advancing the Phase I study for 5525.
For our hepatitis B program, any further development will be contingent upon securing a development and commercialization partner. We continue to apply financial discipline as we deploy resources toward advancing these key programs to create value and benefit for patients. With that, I'll hand it back to Rich to initiate the Q&A session.

Richard Lepke

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

Question and Answer Session

Operator

Gena Wang, Barclays.

Gena Wang

I have two questions. So maybe the first one regarding the Alnylam decision. Did they see most up-to-date data for both HBV and HDV? And what was the reason they provided for not opting? And the second question is thinking about you have so many programs progress so rapidly in the oncology space.
So when should we see the next update from the programs and which will be likely the venue when we'll see those data update?

Marianne De Backer

Yes. Thank you, Gena, for those questions. Maybe I'll start with the last one first. So when the next oncology data update will be coming. So the way we think about it for any next data update, what we would be anticipating to share is, first of all, obviously, more mature data at higher dose levels beyond what we presented just a couple of months ago in January.
We would also want to share comparative data between weekly and every 3-week dosing. We think the latter is especially relevant for our ambition to go into earlier lines. Also a clearer picture, obviously, on dose response relationships, additional insights into the safety profile at higher doses and, of course, also PSA responses. So once we have all that for 500 and for 5818, we will be sharing it, of course, either through a medical congress or through a more focused investor event. So as soon as we are ready, we will do so.
Your second question, Gena, related to Alnylam. So Alnylam made their decision to opt out of the profit-sharing arrangement before our most recent HBV functional cure data was available. As you know, that data is only going to be presented for the first time on Friday at EASL on May 9. So this decision was really based on their own strategic portfolio prioritization.

Operator

Paul Choi, Goldman Sachs.

Paul Choi

I want to ask about -- first about EASL, and it looks like you have a late breaker of the doublet in combination with the Virion 200 asset. Just curious, I think that's the first look we'll get at that program. And so just curious sort of what the rationale is behind that new triplet combination strategy there and just sort of how you think about the development plans for that versus your other combinations? And my second question is, can you comment maybe in broad strokes on how you're thinking about completing enrollment or completing either the ECLIPSE1 or ECLIPSE-2 studies. This will be helpful to understand in the context of your cash guidance runway to 2027 since you're just putting in first patient in the first quarter here?
Just some context on that timing would be helpful.

Marianne De Backer

Thank you, Paul. So maybe the first question on the Virion combination. Mark, do you want to answer that?

Mark Eisner

Yes. So thanks, Paul, for the questions. I mean, first of all, that's a study conducted by Virion, and we did provide access to tobevibart and elebsiran for that study. But we're not -- it's being run by Virion, and it's in their portfolio and not ours. So I think the data are interesting in terms of some of the early responses in terms of surface antigen decline, but that's really in their portfolio rather than ours.
You're asking a really good question about HDV and our time lines. We did announced first patient dosed for ECLIPSE-1, and we have a study estimated completion date of the end of 2026. So that means we would be aiming to complete enrollment in that study by the end of this year. I mean that's an aggressive target, but we are putting all of our resources behind getting these ECLIPSE trials up and running. For ECLIPSE-2, we haven't provided guidance yet, but I can assure you that we are laser-focused on getting that study up and running.
It's important to note that the ECLIPSE-2 actually has a 24-week endpoint. So even though it's starting dosing a little bit later, it will have a 24 versus 48-week readout. So the timing will provide some more guidance when we're able to do that, but that's an important point to consider.

Operator

Mike Ulz, Morgan Stanley.

Avraham Novick

This is Avi Novick on the line for Mike. So a competitor of yours recently shared updated data from its TCE PSMA targeting program in metastatic CRPC. So I was wondering if you had any updated thoughts on your -- on the competitive positioning of AR-5500? And do you see a median PFS of around 7.5 months as, I guess, a fair and achievable benchmark for your program?

Marianne De Backer

So yes, I can take that question. First of all, we're actually very encouraged about the continued progress for T-cell engagers in general, including the fact that JANX continues to prove proof-of-concept that masking technology actually extends the therapeutic index. And while I can't comment directly on how we would be compared, because we are relatively earlier in our dose escalation compared to where they are, we do think that we are quite differentiated in that our PRO-XTEN is a dual mask technology. It's quite a different masking technology than the other masks that are out there. It's a universal mask.
It's the only clinically validated mask in terms of having clinical validation in other platforms such as the drug Altuvia, a hemophilia drug. And we do think that we have a really very favorable safety profile. We demonstrated in our January update that we have a very low rate of CRS. We do not use any prophylactic steroids. We know that every other T-cell engager program needs some form of prophylaxis.
And despite the lack of use of corticosteroids, we have this very low-grade CRS and also no evidence of significant IL-6 elevations. And despite that, we are seeing some nice really early activity. The other big differentiator, which I think is important, both for safety and is in the front line is that we have a longer half-life of 8 to 10 days, which enables our Q3 week dosing schedule. We know that for convenience and quality of life in the frontline setting for prostate cancer, in particular, these types of differentiation is going to be critically important for overall tolerability, a huge unmet need where we think these drugs could potentially offer significant convenience for that.

Operator

Eric Joseph, JPMorgan.

This is Ron on for Eric. I wanted to ask how does the recent bulevirtide update impact your thinking around the potential finite versus long-term chronic treatment with the combination for HDV?

Marianne De Backer

Sure. Mark, do you want to take for the question?

Mark Eisner

So I think your question is about bulevirtide and their long-term outcome data and their ability to achieve finite treatment, how does that affect our program? So we -- just to remind everybody, I mean, we achieved in our SOLSTICE study very high rates of target not detected or complete viral suppression. We're achieving it in the majority of patients by week 24 and week 36. And we're getting to 64% at week 36. So that compares to bulevirtide in week 48 of only 12%.
So we think we can achieve very high rates of viral suppression in terms of long-term suppression. Gilead, the bulevirtide data that are related to finite treatment are with their higher dose. So that's one thing to consider. And it's not really something that's in their label right now. So we are aiming for a chronic viral suppressive regimen.
We think we can suppress the virus in the vast majority of patients. We're also achieving 3 log declines in hepatitis B surface antigen, again, just pointing to the potency and the depth and breadth of our viral suppression for delta. So we're really excited to be moving into the Phase III program.

Operator

Roanna Ruiz, Leerink Partners.

Nikola Gasic

This is Nick Gasic on for Roanna. Maybe first on HBV. How should we think about your expectations heading into the 24-week off-treatment data for March at EASL? What are you hoping to see from a functional cure standpoint relative to the end of treatment data we got at AASLD? And maybe what implications could this new data have for potential partnership discussions in HBV?

Marianne De Backer

Go ahead, Mark. No, go ahead.

Mark Eisner

So I was just going to say we are looking forward to presentation of our March data, 24-week off-treatment data this Friday at EASL. This will be the look at our functional cure rate. As you might imagine, we are going into a quiet period because it is just a very short period between now and then. So we don't want to comment extensively except to say that we have been signaled in the past that we're looking for 20% in the doublet and a 30% functional cure rate in the triplet. But I think stay tuned, and you'll see the full data at EASL in just a couple of days.

Marianne De Backer

Yes. The only thing I would add is that, as we have already mentioned, in January, any further development on the HBV program is contingent on securing a worldwide development and commercialization partner.

Operator

Phil Nadeau, with TD Cowen.

Philip Nadeau

Two from us. First, on 5500, you mentioned that there have been multiple doses tested since the data in January. We're wondering if you would care to comment on whether those additional doses have continued to suggest a dose response in efficacy in terms of PSA response rate and durability. That's the first question. And then second, on HDV, the RNA positive figures that you gave for the prevalence of the condition, can you clarify, are those overall prevalence or patients diagnosed having positive RNA?
And if it's not diagnosed, do you have a sense of what the diagnosis rate is? Yes. Thank you, Phil. Maybe I'll start with your last question on delta prevalence. So what we did is we really looked across all available studies, all available reports on delta prevalence.
And we sort of started out with determining that based on all the numbers we could get our hands on, that there are about 2 million patients in U.S. that are HPV positive. And again, through a very extensive literature search talking to KOLs, different sources, we found that on average, about 4.7% of those B patients are delta antibody positive. And again, then further drilling down, so that gives you about 92,000 patients actually in the United States. But if you then think about the patients that are actually going to get treated, those are the patients that are RNA positive that are actively viremic.
And so again, based on a lot of sources, we came to the conclusion, as we shared that about 61,000 patients in the United States would be RNA positive and eligible for treatment for our regimen. So that's sort of the breakdown of how we got to the numbers. And then your first question related to 5,500 dosing, maybe, Mika, you can comment.

Mika Derynck

Yes. We have continued the dose escalation, both at the Q week and the Q3 week dosing. But really, we are not prepared to make any comments. We are encouraged with the 5818 data that also showed a nice dose response. We have that one patient who clearly had a dose response within that -- while he intra-patient dose escalated, a colorectal cancer patient who went from 60 micrograms per kg up to 600 micrograms per kg and continue to have a long durability of response lasting over 18 months.
But just sit tight and hopefully, we'll be able to say something soon.

Operator

Alec Stranahan, Bank of America.

This is Matthew on for Alec here. Maybe a couple from us on 5525. We saw recently that the trial design on clin trials for 5525 includes 4 parts: monotherapy escalation/expansion and then combos with pembro escalation/expansion. Would be helpful to have any color on why you chose this design, maybe the ordering of the parts and whether you would still explore combination options if initial monotherapy data looks good.

Marianne De Backer

So yes, I'm happy to answer that. Thank you for the question. Yes, we're very excited about having our third PRO-XTEN T-cell engager program go into the clinic. We believe we've shown some nice early proof of concept with the prior 2 molecules. And in terms of the trial design, we do know that there's good scientific rationale for combining with a checkpoint inhibitor.
What we've seen with prior T-cell engagers is that you can see upregulation of PD-L1 upon treatment with the T-cell engager. And so it really makes sense in terms of combining with a checkpoint inhibitor as well with combinations, again, in the context of other T-cell engagers, is that we've seen deeper responses and more durable responses with the combination. Hence, we are considering the combination for the 5525 program as well. And as you mentioned, there are 4 parts. The first part is dose escalation as monotherapy.
The second part is to look at specific indications in expansion cohorts as monotherapy and then Parts 3 and 4 is similar except in combination, a dose escalation component with pembrolizumab followed by an expansion cohort with combination at, again, a data-driven decision on which combination -- which indications that we would pursue.

Operator

Patrick Trucchio, H.C. Wainwright.

Marianne De Backer

Patrick, we cannot hear you.

Patrick Trucchio

Just the first question is on the CHB program. I'm wondering if you can tell us in terms of the functional cure rates that you're looking for, would you be looking for those rates in kind of certain levels of HB surface antigen at baseline? And separately, I'm wondering on the HDV program, do you need data from all the ECLIPSE trials in order to submit for regulatory approval? Or how should we think about potential for accelerated approval? Is that a possibility?
And then just the last question is just in terms of partnering or collaborations, how should we think about both the CHB program, but as well any of the PRO-XTEN programs? And in particular, is there 7 additional programs in preclinical development.

Marianne De Backer

Yes. Thank you, Patrick, for that question. Maybe I'll ask Mark first to address your questions on the hepatitis B and delta programs.

Mark Eisner

Sure. Thanks for the question. So for the MARCH Phase II study in chronic hepatitis B, as we presented at AASLD, we saw the best responses at end of treatment in those patients with surface antigen levels at baseline of less than 1,000. This is very consistent with what others are seeing with different mechanisms of action in the field that patients with low surface antigen at baseline are responding better than patients who have surface antigens that are very elevated at baseline. So we will present the data, both all comers and divided by surface antigen as we did for the end of treatment data for the functional cure data in 2 days.
So look forward to that. For your HDV question, your question was, do we need all 3 ECLIPSE studies for approval. I do not believe so. I believe we need ECLIPSE-1 and ECLIPSE-2 as our base case for a filing package that should be sufficient for approval. We would be looking for an accelerated approval based on in ECLIPSE-1, the composite of target not detected in ALT normalization and for ECLIPSE-2, target not detected at virologic end point.
Of course, we have breakthrough therapy designation in the U.S., and we have Prime in Europe as well as orphan in Europe. So we are in active dialogue with regulators globally about the program, how to accelerate the program and how to get this drug combination to patients as quickly as possible because the unmet need is so high. Just one other comment about partnering, and I'll turn it back to Marianne is for hepatitis B, as we've said, that we are only going to be able to move hepatitis B forward if we have a global development and commercialization partner, whereas for hepatitis delta, we are in full study start-up mode for all 3 ECLIPSE studies, and we are running those studies as Vir Biotechnology on our own.

Marianne De Backer

Thank you, Mark. And I would just add related to your question on partnering of the preclinical programs, Patrick. I mean what is really unique is that the universal nature of the PRO-XTEN platform allows us to come up very efficiently with new potential therapeutic molecules, right, which are going to be, from a T-cell engager perspective, very well engineered because that's a capability we've had here at Vir for a very long time, and we can now combine it really with that masking capability. So the 7 preclinical programs that we are -- that we have started, it will be -- we envision a mix of approaches. Some of them will be kept for internal development on a number of select really high-priority targets that align well with our strategic focus.
And some are open to partnerships and especially those where we think there could be complementary expertise elsewhere. So it's going to be really a mix of both strategies.

Operator

Joseph Stringer, Needham & Company.

Joseph Stringer

Just given some of your recent work updating your HDV patient estimates, I had a question on HDV diagnosis. Have there been any changes to U.S. guidelines? And I suppose, do you anticipate any updates to this in the near term? And how big of an impact could this be to the potentially addressable patient population in the U.S.?

Marianne De Backer

Thank you for that question. No changes yet to the guidelines for delta diagnosis or reflex testing here in the United States. We do believe that there is a heightened awareness also in the context of the American Association of Liver Diseases. So we are hopeful that we will continue to have that conversation, obviously, and that when we have AASLD coming up later in the year that there might be some announcements in that regard. But thus far, no changes on reflex testing.
That is, however, very effectively already deployed in Europe. And they are really seeing that if you just base diagnosis based on risk factors, et cetera, you're really not finding the patients. It's really only when patients are tested for hepatitis B and when they are found to be positive, they're automatically tested for delta that you end up identifying many more patients. Mark, anything to add there from your perspective?

Mark Eisner

No, I think you captured it very well, Marianne. Just to state that we do believe that the prevalence of diagnosed HDV or delta is underestimated because of the lack of reflex testing in the United States. I think once we have our therapy approved and on the market, assuming success that we would expect with such an effective product that this will drive more diagnosis and more disease prevalence. I think there's other examples of similar cases like this in medicine. But to your point, we're still not seeing the reflex testing deployed in the United States at this time.

Operator

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

Richard Lepke

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