Arvinas, Inc.

Thank you for standing by. At this time, I would like to welcome everyone to our VINA's second quarter 2025 earnings call. All lines have been placed on mute to prevent any background noise. After the speakers' remarks, there will be a question and answer session. If you would like to ask a question during this time, simply press star followed by the number one on your telephone keypad. Thank you. I would now like to turn the conference over to Jeff Boyle, our VINA's Vice President of Investor Relations. Please go ahead.

Good morning, everyone, and thank you for joining us.

Earlier today, we issued a press release with our second quarter 2025 financial results, which is available in the investor and media section of our website at ourvinas.com. Joining the call today are John Hewson, our VINA's Chief Executive Officer, President, and Chairperson, Noah Berkowitz, our Chief Medical Officer, Angela Kakey, our Chief Scientific Officer, and Andrew Stake, our Chief Financial Officer. Before we begin the call, I'll remind you that today's discussion contains forward-looking statements that involve risks, uncertainties, and assumptions. These risks and uncertainties are outlined in today's press release and in the company's recent filing with the Securities and Exchange Commission, which I urge you to read. Our actual results are many different materially from what is discussed on today's call. And now I'll turn the call over to John. John?

Thanks, Jeff. Good morning, everyone, and thank you for joining us today. As outlined in our second quarter earnings released this morning, our business is in a solid position with strong momentum. It was an eventful and exciting quarter at our VINA's with significant clinical and regulatory programs across our pipeline of pro-tag degraders. We continued making significant strides across our early stage programs, where we are enrolling patients in three phase one trials across our neuro and oncology portfolio, including the recently initiated trial with our KRAS G12D degrader, ARV806. During the quarter, we also presented compelling first in human data from ARV102, or RAR2 degrader, and pre-clinical data for our BCL6 degrader, ARV393. I'm also pleased to share an update on our antigen receptor degrader, lux degalutamide, which we licensed to Novartis in 2024. We are pleased to see that Novartis is rapidly progressing the asset and announced the recent initiation of two combination phase two trials that will further advance lux degalutamide towards patients. One trial is in metastatic castration-resistant prostate cancer, and the other is metastatic hormone sensitive prostate cancer. And both will identify recommended phase three doses, and we believe further validate our ability to develop potentially -in-class protein degraders. As a reminder, our license agreement with Novartis includes up to $1 billion in development, regulatory, and commercial milestones, as well as tiered royalties. The accomplishments from across our portfolio are the latest in the long stream of successes at Arvinis. At the same time, we have recognized the ongoing need to enhance our financial position and set Arvinis up for future success. To that end, last quarter, we announced a company-wide restructuring that extended our cash runway and included two key elements. First, we re-prioritized our research pipeline, cutting a number of programs, and continuing investment in our assets with the greatest potential value. And second, we streamlined operations across the organization by reducing our workforce by approximately one third. While difficult, these decisive actions bolstered our financial profile and drove efficiencies across the company. They also enabled us to turn our full attention to our near-term imperatives, which are, first, working with Pfizer or identifying another partner to advance VETDEG towards commercial launch, second, achieving critical data milestones from our pipeline in the next 12 months, and third, carefully allocating capital to support those milestones efficiently. I'll return to those three imperatives in a few moments, but I'd first like to say a few words about the recent announcement of my planned retirement and the CEO transition for Arvinis. Having recently strengthened our financial profile and with a clear line of sight into those near-term imperatives, the board and I agreed it is the right time to initiate a search for a new CEO. As with any public company, succession planning is a priority for our board of directors, and I have been talking to the board about the potential timing of this transition for well over a year. While it never seems to be a good time, we agreed that waiting until after our first pivotal data readout was essential. We are now conducting a rigorous and thoughtful CEO search process, spearheaded by independent directors on our nominating and corporate governance committee with the assistance of a leading executive search firm. The board is fully engaged and intent on finding the right CEO to lead Arvinis into our next chapter and help shape our long-term strategy to create value for shareholders and deliver on our mission to serve patients. I'm also honoured to continue as chair of the Arvinis board once I step down from the CEO role. For now, our long-term strategy is driven by the imperatives I mentioned above, advancing VETDEC to launch by Pfizer or another partner, achieving critical data milestones, and efficiently allocating capital. I'll spend a few minutes discussing our VETDEC strategy before turning the call over to Noah and Angela, who will provide updates and discuss upcoming milestones for our clinical programs. Andrew will then provide a financial overview and some thoughts on capital planning. First, regarding VETDEC, our collaboration with Pfizer was signed in 2021 with the intention for VETDEC to be developed as a monotherapy and in combinations across the adjuvants, first and second line settings. With that plan, the idea of having 50-50 co-development and commercialization was very attractive. We are now on the threshold of VETDEC potentially becoming a -in-class treatment in its first indication. Second line monotherapy treatment in ESL-1, ER positive, HER2 negative metastatic breast cancer. However, the recent decision to remove the combination pivotal trials from our development plans with Pfizer has created a situation where a 50-50 co-commercialization agreement no longer makes sense, and we're actively reworking our collaboration. Should the negotiation lead to VETDEC being returned to our business, we are prepared to seek a party to commercialize and further develop VETDEC. Reaching a positive conclusion for VETDEC is a critical step in maximizing its value while also allowing us to focus on a promising clinical pipeline. Preclinical data has shown that ARV102, ARV393, and ARV806 are all differentiated from inhibitors and other degraders. With compelling clinical data milestones over the next year, we believe our maturing pipeline will be a significant value driver for the company and our shareholders. Taken together, we are advancing a very exciting pipeline and applying our ProTac technology to new areas in both neuroscience and oncology, where we can truly differentiate from other mechanisms of action. Operating from a strong financial position, underpinned by an extended cash runway, efficient capital allocation, and a development strategy that unlocks the potential of our platform to bring patients important treatments, we are confident in our path forward and in our ability to maximize value for shareholders and benefits for patients. With that, I'll turn the call over to Noah.

Thanks, John, and good morning, everyone. Our pipeline continues to progress at a remarkable pace, demonstrating the vast potential of our ProTac platform. I'll begin with our most advanced neuroscience program, ARV102. We have designed investigational oral ProTac degraders to cross the blood-brain barrier and selectively degrade -rich-repeat kinase 2, or LARC2. LARC2 is a large multi-domain scaffolding kinase that plays a critical role in effective endolysosomal trafficking. Unlike traditional small molecule inhibitors that only block LARC2's kinase activity, LARC2 degraders eliminate pathologic scaffolding function, GTPase activity, and the kinase activity of LARC2 implicated in this disease. We believe our lead LARC2 degrader, ARV102, is particularly well-positioned to be evaluated in two diseases where there are no disease-modifying therapies available. The first is Parkinson's disease, or PD, a disease where increased LARC2 expression and activity contributes to neurodegeneration and its pathogenesis, making it a rational therapeutic target. And the second is progressive supranuclear palsy, or PSP, a disease where genetic variations in LARC2 are associated with PSP progression. Additionally, we have published data associating the cow pathology of PSP with LARC2-mediated endolysosomal dysfunction, which again makes this a very rational therapeutic target. ARV102 is the only protact we know of in the clinic to demonstrate deep brain penetration in non-human primates and now blood-brain barrier penetration in humans. As presented at the ADPD Congress, ARV102 is well tolerated at single doses up to 200 milligrams and at multiple doses up to 80 milligrams. No serious adverse events after single and multiple oral doses and healthy volunteers were observed. Single and multiple doses of ARV102 demonstrated dose-dependent exposure in the central nervous system by cerebrocinal fluid, or CSF, sampling. This was associated with substantial degradation of LARC2 protein in the peripheral blood and the CSF and on-target activity with levels of engagement not reported with inhibitors currently in the clinic. We believe the high levels of target engagement, enhanced potency, and pathway engagement demonstrated with ARV102 will differentiate it from clinical stage inhibitors, which in preclinical studies have not shown the same ability as ARV102 to move important biomarkers in the CSF. These PK and PD properties and acceptable safety and tolerability profile support further study of LARC2 degraders in PD and PSP. Dosing of the phase one single ascending dose cohort in patients with Parkinson's disease is complete and we expect to present initial data confirming pathway engagement later this year. We will also initiate multiple dose cohorts in patients with PD in the coming weeks, as well as a trial in PSP in the first half of 2026. In parallel to the advancement of ARV102, we are making nice progress with ARV393, our BCL6 degrader, and ARV806, our KRASG12D degrader, which entered the clinic in the second quarter. It is too early for me to share clinical results for these exciting new clinical stage assets, but Angela will share some of the compelling preclinical data supporting the advance of both in the clinic. But first, I would like to provide some regulatory updates regarding VEPTEC. We have submitted the new drug application for VEPTEC. This represents another significant first for Arvinis, the first protractor grader to enter clinical trials and have a positive readout in a phase three trial. It's also the first ever new drug application submitted for a protract. The NDA was supported by VeriTEC2 data that were presented at the ASCO oral late breaking session and simultaneously published in the New England Journal of Medicine. The enthusiasm among physicians generated by VeriTEC2 data was very rewarding. Later this year, we plan to present the patient reported outcomes data from the VeriTEC2 trial. We believe these data disclosures reinforce VEPTEC's profile as a potential best in class monotherapy. I'll now turn the call over to Angela. Angela?

Thanks, Noah, and good morning, everyone. ARV393, our investigational oral protract designed to degrade B-cell lymphoma 6 protein, or BCL6, is an exciting asset that demonstrates the power and breadth of our platform. BCL6 is a previously undrugged transcription factor, a master regulator of multiple cellular processes during B-cell development, including proliferation, survival, and apoptosis. Altered BCL6 activity has been implicated as an oncogenic driver in several subtypes of non-Hodgkin lymphoma, making it a rational therapeutic target with initial clinical validation emerging. Protract mediated degradation has the potential to overcome the historically undruggable nature of BCL6. With its iterative activity, ARV393 potently and rapidly degrades the BCL6 protein, which is critical to overcoming its rapid resynthesis rate and sustaining anti-tumor activity. In second quarter of 2025, we presented two sets of preclinical data for ARV393. First, at the American Association for Cancer Research annual meeting in April, we presented new preclinical data highlighting the therapeutic potential of ARV393 in combination with standard of care biologics, chemotherapy, and small molecule inhibitors targeting cooperative oncogenic drivers. ARV393 combinations demonstrated increased tumor growth inhibition, including tumor regressions in preclinical models of aggressive B-cell lymphoma. These data underscore the potential of ARV393 to become a backbone therapy for development of rational, mechanism-informed chemo-free, or all oral therapeutic options with the potential to improve patient outcomes and convenience. In June, at the European Hematology Association Conference, we presented new data demonstrating the potent single-agent efficacy of ARV393 in patient-derived systemic models of angioimmunoblastic T-cell lymphoma and transformed follicular lymphoma. To our knowledge, these are the first preclinical evidence of an efficacious PCL6-targeted degrader in human models of these diseases. These data highlight the broad utility of ARV393 across non-Hodgkin lymphoma subtypes with unmet need beyond DLBCL. Later this year, we also expect to share preclinical data showing the combinability of ARV393 with glyphidimab, a CD3, CD20 bispecific antibody, and an emerging standard of care for DLBCL that supports our plan to evaluate this combination in an upcoming trial. We are excited about the potential here, given ARV393's ability to increase CD20 expression, which provides rationale for the exploration of ARV393 with CD20-targeted agents and in the context of low or loss of CD20 expression. We also plan to share the initial clinical data with ARV393 later this year. As you have heard from Noah, I'm pleased to report that we have initiated a phase one clinical trial of ARV806, our novel protactagreater targeting KRAS-G12D. The trial has progressed rapidly through the first patient cohort, reflecting strong interest from clinical investigators and underscoring the high unmet need for effective KRAS-targeted therapies. KRAS-G12D is a well-characterized oncogenic driver associated with poor prognosis and resistance to standard treatments across major tumor types, including pancreatic, colorectal, and non-small cell lung cancers. ARV806 has demonstrated compelling preclinical activity with high potency and clear differentiation from both KRAS inhibitors and other degraders currently in the clinic. Notably, because of the catalytic activity of our protact, ARV806 has shown it can overcome KRAS resynthesis and increased expression, a major clinically relevant emerging mechanism of resistance that existing inhibitors have failed to address. Our protact binds to and degrades both the active and inactive forms of KRAS-G12D, achieving potent and durable elimination of the target, rather than inhibition in all models tested. In preclinical studies, ARV806 achieved in vitro potency approximately 25 times greater than KRAS inhibitors and 40 times greater than the leading clinical stage degrader, demonstrating strong potential for differentiation from both KRAS inhibitors and degraders currently in the clinic. Furthermore, ARV806 exhibits dose-dependent, selective, robust anti-tumor activity, culminating in regressions across preclinical models of KRAS-G12D mutant cancers. These results highlight the strong therapeutic potential of ARV806 and support its continued and rapid advancement in the clinic. We look forward to updating you on our clinical progress and anticipate sharing preclinical data from ARV806 and the first ever data from our oral pan-KRAS degrader program later this year. With that, I'll turn the call over to Andrew to review our quarterly financial information.

Thanks, Angela, and good morning, everyone. I'm pleased to provide financial highlights for the second quarter and the June 30th, 2025, and expand on our approach to capital allocation and development strategy. As a reminder, detailed financial results for the second quarter are included in the press release we issued this morning. During the quarter, we took significant action to reduce costs and increase efficiency across the organization. These actions included a reprioritization and reduction to our research portfolio, as well as a reduction of approximately one-third of our total workforce. When combined with the announced changes to our VEPDEG development plan, our cash runway was extended into the second half of 2028. These changes will make us leaner and more efficient as we work towards a promising stretch of catalysts over the next 12 months. As I mentioned previously, the restructuring was focused on reducing internal costs without having an impact on the clinical stage programs that will drive value over the next several years. We will maintain our disciplined and focused approach to capital allocation, and our development strategy will be focused on bringing pipeline programs through major clinical inflection points. With respect to VEPDEG, we anticipate relatively minimal costs to prepare the market in the coming months. Our current agreement with Pfizer includes establishing a -to-market strategy that will benefit both sides of the partnership. While we continue to believe that VEPDEG is a potentially -in-class asset, given the changes to the development plan, we have determined that it is no longer viable for us to build out our commercial infrastructure as we had previously planned. As John said earlier, we are in active discussions with Pfizer to rework our collaboration to determine the most efficient way to make this important drug available to patients, if approved. Across our pipeline, we have a rich bed of catalysts coming up in the next year for both our oncology and neuroscience portfolios. With our strong balance sheet, we have sufficient resources to move these exciting programs forward to key value inflection points. We've seen great clinical success here in the past, both in the development of VEPDEG in partnership with Pfizer and in the platform validating out-licensing of Lex-Degalutamide to Novartis. We are excited to continue development of the next generation of Arvinis Pro-Tex. I'll now briefly touch on some key financial highlights for the second quarter of 2025. At the end of the second quarter, we had approximately $861.2 million in cash equivalents and marketable securities on the balance sheet, compared with $1.04 billion as of December 31, 2024. Revenue for the three months into June 30, 2025, totaled $22.4 million, compared to $76.5 million for the three months into June 30, 2024. The decrease of $54.1 million was primarily driven by $45.6 million of decreased revenue from the Novartis license agreement and the Novartis asset agreement, both of which were entered into during the three months and the June 30th, 2024, and were completed by December 31, 2024 as the technology transfer of our ongoing planned clinical trials of Lex-Degalutamide were transitioned to Novartis. Revenue from the VEPDEG collaboration agreement with Pfizer decreased $6.8 million related to the removal of two phase three trials from the development plan during the first quarter of 2025.

General

and administrative expenses were $25.3 million in the second quarter, compared to $31.3 million for the same period of 2024. The decrease of $6 million was primarily driven by a decrease in personnel and infrastructure related costs of $4.8 million and professional fees of $2.2 million, partially offset by an increase in costs related to developing our commercial operations of $1.1 million. Research and development expenses were $68.6 million in the second quarter, compared to $93.7 million for the same period of 2024. The decrease of $25.1 million was primarily driven by a decrease in the VEPDEG program of $10 million, a decrease in the LuxTegalutamide program of $9.5 million, and decreases in personnel expenses and non-program specific expenses of $10.3 million, offset by an increase in the LARC-II program of $2.1 million and the KRAS program of $1.5 million. Restructuring costs in the quarter amounted to $7.4 million of cash expenses, consisting primarily of employee related expenses, which were offset by a reversal of non-cash employee stock compensation and bonus expenses of $6.4 million. The announced restructuring is now complete and the full benefit in terms of cost reduction will be seen starting in the third quarter. We are maintaining our prior cash runway guidance into the second half of 2028. We are focused on staying disciplined by investing in areas that will maximize shareholder value as we move towards important catalysts in the coming months. In addition, we will continue to look at ways to reduce costs and increase efficiency while continuing to focus on our goals of progressing our very promising early pipeline. With that, I'll turn the call over to John for closing remarks, John.

Thanks, Andrew. As you've heard, we see multiple near-term milestones across our clinical development and regulatory efforts. Our programs offer a rich set of catalysts over the next 12 months, including clinical data from ARV 102 and ARV 393 and potentially initial clinical data from ARV 806 and of course, the potential for the first ever approval of our ProTag. During this time, we will also advance ARV 102 in its ongoing trial in patients with Parkinson's and initiate a trial with ARV 102 in progressive super nuclear palsy. Before opening a call for Q&A, I'd like to reiterate our confidence in our near-term plan to create value for patients and shareholders. This includes advancing VetDegs to launch by Pfizer or another party, achieving the important data milestones I just described and allocating capital to ensure we reach those milestones efficiently. While we made sweeping changes in the first half of 2025, we are always evaluating the best ways to create shareholder value. With that, I'll turn the call over to Jess to begin the Q&A portion of the call.

Jess. Thanks, John. Operator, can you please open the queue?

Thank you. As a reminder, to ask a question, you will need to press star, then the number one on your telephone keypad. And to redraw your question, press star one again. And our first question comes from the line Ted Tannof with Piper Sandler. Your line is open.

Thank you very much. Andrew, just one quick housekeeping. The restructuring cards that you mentioned, was that primarily in the G&A line? And then I have a pipeline question for you guys.

Yeah, hey Ted. No, it was actually split up between research and development and G&A. And indeed, most of the stock-based comments would have been recorded in the R&D section.

Great, that makes sense, awesome. So can you give us a little bit more color on what to expect from 102 data this year? I know that we've still got more to hear about the healthy volunteers for the multiple ascending cohorts. But what should we expect from the single ascending doses from Parkinson's patients? Thanks.

Thank you, Ted. And yeah, the trials are going well. I'll hand over to Noah to give you some of the details.

Hi Ted, thanks for the question. Hey Noah. Yeah, good morning. So as you said, I think you summed it up. We're going, we expect that a conference, an upcoming conference, to summarize the full healthy volunteer data set that we assembled. And in addition to that, if things work out, we'll be able to present some SADS data, which will, I'm not gonna go into the details of what we'll present exactly, but should be able to signal that we're on track with, when you compare it to the healthy volunteer funds.

Great, all right, looking forward to that and excited about the emerging

pipeline. Thanks, Ted.

Next question

comes from the line of Jonathan Miller with Evergar ISI. Your line is open.

Hi guys, thanks so much for taking my question and congrats on, as I should say, congrats if it's the wrong word, but good job on getting your restructuring going. I'd love to follow up on 102 question. Maybe it's a little too early to say exactly what you'll give us in patients this year, but maybe could you talk a little bit about what you hope to see in a more full patient data set? What are your bars for success in patients that can give you confidence going into later on in advocacy readouts?

Thanks, Jonathan. Noah? Sure. Jonathan, so thanks for the interest here. I think we've outlined that we expect to start a Parkinson's disease multiple dose study. Over the course of the next month or so. And what we, well, I can't really comment about when those data will be presented. The idea is that we're enrolling patients with the insights gained from healthy volunteers regarding a dose range. And that will allow us to establish that in patients who have higher baseline LARC 2 levels, and also patients that are more elderly because healthy volunteers tend to be very young, like a little more than college age. And Parkinson's disease are gonna be more than twice that on average, I suspect. So we'll be able to demonstrate that we have the same exciting results that we previously reported in healthy volunteers of orally bioavailable brain penetrant ProTAC and the ability to move biomarkers, which also now we have much more insight into than we did many months ago. So we continue to do work to understand what are the best biomarkers that we can track and are gonna be most predictive of an impact in the endo-lifesomal trafficking and neuroinflammation that is characteristic of Parkinson's disease and PSP. And so we expect we can start tracking this in real patients rather than the healthy volunteers.

Awesome, thank you. And then maybe on the BCL-6, you mentioned in the press release in this call the glutidomab combination results to present this year, but you've presented on a number of different combos pre-clinically, can you give us a sense of where you might wanna start in patients, what combo therapies you might wanna start with?

I think I've been signaling in conversations, we can certainly speak to patients and speak clearly, very directly about it here, that our interest for BCL-6 is to learn what, find the dose in monotherapy, it's something we're obligated to do, but the real interest is moving forward in combinations, in particular in DLBCL. And I think it should be clear to everyone that by specifics in second line plus DLBCL and maybe eventually in not that far in the future, in first line are important drugs in that space. So if we can combine with by specifics in human beings and get results that look anything like what we've seen pre-clinically, we think we're well positioned for a new modality of therapy with a real orthogonal approach that enhances the activity of the by specific. And remember, one of the great combination properties here is that we recognize that our AR-593 can increase the expression of CD20, which could potentially make the by specifics even more active. And on top of that, we've been reporting out the great potency with our drone that if that translates into the clinic, then that gives us a great competitive advantage against the only other degrader

that's in the clinic currently. Thank you so much.

Next question comes

from the line of Derek Arquilla with Wells Fargo. Your line is open.

Good morning, this is Harco, good evening for Derek. Thank you for the question. So I guess for ARV102, could you talk a little bit more on the elevated level in PD patients in terms of how much should we expect and how to maybe feel confident that similar more than 50% degradation can be achieved in CSF? And then on the MEPDEC, the label potentially, could you talk about maybe the base case will put some potential differentiation to predict your competitors? Thank you so much.

I think I captured

the second question with MEPDEC, but there was a lot of cracking of the in the transmission to the first question. Did anyone here catch that? Yeah,

could you maybe just repeat the first question?

Yeah, of

course. I'm sorry about

that. So for ARV102, I guess the question is the elevated lock to level in PD patients. Could you talk about the expectation of the elevation and how to feel confident that more than 50% degradation in CSF can be achieved?

Yeah, so I think it's a great question. So fundamentally, I think it's been established by external sources that there's increased a lock to protein expression in the brain and in the CSF of patients with Parkinson's disease. In our own hands, we've already seen in the SAD that there are higher baseline levels of Parkinson's, of LARC2 than we observed in the healthy volunteers. So that's already kind of consistent, but not a surprise to us at all. That was the expectation. In terms of one of the great properties of the degrader that I think differentiates it beautifully from an inhibitor is that we've already established in the healthy volunteers that we can get really good target engagement in the brain. And we know that the inhibitors just don't do that well. They're only achieving 30% or so inhibition in the brain. We know pre-clinically they're not reaching deep brain regions as effectively as our degrader can. So we're getting higher engagement. And because we have a degrader here, which has that iterative property that at even lower exposures, you get continued degradation of the target, we think that we should be well poised to reduce LARC2 levels. That's the underlying premise that's been borne out in pre-clinical models. We've shown it in healthy volunteers. And now we think we can confirm it in the multiple doses and parts of these patients. Regarding the second question, I think the question was what differentiates us essentially from with our depth eggs from competitors in the space? And more or less it comes down to efficacy, the better PFS that's been seen when compared to full vestment control, monotherapy control, which in our hands, we're talking about three months improvement, which other drugs really haven't achieved. On top of that, we're leaning into some PRO data that you'll see soon that show that the patients experience the drug very well. Certainly the adverse event profile is more attractive, which is to say that there's a lot of GI toxicity seen with other agents in this space. We have reported half or even 33% of that when you compare to different drugs. And I think that that combination of benefit risk really stands out for depth egg

when compared to other agents.

Thank you.

Next question

comes from the line of Tazin Ahmad with Bank of America. Your line is open.

Hi, good morning. Thanks for taking my questions. I maybe wanted to focus on some commercial questions. So as you think about depth eggs and the upcoming launch, you're obviously bullish about its place potentially in monotherapy, but you also talked about the potential to launch about needing to be careful about how you're prepping for the launch. So how does this work in terms of setting up a sales force? When do you start prepping for that? How has that plan changed relative to what you would have planned for before? And then secondly, if Pfizer returns rights for the program to the company, would there be a gap in between when Pfizer returned the rights and when you'd be able to secure a new partner or are you kind of in process now for seeking a potential replacement should Pfizer return those rights? Thanks.

Yeah, no, thank you

for the question. Yeah, so in the second part, I'll talk about first, clearly we're in negotiation with Pfizer right now. The original deal that we signed in 21 was the 50-50 code of elements, co-commercialization, very attractive deal at the time. We had planned for doing second line monotherapy, first line adjudant, and that would have been a very significant market and a very significant opportunity to share 50-50. With the decision not to go forward with the first line or the second line combo, it puts us into a position where VET at the moment is only focused on second line monotherapy. So a smaller market really doesn't move the dial for Pfizer in terms of 50-50 and not particularly attractive for our events either. So the dialogue we've been having actively with Pfizer is about how we redo the collaboration so that either they get more of the economics or we get more of the economics. And the scenario where potentially we get the asset back, our plan is clear that we would immediately look to find the next partner that would help to develop them and launch them. Which goes back to the first question, which is, as we stated, we are really not building out a sales force at all. Right now we're focused on, first of all, getting VET approved and also getting launch ready, which is a relatively minimal amount of money that we're spending between now and the end of the year. So the idea would be that with that launch readiness, if we got the asset back, we'd run a active process and be in a position for another company to take on the development and launch of VET fairly rapidly. So we're hoping there wouldn't be a particular

gap. Okay, but as of today, could there be a gap between when it got approved and when it launched if you are not able to secure the right terms? Okay.

Oh,

sorry, say

that last bit again. Say the last bit of the question,

sorry. I just wanted to clarify whether there would be a gap in the launch if you wouldn't find a suitable partner in time once it's approved.

Actually, so yeah, we said the suitable partner. So at the moment, the plan is there'd be no gap between getting approval, ideally having a partner in place or having Pfizer launch. There'd be no gap at all. I think your question there is if you get the asset back and you don't get a partner, then yeah, we'd be taking stock of that. Our plan is that we'd find a partner.

Okay. If we get the...

Next question comes from the line

of Andrew Berens with Learing Partners. Your line is open.

Hi everyone, this is Amanda on Francity. We wanted to get your thoughts on the recent readout from the phase three trial evaluating the GATA and second line HR positive breast cancer in patients that don't have a PIC3C mutation, which then would include some ESR1 mutant patients. And we're wondering how does this change, or if this changes your outlook second line ESR1 mutation patients and if you would ever consider a combination with GATA to address a broader population. Thank you.

Thanks for the question. Noah? Sure.

Yeah, so we really are not surprised by the result. We recognize the opportunity for PIC3 mutation directed drugs in breast cancer. There is overlap as you have suggested between ESR1 mutations and PIC3CA. So the question comes down to whether it's in our modeling and overall where my impression is that it will have little impact on the modeling. I could turn it over to my colleague Alex from commercial to offer further comments. But part of your question was whether we would develop it with an agent like that. And the answer to that is someone may, but we won't. Because we've already established that we're not doing further development on the drug, initiating new studies and combinations. And it would be something that should be very much of interest to another company. We've already scouted that out, but

it's not something we'll be embarking

on. Next question comes from the line of Lee Watzek with

Cantor Fitzgerald. Your line is open.

Hey, good morning guys. Thank you for taking our questions and nice progress on the pipeline. I guess for VEPDAG, the submission sounds like you know the PADUFA date very soon. Should we anticipate priority review here? And any guidance on your part for the global filing strategy? Do you need maybe to look for more mature OS data?

Yeah, but the second part of that question I'll hand over to Noah. For the first part, yeah, we're still awaiting details from the FDA and as soon as we get that information, we'll pass that on. So we don't have to do the date yet. Noah, do you want to tackle that second part of the question?

Yeah, you know, what we've shared, what we've offered guidance to is our filing of the NDA in the US and obviously we're waiting on feedback regarding PADUFA date, but regarding global strategy, we haven't offered guidance on that yet. So I think it would

be pretty mature.

Okay, and then in terms of finding maybe a potential new partner for VEPDAG in the case that you got the molecule back, can you elaborate some of the considerations that you prioritize what's important for you guys in terms of maximizing the value?

Yeah, great question. I mean, clearly we believe VEPDAG is an

important drug. We believe it has a lot of value. Because of the partnership we're in with Pfizer and the decisions that have been made, maximizing that value is gonna be somewhat difficult. So that's why we're in discussion with Pfizer about changing the nature of the collaboration. And ideally, as I said, either Pfizer or Vepa should go forward with the asset more kind of full of economics. And in the scenario where maybe we get the compound back, yes, we'll be looking to partner, ideally a partner that does have the kind of the zeal and interest to develop the asset further, both from the US and the global setting. Our involvement in that, I think would be relatively minimal in terms of development. Our view is that we want VEPDAG in the hands of a partner, be it Pfizer or another company that really takes the compound forward, launches it and progresses

it with further development.

Next question comes from the line of

Akash Vewari with Jeffreys, your line is open.

Hey, this is Manoj on for Agarj. Thanks for taking our question. What are your expectations around the Denadly LLRK2 data in the first half of next year? And if that trial fails or doesn't meet expectations, what signals from that study would you be looking to give confidence for your own degrader program? Thanks.

Yes, thanks for the question.

If the question was expectations for the Denadly program last year, I think it's a fantastic question. We think that LLRK2 is an outstanding target and I think the entire key opinion leader community would agree with us on that. The question is, what is the best drug to address that target? And so we see some virtue in an inhibitor, but it has challenges and I outlined that earlier that the inhibitor doesn't seem to kind of trace the brain as deeply as let's say our degrader. And on top of it, it doesn't necessarily engage its target as effectively. We have a broader engagement. Not only are we binding it and degrading it and we're eliminating because of that degradation, the LLRK2 kinase activity, the GTPs activity, gap holding function. So all of those features make a degrader more attractive than inhibitor. So we think that they may succeed. We know they have the right target and we're looking forward to learning from their results, learning if there's something about patient selection that could be incorporated and overall, whatever signals can come out of

their trial.

Thanks.

Next question comes from the line of Ivan Segerman with BMO Capital Markets. Your line is open.

Hi there, this is Connor McKay on PREV and thanks for taking our question. We just had a quick one on the submission of EPDA. Given the current environment at FDA, we were just wondering if you'd be willing to characterize your recent interactions with the agency and maybe comment on level of alignment there. And then just one quick follow up on ARV806. Would you be able to share a little bit more on how you're thinking about positioning this asset versus the K&K RAS agent you mentioned today? Thank you.

Yeah, thanks for the question. The second one I'll hand over to Noah and Angela. The first one, I'd have to say our whole process with the FDA has gone very smoothly. The interactions have been excellent. Their timing in terms of getting back to us has been really good. So even though we know that there's lots of other pressures on the FDA and it could impact timeline, we haven't seen that yet with our interactions on BENTEC, which is a really good positive thing for us. And Noah, do you want to tackle?

Yeah, regarding 806, I'll make some comments about clinical and I'll turn it when I'm done to Angela, we may have some comments about some of that interesting differentiation, the clinically. So this drug entered the clinic a little faster than we expected because of great efficiencies that the team loved. Then what we noticed is that there is tremendous appetite for drugs like ours in this space because our cohorts are in demand. So we're advancing through early dose escalation now. We don't, overall we expect that there are gonna be five or fewer dose levels in this escalation. So that's gonna give you a sense of where we're headed. The key is to look at where we are in monotherapy, compares ourselves to data that's out for inhibitors and the very, very modest and unimpressive data that have been presented by a degrader in the clinic, which is limited, had dose limiting toxicity relating to a panic function. So we'll compare ourselves to that. We have good go, no go criteria, but then the intention is to move our IV degrader, which has once a week, possibly once every two week dosing, that's something we'll learn from this process inflation in combination with EGFR inhibitors and with chemotherapy. And that's built into our plan and that allows us to start moving into eventually first line colorectal cancer and pancreatic cancer and also opportunities in non-small cell lung cancer. I'll turn it to Angela.

Sure, thanks Noah. So just to comment on some of the other differentiation features of our 806 molecule. It's very potent with respect to its activity. We're 25 times greater in terms of potency for anti-proliferative activity with respect to the inhibitors and then 40 times more effective than the clinical stage degrader. The other piece that I'll mention is that catalytic activity that we have overcomes this K-rath 3 synthesis rate that has been observed as a major mechanism of resistance in the clinic with RMC, certainly with RMC 6236. So it's something we're excited about. We think this is a very strong differentiator. Of course, we'll see what happens clinically.

So I hope that helps. Yes, thank you.

Next question comes

from the line of three. Creepa de Veraconda with Three Securities. Your line is open.

Hi, this is Anna on Creepa. Thanks for taking our questions. So in regards to 102, I know you mentioned the elevated LRK2 level in Parkinson's. Could you remind us as to what percent of Parkinson's patients could be eligible for an LRK2 targeting drug? And then a second question in regards to new adjuvant VEP-deg and that potential data readout, how would this potentially inform any room for VEP-degs to be used earlier in the treatment paradigm, and besides commercializing in second line at monotherapy and at fixed combo, any additional plans for development? Thank you.

Yeah, thank you for the question. Noah, next, would you like to go to the LRK2? Yeah,

so LRK2 levels are higher in the Parkinson's disease patients. Now we haven't made a choice that we're only treating patients with elevated LRK2, and by the way, I should say that that's something that might be on the table, it's something that we're gonna explore. We're gonna look at our own data sets as they evolve. We'll look at what's coming out of the Denali program if it's shared, so that's a possibility. If your question implies, you know, genetically, since LRK2 is so implicated genetically in diseases like Parkinson's disease, if we, you know, when we move forward in Parkinson's disease, what patients, what percentage of patients have LRK2 implicated disease? Well, in idiopathic, well, in familial Parkinson's, about 15% of patients have LRK2 mutations, and there's a higher percentage that have LRK2 pathway mutations that contribute to other types of familial Parkinson's disease. When you look at idiopathic, it's down in the few percent range, so, but beyond those LRK2 mutations themselves, there are all kinds of pathway perturbations that suggest that LRK2 could be at the center of this endolysomal dysfunction that is characteristic of Parkinson's disease and PD. So you start to have 30% of patients that can have SNPs and other biomarkers that are associated with this LRK2 dysregulation and may lead to LRK2 elevation, and we have a particular interest in that subset of patients and that's why we're engaging in a lot of biomarker analysis. We've been a long time collaborator with the Michael J. Fox Parkinson's Disease Biomarker Initiative, and this is bearing fruit for us. So I think that we'll, we have no kind of guidance yet about whether we're doing patient selection or patient enrichment or going for all comers, but these are the types of questions we are investing in right now to ensure that we have the best development plan in the world. Now the second question was about neoadjuvant VEPTEC.

So- And positioning the potential for VEPTEC in an early stage. Yeah,

so really we have to keep in mind there have been no evidence to date to suggest that VEPTEC shouldn't be working in the adjuvant setting and in first line. We have every reason to believe that we can be very effective in that space. We know the drug is very tolerable. Cross-study comparisons suggest maybe we're more tolerable than aromatase inhibitors. That could be very important in both of those settings. There's, so, but ultimately a decision is being made in this partnership that because of where we are with timing and the interest probably more than with our partner, in this case Pfizer, in first line, that we're just not gonna be going forward in those early lines. And that's why we've been giving so much guidance to our, for our intent to outlicense this, you know, or proceed with renegotiation with Pfizer. But I don't think that we should draw any conclusions that there are any problems in the neo-adjuvant setting or in

first line.

Great, thank you so much. Next question comes from the line

of Jeet Mukherjee with BTIG. Your line is open.

Great, thanks for taking my question. So perhaps just coming back to the discussions with Pfizer over VEPTEC, you know, you've talked about scenarios where perhaps Pfizer gets more economics or you get more economics or perhaps you find a new partner altogether. So based upon where your discussions are right now, would you say that you and Pfizer have very different views on how to maximize value for VEPTEC? And are you in active dialogue with other partners? If yes, how are those discussions going? Thanks.

Yeah, great question. I would say that Pfizer and our business and the discussions we are having are aligned in terms of what the best way to get value for VEPTEC is. Even though we might have different views about the development future of VEPTEC, I think Pfizer and our business truly believe those values we had there. And that's why we're in these discussions. Clearly, if the asset does come back, and again, that's just one of the scenarios. The other scenario is that Pfizer takes the compound form. But in the scenario where it comes to us, yes, we'd run an active process. But obviously, we cannot run an active process right now because we're in a collaboration with Pfizer and we don't have the ability to do that. Our belief is if we get the asset back, we run a process, there would be companies extremely interested in taking a near approved drug and with the potential to develop it, not only in the first-line setting, but even earlier. So we are very pleased with the progress in terms of discussion with Pfizer. Like I say, if they want to take it forward aggressively and launch it themselves, that would be extremely positive. But if they don't and the outcome is we get the compound, then yes,

we'd run an active process.

Next question comes from the line of Ellie Merle with UBS.

Your line is open.

Hi, this is Hagesan for Ellie. Thanks for taking our question. I think you talked a little bit about some of the preclinical data for the KRAS inhibitors. Can you talk a little bit more about what we should expect with more data later this year and how might that inform what we think about in the phase one?

Great, thanks for the question. I'll hand that

over to Angela.

So for the KRAS inhibitors, for 806, certainly you can expect to see some preclinical data just showing the differentiation profile that we see relative to inhibitors that are in the clinic. We'll also show some additional data just showing the combinability of the molecule. Noah had mentioned with EGFR mechanisms. That's difficult with the PAN inhibitors, certainly in the clinic, showing some side effects that would basically preclude that combination. We'll also show data that we think is really compelling from our oral and KRAS program, showing that we're making really great strides there as well. Other additional comparative data that we'll have will include some other models where we're looking at combinability with immuno-oncology approaches and some of the unique features of ProTax, we think, in this space, also with respect to the resistance mechanisms and overcoming that upregulation that is seen clinically with the inhibitors as well. So we think we have a very differential profile and it's an exciting opportunity, certainly. And we're seeing that with the over-enrollment and the interest from the investigators that treat patients. So I think it's an exciting time. And I'm sure Noah and your team will be sharing

clinical data as soon as we have it. Hope that helps.

Next question comes from the line of Peter Lawson with Barclays. Your line is open.

Great, thank you so much. Maybe just leading on from the prior question. For the G12B and the update, when should we expect the initial

first

in human data update and kind of if you could talk through how enrollment is going and the number of sites that are open and any other details around that trial? And then I have a follow-up. Thanks, Peter. Noah, try to get a share.

So Peter, we just announced that we opened the study for enrollment a little ahead of schedule and the immediate reaction seems to be very favorable. We haven't offered guidance yet on when we will be sharing data. But you're gonna get it soon. You'll get the guidance soon, meaning it'll be sometime next year, obviously. In terms of, I would suggest just track things on clinicaltrials.gov because we wouldn't typically be giving you site numbers and things like that for a phase one study.

Gotcha, thank you. And I apologize, I arrived late on the call. For the BCL-6, so that's what, 353, the data in the second half, what should we focus on as regards to the data and other metrics that we may be delivering in that data set,

thank you. Sure, so

we've shared that we'll provide some update of our data set in the second half of this year. I really don't wanna get ahead of ourselves and share what that disclosure will be, but the idea is that we're advancing through our our dose escalation program, and obviously in dose escalation programs, the data that you're gonna see are gonna be more like, but before you're done with it, safety and PK and early signs of efficacy. So I think you can look for those. Obviously, as we approach the completion of that, whereas we achieve the completion of that dose escalation or ready for expansion, we'd be armed with more efficacy data, but still a focus on targeting the age and through PK PD.

Gotcha, would that be kind of like the range of like, 10 to 20 patients or, and I presume kind of heavily pretreated, any details there, Angeline? Yeah, I would say that's

a reasonable guess. Thank you so much.

Next

question comes from the line of Sudan Luganesan with Stiefens, your line is open.

Hey, this is Keith Alv on behalf of Sudan. Thank you for taking your question. So regarding the recent clinical data published by Celciwadi on their advanced breast cancer asset, could you kind of just comment on your insights and what your perspective on that data is and where do you see that there's competitive positioning within the treatment landscape? Thank you.

No, thank you for the question. Noah, I know you've tackled this earlier. Yeah,

I'm not sure if I have more to add than what was said earlier. We have always recognized that that a drug like Celciwadi could demonstrate an attractive benefit risk in the second line setting and the first line setting. There is an overlap between ESR1 mutant and PI3 kinase targeting agents. In the end, what physicians are looking for are oral protacts, I have oral degraders, so in our case, a protact that has an attractive benefit risk profile. So we think we're delivering that and physicians kind of want to avoid toxicity as much as possible and you get all the benefit they can after first line therapy before adding drugs that have some toxicity. So the impact on market opportunity in that second line setting is probably modest, but we haven't been offering specific guidance on market opportunities, so it's difficult to measure

that modesty.

Thank you. Next question comes

from the line of Michael Schmidt with Guggenheim Partners. Your line is open.

Hi, this is Sarah, long time, Michael. Thanks so much for taking my question. I wanted to quickly go back to the oral DNA KRS that you mentioned. I would love to hear more details on that and specifically how you would expect to differentiate from later stage pan-KRS.

Sorry, we couldn't understand the question. Could you repeat it one more time? There's a lot of echo.

Oh, one second.

So the full pan-KRS

and

how it differentiates

from other KRS? Yes, exactly. So the question

was about the pan-KRS and any thoughts on differentiating from later stage pan-KRS and pan-RAS programs?

Sure, sure. So, as you know, we differentiate at least with ARV 806 from what we said publicly, but our pan-KRAS program, we aim to have the same level of potency differentiation as well. We do bind to and degrade, so we degrade. We don't inhibit. So we avoid that upregulation that's observed clinically. So as you're aware, the clinical inhibitors of the pan-RAS inhibitor has shown a major mechanism of upregulation of KRAS as a resistance mechanism in the clinic. So they're claiming around 20 to 30% of patients they're seeing this. So it's pretty profound. So we think we have an opportunity there. Our oral pan-KRAS also will have great combinability will speak a bit about some of the differential profiles of our molecule relative to the pan-RAS molecules that are in the clinic. We expect that we'll have greater combinability with the immune stimulatory mechanisms like the Katrina and other IO agents, because we will not inhibit T-cell receptor activity. So we think that combinability will also provide a major advantage to other mechanisms clinically. So there's a number of other differential activities that we're observing that we'll be discussing as we move forward and advance the program, but it's an exciting time for us. So stay tuned for more data this year

at the TRPL meeting.

Great, thank you. Next question

comes from the line of Terrence Flynn with Mark and Sandy. Your line is open.

Hi, good morning. This is Chris on for Terrence. Just one question from us for 393, beyond safety, what do you need to see in order to advance the asset into a combo trial with Grofie? Thank you.

Thanks, Chris. Noah, do you want to answer? Sure. So probably not a lot. Like we weren't expecting any hematopoietic toxicity, which would be the principal toxicity of Glophis beyond the CRS seen in the first cycle, but well managed with Glophie's dosing over the first month or first three weeks. So it's just a matter of reinforcing that we're not seeing any unexpected toxicities.

And I don't have much more to add than that. Pretty clean drug, pretty clean. Yep. Thank you.

Next question comes

from the line of Yigal Nukomovic with Citi. Your line is open.

Hi, this is Julian Kim on for Yigal. Thanks for taking our question. Maybe just one quick one from us. Can you comment on whether AI was utilized to facilitate the compilation and submission of modules from WebDAG to the FDA, and more broadly, any potential utilization in the early drug development pipeline? Thanks.

That's a great question. I suppose it's your definition of the AI. Yeah, we've certainly used a lot of kind of artificial intelligence in all of our research programs, and Angela could talk to the different features of that. And whether or not it was using the actual NDA flag application. No, I'm not sure how

much

of

that. Well, part of the NDA is submission process. We do work with some vendors. So there is AI that's going on there through our vendors. But in terms of our business overall, and the development part of our business, think of it AI as being able to help us with a lot of medical writing, right? So we're gonna be able to take documents that we have previously generated, across different assets, and learn from them. These are things we're doing currently. And learn from them to impact our medical writing cost and efficiency in the future. Think of it also as something that helps in clinical operations to more efficiently review our vendor management, our contracts, that there's more clear accountability, and roles and responsibilities across different contracts for a company that does rely on a lot of externalized work in cleanups. And then obviously we're using it all the time with our stats programming. Like that's something that's been ongoing. There are many other areas in the company that are beginning to use it. But at least that gives you a sense of how it could have been used for an NDA in our development

programs. And I can comment on how we're using it in research. So we have computational chemistry and computational biology teams that use AI all the time in machine learning algorithms. We've been applying AI to our ProTac design features. As we've been in this for 13 years, we've actually accumulated a lot of real world data on ProTac activity and optimization. We are applying that and learning from it. So we iterate our ProTac designs much faster now. And so we're seeing a big benefit in how we move the speed in research. And so this includes pharmacokinetic properties of these molecules and absorption features as well, which as you probably know is really key for ProTac design. On the computational biology side, we're using it all the time for how do we go about analyzing our ligand identification data. So this enables us to go after previously undrugged targets and optimize those warheads to utilize in ProTacs for targeted protein degradation. In addition, I would say we use AI to mine real world data from biomarker features that exist in publicly available data sets. And this sets us up well for deep understanding of pathway biology. And this is how we've been approaching our Parkinson's disease and also our PSP as well as other neurodegenerative diseases and really mining CSF protein changes in those diseases and how to set the clinical group up really well to understand how we might use those biologic features to stratify patients. So

thank you for the question. Got it, thanks so much.

Next question

comes from the line of Spiler Van Buren with TD Cowan, your line is open.

Hi, this is Ekenna Onfotiler, thank you for taking our question. Just to go back to the VEPDAG and Pfizer collaboration, has Pfizer indicated its willingness to revise the collaboration or give back rights to VEPDAG and why would they be motivated to give VEPDAG back given the amount they've invested to date? Also, wouldn't that require a significant cash outlay by Venice and are you willing to use the existing cash on hand with milestones or royalties to do that?

Yeah, just to reiterate,

we're in a current 50-50, the attraction for that 50-50 was the planning on second line, first line and new adjuvant trials. Now we're currently left in a situation where there's only second line monotherapy, so less attractive in terms of our market size for Pfizer. They have shown no interest to develop that further. So that's the first and second line. The second and third line is that Pfizer but it's an important thing that VEP would not be developed further by Pfizer. We're in negotiation right now about what's the best way forward in terms of moving away from the 50-50 collaboration we had where either Pfizer takes the asset and launches it and gets more economics or they had the compound back to us. I've said really clearly, I'll say it again, if the compound comes back to us, we are not spending any money on the further development of VEP, none at all. We'd be running a process to find a partner who would then ideally launch the drug and ideally further develop the drug. And we gain in the benefit, the forward benefit of seeing the drug on the market. But we have no plans to further develop

VEP if we've got the compound back to us. Thank you.

That concludes our Q&A

session. I'd like to turn the call back over to John Houston for closing remarks.

Thank you, operator, and thanks, everyone, for joining us this morning and all the fabulous questions. Obviously, we look forward to providing additional updates in the coming months, but thank you so much for your time today.

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