NASDAQ:ARVN Arvinas Q1 2025 Earnings Report $6.61 -0.20 (-2.94%) As of 05/9/2025 04:00 PM Eastern Earnings HistoryForecast Arvinas EPS ResultsActual EPS$1.14Consensus EPS -$0.93Beat/MissBeat by +$2.07One Year Ago EPS-$0.97Arvinas Revenue ResultsActual RevenueN/AExpected Revenue$41.87 millionBeat/MissN/AYoY Revenue Growth+646.20%Arvinas Announcement DetailsQuarterQ1 2025Date5/1/2025TimeBefore Market OpensConference Call DateThursday, May 1, 2025Conference Call Time8:00AM ETUpcoming EarningsArvinas' Q2 2025 earnings is scheduled for Tuesday, July 29, 2025, with a conference call scheduled on Friday, August 1, 2025 at 12:30 PM ET. Check back for transcripts, audio, and key financial metrics as they become available.Conference Call ResourcesConference Call AudioConference Call TranscriptPress Release (8-K)Quarterly Report (10-Q)SEC FilingEarnings HistoryCompany ProfilePowered by Arvinas Q1 2025 Earnings Call TranscriptProvided by QuartrMay 1, 2025 ShareLink copied to clipboard.There are 16 speakers on the call. Operator00:00:00It is now my pleasure to turn today's call over to Arvina's Vice President of Investor Relations, Jeff Boyle. Please go ahead. Speaker 100:00:08Thank you, and good morning, everyone. Thanks for joining us. Earlier today, we issued a press release with our first quarter twenty twenty five financial results, which is available in the Investor and Media section of our website at arvinas.com. Joining the call today are John Houston, Arvinas' Chief Executive Officer, President and Chairperson Noah Berkowitz, our Chief Medical Officer and Andrew Szek, our Chief Financial Officer. Our Chief Scientific Officer, Ann Cacasse, was scheduled to join us this morning, but had an unanticipated personal event and will not be able to. Speaker 100:00:40Before 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 filings with the Securities and Exchange Commission, which I urge you to read. Our actual results may differ materially from what is discussed on today's call. And now I'll turn the call over to John. Speaker 200:01:03Thanks, Jeff. Good morning, everyone, and thank you for joining us today. As you saw in our earnings release this morning, we have reached an important moment in our business' progress as a company. We recently shared the first ever positive pivotal data for a protact degrader vebbegastran, which we are moving towards filing and registration. In addition, we continue making great progress with our pipeline and shared exciting first in human data for ARV-one hundred two, our LARC2 degrader and excellent preclinical combination data for ARV-three ninety three, our BCL6 degrader in hematology. Speaker 200:01:38We also recently received a safety proceed from the FDA for ARB-eight zero six, our KRAS G12D degrader. We will discuss each of those items on the call today. Noel will review the clinical progress for bebbegastrant or bebdeg and for ARB-one hundred two. He will also then review our recent preclinical combination data for ARB-three ninety three and provide an update on ARB-eight zero six. Finally, Andrew will provide a financial overview including our capital allocation priorities and updated cash runway guidance. Speaker 200:02:14However, before we get into our data updates, I'd like to cover three important topics upfront. First, we are making excellent progress towards our filing and registrational plans for VetDeg in the second line plus ESR1 mutant breast cancer. Based on the strong data from the VERTECH two study, we have a high conviction that VetDeg has the potential to be a best in class monotherapy treatment for patients in a second line ESR1 mutant setting. We are on track to submit a regulatory filing with health authorities in the coming months. We believe there is an attractive opportunity for VetDeg as a second line plus ESR1 mutant treatment in metastatic breast cancer and we will discuss this opportunity in greater detail after our ASCO presentation in June. Speaker 200:03:02Secondly, we have aligned with Pfizer on the removal of the two Phase three combination trials from our joint development plan that were planned for this year. The first of these trials was a combination with a CDK4six inhibitor in the second line setting. And based on recent discussions with health authorities and our observations from other trials involving biomarker selected populations, we believe ER therapies will be restricted to patients with ESR1 mutations in the second line plus setting. With this in mind, we have removed the second line ITT combination trial, which was planned to initiate in 2025 from our joint development plan. The second trial was the first line combination trial with the tirmaciclib, Pfizer's CDK4 inhibitor, which was also planned to initiate in 2025. Speaker 200:03:55After reviewing the totality of emerging information including external data results, the evolving treatment landscape in metastatic breast cancer and long term capital allocation, we have aligned with Pfizer to remove this first line combination study from our joint development plan as well. We and Pfizer will continue to evaluate our ongoing combination studies in the second line plus setting and generate valuable data in metastatic breast cancer to inform our path forward. In addition, Pfizer is adding a VebDeg combo cohort to their ongoing Phase one clinical trial with our investigational CAT6 inhibitor. This trial will be operationalized and funded solely by Pfizer. As these trials complete, we'll make data driven decisions about whether further investment in each of these combinations is warranted. Speaker 200:04:46I look forward to sharing additional details in the coming months as our trials continue. The third major topic is our company wide cost reduction effort. The recent challenges in the capital markets are prompting us to extend our cash runway and ensure our programs reach data milestones before additional capital is needed. An important step in this process is maximizing our efficiency and reducing our operating expenses wherever possible. We have implemented a restructuring that includes a workforce reduction of approximately one third of the company, portfolio reprioritization and overall cost reductions of approximately $80,000,000 annually on a full year run rate basis. Speaker 200:05:32Although difficult, the workforce reduction which will result in streamlined operations across the entire organization is a prudent decision that we believe will appropriately size the company for future success. We have also reprioritized our research portfolio to focus on assets that have the greatest potential to deliver the most value for patients, physicians and shareholders. Our clinical programs ARV-one hundred two in neurodegeneration and ARV-three ninety three in hematology remain on track to deliver important clinical data later this year. Overall, these steps will result in a combination of cost savings and cost avoidance of approximately $500,000,000 over the next three years. The net results of these actions is a change in our guidance to extend our cash runway into the second half of twenty twenty eight. Speaker 200:06:26We believe these significant cost savings and a refined capital allocation strategy in addition to our strong balance sheet will allow us to advance our early development portfolio in a timely and efficient manner as well as ensuring a financially disciplined approach to commercial readiness. Before I continue, I do want to thank all the talented employees who are directly impacted by this decision. I'm proud of the progress we have made together and want to acknowledge their contributions and commitment to discovering and developing new treatment options for patients with life altering diseases. We wish the best for these colleagues as they transition to new opportunities. I also want to thank the employees who are continuing the journey with Azarovindis as each of them will be instrumental in helping us achieve the ambitious goals we have laid out for the company. Speaker 200:07:15I'll now turn the call over to the team to review our recent data and the details from the quarter. I'll return at the end of the call to review the milestones that we anticipate for the remainder of 2025. But for now, I'll turn the call over to Noah. Speaker 300:07:31Thanks, John, and good morning, everyone. Together with Pfizer, we Speaker 400:07:35were pleased to announce positive Phase III results from the VERITECK-two trial earlier in the first quarter. These data, the first from a pivotal trial with a protracted radar represents an exciting and validating step forward for our platform. As John mentioned, we are excited to announce that data from the VERITECK-two trial were selected for a late breaking oral presentation at the American Society of Clinical Oncology or ASCO meeting in late May and will also be featured in the ASCO press program. The VERITECH II abstract has also been selected for inclusion in the twenty twenty five Best of ASCO program in July. This program is important. Speaker 400:08:18It's run by ASCO to increase access to clinically impactful research for those who are unable to attend the annual meeting. Given our plans to present the full data set at ASCO, which imposes an embargo on the presentation, I will only be providing commentary on the information previously disclosed in the top line data release. In patients with ESR1 mutant tumors, VEPdEG exceeded the pre specified hazard ratio of 0.6 and demonstrated a clinically meaningful improvement in progression free survival over fulvestrant. Additionally, Vepdeg continued to demonstrate a safety and tolerability profile consistent with our previous studies. We believe Vepdeg has a best in class profile and our plans to seek global regulatory approvals remain on track. Speaker 400:09:12While we are no longer planning new registrational trials for VEPTIC, we will continue to generate valuable data in our ongoing combination trials and we welcome Pfizer's addition of Beptig in combination with their CAD6 inhibitor to their ongoing Phase one trial. I'll now turn to our most advanced neuroscience program. We have designed investigational oral pro type upgraders to cross the blood brain barrier and selectively degrade leucine rich repeat kinase two or LRRK2. LRRK2 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 the pathological scaffolding function, the GTPase activity and the kinase activity of LRRK2. Speaker 400:10:07ARV102 is our lead LRRK2 degrader. We believe our LRRK2 degraders are particularly well positioned to be evaluated in two diseases Parkinson's disease or PD and progressive supranuclear palsy or PSP. Familial and idiopathic Parkinson's disease have been associated with LARC2 on the basis of genetics and models of lysosomal dysfunction. PSP disease severity is associated with LARC2 genetic findings. Additionally, we have published data associating the tau pathology of PSP with LARC2 mediated endolysosomal dysfunction. Speaker 400:10:47Previously, we have shared preclinical data demonstrating ARB-one hundred two's superior target engagement, enhanced potency and lysosomal pathway engagement Speaker 300:10:57when Speaker 400:10:57compared to LAR2 inhibitors. In nonhuman primates, ARB-one hundred two, across the blood brain barrier, where it achieved LRRK2 targeted protein degradation in deep brain regions and reduced LRRK2 protein as well as neuroinflammatory biomarkers in cerebrospinal fluid or CSF. I am now pleased to share with you that we have observed a similar pattern of activity in our first in human Phase one clinical trial in healthy volunteers. These data were presented last month at ADPD. Our trial evaluated single doses of ARD-one hundred two ranging from ten milligrams to two hundred milligrams and multiple doses ranging from ten milligrams to eighty milligrams. Speaker 400:11:38We met our objective of 50% LARC2 reduction in CSF after a single oral dose of at least sixty milligrams and once daily repeated oral doses of at least twenty milligrams. This indicates substantial central LARC2 protein degradation. In the Phase one clinical trial, ARV-one hundred two was safe and well tolerated with no serious adverse events or discontinuations reported after single or multiple doses. ARV-one hundred two also demonstrated dose dependent median reductions in LRRK2 protein levels compared to baseline in peripheral blood mononuclear cells confirming target engagement in the peripheral compartment. Taken together, pharmacodynamic changes of LRRK2 reduction in the CSF reduced biomarker levels in the periphery and an acceptable safety and tolerability profile supports further study of LRRK2 degraders in PD and PSP. Speaker 400:12:37That further work is ongoing. Dosing of the Phase one single ascending dose cohort in patients with Parkinson's has already begun and the multiple ascending dose cohort will begin in the second half of the year. We anticipate providing an update on PKPD safety and tolerability from the Phase one SAD cohort in patients with PD later in the year. The data I've shared demonstrate that we can make orally bioavailable PROTECTs that are brain penetrant. While our lead program is focused on LRRK2 for PSP and PD, our discovery portfolio focuses on additional targets that may be relevant for Huntington's and Alzheimer's disease. Speaker 400:13:18We look forward to sharing updates on these in the coming months and years. Turning back to oncology, ARB-three ninety three is our investigational oral PROTECT designed to degrade B cell lymphoma six protein or BCL6. BCL6 is a 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. PROTECT mediated degradation has the potential to overcome the historically undruggable nature of Bcl-six. Speaker 400:14:05ARV-three 93 potently and rapidly degrades Bcl-six protein with iterative activity, which is critical to overcoming Bcl-six's rapid resynthesis rate and its sustaining anti tumor activity. In 2024, we shared preclinical data demonstrating that ARB-three ninety three drives tumor regressions in multiple in vivo models of B cell driven non Hodgkin lymphoma including large B cell lymphoma. We are enrolling patients with non Hodgkin lymphoma in a Phase one clinical trial and are on track to share initial data by the end of the year. At AACR this past week, we presented new preclinical in vivo data for ARV-three ninety three in combination with standard of care biologics and chemotherapy as well as oral investigational small molecule inhibitors. These new data highlight the potential of ARB-three ninety three to drive synergistic antitumor activity across multiple aggressive large B cell lymphoma xenograft models. Speaker 400:15:10ARB-three ninety three enhanced tumor regressions when combined with current standards of care, including R CHOP and various biologics. Notably, ARB-three ninety three monotherapy upregulated CD20 expression, providing mechanistic rationale for synergy with anti CD20 therapies such as rituximab. Additionally, ARB-three ninety three demonstrated enhanced tumor regressions when paired with targeted small molecule inhibitors of BCL2, EZH2 and BTK, key oncogenic partners of BCL6. These results suggest that ARV-three ninety three may enable highly effective chemotherapy free regimens, whether in combination with biologics or as part of an all oral therapeutic strategy. We will present new preclinical data in a patient derived model of angioimmunoblastic T cell lymphoma or AITL at the European Hematology Association Conference in June of this year. Speaker 400:16:12This is an orphan indication with high unmet and limited treatment options. We believe this will be the first preclinical data to show human AITL dependency on Bcl-six. We also plan to present preclinical combination data with an emerging standard of care bispecific antibody in a model of aggressive large B cell lymphoma in the second half of the year. And finally, we filed an IND for our KRAS G12D degrader ARV-eight zero six and recently received a safe to proceed letter from the FDA. We anticipate beginning a Phase one trial in patients with solid tumors harboring KRAS G12D mutations in the second half of this year. Speaker 400:16:57KRAS is a driver oncogene in several major tumor types and is associated with poor prognosis and resistance to standards of care. Our degrader has demonstrated high potency and differentiation from inhibitors and other degraders currently in the clinic. In addition to selectivity in the preclinical setting, demonstrates robust antitumor activity from dose responsive degradation of KRAS G12D in mutated cancers including pancreatic and colorectal cancers. In preclinical studies, our PROTECT degrader has demonstrated the ability to bind both the active and inactive states of KRAS G12D ARB-eight zero six will eliminate rather than inhibit KRASG12D with in vitro potency. And those that potency can be 30 fold greater than inhibitors and degraders currently in the clinic. Speaker 400:18:03In totality, these preclinical data give us confidence and we intend to show differential biology of our KRAS degraders at a conference later this year. I look forward to updating you on our progress in the coming months. With that, I'll turn the call over to Andrew to review our quarterly financial information. Speaker 300:18:23Thanks, Noah, and good morning, everyone. I'm pleased to share financial highlights for the first quarter ended 03/31/2025. As a reminder, detailed financial results for the first quarter are included in the press release we issued this morning. Let me start with the financial implications of the corporate restructuring and the removal of the two Phase three combination trials from the Vepdeg development plan. The corporate restructuring and associated workforce reduction were difficult decisions to make and are impacting many talented employees. Speaker 300:18:55They were however necessary to meet our goals of reducing our cost structure and extending our cash runway to support our promising pipeline. The reductions were focused on reducing internal costs without having an impact on clinical stage programs that will drive value over the next several years. We estimate the restructuring will result in a reduction of our ongoing infrastructure costs of approximately $80,000,000 annually with savings expected to begin to be fully realized in the fourth quarter of twenty twenty five. In addition, we anticipate cost avoidance of approximately $350,000,000 to $400,000,000 over the next three to five years as a result of the removal of the two Phase three combination trials from the bebptide development plan. These actions will allow us to continue progressing our promising pipeline without the need for a near term cash infusion and maintain a strong financial position with a cash runway now into the second half of twenty twenty eight. Speaker 300:19:56I'll now briefly touch on some key financial highlights for the first quarter of twenty twenty five. At the end of the first quarter, we had approximately $954,000,000 in cash, cash equivalents and marketable securities on the balance sheet compared with $1,040,000,000 for the year end 2024. Revenue for the three months ended 03/31/2025 totaled $188,800,000 compared to $25,300,000 for the three months ended 03/31/2024. The increase in revenue was primarily due to the accounting impact of the reduction in the BepteG collaboration agreements program budget due to the removal of the first and second line Phase three trials from the development plan. The revenue recognition accounting for this agreement uses the percentage of completion method. Speaker 300:20:45As the budgeted costs serve as a denominator in the percent complete calculation, a reduction in that budget compared the same actual incurred costs resulted in the higher percent completion and therefore higher revenue recognized in the first quarter. General and administrative expenses were $26,600,000 for the first quarter compared to $24,300,000 for the same period of 2024. Research and development expenses were $90,800,000 in the first quarter compared to $84,300,000 for the same period of 2024. The increase of $6,500,000 was primarily driven by a one time inventory charge of $10,000,000 for Vepdeg partially offset by lower than expected Vepdeg development costs and an increase in the LARC2 program of $5,200,000 offset by a reduction in non specific research and personnel expenses of $3,600,000 As I mentioned earlier, taking into account the anticipated impact of the restructuring, the reprioritization of the research portfolio and Vepdeg development plan and the anticipated launch of Vepdeg, our updated cash runway guidance is now into the second half of twenty twenty eight. We believe our efforts are focused on areas that will maximize shareholder value as we move forward as we move towards important catalysts in the coming months. Speaker 300:22:08With that, I'll turn the call back over to John for closing remarks. Speaker 200:22:12Thanks Andrew. These actions should offer significant clarity around our focus over the next few years and will allow us to hit a number of key data inflection points from our early development programs as well as the potential commercial launch of VetDag with our partner Pfizer. As we progress through 2025, there will also be many opportunities to showcase why our belief in our portfolio is strong. These include data from the VERITAGE II trial in the late breaking oral presentation at ASCO in June, the first Phase I data for a LRRK2 degrader, ARV102 in patients with Parkinson's disease and first in human Phase one data for our BCL6 degrader, ARV393. We believe our progress will continue to demonstrate the potential of our prototype degraders to add meaningful value for patients, their caregivers and our shareholders. Speaker 200:23:05As we embark on this new chapter, want to thank you for your continued support. And with that, I'll turn the call over to Jeff to begin the Q and A portion of the call. Speaker 100:23:14Thanks, John. Before I turn the call over to the operator, I do want to remind you that in order to comply with the ASCO embargo policy, we aren't able to answer questions about the VERITECK II data beyond the top line results reported in our press release on March 11. So with that, operator, will you Speaker 500:23:30please open up the queue? Operator00:23:49Okay. So your first question comes from the line of Michael Schmidt with Guggenheim. Please go ahead. Speaker 600:23:58Hey, guys, good morning. Thanks for taking our questions. I just had a few follow-up questions on WebDAG. Maybe just help us understand a little bit more on how much of the decision to not advance the foursix inhibitor combinations was driven by emerging data on the class overall versus specifically the VERITAG-two result? And in the second line setting, how do you think Rebtech will be positioned relative to other oral SERDs? Speaker 600:24:29And help us understand how much you need to invest in a commercial infrastructure as you potentially maybe commercializing the product in The U. S. Next year? Thanks so much. Speaker 200:24:42Thanks. Great question. So yes, the first question in relation to is this a decision based on specific information related to VEDDAG or the class. I think we've had a general discussion with Pfizer as we as you see our SERD during the market as an ESR1 mutant only drug. We saw some of the data coming from immunostrin, which also had a very strong ESR1 mutant only profile. Speaker 200:25:10And clearly, the data we had for Veratag, which we can't discuss in detail, but we already told you it has strong ESR1 mutant data, but we didn't hit ITT. So the general discussion we had with Pfizer was around whether or not in that second line setting would the drugs really just be ESR1 mutant only. And we came to the conclusion that's likely to be the case. And therefore the design of the study that we had was for an ITT combination with CDK4six. So we decided we would drop that. Speaker 200:25:49So that I think that's I think a logical rationale for dropping that particular study based on the emerging data on in the second line setting of whether or not you're going to have just the ESR1 mutant only profile overall. In terms of positioning VebDeg, I think as Noah said, I think again you'll see the data at ASCO where we believe we've got the opportunity to be the best in class of the degraders in that second line plus setting. And with that our positioning would be I think very strong in terms of our overall data centers of tolerability and overall activity. So we have great confidence of actually be if we get approval and get to the point of launch once we get through the regulatory hurdles. I think we've been in very strong position for positioning VEP in that marketplace. Speaker 200:26:46And I think with the third question was Commercial Yes, commercial investment. Clearly, it's a fifty-fifty coco with Pfizer. We are the lead for that. And what we've done is done a very kind of prudent approach to commercial build. It has been very small. Speaker 200:27:05It's all going to be data driven and the point of approval. So yes, there will be a kind of significant back end recruitment to get a sales force in place. But right now our commercial footprint is really, really very small. We also have the ability to have ongoing discussions with Pfizer about the best way to take the molecule forward in a commercial setting both in The U. S. Speaker 200:27:30And commercially. And we'll be able to update all of you on that as we complete those discussions. Operator00:27:43Your next question comes from the line of Andrew Berens with Leerink Partners. Please go ahead. Speaker 700:27:51Hi, thanks. I'm sure you guys have had to make some difficult decisions over the last few weeks. So my question is about the future neuro efforts in LRRK2. You did give some color in the prepared comments about the role of LRRK2 in neuro diseases, but wondering how much LRRK2 degradation you think is going to be clinically relevant and whether these would eventually be combination approaches? Speaker 200:28:15Yes. I'll hand over to Noah for a specific answer to that. But we're very excited by the data we see so far with LRRK2, our first neurodegeneration asset, the first protect in this space and the first to show brain penetrance as well. So the profile we're seeing initially is very exciting. But Noah, do you want to add some more color to that? Speaker 400:28:37Sure. So Andrew, thanks for the interest in what's a very exciting first neurodegeneration directed ProTAC for our company. So indeed, we think that there are few opportunities for us to develop this year. And as I outlined earlier in the call, that's because there's both genetics that support it and then also underlying biology in these two diseases that were highlighted, PSP and Parkinson's disease. Your question around how much degradation we want to achieve, well, the goal right now what had been and remains to achieve more than 50% degradation. Speaker 400:29:19We don't want to completely eliminate it, because there's obviously functional there's this to this protein in terms of endo lysosomal trafficking. But when there's overexpression, when there's increased activity, you get missed trafficking and that's tightly tied to the pathology of these diseases. We know that on average Parkinson's disease patients have twice the level of LARC2 in their CSF compared to age match controls. And so we think it's prudent therefore to target something in the fifty percent range. And so far we've seen in healthy volunteers that we can achieve that and as well as achieve appropriate downstream signaling. Speaker 400:30:07So we know that it's on target. We think on mechanism and the next thing is to really look at the data from the PD patients in the studies that are ongoing. Speaker 700:30:19Okay. And do you think it will be a combination eventually? Speaker 400:30:24Well, when you say combination, right now there really aren't disease altering drugs in the that are standard of care. So it's just a this may be on top of L dopa type of treatment for patients. But this is disease altering. So I'm not sure what you mean by combinations. Speaker 700:30:52Right. I'm asking whether you think it would be on top standard of care currently. Speaker 400:30:57Yeah, on top of standard of care for sure. Speaker 700:31:01Okay, thank you. Speaker 800:31:02Thank you. Your Operator00:31:07next question comes from the line of Eli Merle with UBS. Please go ahead. Speaker 500:31:13Hi, this is Joseph asking for Eli. Thanks for taking our question. What is your view on the market size of VEDDAC in the second line plus monotherapy setting alone? And I have a follow-up. Speaker 200:31:28And you have a follow-up? Do you want to ask it now or? Speaker 500:31:32Sure. So, how do you think about the cadence of cost reductions from a modeling perspective and in terms of VEBTQ monotherapy after the Veritac-two data, can you help us think about what milestones you might be entitled to from Pfizer on approval in this setting? Speaker 200:31:55So the first question was related to the market size. Yes. So we would think there's a really significant opportunity in that second line plus setting. There's forty thousand new patients in the second line setting every year. Of that forty percent are ESR1 mutant only and that's our estimate. Speaker 200:32:15Some others estimate around fifty percent. So that's twenty five thousand new patients in the second line third space each year. And drugs as you know like I said they were out in that space. They're probably capturing about a third of that. So there's a really significant opportunity there for a good profile of a degrader like the Begastrant to hopefully capture quite a significant part of that market. Speaker 200:32:42So we're very excited about the opportunity in that space. The second question, Andrew, think it's more related to kind of financial questions. Speaker 300:32:52Yes, sure. So with regard to the restructuring, notifications to employees have gone out this week. So the restructuring has begun. As with all restructurings, there's a combination of employee reduction and cost control. I stated in my prepared remarks that we would have the full impact of the reductions by Q4. Speaker 300:33:16We'll obviously start seeing benefit prior to that, right. So we're offering our colleagues severance packages that will be paid up in Q2, so you won't see a charge in our Q1 financial statements that the notifications went out in Q2. Speaker 200:33:31So it was a subsequent event for the Speaker 300:33:33purposes of our financial statements in the first quarter. But for modeling purposes, you can assume that you'll start seeing savings relatively quickly. Q3 will have a significant amount of savings and full impact in the fourth quarter. Operator00:33:56Your next question comes from the line of Derek Archila with Wells Fargo. Please go ahead. Good morning. This is Simone on for Derek. Thank you for taking our questions. Operator00:34:09I just have two. So, I know you said that for the log two degrader you need to see 50% degradation, but how exactly de risk is the target and what can we expect from the SAD cohort in PD patients in 2F of 25? Speaker 200:34:27Noah, do want to take that? Speaker 400:34:28Sure. I'm not sure I caught the second part, but to Speaker 200:34:32the first Yes, to do with that. Speaker 400:34:33How derisked. So in general, when you say derisked, I guess that could be that could focus us on what are some Speaker 200:34:46of the Speaker 400:34:46liabilities associated with that target, right? So we do know that there are findings with type two pneumocyte enlargement or proliferation that could be associated with collagen deposition in the lung. We also know that there's some vacuolization seen with and these are all the inhibitors, right? So vacuolization seen in the proximal tubule in the kidney. There's some typing going on in the background. Speaker 400:35:22So whoever's doing that, if you can pause, please. Thank you. So that's known and that's been a challenge for inhibitors. For reasons that we have our own hypotheses and it's probably too much to go into on the call right now, we have seen minimal evidence for the type two pneumocyte enlargement. We have associated the much reduced pneumocyte proliferation that we observed with our degrader rather than what's observed with inhibitors. Speaker 400:35:57We associate that with different protein different profile of protein deposition in the alveoli. So we think that we have a differentiated profile when compared to inhibitors and we're tracking patients in the meantime in our study. We look at diffusion capacity in the lung and we're measuring renal function on an ongoing basis and so far things have been safe to proceed. In terms of your second question that to do with the SAD cohort expectation, but I'm not sure what you meant by the expectation there in terms of timing or results? Operator00:36:40Results, like what type of results can we expect to see? Speaker 400:36:44What could we see? Well, as I mentioned earlier, PV patients have twice the level of LRRK2 protein levels in the CSF and presumably in deep brain regions compared to healthy volunteers. So we would expect in our SAD and our MAD studies, we can recapitulate what we saw in healthy volunteers. We could see now with higher baseline LARC2 levels degradation that's achieving greater than 50% reduction, which is our target. And then on top of that, because they also have neuroinflammation and other signs of neuronal fragility or neuronal death, that we can capture some signals of this with 28 of treatment in the MAD study. Speaker 400:37:46So we are looking at biomarkers, and this should we would hope that we can see that signal in the map. Operator00:37:55Thank you. Your next question comes from the line of Akash Tewari with Jefferies. Please go ahead. Speaker 900:38:06Hey, this is Manojin for Agas. Just one question, will you need any overall survival data trend for peptide regulatory submission? Or like what's the expected timeline for market entry there? Just one more on like, are you considering any partnership for like neuro programs there? Thanks. Speaker 400:38:26Going back to that I'm sorry, John. Just going back to that first question, could you repeat that in terms of regulatory filing? Speaker 900:38:36Any overall survival trend for regulatory submission? Operator00:38:43Oral Speaker 400:38:45what? Speaker 900:38:46Overall survival data trend. Speaker 200:38:49Overall survival data? Speaker 400:38:52I'm sorry. So overall, we can't really talk about our data beyond what has been shared in our top line results. And we recommend that you join us at ASCO to hear the presentation. Certainly, in answer to your question about how that impacts submissions ultimately, regulators generally want to see that there are no adverse overall survival findings when one looks at PFS, which is a surrogate for OS. But it's something that is there just isn't any companies don't power for OS when they submit. Speaker 200:39:41And then the second question you asked that about neuroscience and partnering. Clearly, as we move forward in the space both in PSP and Parkinson's disease, we've always said that this would be an area that could lend itself to having a strategic partner. These would end up being certainly in the Parkinson's area quite significant size trials. But right now, we're in a good position to be able to move our program forward to a significant data inflection points and we'll review potential partners at that point. Speaker 400:40:16Yes. Thanks. Operator00:40:22Your next question comes from the line of Jonathan Miller with Evercore ISI. Please go ahead. Speaker 1000:40:30Hi guys, thanks for taking my question. I'll do one more on VetDeg maybe since we haven't spoken about the first line potential there. You were a little more vague about the rationales for not proceeding with the Atirmo Phase three. Is your expectation that next gen estrogen receptor directed therapies are not going to be relevant in first line in general or is this more to do with VEPTEGS profile or more to do with ATIRMO's profile or the data you've seen in the combination so far? And maybe I guess I'll start with that. Speaker 1000:41:07And then secondly, in BCL on the BCL6 program, how much data in NHL patients can we expect to see in the next handful of releases? And would you expect to be able to show ORRs or at least meaningful efficacy data that will allow us to comp to other recent NHL datasets? Speaker 200:41:31Yes. Great questions. And I'll take the first one and Noah can take the second one. Yes. Certainly, big decisions like this around going forward and over the first line study, they don't happen overnight. Speaker 200:41:46So, lots of discussion with our colleagues at Pfizer. I suppose the genesis of the final decision was Pfizer looking at basically our press release from our BERTAC-two data where we say that we've hit ESR1 mutant only but we haven't hit ITT. And without going into the data, if you just take that as the opening gambit, it probably started a conversation around do ER degraders work against wild type either in the second line setting which is a reasonable question. But then I think Pfizer then took it to the next level which is do they work in the first line setting. So I'll give you the Arvinus view. Speaker 200:42:33We believe they do. We believe that vegastrant will work very effectively in the frontline setting. For several years we've talked about the difference between first line and second line disease. In the second line disease, probably around forty percent of the patients have ESR1 mutations that basically give them an endocrine sensitivity. And around sixty percent of the patients have tumors that have wild type and other driving mutations that are largely endocrine insensitive. Speaker 200:43:03Our hope with the second line trial was that we'd be able to capture whatever endocrine sensitive group of tumors that are in that broader ITT net. But in reality what you saw is that we missed the ITT, which is telling you that there's not as many endocrine sensitive tumors in that space. However, in the first line setting, we believe it's a very different story. We believe that maybe ESR mutations represent maybe only five percent of what you see in the first line setting. The vast majority of the tumors would be wild type, but most significantly we believe that those would be endocrine sensitive and therefore available to be tackled by a drug like vebegastram. Speaker 200:43:47So that's our belief it still is. But we're in a partnership with Pfizer and I think they want to have more mature data not just from our internal programs and data sets, but also the external world. They want to see what's going to happen with Gerodestrin, the Roche ER degrader which is in the first line. So if that comes out and it's positive in the first line setting that's going be a great signal for all the ER therapies. Camazestrin as well, again interesting data coming out from SERENO6 with more mature data there could also influence it. Speaker 200:44:25And of course as our data matures overall. I think Pfizer also want to see our current atirimaciclib VEP combo mature in terms of that data set also. So yes, there's a number of different things that Pfizer would like to see in terms of maturity of data both our internal data and the external data. And as to say, we're in a partnership. Good partners can look at two different data sets in two different scenarios and maybe come out with different options. Speaker 200:44:56But we're going along with this decision from the team to opt out of the first line study. And we move on. Basically, we have taken the money that was targeted for that study that's now out of the budget, allows us to plan to fund the rest of our portfolio, which is a very exciting portfolio in a more aggressive way. And as data matures, if Pfizer come back to us and say, they actually do want to do a first line study, we could assess that at a later date. But right now that is not in our plan and we move on. Speaker 200:45:34BCL6? Speaker 400:45:36Regarding BCL6, we're early in the dose escalation, but we've shared that we expect to share results later in the year. I don't think we can order or offer more guidance than that right now. Think of it as several cohorts. Speaker 200:45:58Do you expect to be for that one moment. Speaker 500:46:06Yeah. Speaker 400:46:09Do we expect we would share where we are in terms of safety and efficacy within any data that we make. Speaker 200:46:21But do you expect to Speaker 1000:46:22be in the active dosing range? Would you expect to be reaching dose levels that are where you want them to be from the perspective of the level of degradation you're expecting to drive efficacy? Speaker 400:46:35We may be, yes. Speaker 1000:46:40All right. Thanks so much. Operator00:46:46Your next question comes from the line of Tazeen Ahmad with Bank of America. Please go ahead. Speaker 1100:46:54Okay. I have a few questions as well. I think a few minutes ago you had talked about the market opportunity for these Veritec two patients that were positive in the study. You mentioned that for oserdo, one third of the twenty five thousand patients are on that drug. Does your market data give you any feedback about what the profile of those one third of patients are? Speaker 1100:47:21And is there anything different about the other two thirds that could make Bebtel potentially more attractive for patients? And then can you just provide any color on the remaining Pfizer milestones you expect to realize from here on out? And if there are any specifically related to the CAP6 collaboration? And then the last one, I'm sorry if I missed this, but are you still planning on exploring BepDeg in first line metastatic breast? Speaker 200:47:51First First So first of all, yes, in terms of the patient population in the second line, yes. So we think based on our assessments and some of the other external data forty thousand new patients in that second line setting, which we believe as I said before forty percent are ESR1 mutant. So in that second line plus overall setting that ESR1 mutant only that's probably sixteen to twenty five thousand patients that are then available. I think ORSERDU has done remarkably well to capture a significant number of those patients. I think there's a growing opportunity in that market to have more effective drugs in there. Speaker 200:48:42And so it's a growing I think it's a growing space. So yes, we think with as I said before, really significant opportunity. And we also believe it's a very good opportunity to have a very targeted launch into that space. There's probably around 6,000 oncologists that drive 70% to 80% of the prescriptions in this space. So we can also target this prescribing population I think very effectively. Speaker 200:49:11So I think yes, a really significant exciting opportunity. As it relates to CAT six and general milestones in Pfizer? Speaker 300:49:21Yes. So with regard to the Pfizer agreement, we are entitled to a milestone on first approval. I do not believe we've disclosed the exact amount of that. So I won't disclose it now, but we are entitled to something. And then there I think you asked a question specifically regarding CAT six. Speaker 300:49:41There's certainly nothing in the contract specifically regarding CAT six. So no, it would be related to the first approval which would be obviously VEPTEG. Speaker 200:49:50And then the final thing you asked was I think do you see any opportunity to test out VEPTEG in the first line? Well, my answer I mean clearly the decision we've made right now with Pfizer is not to go forward in the first line setting. We've also said that from an awareness perspective, we think Vepdeg would do well in that first line setting. So let's see how data matures over the whatever period of time the data is needed to mature. But as I said earlier, right now we move on. Speaker 200:50:23The money that we had sequestered for that first line study is now going to get moved to other parts of our portfolio and we are very excited about those opportunities as well. Operator00:50:41Your next question comes from the line of Peter Lawson with Barclays. Please go ahead. Speaker 1200:50:47Great. Thank you. Thanks for taking the questions. Just a couple of questions on the commercialization. So, Vepdeg, have you kind of worked through the size of the sales force you need? Speaker 1200:50:58And then your comments just around Vepdeg and first line. Does the Pfizer partnership preclude you from going off and finding a different partner to run that first line study? Just if you could walk through kind of that process of potentially rekindling for a first line study? Speaker 200:51:18Yes. So starting off with the size of the sales force, as I mentioned, it's going to be a fairly targeted I think financially prudent approach that we'll be taking. Obviously in a fifty-fifty setting, whatever we do Pfizer will match in The U. S. Six Thousand Oncologists that where we can target, which drive that 70 to 80% of prescriptions. Speaker 200:51:42So I think we're going to have an effective, but appropriately sized sales force to hit there. In terms of other partners, absolutely not. No, we're in a partnership with Pfizer. We're very pleased with the partnership we've had with Pfizer over the last year. They've been very supportive. Speaker 200:52:04And good partners can also have different views. And that's right now we've got a different view about the first line setting, but we agree overall with the decision. And we'll see what happens as data matures for Pfizer. But as I said, right now we take the money that we had sequestered for that and we move it into other things in our portfolio. And I think that's going be a big value driver for Arvindis. Speaker 1200:52:27Got you. Thank you. And then just on the CAT six combination, is that under the same kind of profit share terms of agreement with Pfizer? Or is that a separate entity? Speaker 200:52:37Well, in one sense, yes, because veptegastrant is everything they do with veptegastrant, everything we do with VetDegastrant is in that partnership. Cat six is wholly owned by Pfizer. So in that scenario as we've talked about before, we wanted to profile Vet against a whole series of different potential combinations. So we're actually excited to see Pfizer putting VEP into that CAT six study. They're paying for it. Speaker 200:53:07And if it works out well, we'll get the benefit through the degestrant side of that. Speaker 1200:53:14Great. Thanks for taking the questions. Operator00:53:19Your next question comes from the line of Paul Foy with Goldman Sachs. Please go ahead. Speaker 500:53:26Hi, thank you. Good morning, everyone, and thanks for taking the question. I just wanted to ask if you have any sort of gating items or any remaining things to do prior to scheduling your pre NDA meeting? And will that come presumably post ASCO here? Just some clarity on the color of when you plan to meet with FDA would be helpful as part of your second half of this year filing timeline. Speaker 500:53:53And my second question is just on the LRRK2 program in Parkinson's, just sort of when the next sort of data update could potentially be expected from that program? I think the early data that you presented looked interesting and promising. Just curious sort of what timelines for next into the next data set might be. Thanks for taking our questions. Speaker 200:54:12Thank you. Noah, do you want to tackle those? Speaker 400:54:16Sure. So we've met with the FDA for the pre NDA meeting and we feel that we're clear to move forward. And that's Speaker 700:54:27why Speaker 400:54:27we've conveyed in this in the prepared remarks that we're moving ahead with our submission enthusiastically. Regarding LARC2 next data sets, we've said that we'll share information later this year. It will even though we said that we'll start the MAD in the second half, I'm not sure if we can squeeze in those data at any meaningful conference by the end of the year. So we expect that we'll be sharing data from the SAD portion of the PD Phase one. No naming conference yet. Speaker 500:55:05Okay. Thank you very much. Operator00:55:11Your next question comes from the line of Tyler Van Buren with TD Securities. Please go ahead. Hi, this is Frances on for Tyler. So first question, are you still confident in Pfizer's commitment to the partnership to commercialize Vepdeg in the second line ESR1 mutant setting? Are you in any discussions to reevaluate the details of the partnership, such as selling the asset to Pfizer for royalties? Operator00:55:38And then my next question is, where do you envision the Cat six combo in the treatment paradigm could potentially serve as a backbone treatment? Speaker 200:55:47Yes. Thanks for the question. And Noah can take the second one. No, all of the interactions we have with Pfizer on VEP and the planning for regulatory filing, the NDA, getting ready for hopefully an approval and potential launch are all full blast. The team the joint teams are laying out significant plans as you'd expect for a launch that could be at some point next year both from a global setting and from a U. Speaker 200:56:17S. Setting. So, all of that's going forward well. And as I said before, think there's a significant opportunity. In terms of the change and there's no ambiguity. Speaker 200:56:28There's a change there overall in terms of the broader scope of what we initially had as a collaboration with Pfizer. When we started off, we were hoping for monotherapy first line adjuvant, which is quite a significant opportunity. Right now, we're going to be very focused on making that the best ESR1 mutant degrader in that second line plus setting. And I think as I said earlier, we wait to see how data matures for Pfizer over whatever period of time. But as we move on, we move on in terms of making sure that we can get the best launch possible once we hopefully get an approval. Speaker 200:57:07And we develop an ESR1 mutant only profile in that second line third line opportunity. It's clear that physicians are looking for additional options in that space and we believe VEP will provide that and we look forward to moving it forward. So yes, there's no change in the game plan with Pfizer. Speaker 400:57:33Regarding the Cat six question. So in the prepared remarks, you've heard us mentioned that while there are no registration trials planned for bep dengue. We continue to produce data from ongoing studies. And in fact, there is a new study as it were that will start. We're adding VEP deck to CAT six. Speaker 400:57:58And I think it's well premature to project what that can lead to because it's simply a Phase one study. But I think it just demonstrates that we're looking to combine that as we march into the second line space with other drugs to explore combinations that can bring more value to patients. So we'll have to wait to see those results. Operator00:58:24Thank you so much. Your next question comes from the line of Kripa Devarakonda with Truist Securities. Please go ahead. Speaker 1300:58:36Hey, guys. Thank you so much for taking my question. I have a couple. First, for ARV-three ninety three, I know you're currently enrolling Phase I trials. Just wondering how easy it has been to enroll patients. Speaker 1300:58:48You do seem to have a lot of centers open. And also based on the recent preclinical combo data that you presented at AACR, are you getting a better sense of where you think the drug and the combinations might fit in the landscape? And then just a question on your FDA communications. With some of the changes happening at the FDA, is there any concern in terms of delayed timelines for meetings or review processes? Thank you. Speaker 200:59:17Yes. I'll take the second one first then Noah can talk about March. Clearly, there's a lot of external changes that we're monitoring in this space and certainly with the FDA. From an Adventist perspective, we have noticed no delay and no impact with our interactions with the FDA, which is great. But obviously, we're going to continue to monitor that. Speaker 200:59:43And as we've seen in the press some other companies have had maybe a different experience. So far so good with us, but I could say we'll monitor that going forward. Noah, three ninety three? Speaker 400:59:56Yes. So March, I think we could say that while the study began last year enrollment was slow at the beginning. This is a Phase one study. So by nature it's slow. So it was I think a bit slow last year. Speaker 401:00:12There's a lot of enthusiasm and we see that we can generate a backlog of patients now and it's enrolling steadily. In terms of where three ninety three can fit into the landscape, well certainly depending on the data that we generate, there's the possibility of it being monotherapy. We'll have to see, what the overall benefit risk is as monotherapy. But we're quite enthusiastic about from the preclinical models that we've shared recently is its ability to combine with many other drugs, but particularly with bi bispecifics and particularly because it also seems to increase CD20 expression, which could create a real synergistic opportunity. Speaker 1301:01:05Thank you. Speaker 501:01:08Your Operator01:01:10next question comes from the line of Yigal Nochomovitz with Citigroup. Please go ahead. Speaker 1401:01:17Hi, great. Thank you very much for taking the questions. I three questions. So the first one is given the combo with the CAT six and the VEP deG, have you or Pfizer produced any preclinical work that would support that combo? Or could you discuss the rationale for that combo on a scientific medical basis? Speaker 1401:01:38Second question is, you haven't talked much about supply chain. Could you just review the structure and geographic location for the manufacturing supply chain for bepdag as well as where the IP is domiciled? And then the last question, John, you gave a very comprehensive answer with respect to the rationale for Pfizer stopping the frontline study. I'm just wondering if the factors related to the novel novel combo with the Thermo as well as the potential to do a or need to do a forearm study perhaps to tease out contribution of components was a relevant factor in that decision or not? Thank you. Speaker 201:02:18Thanks, Yigal. So yes, the first one, did we do any preclinical work with Cat six and VEDDIG? I think the answer to that is no. I think the rationale is really related to the fact that Pfizer very excited by the profile of Cat six. I do think they see the potential of the combination with bemdag enhancing potentially what they see with Cat six and positioning Vevdeg and Cat six as being a really strong combination. Speaker 201:02:54No, anything you'd add to that? Speaker 401:02:55Yes. Just some experience with fulvestrant that looks attractive. So that would be one of the reasons. Speaker 201:03:03In terms of supply chain, so Pfizer are accountable for the supply of that that's based in Ring of Skinny in Ireland. So we haven't had any supply chain issues. I think you asked the question where does the IP reside? That resides here with us with The U. S. Speaker 201:03:24With Arvinis. And then a really interesting question Yigal the novel novel with the terminal composition of components. I'm sure that has factored into some of the thinking. The broader view I gave is maturation of data, the external environment. I'm sure that's part of the rationale that Pfizer want to see our current Aturmo VEP data mature that's in the second line setting, but they want to see what that looks like overall. Speaker 201:03:57So I'm sure that has factored into the broader decision making around data sets and changing landscape. But yes, great questions. Thank you. Speaker 1401:04:08Okay. Thank you very much. Operator01:04:13Your next question comes from the line of Evan Seigerman with BMO Capital Markets. Speaker 501:04:19Please go ahead. Hi. This is Malcolm Hoffman on for Evan. Thanks for taking our question. Thinking about the LRRK2 degrader again, I know Biogen just announced today that enrollment in their Phase two study is now complete with results in 2026. Speaker 501:04:36I just wanted to ask how you are starting to think of competitive positioning for your degrader versus others? And what your confidence is that yours could be differentiated versus slightly more advanced programs? Noah, Speaker 201:04:50do want to take that? Speaker 401:04:51Sure. Yes. So thanks. We certainly look at it, Biogen Denali partnership enthusiastically. We think it's validating to some degree. Speaker 401:05:04But validating for an inhibitor that doesn't get brain penetration and does not even deliver significant inhibition in the brain. And so therefore with the degrader that gets significant brain penetration and can lead to more than 50% degradation eliminating all functions of LRRK2 not just kinase activity. We think that puts us in a very competitive spot. So we're looking forward to those results if they if it's successful then I think where there'll be a lot of enthusiasm If their study is the Phase three program failed, but it has some directional data that's supported, there's also going to be quite significant enthusiasm. Speaker 401:05:58But overall, we just do not believe that inhibitors get you there. And the fact that you'll see the continuing our continuous updates from our studies to see the benefits from the degrader. Speaker 501:06:17Appreciate it, guys. Thank you. Your Operator01:06:23next question comes from the line of Lee Wacek with Cantor Fitzgerald. Please go ahead. Speaker 801:06:30Hey, guys. Thanks for taking our questions. Maybe a BD strategy question. Are you open to bringing in maybe external assets just given your balance sheet? And then you've got three earlier assets in the pipeline. Speaker 801:06:46Maybe talk a little bit about your conviction and development strategy there. It sounds like you're gonna have some data later this year. Will you be making some decisions then? And then secondly, just for the CATCH-six combo, when should we expect to see the data? And then what would be the bar that you have to head given it's early Phase I trial? Speaker 801:07:13And then can you clarify, is it going to be in the ESR1 near term patients or it's going to be in all comers? Thank you. Speaker 201:07:24Noah can tackle the CAT six and that part of it. In terms of the BD strategy, I think overall we have always been out there looking at opportunities to supplement certainly our technology. And as we go forward, if there was an asset out there that complemented our lead programs, I think we'd be open to that. Obviously, we've been our Genesis as a company has been a platform based company We're very proud of that and our portfolio is replete with really exciting degraders. But yes, if there was a significant opportunity to get an asset that complemented that, I don't think we'd have any issue with that. Speaker 201:08:09There was another subset in there. I can't remember the subset of the Regarding Speaker 401:08:13CAT six. So yes, again just to frame this study, this is a Phase one study that's just very exploratory. So there are no timelines associated with it. We haven't even dosed the first patient yet. It's really shared in the spirit of that we'll continue to look for nice combinations that can be practice informing and continue to expand the attractiveness of our already potentially best in class gut take in the second line setting. Speaker 401:08:48And so that would be the case with this CAT six combination also. It's Pfizer's wholly owned drug. We don't call the shots there in any way and we're just looking to see what we can generate with that combo. And right now the thought is for commerce. Speaker 801:09:07Okay, thank you. Sure. Operator01:09:14Your next question comes from the line of Shweta Mukherjee with BTIG. Please go ahead. Speaker 1501:09:21Great. Thank you for taking the question. Was wondering if you've thought about potential NCCN guideline inclusion for some of your, Vepdeg CDK4six data, to support combination use, just given some of the notable PFS data you had shown at San Antonio Twenty Twenty Three and thereby allow doctors to use a CDK foursix off label in combination with Zepdeg in the second line setting? And my second question was just around your G12D degrader. Can you maybe talk about how that compares to Astellas' degrader and some of the perhaps subpar efficacy and safety it had shown at last year at ESMO? Speaker 1501:09:57Thanks. Speaker 201:09:59Noah, do want to take that? Speaker 401:10:00Sure. The first question second one was about G12T. The first was NCCN. NCCN. Yes. Speaker 401:10:09So look, we continue to generate we're going to be sharing the maturation of our combination datasets. We will this will be discussed with the commercial and medical affairs team about how to best share this information and be as practice informing as possible. So I don't want to get ahead of myself and speak about NCCN guidelines. But overall, we would share whatever physicians need to make the best decisions though obviously we're seeking a monotherapy label and that's the only way we will be marketing the drug for monotherapy use. Regarding the G12D degrader, I think I had mentioned in the prepared remarks that we've seen that we have 30 times the potency of some other inhibitors and degraders in the space. Speaker 401:11:11One of the challenges for a leading degrader in this space is the hepatotoxicity or I guess as evidenced by transaminitis that has been seen that may be limiting in the dosing of that drug. In our case, we don't believe that this will be a limitation for our drug ARB-eight zero six. And but of course, we're just starting our dosing of patients in the second half of this year. Speaker 1501:11:42Thank you. Speaker 401:11:44Your Operator01:11:47next question comes from the line of Sudan Loganathan with Stephens Inc. Please go ahead. Speaker 1501:11:54Hi, good morning and thank you for taking my questions this morning. I wanted to kind of dig deeper into the details for the ESR1 mutant patients again that are naive to treatment. I believe you mentioned earlier in the call about approximately five percent are of ESR mutant is in the first line setting. Is VepGag with the monotherapy design actually going to be well positioned to be more of the standard of care even also in the first line that kind of demonstrate the CSR1 mutant as well or will there be some additional trials or anything else that needs to be done there? Then with the total of about forty percent I guess of second line patients that have ESR mutant, is that only specific to first line patients that were treated on CDK4six inhibitors or also other treatments as well? Speaker 1501:12:41Thanks. Speaker 201:12:43Yes. So just for clarity, in the second line setting, we believe around forty percent of the patients have tumors that have ESR1 mutant profiles. And that offers up a potential of forty thousand patients that could be amenable to a drug like bevdegastrant. So that's exciting. That's a great opportunity. Speaker 201:13:07In the first line setting, it's different. There's maybe only about five percent of the patients have tumors that have ESR1 mutation. The rest have wild type. And the biggest difference we believe is wild type in the second line setting is probably endocrine insensitive, but wild type in the first line setting is endocrine sensitive. So there's a significant opportunity there. Speaker 201:13:32So our belief is that VEP was in that setting it would do well. But we've made this joint decision with Pfizer not to go there and we move on to other things. And in the second line setting where we still see a significant opportunity, we'll be seeking approval for a drug in that setting and ideally then launching into that second line setting along with our partners Pfizer. So significant opportunity there. And as I said before, we wait to see what the maturing information is in the first line setting both from a point of view of our data, but also the data coming from other companies. Speaker 1501:14:13Appreciate it. Thanks for the clarity there. Speaker 201:14:16Thank you. Operator01:14:20And that concludes our Q and A session for today. I will now turn the call back over to John Houston. Please go ahead. Speaker 201:14:27Well, thanks operator and thank you everyone. We gave you a lot of information today to digest. Remains for me just to say that we're incredibly confident about the future direction of the company and you'll be hearing more from us with additional updates through the year. So thank you very much for your time this morning. Operator01:14:49Thank you everyone. That concludes today's call. You may now all disconnect. Have a nice day ahead.Read morePowered by Conference Call Audio Live Call not available Earnings Conference CallArvinas Q1 202500:00 / 00:00Speed:1x1.25x1.5x2x Earnings DocumentsPress Release(8-K)Quarterly report(10-Q) Arvinas Earnings HeadlinesContrasting Arvinas (NASDAQ:ARVN) and Mustang Bio (NASDAQ:MBIO)May 9 at 1:53 AM | americanbankingnews.comTruist Financial Reiterates Hold Rating for Arvinas (NASDAQ:ARVN)May 7 at 2:09 AM | americanbankingnews.comMarket Panic: Trump Just Dropped a Bomb on Your Stockstock Market Panic: Trump Just Dropped a Bomb on Your Stocks The market is in freefall—and Trump's new tariffs just lit the fuse. Millions of investors are blindsided as stocks plunge… but this is only Phase 1. If you're still holding the wrong assets, you could lose 30% or more in the coming weeks.May 10, 2025 | American Alternative (Ad)BMO Capital Markets Has Lowered Expectations for Arvinas (NASDAQ:ARVN) Stock PriceMay 7 at 2:09 AM | americanbankingnews.comAnalysts Offer Insights on Healthcare Companies: Pliant Therapeutics (PLRX), Design Therapeutics (DSGN) and Arvinas Holding Company (ARVN)May 6, 2025 | theglobeandmail.comINVESTOR ALERT: Pomerantz Law Firm Investigates Claims On Behalf of Investors of Arvinas, Inc. ...May 6, 2025 | gurufocus.comSee More Arvinas Headlines Get Earnings Announcements in your inboxWant to stay updated on the latest earnings announcements and upcoming reports for companies like Arvinas? Sign up for Earnings360's daily newsletter to receive timely earnings updates on Arvinas and other key companies, straight to your email. Email Address About ArvinasArvinas (NASDAQ:ARVN), a clinical-stage biotechnology company, engages in the discovery, development, and commercialization of therapies to degrade disease-causing proteins. The company engineers proteolysis targeting chimeras (PROTAC) targeted protein degraders that are designed to harness the body's own natural protein disposal system to degrade and remove disease-causing proteins. Its product pipeline includes Bavdegalutamide and ARV-766, investigational orally bioavailable PROTAC protein degraders for the treatment of men with metastatic castration-resistant prostate cancer, which are in Phase 1/2 clinical trials; and ARV-471, an orally bioavailable estrogen receptor degrading PROTAC targeted protein degrader for the treatment of patients with locally advanced or metastatic estrogen receptor+/human epidermal growth factor receptor 2-breast cancer, which is Phase 3 clinical trial. Arvinas, Inc. has collaborations with Pfizer Inc., Genentech, Inc., F. Hoffman-La Roche Ltd., Carrick Therapeutics Limited, and Bayer AG. The company was founded in 2013 and is based in New Haven, Connecticut.View Arvinas ProfileRead more More Earnings Resources from MarketBeat Earnings Tools Today's Earnings Tomorrow's Earnings Next Week's Earnings Upcoming Earnings Calls Earnings Newsletter Earnings Call Transcripts Earnings Beats & Misses Corporate Guidance Earnings Screener Earnings By Country U.S. Earnings Reports Canadian Earnings Reports U.K. Earnings Reports Latest Articles Why Nearly 20 Analysts Raised Meta Price Targets Post-EarningsOXY Stock Rebound Begins Following Solid Earnings BeatMonolithic Power Systems: Will Strong Earnings Spark a Recovery?Datadog Earnings Delight: Q1 Strength and an Upbeat Forecast Upwork's Earnings Beat Fuels Stock Rally—Is Freelancing Booming?DexCom Stock: Earnings Beat and New Market Access Drive Bull CaseDisney Stock Jumps on Earnings—Is the Magic Sustainable? 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There are 16 speakers on the call. Operator00:00:00It is now my pleasure to turn today's call over to Arvina's Vice President of Investor Relations, Jeff Boyle. Please go ahead. Speaker 100:00:08Thank you, and good morning, everyone. Thanks for joining us. Earlier today, we issued a press release with our first quarter twenty twenty five financial results, which is available in the Investor and Media section of our website at arvinas.com. Joining the call today are John Houston, Arvinas' Chief Executive Officer, President and Chairperson Noah Berkowitz, our Chief Medical Officer and Andrew Szek, our Chief Financial Officer. Our Chief Scientific Officer, Ann Cacasse, was scheduled to join us this morning, but had an unanticipated personal event and will not be able to. Speaker 100:00:40Before 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 filings with the Securities and Exchange Commission, which I urge you to read. Our actual results may differ materially from what is discussed on today's call. And now I'll turn the call over to John. Speaker 200:01:03Thanks, Jeff. Good morning, everyone, and thank you for joining us today. As you saw in our earnings release this morning, we have reached an important moment in our business' progress as a company. We recently shared the first ever positive pivotal data for a protact degrader vebbegastran, which we are moving towards filing and registration. In addition, we continue making great progress with our pipeline and shared exciting first in human data for ARV-one hundred two, our LARC2 degrader and excellent preclinical combination data for ARV-three ninety three, our BCL6 degrader in hematology. Speaker 200:01:38We also recently received a safety proceed from the FDA for ARB-eight zero six, our KRAS G12D degrader. We will discuss each of those items on the call today. Noel will review the clinical progress for bebbegastrant or bebdeg and for ARB-one hundred two. He will also then review our recent preclinical combination data for ARB-three ninety three and provide an update on ARB-eight zero six. Finally, Andrew will provide a financial overview including our capital allocation priorities and updated cash runway guidance. Speaker 200:02:14However, before we get into our data updates, I'd like to cover three important topics upfront. First, we are making excellent progress towards our filing and registrational plans for VetDeg in the second line plus ESR1 mutant breast cancer. Based on the strong data from the VERTECH two study, we have a high conviction that VetDeg has the potential to be a best in class monotherapy treatment for patients in a second line ESR1 mutant setting. We are on track to submit a regulatory filing with health authorities in the coming months. We believe there is an attractive opportunity for VetDeg as a second line plus ESR1 mutant treatment in metastatic breast cancer and we will discuss this opportunity in greater detail after our ASCO presentation in June. Speaker 200:03:02Secondly, we have aligned with Pfizer on the removal of the two Phase three combination trials from our joint development plan that were planned for this year. The first of these trials was a combination with a CDK4six inhibitor in the second line setting. And based on recent discussions with health authorities and our observations from other trials involving biomarker selected populations, we believe ER therapies will be restricted to patients with ESR1 mutations in the second line plus setting. With this in mind, we have removed the second line ITT combination trial, which was planned to initiate in 2025 from our joint development plan. The second trial was the first line combination trial with the tirmaciclib, Pfizer's CDK4 inhibitor, which was also planned to initiate in 2025. Speaker 200:03:55After reviewing the totality of emerging information including external data results, the evolving treatment landscape in metastatic breast cancer and long term capital allocation, we have aligned with Pfizer to remove this first line combination study from our joint development plan as well. We and Pfizer will continue to evaluate our ongoing combination studies in the second line plus setting and generate valuable data in metastatic breast cancer to inform our path forward. In addition, Pfizer is adding a VebDeg combo cohort to their ongoing Phase one clinical trial with our investigational CAT6 inhibitor. This trial will be operationalized and funded solely by Pfizer. As these trials complete, we'll make data driven decisions about whether further investment in each of these combinations is warranted. Speaker 200:04:46I look forward to sharing additional details in the coming months as our trials continue. The third major topic is our company wide cost reduction effort. The recent challenges in the capital markets are prompting us to extend our cash runway and ensure our programs reach data milestones before additional capital is needed. An important step in this process is maximizing our efficiency and reducing our operating expenses wherever possible. We have implemented a restructuring that includes a workforce reduction of approximately one third of the company, portfolio reprioritization and overall cost reductions of approximately $80,000,000 annually on a full year run rate basis. Speaker 200:05:32Although difficult, the workforce reduction which will result in streamlined operations across the entire organization is a prudent decision that we believe will appropriately size the company for future success. We have also reprioritized our research portfolio to focus on assets that have the greatest potential to deliver the most value for patients, physicians and shareholders. Our clinical programs ARV-one hundred two in neurodegeneration and ARV-three ninety three in hematology remain on track to deliver important clinical data later this year. Overall, these steps will result in a combination of cost savings and cost avoidance of approximately $500,000,000 over the next three years. The net results of these actions is a change in our guidance to extend our cash runway into the second half of twenty twenty eight. Speaker 200:06:26We believe these significant cost savings and a refined capital allocation strategy in addition to our strong balance sheet will allow us to advance our early development portfolio in a timely and efficient manner as well as ensuring a financially disciplined approach to commercial readiness. Before I continue, I do want to thank all the talented employees who are directly impacted by this decision. I'm proud of the progress we have made together and want to acknowledge their contributions and commitment to discovering and developing new treatment options for patients with life altering diseases. We wish the best for these colleagues as they transition to new opportunities. I also want to thank the employees who are continuing the journey with Azarovindis as each of them will be instrumental in helping us achieve the ambitious goals we have laid out for the company. Speaker 200:07:15I'll now turn the call over to the team to review our recent data and the details from the quarter. I'll return at the end of the call to review the milestones that we anticipate for the remainder of 2025. But for now, I'll turn the call over to Noah. Speaker 300:07:31Thanks, John, and good morning, everyone. Together with Pfizer, we Speaker 400:07:35were pleased to announce positive Phase III results from the VERITECK-two trial earlier in the first quarter. These data, the first from a pivotal trial with a protracted radar represents an exciting and validating step forward for our platform. As John mentioned, we are excited to announce that data from the VERITECK-two trial were selected for a late breaking oral presentation at the American Society of Clinical Oncology or ASCO meeting in late May and will also be featured in the ASCO press program. The VERITECH II abstract has also been selected for inclusion in the twenty twenty five Best of ASCO program in July. This program is important. Speaker 400:08:18It's run by ASCO to increase access to clinically impactful research for those who are unable to attend the annual meeting. Given our plans to present the full data set at ASCO, which imposes an embargo on the presentation, I will only be providing commentary on the information previously disclosed in the top line data release. In patients with ESR1 mutant tumors, VEPdEG exceeded the pre specified hazard ratio of 0.6 and demonstrated a clinically meaningful improvement in progression free survival over fulvestrant. Additionally, Vepdeg continued to demonstrate a safety and tolerability profile consistent with our previous studies. We believe Vepdeg has a best in class profile and our plans to seek global regulatory approvals remain on track. Speaker 400:09:12While we are no longer planning new registrational trials for VEPTIC, we will continue to generate valuable data in our ongoing combination trials and we welcome Pfizer's addition of Beptig in combination with their CAD6 inhibitor to their ongoing Phase one trial. I'll now turn to our most advanced neuroscience program. We have designed investigational oral pro type upgraders to cross the blood brain barrier and selectively degrade leucine rich repeat kinase two or LRRK2. LRRK2 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 the pathological scaffolding function, the GTPase activity and the kinase activity of LRRK2. Speaker 400:10:07ARV102 is our lead LRRK2 degrader. We believe our LRRK2 degraders are particularly well positioned to be evaluated in two diseases Parkinson's disease or PD and progressive supranuclear palsy or PSP. Familial and idiopathic Parkinson's disease have been associated with LARC2 on the basis of genetics and models of lysosomal dysfunction. PSP disease severity is associated with LARC2 genetic findings. Additionally, we have published data associating the tau pathology of PSP with LARC2 mediated endolysosomal dysfunction. Speaker 400:10:47Previously, we have shared preclinical data demonstrating ARB-one hundred two's superior target engagement, enhanced potency and lysosomal pathway engagement Speaker 300:10:57when Speaker 400:10:57compared to LAR2 inhibitors. In nonhuman primates, ARB-one hundred two, across the blood brain barrier, where it achieved LRRK2 targeted protein degradation in deep brain regions and reduced LRRK2 protein as well as neuroinflammatory biomarkers in cerebrospinal fluid or CSF. I am now pleased to share with you that we have observed a similar pattern of activity in our first in human Phase one clinical trial in healthy volunteers. These data were presented last month at ADPD. Our trial evaluated single doses of ARD-one hundred two ranging from ten milligrams to two hundred milligrams and multiple doses ranging from ten milligrams to eighty milligrams. Speaker 400:11:38We met our objective of 50% LARC2 reduction in CSF after a single oral dose of at least sixty milligrams and once daily repeated oral doses of at least twenty milligrams. This indicates substantial central LARC2 protein degradation. In the Phase one clinical trial, ARV-one hundred two was safe and well tolerated with no serious adverse events or discontinuations reported after single or multiple doses. ARV-one hundred two also demonstrated dose dependent median reductions in LRRK2 protein levels compared to baseline in peripheral blood mononuclear cells confirming target engagement in the peripheral compartment. Taken together, pharmacodynamic changes of LRRK2 reduction in the CSF reduced biomarker levels in the periphery and an acceptable safety and tolerability profile supports further study of LRRK2 degraders in PD and PSP. Speaker 400:12:37That further work is ongoing. Dosing of the Phase one single ascending dose cohort in patients with Parkinson's has already begun and the multiple ascending dose cohort will begin in the second half of the year. We anticipate providing an update on PKPD safety and tolerability from the Phase one SAD cohort in patients with PD later in the year. The data I've shared demonstrate that we can make orally bioavailable PROTECTs that are brain penetrant. While our lead program is focused on LRRK2 for PSP and PD, our discovery portfolio focuses on additional targets that may be relevant for Huntington's and Alzheimer's disease. Speaker 400:13:18We look forward to sharing updates on these in the coming months and years. Turning back to oncology, ARB-three ninety three is our investigational oral PROTECT designed to degrade B cell lymphoma six protein or BCL6. BCL6 is a 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. PROTECT mediated degradation has the potential to overcome the historically undruggable nature of Bcl-six. Speaker 400:14:05ARV-three 93 potently and rapidly degrades Bcl-six protein with iterative activity, which is critical to overcoming Bcl-six's rapid resynthesis rate and its sustaining anti tumor activity. In 2024, we shared preclinical data demonstrating that ARB-three ninety three drives tumor regressions in multiple in vivo models of B cell driven non Hodgkin lymphoma including large B cell lymphoma. We are enrolling patients with non Hodgkin lymphoma in a Phase one clinical trial and are on track to share initial data by the end of the year. At AACR this past week, we presented new preclinical in vivo data for ARV-three ninety three in combination with standard of care biologics and chemotherapy as well as oral investigational small molecule inhibitors. These new data highlight the potential of ARB-three ninety three to drive synergistic antitumor activity across multiple aggressive large B cell lymphoma xenograft models. Speaker 400:15:10ARB-three ninety three enhanced tumor regressions when combined with current standards of care, including R CHOP and various biologics. Notably, ARB-three ninety three monotherapy upregulated CD20 expression, providing mechanistic rationale for synergy with anti CD20 therapies such as rituximab. Additionally, ARB-three ninety three demonstrated enhanced tumor regressions when paired with targeted small molecule inhibitors of BCL2, EZH2 and BTK, key oncogenic partners of BCL6. These results suggest that ARV-three ninety three may enable highly effective chemotherapy free regimens, whether in combination with biologics or as part of an all oral therapeutic strategy. We will present new preclinical data in a patient derived model of angioimmunoblastic T cell lymphoma or AITL at the European Hematology Association Conference in June of this year. Speaker 400:16:12This is an orphan indication with high unmet and limited treatment options. We believe this will be the first preclinical data to show human AITL dependency on Bcl-six. We also plan to present preclinical combination data with an emerging standard of care bispecific antibody in a model of aggressive large B cell lymphoma in the second half of the year. And finally, we filed an IND for our KRAS G12D degrader ARV-eight zero six and recently received a safe to proceed letter from the FDA. We anticipate beginning a Phase one trial in patients with solid tumors harboring KRAS G12D mutations in the second half of this year. Speaker 400:16:57KRAS is a driver oncogene in several major tumor types and is associated with poor prognosis and resistance to standards of care. Our degrader has demonstrated high potency and differentiation from inhibitors and other degraders currently in the clinic. In addition to selectivity in the preclinical setting, demonstrates robust antitumor activity from dose responsive degradation of KRAS G12D in mutated cancers including pancreatic and colorectal cancers. In preclinical studies, our PROTECT degrader has demonstrated the ability to bind both the active and inactive states of KRAS G12D ARB-eight zero six will eliminate rather than inhibit KRASG12D with in vitro potency. And those that potency can be 30 fold greater than inhibitors and degraders currently in the clinic. Speaker 400:18:03In totality, these preclinical data give us confidence and we intend to show differential biology of our KRAS degraders at a conference later this year. I look forward to updating you on our progress in the coming months. With that, I'll turn the call over to Andrew to review our quarterly financial information. Speaker 300:18:23Thanks, Noah, and good morning, everyone. I'm pleased to share financial highlights for the first quarter ended 03/31/2025. As a reminder, detailed financial results for the first quarter are included in the press release we issued this morning. Let me start with the financial implications of the corporate restructuring and the removal of the two Phase three combination trials from the Vepdeg development plan. The corporate restructuring and associated workforce reduction were difficult decisions to make and are impacting many talented employees. Speaker 300:18:55They were however necessary to meet our goals of reducing our cost structure and extending our cash runway to support our promising pipeline. The reductions were focused on reducing internal costs without having an impact on clinical stage programs that will drive value over the next several years. We estimate the restructuring will result in a reduction of our ongoing infrastructure costs of approximately $80,000,000 annually with savings expected to begin to be fully realized in the fourth quarter of twenty twenty five. In addition, we anticipate cost avoidance of approximately $350,000,000 to $400,000,000 over the next three to five years as a result of the removal of the two Phase three combination trials from the bebptide development plan. These actions will allow us to continue progressing our promising pipeline without the need for a near term cash infusion and maintain a strong financial position with a cash runway now into the second half of twenty twenty eight. Speaker 300:19:56I'll now briefly touch on some key financial highlights for the first quarter of twenty twenty five. At the end of the first quarter, we had approximately $954,000,000 in cash, cash equivalents and marketable securities on the balance sheet compared with $1,040,000,000 for the year end 2024. Revenue for the three months ended 03/31/2025 totaled $188,800,000 compared to $25,300,000 for the three months ended 03/31/2024. The increase in revenue was primarily due to the accounting impact of the reduction in the BepteG collaboration agreements program budget due to the removal of the first and second line Phase three trials from the development plan. The revenue recognition accounting for this agreement uses the percentage of completion method. Speaker 300:20:45As the budgeted costs serve as a denominator in the percent complete calculation, a reduction in that budget compared the same actual incurred costs resulted in the higher percent completion and therefore higher revenue recognized in the first quarter. General and administrative expenses were $26,600,000 for the first quarter compared to $24,300,000 for the same period of 2024. Research and development expenses were $90,800,000 in the first quarter compared to $84,300,000 for the same period of 2024. The increase of $6,500,000 was primarily driven by a one time inventory charge of $10,000,000 for Vepdeg partially offset by lower than expected Vepdeg development costs and an increase in the LARC2 program of $5,200,000 offset by a reduction in non specific research and personnel expenses of $3,600,000 As I mentioned earlier, taking into account the anticipated impact of the restructuring, the reprioritization of the research portfolio and Vepdeg development plan and the anticipated launch of Vepdeg, our updated cash runway guidance is now into the second half of twenty twenty eight. We believe our efforts are focused on areas that will maximize shareholder value as we move forward as we move towards important catalysts in the coming months. Speaker 300:22:08With that, I'll turn the call back over to John for closing remarks. Speaker 200:22:12Thanks Andrew. These actions should offer significant clarity around our focus over the next few years and will allow us to hit a number of key data inflection points from our early development programs as well as the potential commercial launch of VetDag with our partner Pfizer. As we progress through 2025, there will also be many opportunities to showcase why our belief in our portfolio is strong. These include data from the VERITAGE II trial in the late breaking oral presentation at ASCO in June, the first Phase I data for a LRRK2 degrader, ARV102 in patients with Parkinson's disease and first in human Phase one data for our BCL6 degrader, ARV393. We believe our progress will continue to demonstrate the potential of our prototype degraders to add meaningful value for patients, their caregivers and our shareholders. Speaker 200:23:05As we embark on this new chapter, want to thank you for your continued support. And with that, I'll turn the call over to Jeff to begin the Q and A portion of the call. Speaker 100:23:14Thanks, John. Before I turn the call over to the operator, I do want to remind you that in order to comply with the ASCO embargo policy, we aren't able to answer questions about the VERITECK II data beyond the top line results reported in our press release on March 11. So with that, operator, will you Speaker 500:23:30please open up the queue? Operator00:23:49Okay. So your first question comes from the line of Michael Schmidt with Guggenheim. Please go ahead. Speaker 600:23:58Hey, guys, good morning. Thanks for taking our questions. I just had a few follow-up questions on WebDAG. Maybe just help us understand a little bit more on how much of the decision to not advance the foursix inhibitor combinations was driven by emerging data on the class overall versus specifically the VERITAG-two result? And in the second line setting, how do you think Rebtech will be positioned relative to other oral SERDs? Speaker 600:24:29And help us understand how much you need to invest in a commercial infrastructure as you potentially maybe commercializing the product in The U. S. Next year? Thanks so much. Speaker 200:24:42Thanks. Great question. So yes, the first question in relation to is this a decision based on specific information related to VEDDAG or the class. I think we've had a general discussion with Pfizer as we as you see our SERD during the market as an ESR1 mutant only drug. We saw some of the data coming from immunostrin, which also had a very strong ESR1 mutant only profile. Speaker 200:25:10And clearly, the data we had for Veratag, which we can't discuss in detail, but we already told you it has strong ESR1 mutant data, but we didn't hit ITT. So the general discussion we had with Pfizer was around whether or not in that second line setting would the drugs really just be ESR1 mutant only. And we came to the conclusion that's likely to be the case. And therefore the design of the study that we had was for an ITT combination with CDK4six. So we decided we would drop that. Speaker 200:25:49So that I think that's I think a logical rationale for dropping that particular study based on the emerging data on in the second line setting of whether or not you're going to have just the ESR1 mutant only profile overall. In terms of positioning VebDeg, I think as Noah said, I think again you'll see the data at ASCO where we believe we've got the opportunity to be the best in class of the degraders in that second line plus setting. And with that our positioning would be I think very strong in terms of our overall data centers of tolerability and overall activity. So we have great confidence of actually be if we get approval and get to the point of launch once we get through the regulatory hurdles. I think we've been in very strong position for positioning VEP in that marketplace. Speaker 200:26:46And I think with the third question was Commercial Yes, commercial investment. Clearly, it's a fifty-fifty coco with Pfizer. We are the lead for that. And what we've done is done a very kind of prudent approach to commercial build. It has been very small. Speaker 200:27:05It's all going to be data driven and the point of approval. So yes, there will be a kind of significant back end recruitment to get a sales force in place. But right now our commercial footprint is really, really very small. We also have the ability to have ongoing discussions with Pfizer about the best way to take the molecule forward in a commercial setting both in The U. S. Speaker 200:27:30And commercially. And we'll be able to update all of you on that as we complete those discussions. Operator00:27:43Your next question comes from the line of Andrew Berens with Leerink Partners. Please go ahead. Speaker 700:27:51Hi, thanks. I'm sure you guys have had to make some difficult decisions over the last few weeks. So my question is about the future neuro efforts in LRRK2. You did give some color in the prepared comments about the role of LRRK2 in neuro diseases, but wondering how much LRRK2 degradation you think is going to be clinically relevant and whether these would eventually be combination approaches? Speaker 200:28:15Yes. I'll hand over to Noah for a specific answer to that. But we're very excited by the data we see so far with LRRK2, our first neurodegeneration asset, the first protect in this space and the first to show brain penetrance as well. So the profile we're seeing initially is very exciting. But Noah, do you want to add some more color to that? Speaker 400:28:37Sure. So Andrew, thanks for the interest in what's a very exciting first neurodegeneration directed ProTAC for our company. So indeed, we think that there are few opportunities for us to develop this year. And as I outlined earlier in the call, that's because there's both genetics that support it and then also underlying biology in these two diseases that were highlighted, PSP and Parkinson's disease. Your question around how much degradation we want to achieve, well, the goal right now what had been and remains to achieve more than 50% degradation. Speaker 400:29:19We don't want to completely eliminate it, because there's obviously functional there's this to this protein in terms of endo lysosomal trafficking. But when there's overexpression, when there's increased activity, you get missed trafficking and that's tightly tied to the pathology of these diseases. We know that on average Parkinson's disease patients have twice the level of LARC2 in their CSF compared to age match controls. And so we think it's prudent therefore to target something in the fifty percent range. And so far we've seen in healthy volunteers that we can achieve that and as well as achieve appropriate downstream signaling. Speaker 400:30:07So we know that it's on target. We think on mechanism and the next thing is to really look at the data from the PD patients in the studies that are ongoing. Speaker 700:30:19Okay. And do you think it will be a combination eventually? Speaker 400:30:24Well, when you say combination, right now there really aren't disease altering drugs in the that are standard of care. So it's just a this may be on top of L dopa type of treatment for patients. But this is disease altering. So I'm not sure what you mean by combinations. Speaker 700:30:52Right. I'm asking whether you think it would be on top standard of care currently. Speaker 400:30:57Yeah, on top of standard of care for sure. Speaker 700:31:01Okay, thank you. Speaker 800:31:02Thank you. Your Operator00:31:07next question comes from the line of Eli Merle with UBS. Please go ahead. Speaker 500:31:13Hi, this is Joseph asking for Eli. Thanks for taking our question. What is your view on the market size of VEDDAC in the second line plus monotherapy setting alone? And I have a follow-up. Speaker 200:31:28And you have a follow-up? Do you want to ask it now or? Speaker 500:31:32Sure. So, how do you think about the cadence of cost reductions from a modeling perspective and in terms of VEBTQ monotherapy after the Veritac-two data, can you help us think about what milestones you might be entitled to from Pfizer on approval in this setting? Speaker 200:31:55So the first question was related to the market size. Yes. So we would think there's a really significant opportunity in that second line plus setting. There's forty thousand new patients in the second line setting every year. Of that forty percent are ESR1 mutant only and that's our estimate. Speaker 200:32:15Some others estimate around fifty percent. So that's twenty five thousand new patients in the second line third space each year. And drugs as you know like I said they were out in that space. They're probably capturing about a third of that. So there's a really significant opportunity there for a good profile of a degrader like the Begastrant to hopefully capture quite a significant part of that market. Speaker 200:32:42So we're very excited about the opportunity in that space. The second question, Andrew, think it's more related to kind of financial questions. Speaker 300:32:52Yes, sure. So with regard to the restructuring, notifications to employees have gone out this week. So the restructuring has begun. As with all restructurings, there's a combination of employee reduction and cost control. I stated in my prepared remarks that we would have the full impact of the reductions by Q4. Speaker 300:33:16We'll obviously start seeing benefit prior to that, right. So we're offering our colleagues severance packages that will be paid up in Q2, so you won't see a charge in our Q1 financial statements that the notifications went out in Q2. Speaker 200:33:31So it was a subsequent event for the Speaker 300:33:33purposes of our financial statements in the first quarter. But for modeling purposes, you can assume that you'll start seeing savings relatively quickly. Q3 will have a significant amount of savings and full impact in the fourth quarter. Operator00:33:56Your next question comes from the line of Derek Archila with Wells Fargo. Please go ahead. Good morning. This is Simone on for Derek. Thank you for taking our questions. Operator00:34:09I just have two. So, I know you said that for the log two degrader you need to see 50% degradation, but how exactly de risk is the target and what can we expect from the SAD cohort in PD patients in 2F of 25? Speaker 200:34:27Noah, do want to take that? Speaker 400:34:28Sure. I'm not sure I caught the second part, but to Speaker 200:34:32the first Yes, to do with that. Speaker 400:34:33How derisked. So in general, when you say derisked, I guess that could be that could focus us on what are some Speaker 200:34:46of the Speaker 400:34:46liabilities associated with that target, right? So we do know that there are findings with type two pneumocyte enlargement or proliferation that could be associated with collagen deposition in the lung. We also know that there's some vacuolization seen with and these are all the inhibitors, right? So vacuolization seen in the proximal tubule in the kidney. There's some typing going on in the background. Speaker 400:35:22So whoever's doing that, if you can pause, please. Thank you. So that's known and that's been a challenge for inhibitors. For reasons that we have our own hypotheses and it's probably too much to go into on the call right now, we have seen minimal evidence for the type two pneumocyte enlargement. We have associated the much reduced pneumocyte proliferation that we observed with our degrader rather than what's observed with inhibitors. Speaker 400:35:57We associate that with different protein different profile of protein deposition in the alveoli. So we think that we have a differentiated profile when compared to inhibitors and we're tracking patients in the meantime in our study. We look at diffusion capacity in the lung and we're measuring renal function on an ongoing basis and so far things have been safe to proceed. In terms of your second question that to do with the SAD cohort expectation, but I'm not sure what you meant by the expectation there in terms of timing or results? Operator00:36:40Results, like what type of results can we expect to see? Speaker 400:36:44What could we see? Well, as I mentioned earlier, PV patients have twice the level of LRRK2 protein levels in the CSF and presumably in deep brain regions compared to healthy volunteers. So we would expect in our SAD and our MAD studies, we can recapitulate what we saw in healthy volunteers. We could see now with higher baseline LARC2 levels degradation that's achieving greater than 50% reduction, which is our target. And then on top of that, because they also have neuroinflammation and other signs of neuronal fragility or neuronal death, that we can capture some signals of this with 28 of treatment in the MAD study. Speaker 400:37:46So we are looking at biomarkers, and this should we would hope that we can see that signal in the map. Operator00:37:55Thank you. Your next question comes from the line of Akash Tewari with Jefferies. Please go ahead. Speaker 900:38:06Hey, this is Manojin for Agas. Just one question, will you need any overall survival data trend for peptide regulatory submission? Or like what's the expected timeline for market entry there? Just one more on like, are you considering any partnership for like neuro programs there? Thanks. Speaker 400:38:26Going back to that I'm sorry, John. Just going back to that first question, could you repeat that in terms of regulatory filing? Speaker 900:38:36Any overall survival trend for regulatory submission? Operator00:38:43Oral Speaker 400:38:45what? Speaker 900:38:46Overall survival data trend. Speaker 200:38:49Overall survival data? Speaker 400:38:52I'm sorry. So overall, we can't really talk about our data beyond what has been shared in our top line results. And we recommend that you join us at ASCO to hear the presentation. Certainly, in answer to your question about how that impacts submissions ultimately, regulators generally want to see that there are no adverse overall survival findings when one looks at PFS, which is a surrogate for OS. But it's something that is there just isn't any companies don't power for OS when they submit. Speaker 200:39:41And then the second question you asked that about neuroscience and partnering. Clearly, as we move forward in the space both in PSP and Parkinson's disease, we've always said that this would be an area that could lend itself to having a strategic partner. These would end up being certainly in the Parkinson's area quite significant size trials. But right now, we're in a good position to be able to move our program forward to a significant data inflection points and we'll review potential partners at that point. Speaker 400:40:16Yes. Thanks. Operator00:40:22Your next question comes from the line of Jonathan Miller with Evercore ISI. Please go ahead. Speaker 1000:40:30Hi guys, thanks for taking my question. I'll do one more on VetDeg maybe since we haven't spoken about the first line potential there. You were a little more vague about the rationales for not proceeding with the Atirmo Phase three. Is your expectation that next gen estrogen receptor directed therapies are not going to be relevant in first line in general or is this more to do with VEPTEGS profile or more to do with ATIRMO's profile or the data you've seen in the combination so far? And maybe I guess I'll start with that. Speaker 1000:41:07And then secondly, in BCL on the BCL6 program, how much data in NHL patients can we expect to see in the next handful of releases? And would you expect to be able to show ORRs or at least meaningful efficacy data that will allow us to comp to other recent NHL datasets? Speaker 200:41:31Yes. Great questions. And I'll take the first one and Noah can take the second one. Yes. Certainly, big decisions like this around going forward and over the first line study, they don't happen overnight. Speaker 200:41:46So, lots of discussion with our colleagues at Pfizer. I suppose the genesis of the final decision was Pfizer looking at basically our press release from our BERTAC-two data where we say that we've hit ESR1 mutant only but we haven't hit ITT. And without going into the data, if you just take that as the opening gambit, it probably started a conversation around do ER degraders work against wild type either in the second line setting which is a reasonable question. But then I think Pfizer then took it to the next level which is do they work in the first line setting. So I'll give you the Arvinus view. Speaker 200:42:33We believe they do. We believe that vegastrant will work very effectively in the frontline setting. For several years we've talked about the difference between first line and second line disease. In the second line disease, probably around forty percent of the patients have ESR1 mutations that basically give them an endocrine sensitivity. And around sixty percent of the patients have tumors that have wild type and other driving mutations that are largely endocrine insensitive. Speaker 200:43:03Our hope with the second line trial was that we'd be able to capture whatever endocrine sensitive group of tumors that are in that broader ITT net. But in reality what you saw is that we missed the ITT, which is telling you that there's not as many endocrine sensitive tumors in that space. However, in the first line setting, we believe it's a very different story. We believe that maybe ESR mutations represent maybe only five percent of what you see in the first line setting. The vast majority of the tumors would be wild type, but most significantly we believe that those would be endocrine sensitive and therefore available to be tackled by a drug like vebegastram. Speaker 200:43:47So that's our belief it still is. But we're in a partnership with Pfizer and I think they want to have more mature data not just from our internal programs and data sets, but also the external world. They want to see what's going to happen with Gerodestrin, the Roche ER degrader which is in the first line. So if that comes out and it's positive in the first line setting that's going be a great signal for all the ER therapies. Camazestrin as well, again interesting data coming out from SERENO6 with more mature data there could also influence it. Speaker 200:44:25And of course as our data matures overall. I think Pfizer also want to see our current atirimaciclib VEP combo mature in terms of that data set also. So yes, there's a number of different things that Pfizer would like to see in terms of maturity of data both our internal data and the external data. And as to say, we're in a partnership. Good partners can look at two different data sets in two different scenarios and maybe come out with different options. Speaker 200:44:56But we're going along with this decision from the team to opt out of the first line study. And we move on. Basically, we have taken the money that was targeted for that study that's now out of the budget, allows us to plan to fund the rest of our portfolio, which is a very exciting portfolio in a more aggressive way. And as data matures, if Pfizer come back to us and say, they actually do want to do a first line study, we could assess that at a later date. But right now that is not in our plan and we move on. Speaker 200:45:34BCL6? Speaker 400:45:36Regarding BCL6, we're early in the dose escalation, but we've shared that we expect to share results later in the year. I don't think we can order or offer more guidance than that right now. Think of it as several cohorts. Speaker 200:45:58Do you expect to be for that one moment. Speaker 500:46:06Yeah. Speaker 400:46:09Do we expect we would share where we are in terms of safety and efficacy within any data that we make. Speaker 200:46:21But do you expect to Speaker 1000:46:22be in the active dosing range? Would you expect to be reaching dose levels that are where you want them to be from the perspective of the level of degradation you're expecting to drive efficacy? Speaker 400:46:35We may be, yes. Speaker 1000:46:40All right. Thanks so much. Operator00:46:46Your next question comes from the line of Tazeen Ahmad with Bank of America. Please go ahead. Speaker 1100:46:54Okay. I have a few questions as well. I think a few minutes ago you had talked about the market opportunity for these Veritec two patients that were positive in the study. You mentioned that for oserdo, one third of the twenty five thousand patients are on that drug. Does your market data give you any feedback about what the profile of those one third of patients are? Speaker 1100:47:21And is there anything different about the other two thirds that could make Bebtel potentially more attractive for patients? And then can you just provide any color on the remaining Pfizer milestones you expect to realize from here on out? And if there are any specifically related to the CAP6 collaboration? And then the last one, I'm sorry if I missed this, but are you still planning on exploring BepDeg in first line metastatic breast? Speaker 200:47:51First First So first of all, yes, in terms of the patient population in the second line, yes. So we think based on our assessments and some of the other external data forty thousand new patients in that second line setting, which we believe as I said before forty percent are ESR1 mutant. So in that second line plus overall setting that ESR1 mutant only that's probably sixteen to twenty five thousand patients that are then available. I think ORSERDU has done remarkably well to capture a significant number of those patients. I think there's a growing opportunity in that market to have more effective drugs in there. Speaker 200:48:42And so it's a growing I think it's a growing space. So yes, we think with as I said before, really significant opportunity. And we also believe it's a very good opportunity to have a very targeted launch into that space. There's probably around 6,000 oncologists that drive 70% to 80% of the prescriptions in this space. So we can also target this prescribing population I think very effectively. Speaker 200:49:11So I think yes, a really significant exciting opportunity. As it relates to CAT six and general milestones in Pfizer? Speaker 300:49:21Yes. So with regard to the Pfizer agreement, we are entitled to a milestone on first approval. I do not believe we've disclosed the exact amount of that. So I won't disclose it now, but we are entitled to something. And then there I think you asked a question specifically regarding CAT six. Speaker 300:49:41There's certainly nothing in the contract specifically regarding CAT six. So no, it would be related to the first approval which would be obviously VEPTEG. Speaker 200:49:50And then the final thing you asked was I think do you see any opportunity to test out VEPTEG in the first line? Well, my answer I mean clearly the decision we've made right now with Pfizer is not to go forward in the first line setting. We've also said that from an awareness perspective, we think Vepdeg would do well in that first line setting. So let's see how data matures over the whatever period of time the data is needed to mature. But as I said earlier, right now we move on. Speaker 200:50:23The money that we had sequestered for that first line study is now going to get moved to other parts of our portfolio and we are very excited about those opportunities as well. Operator00:50:41Your next question comes from the line of Peter Lawson with Barclays. Please go ahead. Speaker 1200:50:47Great. Thank you. Thanks for taking the questions. Just a couple of questions on the commercialization. So, Vepdeg, have you kind of worked through the size of the sales force you need? Speaker 1200:50:58And then your comments just around Vepdeg and first line. Does the Pfizer partnership preclude you from going off and finding a different partner to run that first line study? Just if you could walk through kind of that process of potentially rekindling for a first line study? Speaker 200:51:18Yes. So starting off with the size of the sales force, as I mentioned, it's going to be a fairly targeted I think financially prudent approach that we'll be taking. Obviously in a fifty-fifty setting, whatever we do Pfizer will match in The U. S. Six Thousand Oncologists that where we can target, which drive that 70 to 80% of prescriptions. Speaker 200:51:42So I think we're going to have an effective, but appropriately sized sales force to hit there. In terms of other partners, absolutely not. No, we're in a partnership with Pfizer. We're very pleased with the partnership we've had with Pfizer over the last year. They've been very supportive. Speaker 200:52:04And good partners can also have different views. And that's right now we've got a different view about the first line setting, but we agree overall with the decision. And we'll see what happens as data matures for Pfizer. But as I said, right now we take the money that we had sequestered for that and we move it into other things in our portfolio. And I think that's going be a big value driver for Arvindis. Speaker 1200:52:27Got you. Thank you. And then just on the CAT six combination, is that under the same kind of profit share terms of agreement with Pfizer? Or is that a separate entity? Speaker 200:52:37Well, in one sense, yes, because veptegastrant is everything they do with veptegastrant, everything we do with VetDegastrant is in that partnership. Cat six is wholly owned by Pfizer. So in that scenario as we've talked about before, we wanted to profile Vet against a whole series of different potential combinations. So we're actually excited to see Pfizer putting VEP into that CAT six study. They're paying for it. Speaker 200:53:07And if it works out well, we'll get the benefit through the degestrant side of that. Speaker 1200:53:14Great. Thanks for taking the questions. Operator00:53:19Your next question comes from the line of Paul Foy with Goldman Sachs. Please go ahead. Speaker 500:53:26Hi, thank you. Good morning, everyone, and thanks for taking the question. I just wanted to ask if you have any sort of gating items or any remaining things to do prior to scheduling your pre NDA meeting? And will that come presumably post ASCO here? Just some clarity on the color of when you plan to meet with FDA would be helpful as part of your second half of this year filing timeline. Speaker 500:53:53And my second question is just on the LRRK2 program in Parkinson's, just sort of when the next sort of data update could potentially be expected from that program? I think the early data that you presented looked interesting and promising. Just curious sort of what timelines for next into the next data set might be. Thanks for taking our questions. Speaker 200:54:12Thank you. Noah, do you want to tackle those? Speaker 400:54:16Sure. So we've met with the FDA for the pre NDA meeting and we feel that we're clear to move forward. And that's Speaker 700:54:27why Speaker 400:54:27we've conveyed in this in the prepared remarks that we're moving ahead with our submission enthusiastically. Regarding LARC2 next data sets, we've said that we'll share information later this year. It will even though we said that we'll start the MAD in the second half, I'm not sure if we can squeeze in those data at any meaningful conference by the end of the year. So we expect that we'll be sharing data from the SAD portion of the PD Phase one. No naming conference yet. Speaker 500:55:05Okay. Thank you very much. Operator00:55:11Your next question comes from the line of Tyler Van Buren with TD Securities. Please go ahead. Hi, this is Frances on for Tyler. So first question, are you still confident in Pfizer's commitment to the partnership to commercialize Vepdeg in the second line ESR1 mutant setting? Are you in any discussions to reevaluate the details of the partnership, such as selling the asset to Pfizer for royalties? Operator00:55:38And then my next question is, where do you envision the Cat six combo in the treatment paradigm could potentially serve as a backbone treatment? Speaker 200:55:47Yes. Thanks for the question. And Noah can take the second one. No, all of the interactions we have with Pfizer on VEP and the planning for regulatory filing, the NDA, getting ready for hopefully an approval and potential launch are all full blast. The team the joint teams are laying out significant plans as you'd expect for a launch that could be at some point next year both from a global setting and from a U. Speaker 200:56:17S. Setting. So, all of that's going forward well. And as I said before, think there's a significant opportunity. In terms of the change and there's no ambiguity. Speaker 200:56:28There's a change there overall in terms of the broader scope of what we initially had as a collaboration with Pfizer. When we started off, we were hoping for monotherapy first line adjuvant, which is quite a significant opportunity. Right now, we're going to be very focused on making that the best ESR1 mutant degrader in that second line plus setting. And I think as I said earlier, we wait to see how data matures for Pfizer over whatever period of time. But as we move on, we move on in terms of making sure that we can get the best launch possible once we hopefully get an approval. Speaker 200:57:07And we develop an ESR1 mutant only profile in that second line third line opportunity. It's clear that physicians are looking for additional options in that space and we believe VEP will provide that and we look forward to moving it forward. So yes, there's no change in the game plan with Pfizer. Speaker 400:57:33Regarding the Cat six question. So in the prepared remarks, you've heard us mentioned that while there are no registration trials planned for bep dengue. We continue to produce data from ongoing studies. And in fact, there is a new study as it were that will start. We're adding VEP deck to CAT six. Speaker 400:57:58And I think it's well premature to project what that can lead to because it's simply a Phase one study. But I think it just demonstrates that we're looking to combine that as we march into the second line space with other drugs to explore combinations that can bring more value to patients. So we'll have to wait to see those results. Operator00:58:24Thank you so much. Your next question comes from the line of Kripa Devarakonda with Truist Securities. Please go ahead. Speaker 1300:58:36Hey, guys. Thank you so much for taking my question. I have a couple. First, for ARV-three ninety three, I know you're currently enrolling Phase I trials. Just wondering how easy it has been to enroll patients. Speaker 1300:58:48You do seem to have a lot of centers open. And also based on the recent preclinical combo data that you presented at AACR, are you getting a better sense of where you think the drug and the combinations might fit in the landscape? And then just a question on your FDA communications. With some of the changes happening at the FDA, is there any concern in terms of delayed timelines for meetings or review processes? Thank you. Speaker 200:59:17Yes. I'll take the second one first then Noah can talk about March. Clearly, there's a lot of external changes that we're monitoring in this space and certainly with the FDA. From an Adventist perspective, we have noticed no delay and no impact with our interactions with the FDA, which is great. But obviously, we're going to continue to monitor that. Speaker 200:59:43And as we've seen in the press some other companies have had maybe a different experience. So far so good with us, but I could say we'll monitor that going forward. Noah, three ninety three? Speaker 400:59:56Yes. So March, I think we could say that while the study began last year enrollment was slow at the beginning. This is a Phase one study. So by nature it's slow. So it was I think a bit slow last year. Speaker 401:00:12There's a lot of enthusiasm and we see that we can generate a backlog of patients now and it's enrolling steadily. In terms of where three ninety three can fit into the landscape, well certainly depending on the data that we generate, there's the possibility of it being monotherapy. We'll have to see, what the overall benefit risk is as monotherapy. But we're quite enthusiastic about from the preclinical models that we've shared recently is its ability to combine with many other drugs, but particularly with bi bispecifics and particularly because it also seems to increase CD20 expression, which could create a real synergistic opportunity. Speaker 1301:01:05Thank you. Speaker 501:01:08Your Operator01:01:10next question comes from the line of Yigal Nochomovitz with Citigroup. Please go ahead. Speaker 1401:01:17Hi, great. Thank you very much for taking the questions. I three questions. So the first one is given the combo with the CAT six and the VEP deG, have you or Pfizer produced any preclinical work that would support that combo? Or could you discuss the rationale for that combo on a scientific medical basis? Speaker 1401:01:38Second question is, you haven't talked much about supply chain. Could you just review the structure and geographic location for the manufacturing supply chain for bepdag as well as where the IP is domiciled? And then the last question, John, you gave a very comprehensive answer with respect to the rationale for Pfizer stopping the frontline study. I'm just wondering if the factors related to the novel novel combo with the Thermo as well as the potential to do a or need to do a forearm study perhaps to tease out contribution of components was a relevant factor in that decision or not? Thank you. Speaker 201:02:18Thanks, Yigal. So yes, the first one, did we do any preclinical work with Cat six and VEDDIG? I think the answer to that is no. I think the rationale is really related to the fact that Pfizer very excited by the profile of Cat six. I do think they see the potential of the combination with bemdag enhancing potentially what they see with Cat six and positioning Vevdeg and Cat six as being a really strong combination. Speaker 201:02:54No, anything you'd add to that? Speaker 401:02:55Yes. Just some experience with fulvestrant that looks attractive. So that would be one of the reasons. Speaker 201:03:03In terms of supply chain, so Pfizer are accountable for the supply of that that's based in Ring of Skinny in Ireland. So we haven't had any supply chain issues. I think you asked the question where does the IP reside? That resides here with us with The U. S. Speaker 201:03:24With Arvinis. And then a really interesting question Yigal the novel novel with the terminal composition of components. I'm sure that has factored into some of the thinking. The broader view I gave is maturation of data, the external environment. I'm sure that's part of the rationale that Pfizer want to see our current Aturmo VEP data mature that's in the second line setting, but they want to see what that looks like overall. Speaker 201:03:57So I'm sure that has factored into the broader decision making around data sets and changing landscape. But yes, great questions. Thank you. Speaker 1401:04:08Okay. Thank you very much. Operator01:04:13Your next question comes from the line of Evan Seigerman with BMO Capital Markets. Speaker 501:04:19Please go ahead. Hi. This is Malcolm Hoffman on for Evan. Thanks for taking our question. Thinking about the LRRK2 degrader again, I know Biogen just announced today that enrollment in their Phase two study is now complete with results in 2026. Speaker 501:04:36I just wanted to ask how you are starting to think of competitive positioning for your degrader versus others? And what your confidence is that yours could be differentiated versus slightly more advanced programs? Noah, Speaker 201:04:50do want to take that? Speaker 401:04:51Sure. Yes. So thanks. We certainly look at it, Biogen Denali partnership enthusiastically. We think it's validating to some degree. Speaker 401:05:04But validating for an inhibitor that doesn't get brain penetration and does not even deliver significant inhibition in the brain. And so therefore with the degrader that gets significant brain penetration and can lead to more than 50% degradation eliminating all functions of LRRK2 not just kinase activity. We think that puts us in a very competitive spot. So we're looking forward to those results if they if it's successful then I think where there'll be a lot of enthusiasm If their study is the Phase three program failed, but it has some directional data that's supported, there's also going to be quite significant enthusiasm. Speaker 401:05:58But overall, we just do not believe that inhibitors get you there. And the fact that you'll see the continuing our continuous updates from our studies to see the benefits from the degrader. Speaker 501:06:17Appreciate it, guys. Thank you. Your Operator01:06:23next question comes from the line of Lee Wacek with Cantor Fitzgerald. Please go ahead. Speaker 801:06:30Hey, guys. Thanks for taking our questions. Maybe a BD strategy question. Are you open to bringing in maybe external assets just given your balance sheet? And then you've got three earlier assets in the pipeline. Speaker 801:06:46Maybe talk a little bit about your conviction and development strategy there. It sounds like you're gonna have some data later this year. Will you be making some decisions then? And then secondly, just for the CATCH-six combo, when should we expect to see the data? And then what would be the bar that you have to head given it's early Phase I trial? Speaker 801:07:13And then can you clarify, is it going to be in the ESR1 near term patients or it's going to be in all comers? Thank you. Speaker 201:07:24Noah can tackle the CAT six and that part of it. In terms of the BD strategy, I think overall we have always been out there looking at opportunities to supplement certainly our technology. And as we go forward, if there was an asset out there that complemented our lead programs, I think we'd be open to that. Obviously, we've been our Genesis as a company has been a platform based company We're very proud of that and our portfolio is replete with really exciting degraders. But yes, if there was a significant opportunity to get an asset that complemented that, I don't think we'd have any issue with that. Speaker 201:08:09There was another subset in there. I can't remember the subset of the Regarding Speaker 401:08:13CAT six. So yes, again just to frame this study, this is a Phase one study that's just very exploratory. So there are no timelines associated with it. We haven't even dosed the first patient yet. It's really shared in the spirit of that we'll continue to look for nice combinations that can be practice informing and continue to expand the attractiveness of our already potentially best in class gut take in the second line setting. Speaker 401:08:48And so that would be the case with this CAT six combination also. It's Pfizer's wholly owned drug. We don't call the shots there in any way and we're just looking to see what we can generate with that combo. And right now the thought is for commerce. Speaker 801:09:07Okay, thank you. Sure. Operator01:09:14Your next question comes from the line of Shweta Mukherjee with BTIG. Please go ahead. Speaker 1501:09:21Great. Thank you for taking the question. Was wondering if you've thought about potential NCCN guideline inclusion for some of your, Vepdeg CDK4six data, to support combination use, just given some of the notable PFS data you had shown at San Antonio Twenty Twenty Three and thereby allow doctors to use a CDK foursix off label in combination with Zepdeg in the second line setting? And my second question was just around your G12D degrader. Can you maybe talk about how that compares to Astellas' degrader and some of the perhaps subpar efficacy and safety it had shown at last year at ESMO? Speaker 1501:09:57Thanks. Speaker 201:09:59Noah, do want to take that? Speaker 401:10:00Sure. The first question second one was about G12T. The first was NCCN. NCCN. Yes. Speaker 401:10:09So look, we continue to generate we're going to be sharing the maturation of our combination datasets. We will this will be discussed with the commercial and medical affairs team about how to best share this information and be as practice informing as possible. So I don't want to get ahead of myself and speak about NCCN guidelines. But overall, we would share whatever physicians need to make the best decisions though obviously we're seeking a monotherapy label and that's the only way we will be marketing the drug for monotherapy use. Regarding the G12D degrader, I think I had mentioned in the prepared remarks that we've seen that we have 30 times the potency of some other inhibitors and degraders in the space. Speaker 401:11:11One of the challenges for a leading degrader in this space is the hepatotoxicity or I guess as evidenced by transaminitis that has been seen that may be limiting in the dosing of that drug. In our case, we don't believe that this will be a limitation for our drug ARB-eight zero six. And but of course, we're just starting our dosing of patients in the second half of this year. Speaker 1501:11:42Thank you. Speaker 401:11:44Your Operator01:11:47next question comes from the line of Sudan Loganathan with Stephens Inc. Please go ahead. Speaker 1501:11:54Hi, good morning and thank you for taking my questions this morning. I wanted to kind of dig deeper into the details for the ESR1 mutant patients again that are naive to treatment. I believe you mentioned earlier in the call about approximately five percent are of ESR mutant is in the first line setting. Is VepGag with the monotherapy design actually going to be well positioned to be more of the standard of care even also in the first line that kind of demonstrate the CSR1 mutant as well or will there be some additional trials or anything else that needs to be done there? Then with the total of about forty percent I guess of second line patients that have ESR mutant, is that only specific to first line patients that were treated on CDK4six inhibitors or also other treatments as well? Speaker 1501:12:41Thanks. Speaker 201:12:43Yes. So just for clarity, in the second line setting, we believe around forty percent of the patients have tumors that have ESR1 mutant profiles. And that offers up a potential of forty thousand patients that could be amenable to a drug like bevdegastrant. So that's exciting. That's a great opportunity. Speaker 201:13:07In the first line setting, it's different. There's maybe only about five percent of the patients have tumors that have ESR1 mutation. The rest have wild type. And the biggest difference we believe is wild type in the second line setting is probably endocrine insensitive, but wild type in the first line setting is endocrine sensitive. So there's a significant opportunity there. Speaker 201:13:32So our belief is that VEP was in that setting it would do well. But we've made this joint decision with Pfizer not to go there and we move on to other things. And in the second line setting where we still see a significant opportunity, we'll be seeking approval for a drug in that setting and ideally then launching into that second line setting along with our partners Pfizer. So significant opportunity there. And as I said before, we wait to see what the maturing information is in the first line setting both from a point of view of our data, but also the data coming from other companies. Speaker 1501:14:13Appreciate it. Thanks for the clarity there. Speaker 201:14:16Thank you. Operator01:14:20And that concludes our Q and A session for today. I will now turn the call back over to John Houston. Please go ahead. Speaker 201:14:27Well, thanks operator and thank you everyone. We gave you a lot of information today to digest. Remains for me just to say that we're incredibly confident about the future direction of the company and you'll be hearing more from us with additional updates through the year. So thank you very much for your time this morning. Operator01:14:49Thank you everyone. That concludes today's call. You may now all disconnect. Have a nice day ahead.Read morePowered by