Arvinas, Inc. Price & Performance (ARVN)

Now I'll turn the call over to John Houston, our CEO, President and Chairperson. John? Thanks, Jeff. Good morning, everyone, and thank you for joining us this morning. It's a very exciting time for us here at Arvinas as we're on the cusp of some major accomplishments that include our first Phase three topline data results expected later this quarter and first in human data from our first PROTAG targeting neurodegenerative disease. We continue progressing a robust portfolio of exciting development programs that have the potential to transform the treatment landscape across a broad range of cancers and neurodegenerative diseases. Our novel approach to discovering developing and commercializing a new class of medicines has always been the backbone of our company and we're pleased to provide an update this morning at such an important time for the organization. Today, I'll begin with a brief overview of our Venice our ProTag Discovery platform and an update on our pipeline. Noah will then provide an overview of our vibegastrin or VETDA clinical program including reviewing the Phase three VERTAC-two trial and also provide an update on our first neuro clinical program with ARV-one hundred and two, our LARC2 degrader. Angela will provide an update from our earlier stage programs including our BCL-six degrader, ARV-three ninety three, and our KRAS G12Ddegrater And finally, Andrew will provide an overview of our fourth quarter and full year 2024 financials before we open up the call for your questions. [indiscernible] Over the course of the last year, we have made significant progress on our mission to improve the lives of patients with debilitating and life threatening diseases Our pipeline of proteolysis targeting Chimeras or ProTac protein degraders, have been designed to harness the body's natural protein disposal system to selectively and efficiently degrade and remove disease causing proteins.

Our innovative ProTac platform while making significant breakthroughs in targeted protein degradation. These breakthroughs include designing the graders drug like properties that are orally bioavailable and when needed, able to cross the blood brain barrier. VETDEG is the most advanced program in our pipeline and in addition to our ongoing Phase three monotherapy trial, our current development plan includes two additional Phase three combination trials across the first and second line settings in metastatic breast cancer. Agateg is an oral Protec protein degrader specifically designed to target and degrade the estrogen receptor for the treatment of patients with ER positive HER2 negative breast cancer, Together with Pfizer, are developing VETDEG with a goal of becoming the best in class ER targeting backbone therapy first as a monotherapy then with multiple combination strategies. And soon, we expect to have data in hand from Verint two, our first ever Phase three trial. Data from this Phase III clinical trial will be an important milestone for Arvinis and we look forward to sharing top line results later this quarter. If positive, these results will support our first new drug application and mark our potential transition to a commercial stage company. Noah will provide an overview of the trial later in the call.

Now given how close we are to this disclosure, we will not be answering questions about trial progress, or offering additional guidance on expectations for Vertex two during the Q and A portion of our call. Last month, we announced updates to our clinical development plans for VETVEK combination trials in the first and second line settings pending emerging data and health authority feedback. In the first line, we announced that in 2025, we intend to initiate a Phase three trial with VETDEG plus Pfizer's novel investigational CDK4 inhibitor a ternociclib, In the second line, we announced that we plan to initiate a Phase three combination trial evaluating VETDEG with a CDK4six inhibitor which we also expect to initiate in 2025. Beyond VEDDAG, we have a data rich year ahead and we believe there are exciting opportunities for PROTECT across oncology and neuroscience In April, we plan to present the first in human data from ARV-one hundred and two, a LARC2 degrader, which we believe will highlight the potential value our PROTECT degrators can offer to patients with neurodegenerative diseases. Additionally, in 2025, we plan to share preliminary data from our Phase one trial with ARV-three ninety three, our BCL6 degrader in patients with non Hodgkin lymphomas.

And finally, we are in track to file an investigational new drug application for our KRAS G12D degrader this year. Now turn the call over to Noah for an overview of the VETVEG and ARV-one hundred and two programs. Noah? Thanks, John, and good morning, everyone. Last year, together with Pfizer, we made great progress with our VEPTEG program. As John mentioned, in addition to sharing top line results from Varetech two later this quarter, We intend to initiate two new Phase three combination trials in the first and second line setting later this year. We continue to believe VEPTEG has the potential to demonstrate superior efficacy and tolerability and become a best in class ER targeting back bone therapy, preferred by physicians and their patients. Given the proximity to the upcoming top line data readout, I won't spend too much time discussing the VERITEC-two trial which if successful could result in a submission of the new drug application and the first ever regulatory approval of a PROTECT degrader. Recall, the VERATEK-two clinical trial is evaluating the in patients with ER positive HER2 negative advanced breast cancer who have previously received and progressed on a combination of CDK4 inhibitors and endocrine therapy.

Important progress has been made in the treatment of patients with metastatic breast cancer who have progressed after receiving prior treatment with the CDK4six inhibitor. Yet, there is an ongoing need for improvement in treatment. An oral agent approved a few years ago for patients with ESR-one hundred but to three point eight months. This highlights the unmet medical need among patients with advanced metastatic breast cancer and the potential opportunity for vapedegastrant in the VARATEK2 trial. Varetech II has two primary endpoints. PFS and the ITT or intention to treat population and PFS in the ESR1 mutation subpopulation. The study also has secondary outcome measures that include overall survival. Life assessments. It is worth noting that events determining PFS will be assessed by blinded independent central review. We expect to announce the outcome of Veritec II in a top line press release in Q1 and to present full results for the Medical Congress in 2025 where we also intend to host an investor call. In addition to anticipating Veratype two results, we are pleased to be progressing our plans to initiate registration trials evaluating DEPTEG combinations. Later this year, we plan to initiate a first line Phase III trial of Eptag in combination with Pfizer's novel investigational CDK4 inhibitor, a termosiclib, pending emerging data and health authority feedback.

The decision to prioritize bepig plus a termosiclib in the first line setting is based on the totality of evidence evaluating DEPTIG plus the termosiclib in the late line setting and our trials evaluating vepteg plus palbociclib. This evidence in addition to shifting treatment paradigms for early and advanced breast cancer gives us the confidence that VETDEG plus a termosiclib is the best combination to advance as a potential new treatment option in the first line setting. We and Pfizer are excited by the potential this combination represents for a new treatment option in this setting. Our plans also include initiating second line Phase three combination trial of vepteg plus a CDK4six inhibitor in 2025. Pending emerging data and health authority feedback. Compelling efficacy signals have been shared previously for Bepteg in combination with palbociclib or with the bemaciclib, in the second line plus setting. In December 2024, we presented preliminary data from 16 patients in the Phase Ib combination trial of beptag and abemaciclib at the San Antonio Breast Cancer Symposium. This combination demonstrated encouraging clinical activity with a clinical benefit rate of more than sixty percent and an overall response rate of nearly thirty percent, in patients previously treated with the CDK4six inhibitor.

Safety and tolerability of the combination was generally consistent with the demonstrated profile of both agents. Importantly, no significant drug drug interactions were observed and veptig had no clinically meaningful effect on the bemaciclib exposure. The combinability of VEPTEG was also supported by a Phase one pharmacology one concern for the ongoing clinical development of Epteg as a backbone ER therapy. We look forward to initiating the second line Phase three combination trial later this year pending emerging data and regulatory feedback. In totality, the data we have generated continue to support our belief that VETTECH has the potential to provide superior efficacy and tolerability both as a monotherapy and in combination for patients with metastatic We I'm now going to turn to our neuroscience clinical program. Our most advanced neuroscience PROTAC, ARB-one hundred and two, is a novel oral PROTAC designed to cross the blood brain barrier and target leucine rich repeat kinase two or MARC2. MARC2 is a large multi domain scaffolding kinase genetically implicated in progressive supranuclear palsy and Parkinson's disease. Pre clinically, we have shown that ARB-one hundred and two crosses the blood brain barrier and achieves deep brain region penetration and degradation of LART-two in non human primates.

We've also observed differentiation from inhibitors by showing improved effects on lysosomal dysfunction and movements of disease relevant biomarkers in the central nervous system and preclinical studies. In 2024, we initiated dosing in a first in human Phase one clinical trial of ARV-one hundred and two in healthy volunteers. This ongoing Phase one trial was primarily designed to establish the safety of Arvinas hundred and two, but it will also measure BARC2 degradation, in the periphery and in the cerebrospinal fluid or CSF of patients. To establish the ability of ARV-one hundred and two across the blood brain barrier and degrade LARC2 in humans. And I'm pleased to share that initial data from the single ascending dose cohort of the trial will be presented in an oral session at the Alzheimer's disease, Parkinson's disease or ADPD Conference in April. These data confirm that ARV-one hundred and two is orally bioavailable in brain penetrant with dose dependent exposure in the CSF. At the ADPD conference, we will disclose degradation data from the peripheral blood and CSF of healthy volunteers. An exciting milestone that we look forward to sharing. The learnings from this Phase one trial will be valuable as we strive to address the incredibly high unmet medical need in neurodegenerative diseases. Initiated a Phase one ascending dose trial of ARV-one hundred and two in patients with Parkinson's disease and expect to complete enrollment and present the initial data from this study later this year.

It should be noted that we also plan to initiate a multiple ascending dose cohort in patients with Parkinson's disease later this year. Now I'm going to turn it over to Angela, who will talk about ARV-three ninety three our BCL6 degrader our KRAS G12 degrader. Angela? Thanks, Noah, and good morning, everyone. The preclinical profile of ARV-three ninety three our oral PROTAC, designed to degrade B cell lymphoma six protein or BCL6 has been highly positive For background, BCL6 is a transcriptional repressor and a major driver of B cell lymphomas. The BCL6 protein facilitates B cell tolerance of rapid proliferation and somatic gene recombination, through the repression of cell cycle checkpoints terminal differentiation apoptosis and the DNA damage response, which becomes dysregulated in several types of non Hodgkin lymphomas. Protac mediated degradation has the potential to overcome the historically undruggable nature of BCL6. ARV-three differentiated preclinical profile it potently and rapidly degrades BCL6 protein, which is critical to overcoming BCL6's rapid resynthesis rate and sustaining antitumor activity. ARB-three 93 has demonstrated significant antitumor activity in numerous preclinical in vivo models of non Hodgkin lymphoma. We plan on presenting AR V-three 93 preclinical data at the American Association for Cancer Research Conference in April.

These data show the promise of ARD-three 93 as a monotherapy in angioammunoblastic T cell lymphoma patient derived in vivo models. Additionally, we will show ARB-three 93 in combination with standard of care biologic agents and small molecule inhibitors, in high grade and aggressive DLBCL in vivo models, We have made significant progress in enrolling patients with non Hodgkin's lymphoma in a Phase one clinical trial of ARB-three 93, and look forward to sharing initial data this year. As a final note, we remain on track to file an investigational new drug application this year for our KRAS G12D integrator.

KRAS is a driver oncogene in several major tumor types and is associated with poor prognosis and resistance to standards of care. Preclinically, our degrader is a highly selective and potent molecule that demonstrates dose responses degradation of KRAS G12D leading to robust antitumor activity in KRASG12D mutated cancers including pancreatic and colorectal cancers. Our degrader forms a ternary complex with both the active and inactive states of KRAS G12D. This pro TAC induced binding event results in the elimination rather than the inhibition of KRAS G12D. In addition, our KRAS degrader is at least 30 fold more potent in vitro than an inhibitor currently in the clinic. I look forward to updating you on our progress with KRAS G12D and other promising degraders that are in discovery at Andrew?

Thanks, Angela, and good morning, everyone. I'm pleased to share financial highlights for the fourth quarter and full year ended 12/31/2024. As a reminder, detailed financial results for the fourth quarter and year end are included in the press release we issued this morning. As we move into 2025, we are in a strong financial position, with cash on hand sufficient to support operations into 2027. At the end of the fourth quarter, we had just over $1,000,000,000 in cash, cash equivalents and marketable securities on the balance sheet, compared with $1,300,000,000 at the end of 2023. Our strong balance sheet will allow us to advance all of our key strategic objectives, which include progressing the VEPTEG clinical program preparing for our first commercial launch and developing our promising portfolio of earlier stage PROTAC degraders. Let me now turn to the fourth quarter and full year 2024 financial highlights. During the quarter, we recorded $59,200,000 in revenue, compared to a negative $43,100,000 in revenue for the same period of 2023. The increase of $102,300,000 was primarily due to adjustments made in 2023 to revenue from changes in contract estimates which resulted in negative revenue in the fourth quarter of twenty twenty three.

We recorded $263,400,000 in revenue for the year, compared to $78,500,000 in the prior year. General and administrative expenses were $34,100,000 in the fourth quarter compared to $27,000,000 for the same period of 2023. The increase of $7,100,000 was primarily due to developing our commercial operations of $2,600,000 personnel and infrastructure related costs of $2,200,000 and professional fees of $1,800,000 G and A expenses were $165,400,000 for the year compared to $100,300,000 in the prior year.

Research and development expenses were $83,300,000 in the fourth quarter compared to $95,200,000 for the same period of 2023.

The decrease of $11,900,000 was driven by a net decrease of $9,900,000 in external expenses primarily related to the out licensing of ARV-seven 60 For the year ended 12/31/2024, R and D expenses were $348,200,000 compared to $379,700,000 for the prior year. We are well capitalized as we move into 2025 with the potential for an exciting milestone rich year beginning with our first Phase three top line results first in human data in April is another important milestone for the company. Later this year, we expect to share data from the single ascending dose portion of our Phase one trial in patients with Parkinson's disease and initiate the multiple ascending dose cohort in the same study. We also look forward to sharing data from the Phase one study of our BCL-six degrader, ARB-three ninety three, in patients with non Hodgkin's lymphoma. And submitting an IND application for our KRAS G12D degrader. With that, I'll turn the call back over to John for closing remarks. [indiscernible] Thanks, Andrew.

We expect to have a data rich year ahead of us as we prepare for a key clinical trial readout from our Phase three VERITAC-two trial and advance our promising pipeline of protein degraders. As we prepare for our first Phase three data readout, the first ever for a PRO TAG, the exciting here at Adventist is palpable. Want to thank our dedicated team for working tirelessly and enthusiastic to bring this potential new medicine to patients. But none of it would be possible without the patients and physicians who are participating in our clinical trials.

I want to express my sincere gratitude to them as we could not have achieved our success to date without their collective efforts. I also want to thank our shareholders, your continued support and encouragement as we work together to bring the promise of protein degraders to benefit patients across multiple life threatening diseases. With that, I'll now turn the call over to Jeff to begin the Q and A portion of our call. Jeff? Thanks, John. Before I turn the call over to the operator, I'll remind you we will not be answering questions related to the progress or status of the VERATEK-two trial or providing additional guidance on our expectations for data at this time, So with that, operator, will you please open up the queue?

Thank you.

Our first question today will come from the line of Derek O'Cullo of Wells Fargo. Your line is open. Hey, good morning and thanks for taking the questions. Just one in terms of just the TACTIVU cohorts that you'll be reading out this year, if you think about the cadence of that data across different medical meetings and ultimately, are you waiting for that data to really decide on the second line CDK4six combo? Thanks. Thanks, Derek. Hand over directly to Noah and he can answer that.

Hey, thanks, Derek. So Tactivu, as you know, is or for everyone's knowledge is a study that is evaluating DEPTIC in combination with some other agents. So those agents include a CDK7 inhibitor ribociclib and also abemaciclib. So we've shared data about the abemaciclib combination Those data continue to mature. We haven't shared information for the other two yet. We haven't offered guidance about when we will share the specific updates of these. But the hope is that as data mature, we can be sharing more. As to the question about whether or not this will determine the choice of CDK4six inhibitor that's combined with VESTIG. We think at this point, we've established that VEPTEG combines very nicely with Palbo and combines with the bemaciclib So overall, the likely determinant of what we combine with is what will be the best drug to combine in the second line setting. So I don't want to go into more deep next few months.

Understood. And if I can squeeze one more on LARC II. Just in terms of what you plan to share for the SAD, I guess, what level of degradation do you find to be there translate to the human setting? Thanks. Yes. Angela, do you want to answer that question? Certainly. Thanks for the question, Derek.

So based on preclinical data, that's been published by many others showing that 50% reduction of the protein is disease modifying in certain contexts, including in the context of alpha synucleinopathies as well as tauopathies. So those data are published. In addition, human genetics guide us more recently, omics studies that relate to single cell LARC2 expression levels in the brain in particular in microglia that show that there's twofold elevation in LARC2 expression in microglia and this has been confirmed in iPSC derived cells Parkinson's disease patients. Where there's overexpression of LARC2 in idiopathic Parkinson's disease. So we believe that we stand the best chance of testing the LARC two hypothesis by reducing LARC-two 50% in the brain and that's what we aim to show. In the central compartment.

Excellent. Thanks again.

Congrats on the progress. Thank you. Thank you. One moment for the next question please.

And our next question will be coming from the line of Jonathan Miller of Evercore.

Your line is open.

Hi guys. Thanks so much for taking my question.

I guess since we just had a question on the Phase three in the second line, gating factor, I'll ask on the first line. Obviously, you've already chosen the CDK combo here with the CDK4. What's the gating factor to getting that study started How much data do you need in the ATIRMO combo at a ATK2K before you can make those trial design assumptions, do you need six months data to go to the FDA with the trial design for Phase three? Yes, great question. No, no. Thanks, John. So thanks for the question, John.

So Overall, as we've shared, we plan to combine DUC with the termosiclib in the first line. And this is based on the totality of evidence that we have in which we've assessed what we could do with the termosiclib from an earlier data set in which we were looking at two different dose termo combined with Bepteg two hundred. And are now in the expansion part of that. And also reflecting back on palbociclib, how we did in our combination there. These were where we're looking in later line settings but also in the first line setting. And overall recognizing how there's a shift in the use of CDK-46s in line and palbociclib is being used much, much less And we see a great opportunity for termo in the future. As for what's gating, there is a as we've shared, we need to have some health authority discussion and we have to continue to look at data. The good news is that the data continue to mature nicely. It's we do not feel that we needed at least six months of data to have this conversation with the health authorities.

Great. And maybe if I can squeeze one more. I know you're not answering questions about Veritec two, but could you talk to commercial preparations beyond what we assume is going to be a wonderful readout in a couple of weeks.

How does your commercial prep going and what do you think ramp there needs to be to be ready for a launch?

Yes. Clearly, we've been focused on building the initial runway for a commercial organization. We have that in place. All the other aspects of the different components for a launch are getting in place as well. As you know, we'll be launching with Pfizer and will be The U. S. Lead. So a significant amount of planning related to that. So yes, I'm very pleased with the progress getting made by the team. And we're in good shape.

Thanks very much. And our next question will be coming from the line of Lee Wasak of Cantor. Your line is open. Hey, good morning team and thanks for taking our questions.

I wonder if you can maybe just comment on Veritec two, if it has any way to the two Phase three trials that you plan to initiate this year. Any elements of the trial design might be impacted by the results?

Noah, do you want to at least talk about that part of the potential influence? I guess the read through if anything, would be more in the second line setting understanding the scope of the activity we see for the monotherapy in second line.

We don't see it having any read through to first line.

I probably can't go into more details like that. We're in the process of going through our health authority preparation and discussion and also just continuing to evaluate maturity of data in the second month. So I think Understood. And I guess just from a pipeline perspective, you've got three additional programs that you're moving forward into the clinic. I guess what level of investment that you guys are looking to make especially for the larger indications like Parkinson's disease?

Yes. Great question. Yes. And we're very pleased with the progress the portfolio has made through the last year. Clearly, very excited about seeing our first neuroscience neurodegenerative program moving forward.

And PSP and Parkinson's disease, very interesting areas for for us to move that compound into.

And we are well placed to take a lot two degrader to a significant stage of development. We'll see in the future how the progress of the compound is. Or not there's an ideal situation where we find a strategic partner that's all ahead of us. Right now, we're very focused on moving that program forward internally getting it to a significant milestone.

And our next question will come from the line of Akash Tawari of Jefferies.

Your line is open.

Hey, Thanks so much. So Faz just previously mentioned that the decision to progress the vebDx CDK4 combo would be in part an efficacy based decision We know we're going to a first line right now. With that in mind, can you frame expectations on that upcoming combo data? Will we have enough follow-up give an early take on CFS? And if not, what do you think response rate should be for both the first line and second line setting for your go forward dose? And then on Veritec two, this isn't a timing question, but how concerned are you that a six month higher ET requirement is not sufficient to remove ET fast progressors? And what percent of fast progressors do you expect in your study versus what we saw with Lilly?

The second half of that question, again, as we said at the beginning, we won't be answering any questions related to Veratag two. First half of the question, In terms of how much efficacy in safety data we'll be looking at.

It's decisions about going into first line are mostly safety driven. There's a we'll be looking at efficacy as well, but safety is the dominant deciding factor. And you also just want know the overall activity of your drug, which I think we've established already in the second line plus setting from the Phase one programs that we've that we've run So mostly now it's just discussing whether or not the dose that we recommend is going to be acceptable with health authorities. And continued to as we have those discussions to just look at the maturity of the data to see if anything unfolds.

Thank you. One moment for the next question. Next question will be coming from the line of Tazeen Ahmad of Bank of America. Your line is Okay. I think that's me. So maybe I have a couple of questions. The first one is on metastatic breast cancer. So what data do you think you'll need to show to give confidence to KOLs on the profile of that and the turmoil. Just considering that historically they will have had a lot more experience with the other CDK inhibitors like Rydel and Palbo for example. Then I have a follow-up Noah?

Thanks. Yes, thank you for the question. We have so I think if the question is focused on first line what we expect to see, we're not prepared to go into the exact study design, the hazard ratio that's being targeted. The where other features of the statistical plan. But in general terms, all the feedback we get is that investigators would want to see more than five months, six months of improvement in median PFS to know that they have something that's substantially different. Even if we're up against [indiscernible] generic competition a few years from today when when Palbo is generic. And so if you view the first line CDK4six plus AI combination as delivering somewhere between twenty four and twenty eight months of medium PFS you'd want to see something in that range five, six months better to know that you have something special.

Okay, got it. And then if I could ask a question on your KREZ deGrader. Can you talk about how you think it might be differentiated given that this G12, the greater space is pretty competitive. You've got other companies like Astellas in the clinic and what would you want to see in order to to move it forward?

Yes, we're very excited about Keyera program and Angela, do you want to answer that?

Yes, sure.

So based on on the details that are public, we've compared to the Encellis molecule. We know we're 40 fold more potent than that Encellis greater It is encouraging that the Astellas degrader did show some efficacy at [indiscernible] but was I think discontinued for issues due to safety. We feel that we're very competitive with respect to the in vitro profile and in vivo profile based on the data that we've generated. We do believe that in terms of the inhibitors in the G12D space that we're very competitive We have a catalytic mechanism of action We know that we bind to both the inactivated and activated states in terms of our ternary complex, so very different than an inhibitor, the degrader finds both and we know that we're more potent in inhibiting cell proliferation and inducing cell death. We also disrupt the scaffolding functions that are known for G12D KRAS and we have the potential for distinct and non overlapping resistance mechanisms that we can impact with G12 date. And beyond that, we have some very compelling data in terms of some of the neoantigen profile that we're producing that we know inhibitors do not.

So and just to add to that point, Angela, and I think you touched on it. But this potency becomes an important issue because ultimately, the first line the first generation Acelis compound did demonstrate some abnormalities in patients that may have created some dose limitation So we do have the opportunity with ours maybe to to address efficacy before those come in.

Great question. Thank you. Thank you. One moment for the next question. And the next question will be coming from the line of The next question will be coming from the line of Devra Rakhanda of Truist. Your line is open.

Thank you so much for taking my question.

First question is on ARV-three ninety three. Can you talk a little bit about enrollment status for this program and whether there's any focus on a particular subset of NHL patients And given the profile of the target, where do you think this might fit into the landscape with other targets like BTKs or BCL2. Thank you. I have a follow-up.

That's a great question. Thanks, Krippa. No, Thank you, John. Yes, Krippa, great question. We're pretty excited about this compound and let's break it down into a few different areas. In terms of enrollment so far, the study started its enrollment last year. It was a little later than we initially expected, but things going very nicely backlog of patients and making nice progress. In terms of In terms of how this drug may differentiate itself. Well, first of all, it's differentiated in the sense that there are no BCL6 inhibitors that are in the clinic really or approved. There is another degrader that's in development out there and it's probably at a similar stage of development. Not much has been shared. We are very satisfied with combination data, some of which we've shared, more of which is coming and we want you to direct your attention to AACR where there's going to be an opportunity for an update we view what you would see there is a lot of potential combinations that can open up the door to this orthogonal approach towards anti lymphoma activity.

One of the things that we're working out is to what degree do you need BCL6 expression or how much expression is necessary for this pathway to be targeted effectively with this agent. The combinability, the fact that the drug isn't hasn't really demonstrated pre clinically and in our top [indiscernible] real hematopoietic toxicity suggests that there are opportunities for us to combine nicely with any of these agents that you mentioned, whether we're talking about BTKI inhibitor, anti CD20, therapy, whether it's single an antibody therapy or if it's bispecifics. So lots of paths we can follow. And the first step obviously is generating data about a MAC combinability.

Great. We'll keep an eye out for AACR. Just a follow-up question. We got some inbound [indiscernible] the around the Chief Commercial Officer leaving right before a key readout and potentially in a year or so before potential commercial rollout. You talk a little bit about it and help alleviate investor concerns about this?

Yes, absolutely. Yes, Chief Commercial Officer, John Novakar, he had to leave unfortunately because of personal reasons, which I can't get into. Luckily for us and also through great planning, we had a second in line highly experienced executive Alison Tini, who has been able to step into the breach as our Interim Chief Commercial Officer and he's absolutely superb. So I can honestly say we haven't missed a beat. Alex is continued the game plan that was laid out by John and the team is progressing really well. So it was unfortunate, but because we had such a great depth in terms of leadership team there, we'd be able to move on really quite easily.

Thank you so much. And our next question will be coming from the line of Jeet of BTIG Great.

Thank you for taking the question. I was hoping you could elaborate a bit more on what we can expect from the Parkinson's patients' update for ARV-one hundred and two later this year? And are there any biomarkers you'd be looking for that would translate to functional improvements in these patients? I have a follow-up. Thank you.

Thank you. No, it's our [indiscernible] put us on the same page, The immediate like the first step is to demonstrate what or to share what we've demonstrated in healthy volunteers. And so this involves our understanding of PKPD, so understanding how dosing leads to what PK properties can be tracked in the periphery, but also in the central nervous system by virtue of what we see of drug in the CSF. And then of course, there's PD. So what's happening to LARC2 again in the periphery and more importantly in the CSF. And so we expect the first glimpse of those data at the Alzheimer's disease Parkinson's disease conference in Vienna in early April. But as we've also shared, we have begun dosing on Parkinson's disease patients. Unfortunately, we can't offer guidance at this point about exactly when those data will be shared. But recognize that we started off and this is for regulatory reasons with SAD patients, so a single ascending dose. And then we would next move to MAD dosing, so multiple ascending dose in Parkinson's disease patients And depending on the progress of this and it's going very nicely right now, we would hope we can and conference schedule, we hope we can share some of that would be at least sad, but we'll have to see how how much data we can accumulate by the appropriate conference later in the year.

And just to continue, with respect to what no one was saying at least in nonclinical primate studies, we've been able to conduct a discovery effort around biomarkers that we think are large to driven based on published Parkinson's disease progression initiative from the Michael J. Fox Foundation. So we're encouraged by our nonclinical data that suggests that we can move neuroinflammation endpoints as well as lysosome function endpoints. So it's promising and so we await getting towards the MAD portion of Parkinson's disease studies.

To assess this.

Understood. That's helpful. And maybe a Veritas two question, if you just wouldn't mind. You said you'd present full results at a medical conference.

Any abstract embargo rules potentially limit what you could say as part of the top line press release?

Yes, I think there would be So and we'll get more information that as we get past that next stage.

Thank you. One moment for the next question. And our next question will be coming from the line of Brad Paccino.

Of Stifel. Your line is open. Hi, good morning.

Listening to the large pharma earnings, we should expect frontline Phase three oral SERD trials in combination with the CDK foursix inhibitors from Roche and AstraZeneca this year right around the time you and Pfizer will be kicking off the frontline VEP CDK4.

How will Arvenous think about these results of the studies as they pertain to your frontline plan? Thank you.

Yes. Thanks, Brad. Obviously, we're going to be very interested in the data sets coming from both those companies. Noah, do you want to say anything about additional Sure. So thanks, Brad. The I guess the question can be, will this impact standard of care? And the feeling is that with the study that's going to launch this year and take less than a couple of years to enroll. It's not going to have it's not likely to have impacts on our bill on the operational feasibility of a study in any way. So if anything, it's kind of just I guess the create some excitement in this area if there are some positive results. We also recognize at the end of the day that pro tax are very different than SERD because of our target degradation. So whatever we see, we can our [indiscernible] and expectation would be that we can see something stronger from a PROTAC. So we're looking with anticipation, but recognize that it just creates Thank you. One moment for the next question. And our next question will be coming from the line of Sudan Loganathan of Stephens. Your line is open.

Hi, good morning and thank you for taking my questions here. And my first one will be on at tiramarciclib in regards to that first line combination you plan with VEPTEG.

Deck. I think it's 20 fold and four fold increase in productivity.

For CDK4 over CDK6.

Which I believe that probably helps with the neutropenia or any hematologic toxicities that may have showed up with like palacyclis potentially. But curious to how you view the the glucose metabolism component for CDK4 involvement in that? And how that may play out in the safety profile? And just even just your very broad view on what makes Tier one'sicola in your view better than PALBAICICLIB, RogerICLIB or any of the other CDK four sixty inhibitors out there? And I have follow-up. Thanks, Sudan. No.

Sure. Thanks. So Sudan, so you had mentioned specifically the So just as a general observation, we don't really view we don't view VEPTEG as having a neutropenia liability. There was some neutropenia or increased neutropenia, which is really [indiscernible] That was observed in combination with Palbo. And since then, we've shared data probably enough to give a very strong glimpse of safety for an EBEMA combination. And there was no signal of anything like this. So when it comes to DDIs, that whole concept is fading away and we that may have been been particular to PALBO's toxicity. In terms of what to expect in first line, well, we should note that that a terminal combined with AIs is already a Phase three study that that Pfizer has announced. So you can see that listed on clinicaltrials.gov.

That means that it's been presumably that it's been reviewed by health authorities and there's a willingness to let that trial go forward. So the safety profile of that and tolerability profile of the dose that was chosen was acceptable to health authorities. So in our case, we've now been dosing patients with We've been seeing a really attractive safety and early glen of efficacy look fine. So we're we're just planning to have those health authority discussions. Hyperglycemia is not a significant concern of ours right now. And we'll keep you updated, but as we've shared, the hurdles for us are just to reach agreement with health authorities about dose and schedule, which we don't think is a high bar. And then of course, we'll just update you on the trial design.

Great.

No, I appreciate the insight there. And my second one is in regards to the BCL 60 greater ARV three ninety three. Could you share your perspective on the potential efficacy and utilization of the PROTECT technology in comparison to Persim Myers Squibb's [indiscernible] [indiscernible] Degradation for B cell malignancies? And if your strategy has evolved or changed in response to any preliminary data that BMS has provided up to this point? There at the greater?

Yes, nice question. Yes, we're obviously aware of the BMS degrader. We haven't seen much in the way of data from that company. Our belief is our de grader is designed using our technology, our insights we have a belief that our technology and our program will be significantly better. We have to see how that looks going forward. But difficult to mention anything about the BMS degrader because we haven't seen much and we have data there. So we're very focused on our own program and moving that forward and taking that to the next stage.

Thank you. One moment for the next question. And our next question will be coming from the line of Ted Tenthoff of Piper Sandler. Your line is open.

Great. Thanks for taking the question everyone and excited for all the data this year.

Similar question to those asked earlier about kind of how the frontline treatment paradigm is changing But to the second line, [indiscernible] How are you guys seeing sort of the like with the surge in CDK4six upfront in first line, How are you seeing the second line treatment paradigm changing ahead of VEPTEG monotherapy data in VERTEC-two data? Thanks. Thanks, Ted. Great question. I'll hand straight over to Noah. Hi, Ted. So thanks for the question. So certainly there are changes in the treatment landscape. And the bigger trend is that Ribo is being used more and more in the first line setting and somewhat now in the adjuvant setting. And that's even more than ABEMMA. So and Palpo is used to stating there. So the question is what happens Is there use of CDK4six after CDK4six? [indiscernible] some. It's still limited, but in the second line setting, you would think that there would be much less use of of ribo. And the data outside of our experience with combining PALBO and VEPTEG there aren't great data out there for PALVO in the second line setting So there's probably some limit on the part of physicians about their interest in using that combination.

Or using Palpo after other CDK-four sixty inhibitors. So we're but what we do recognize in addition to those general trends is that there are accumulating data for the use of of drugs targeting the PI3K pathway. And that's having some impact. You've obviously seen some exciting data and we know they're a Phase three program that's that's been kicked off for CAT6 in the second line setting. So this is and that's combined with fulvestrant. There's a term mode that's combined with fulvestrant. So there are a bunch of drugs that are being combined with fulvestrant and we hope to do some practice informing work that will demonstrate how various drugs can be combined with VEPTEG in this setting and it will be up to physicians in the end whether they want to be using fulvestrant or they be wanting to use an oral agent in those types of settings and the data will will probably support will just in the end have to support whatever decision they make.

Okay, great. That's really helpful. I appreciate that color. I'm looking for data from the rest of Thanks, Ted.

And the next question will be coming from the line of Eli Morrow of UBS. Your line is open.

Hey, guys. Thanks for squeezing me in. Just in terms of the frontline setting for BevDAG, how are you thinking about potential enrichment strategies for patients who might be more with potential enrichment strategies for patients who might be more responsive to an oral SERD and your latest thinking on what the predictors are of which patients might develop an ESR1 mutation? And then I have a follow-up. Thanks. [indiscernible] [indiscernible] So, yes, so Eli, in the first line, we are not likely to be taking all comers in our study. So there are obviously some patients that have progressed rapidly in the adjuvant setting when they've been exposed to to AIs and standard of care now in these patients would be a CDK4six inhibitor plus fulvestrant. So those are not likely to be included in our study design. As for other enrichment strategies, we have a drug here that we believe degrades ESR-one wild type as well as ESR1 mutant. And so therefore should work very well in a broad population, ninety five percent of patients in first line, something in that range may have ESR1 wild type. So there's no thought of molecular enrichment there. One of the reasons that the first line study may work even better is because maybe we can prevent the evolution of ESR1 mutant clones by effectively suppressing the any clone that would develop because we degrade that as well.

So I don't think ESR1 mutant selection in any way is going to play into the study design. Beyond that, not much to add clinically.

We're happy to discuss that off line with you some more if you have some good ideas And then just a follow-up maybe just a broader strategic question. There's been a lot of focus on STAT6 as a target for degraders. But obviously, there aren't so many companies that have expertise in making degraders. What's your perspective on whether you might expand your focus to targets or say a target in the immunology space?

And just from like a platform perspective, what's the latest on how long it would take from say selecting a target protein to making a PROTAC development candidate?

Yes. Clearly, our focus over the last several years Ellie, as you know, has been oncology and neuroscience. There's been elements of immuno oncology that has brought in elements of immunology as well. So we're always aware of potential targets that we believe at the greater could drive differentiation. So we're not blind to that and we do look at things like that, but our major focus has been neuro and oncology. We continue to be that the foreseeable future. In terms of our approach to moving a target forward, is very dependent on what the starting points are. Clearly, we have abilities to move the Protag design forward fairly rapidly. To get to that point though, you need good starting point in terms of ligands. Against the target. So that is one of the big determinants of speed Do you have a high quality or a good quality ligand that binds to the target of interest? And when you have that, can move a program forward relatively fast because of our insight and then know how to apply the technology. So it's a fairly generic answer, but ligand discovery is an important piece to this early on. Angela, anything you want to add to that?

Yes, I just wanted to add it's great, John.

I just wanted to add some of the learnings that we've had over the past thirteen years that have been built into our platform technologies where we iteratively learn from some of the pharmacokinetic pharmacokinetic [indiscernible] in our molecules that lead to more rapid designs and accelerated movement through our pipeline. So With the constraints that John just defined, of course, building out our ligand capabilities is core to where we're focused now to tackle some of these underdrug targets And then just a point about the the immunology indications course. We are looking at some of our assets in some immune indications. So So BCL6 may play a role in innate immune disorders like MS and other disorders.

So preclinically, we're evaluating. And so we're keeping an eye open there. As well as, LARC two and its role in irritable bowel disease. And Parkinson's disease that may be extended based on some of the biomarkers that we're seeing move at least in preclinical studies. So I think there's a lot of opportunity and a lot of potential in our pipeline.

Understood. Thanks.

Sure.

Thank you. One moment for the next question. And the next question will be coming from the line of Paul Choi of G. S. Your line is open.

Hi, thanks and good morning and thanks for taking our questions. I had just a couple of quick ones on ARV393. Can you maybe just comment on what you'd like to see from your initial clinical data in patients that's coming up later this year to think about potential expansion into the into the post stem cell population.

Or maybe other subpopulations such as the elderly who are traditionally too fragile for standard of care such as our CHOP.

And second, can you just confirm if that initial Phase one data will be either be EHA or ASH? Any clarity there would be great. Okay. Thanks, Paul. Noah here. So we Well, we're not giving guidance as to when we're presenting this. It's a bit far off still and obviously we're also still enrolling patients in this Phase one. In terms of trying to go back, did you say something about [indiscernible] Stem cell. Can you just repeat that for me, so Yes. Post transplant populations, yes. Or or elderly populations who are traditionally too fragile for our CHOP. [indiscernible] So that gets into what's the that gets into study design issues, and opportunities. So we recognize that there are opportunities, there are limitations for our shop in large B cell lymphoma. I'm sorry, recognize that our CHOP in large B cell lymphoma may cure fifty percent of patients upfront. And so it's a preferred treatment. You also see policy being used with chip in this population increase. So that's become more of a standard of care. Yet there are patients that can't be addressed with those treatment options. And so your question, I guess, is can we make inroads in that population?

And we think of it, it's possible. We're showing good preclinical data for combination with anti CD20 therapy. That would be a thought of how to bring this forward. But overall, we'd be looking at and then you referred to the post transplant patients.

So I guess you're talking whether it's an autologous transplant or a bis with bispecifics or with CAR T. And I think it's premature to comment on those populations on one hand.

That's no doubt that's where there's the most significant unmet medical need. But those patients also have very severe disease or rapid progressors and are challenging population to look at as your first indication. So it depends on the data that we continue to accumulate. In our Phase one study. But I think there's some inevitability to combinability or to combining our three ninety three with other agents, whether it's an anti CD20 therapy bispecific or otherations in these advanced late line settings. As a start and then obviously moving two combinations in second line and even hopefully first line.

And then if I could just add to that, the There are key opinion leaders who have collected post CAR T refractory lines that we are taking a look at pre clinically just to assess how ARB-three ninety three performs in that setting. Specifically. So I think more to come.

Okay, great. Thank you.

Thank you. One moment for the next question please. And the next question comes from the line of Michael Schmidt Guggenheim?

Hey, good morning. I'm sorry. A couple more on web deGustrand.

Are you planning to present any of the Veritax three lead in data with PARBO this year? And are there any learnings in terms of efficacy from that experience that can perhaps be applied to the the planned Phase three study with a tiramuciclib for Veritec two, as we are trying to contextualize Lilly's Enbirth data from last to December perhaps relative to the post Monarch data from ASCO, what is your base case assumption for PFS in the vivestrant control arm in ITT and ES1 mutant for that study. Thanks, much. Thanks, Michael.

Yes, recent to our SLI, as some point, we haven't guided. We'll be sharing that data. Clearly, we've moved to the point where a ternociclib is the combination partner of choice in our first line setting. In terms of having informed that decision, it was probably lower lower ranking in terms of the decision making. Clearly, we made the decision at Temer on the entirety of the data we got through the SLI plus the data we've seen with the at termol VETDEG combo. So we're very happy with that decision making. But at some point, once we get past this next big dataset, we'll be talking about when the next data sets will come out and potentially including that SLI. Again, the question related to Veritak, we're really not answering any question As we said in the beginning, related to Veritak and I know that's a very frustrating scenario for the for people on this call. We we're so close to the data set. And once that data set comes in, all questions will be answered.

Thank you. This does conclude the Q and A session for today. I would now like to turn the call back over to John Houston for closing remarks.

Well, thank you, operator, and thanks to everyone for joining us and all the great questions. As you can expect, we're really pleased with our execution and progress in 2024. And we look forward to a very exciting 2025 So thank you for your time this morning and have a great day.

Thank you all for joining today's conference call. You may now disconnect. [indiscernible]