Q4 2024 Arvinas Inc Earnings Call
Speaker Change: Good day, and thank you for standing by. Welcome to the Arvana's 4th Quarter 2024 Earnings Conference Call.
Speaker Change: At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you'll need to press star 1-1 on your telephone.
Speaker Change: You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 1 again. Please be advised that today's conference is being recorded. I would now like to turn the conference over to your speaker for today, Jeff Boyle. Please go ahead.
Jeff Boyle: Good morning, everyone, and thank you for joining us. Earlier today, we issued a press release with our fourth quarter and full year 2024 financial results, which is available in the investors and media section of the website at arvinas.com.
Jeff Boyle: Joining the call today are John Houston, our business's Chief Executive Officer, President, and Chairperson, Noah Berkowitz, our Chief Medical Officer, Angela Tkasey, our Chief Scientific Officer, and Andrew Saik, our Chief Financial Officer.
Jeff Boyle: Before we begin the call, I'll remind you that today's discussion contains forward-looking statements that involve risks, uncertainties, and assumptions. These risks and uncertainties are outlined in today's press release and in the company's recent filings with the Securities and Exchange Commission, which I urge you to read.
Jeff Boyle: Our actual results may differ materially from what is discussed on today's call.
Jeff Boyle: And now I'll turn the call over to John Houston, our CEO, President, and Chairperson. John?
Jeff Boyle: Thanks, Jeff. Good morning, everyone, and thank you for joining us this morning.
Jeff Boyle: 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 III top-line data results, expected later this quarter, and first-in-human data from our first PROTAC targeting neurodegenerative disease.
Jeff Boyle: 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.
Jeff Boyle: 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.
Jeff Boyle: Today, I'll begin with a brief overview of our VENUS, our ProTag Discovery Platform, and an update on our pipeline. Noah will then provide an overview of our VepDegestrin, or VepDeg, clinical program,
Noah: including reviewing the phase 3 VERTAC-2 trial and also provide an update on our first neuroclinical program with ARV-102, our LARC-2 degrader.
Noah: Angela will provide an update from our earlier stage programs, including our BCL 6 degrader, ARV393, and our KRAS G12D degrader. 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.
Noah: 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.
Noah: Our innovative PROTAC platform has enabled us to create a deep pipeline while making significant breakthroughs in targeted protein degradation.
Noah: These breakthroughs include designing degraders with drug-like properties that are orally bioavailable and, when needed, able to cross the blood-brain barrier.
Noah: VET-DEG is the most advanced program in our pipeline and in addition to our ongoing phase 3 monotherapy trial, our current development plan includes two additional phase 3 combination trials across the first and second line settings in metastatic breast cancer.
Noah: GADG is an oral protact protein degrader specifically designed to target and degrade the estrogen receptor for the treatment of patients with ER positive HER2 negative breast cancer
Noah: Together with Pfizer, we are developing VET-DEG with the 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 VERITAC-2, our first ever phase 3 trial.
Noah: Data from this phase 3 clinical trial will be an important milestone for our adventists 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.
Speaker Change: 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 Veritac II during the Q&A portion of our call.
Speaker Change: Last month, we announced updates to our clinical development plans for vet-veg combination trials in the first and second line settings, pending emerging data and health authority feedback.
Speaker Change: In the first line, we announced that in 2025, we intend to initiate a phase 3 trial with VepDeg plus Pfizer's novel investigational CDK4 inhibitor, Atermocyclib.
Speaker Change: In the second line, we announce that we plan to initiate a phase 3 combination trial evaluating VEPDEG with a CDK4-6 inhibitor, which we also expect to initiate in 2025.
Speaker Change: Beyond VET-DEG, we have a data-rich year ahead, and we believe there are exciting opportunities for PROTACs across oncology and neuroscience. In April, we plan to present the first in human data from ARV102, a LARP2 degrader, which we believe will highlight the potential value our PROTAC degraders can offer to patients with neurodegenerative diseases.
Speaker Change: Additionally, in 2025, we plan to share preliminary data from our Phase I trial with ARV393, our BCL6 degrader, in patients with non-Hodgkin lymphomas.
Speaker Change: And finally, we are in track to file an investigational new drug application for our KRAS G12 degrader this year.
Speaker Change: I'll now turn the call over to Noah for an overview of the VET-VEG and ARV-102 programs. Noah?
Noah: Thanks, John, and good morning everyone. Last year, together with Pfizer, we made great progress with our VEPDEG program.
Noah: As John mentioned, in addition to sharing top-line results from Veritec2 later this quarter,
Noah: We intend to initiate two new phase 3 combination trials in the first and second line settings later this year.
Noah: We continue to believe VEPTEC has the potential to demonstrate superior efficacy and tolerability and become a best-in-class ER-targeting backbone therapy preferred by physicians and their patients.
Noah: Given the proximity to the upcoming top-line data readout, I won't spend too much time discussing the VERITEQ-2 trial, which if successful, could result in a submission of a new drug application and the first-ever regulatory approval of a protac degrader.
Noah: Recall, the VERITEC-2 clinical trial is evaluating the efficacy and safety of VEPDEG compared with Sylvestrin.
in patients with ER-positive, HER2-negative advanced breast cancer.
Noah: who have previously received and progressed on a combination of CDK4-6 inhibitors and endocrine therapy.
Noah: Important progress has been made in the treatment of patients with metastatic breast cancer who have progressed after receiving prior treatment with the CDK-46 inhibitor. Yet, there is an ongoing need for improvement in treatment.
Noah: An oral agent approved a few years ago for patients with ESR1 mutations only managed to extend median PFS a few months to 3.8 months.
Noah: This highlights the unmet medical need among patients with advanced metastatic breast cancer and the potential opportunity for Vepdegastrant in the VERITEC-2 trial. VERITEC-2 has two primary endpoints.
Noah: PFS and the ITT or intention to treat population and PFS and the ESR1 mutation subpopulation.
Noah: The study also has secondary outcome measures that include overall survival, anti-tumor activity including objective response, duration of response, and clinical benefit rate, and of course there are safety and quality of life assessments.
Noah: It is worth noting that events determining PFS will be assessed by blinded independent central review.
Noah: We expect to announce the outcome of Veritech II in a top-line press release in Q1, and to present full results at a medical congress in 2025, where we also intend to host an investor call.
Noah: In addition to anticipating VERITEX-2 results, we are pleased to be progressing our plans to initiate registration trials, evaluating DepDeg combinations.
Noah: Later this year, we plan to initiate a first-line Phase III trial of VEPT-EG in combination with Pfizer's novel investigational CDK4 inhibitor, a termocyclin, pending emerging data and health authority feedback.
Noah: The decision to prioritize VEPTEC plus the termocyclin in the first-line setting
is based on the totality of evidence.
Noah: from the ongoing Phase 1b2 Taktiv-K combination trial, evaluating VEPDEG plus the termocyclid in the late-line setting, and our trials evaluating VEPDEG plus palvocyclid.
Noah: This evidence, in addition to shifting treatment paradigms for early and advanced breast cancer, gives us the confidence that VET-DEG plus a termocyclid is the best combination to advance as a potential new treatment option in the first-line setting.
Noah: We in Pfizer are excited by the potential this combination represents for a new treatment option in this setting.
Noah: Our plans also include initiating second-line Phase III combination trial of VEPDEG plus a CDK4-6 inhibitor in 2025, pending emerging data and health authority feedback.
Noah: Compelling efficacy signals have been shared previously for VEPTEG in combination with Pelvocyclib or with Abemocyclib in the second line plus setting.
Noah: In December 2024, we presented preliminary data from 16 patients in the Phase 1b combination trial of VEP-DEG and Abema-Cyclib at the San Antonio Breast Cancer Symposium.
Noah: This combination demonstrated encouraging clinical activity with a clinical benefit rate of more than 60% and an overall response rate of nearly 30% in patients previously treated with the CDK4.6 inhibitor.
Noah: 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 VEPBG had no clinically meaningful effect on the bemacyclib exposure.
Noah: The combinability of VEPDEG was also supported by a phase 1 pharmacology trial of VEPDEG, which demonstrated that DDI potential is not a concern for the ongoing clinical development of VEPDEG as a backbone ER therapy.
Noah: We look forward to initiating the second line phase three combination trial later this year, pending emerging data and regulatory feedback.
Noah: In totality, the data we have generated continue to support our belief that VEDDEC has the potential to provide superior efficacy and tolerability, both as a monotherapy and in combination, for patients with metastatic breast cancer who need new treatment options.
I'm now going to turn to our neuroscience clinical program.
Noah: Our most advanced neuroscience PROTAC, ARB102, is a novel oral PROTAC designed to cross the blood-brain barrier and target leucine-rich repeat kinase 2, or Mark 2.
Noah: LRRK2 is a large multi-domain scaffolding kinase genetically implicated in progressive supernuclear palsy and Parkinson's disease.
Noah: Preclinically, we have shown that ARB102 crosses the blood-brain barrier and achieves deep brain region penetration and degradation of LRK2 in non-human primates.
Noah: We've also observed differentiation from inhibitors by showing improved effects on lysosomal dysfunction and movement of disease relevant biomarkers in the central nervous system in preclinical studies.
Noah: In 2024, we initiated dosing in a first-in-human Phase I clinical trial of ARV-102 in healthy volunteers.
Noah: This ongoing Phase 1 trial was primarily designed to establish the safety of ARB 102, but it will also measure LRK2 degradation in the periphery and in the cerebrospinal fluid, or CSF, of patients.
Noah: to establish the ability of ARV-102 to cross the blood-brain barrier and degrade LRK2 in humans.
Noah: 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.
Noah: These data confirm that ARV-102 is orally bioavailable in brain penetrant with dose-dependent exposure in the CSF.
Noah: 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.
Noah: The learning from this Phase I trial will be valuable as we strive to address the incredibly high unmet medical need in neurodegenerative diseases.
Noah: We intend to explore the potential of ARV-102 in two severe neurodegenerative disorders that are linked to BARK2 dysregulation.
Noah: The first is progressive supranuclear palsy, in which LRK2 mutations are strongly linked with faster-progressing disease. And the second is Parkinson's disease, in which LRK2 has been shown to contribute to disease pathology.
Noah: We recently initiated a Phase I ascending dose trial of ARV-102 in patients with Parkinson's disease and expect to complete enrollment and present the initial data from this study later this year.
Noah: It should be noted that we also plan to initiate a multiple ascending-dose cohort in patients with Parkinson's disease later this year.
Noah: Now I'm going to turn it over to Angela, who will talk about ARV393, our BCL6 degrader and our KRAS G12D degrader. Angela?
Angela: Thanks Noah, and good morning everyone. The preclinical profile of ARV393, our oral PROTAC, designed to degrade B-cell lymphoma 6 protein, or BCL6, has been highly positive.
Angela: For background, BCL-6 is a transcriptional repressor and a major driver of B-cell lymphomas.
Angela: terminal differentiation, apoptosis, and the DNA damage response, which becomes dysregulated in several types of non-Hodgkin lymphomas.
Angela: PROTAC-mediated degradation has the potential to overcome the historically undruggable nature of BCL-6.
Angela: ARV393 has a differentiated preclinical profile. It potently and rapidly degrades BCL6 protein, which is critical to overcoming BCL6's rapid resynthesis rate and sustaining anti-tumor activity.
Angela: ARV393 has demonstrated significant anti-tumor activity in numerous preclinical in vivo models of non-Hodgkin lymphoma.
Angela: We plan on presenting ARV393 pre-clinical data at the American Association for Cancer Research Conference in April.
Angela: These data show the promise of ARV393 as a monotherapy in angioimmunoblastic T-cell lymphoma patient-derived in vivo models.
Angela: Additionally, we will show ARV393 in combination with standard of care biologic agents and small molecule inhibitors in high-grade and aggressive DL-BCL in vivo models.
Angela: We have made significant progress in enrolling patients with non-Hodgkin's lymphoma in a phase 1 clinical trial of ARV393 and look forward to sharing initial data this year.
Angela: As a final note, we remain on track to file an investigational new drug application this year for our KRAF G12D degrader.
Angela: KRAS is a driver oncogene in several major tumor types and is associated with poor prognosis and resistance to standards of care.
including pancreatic and colorectal cancers.
Angela: Our degrader forms a ternary complex with both the active and inactive states of KRS-G12D.
Angela: This PROTAC-induced binding event results in the elimination, rather than the inhibition, of K-RAUS G12D. In addition, our K-RAUS degrader is at least 30-fold more potent in vitro than an inhibitor currently in the clinic.
Angela: I look forward to updating you on our progress with KRAS G12D and other promising degraders that are in discovery at Arvinas in the coming months. With that, I'll turn the call over to Andrew. Andrew?
Andrew: Thanks, Angela, and good morning, everyone. I'm pleased to share financial highlights for the fourth quarter and full year end of December 31st, 2024. As a reminder, detailed financial results for the fourth quarter and year end are included in the press release we issued this morning.
Andrew: As we move into 2025, we are in a strong financial position, with cash on hand sufficient to support operations into 2027.
Andrew: At the end of the fourth quarter, we had just over $1 billion in cash, cash equivalents, and marketable securities on the balance sheet, compared with $1.3 billion at the end of 2023.
Andrew: Our strong balance sheet will allow us to advance all of our key strategic objectives, which include progressing with Update Clinical Program, preparing for our first commercial launch, and developing our promising portfolio of earlier-stage protact degraders.
Andrew: Let me now turn to the fourth quarter and full year 2024 financial highlights.
Andrew: During the quarter, we recorded $59.2 million in revenue compared to a negative $43.1 million in revenue for the same period of 2023.
Andrew: The increase of $102.3 million 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 2023.
Andrew: We recorded $263.4 million in revenue for the year compared to $78.5 in the prior year.
Andrew: General and administrative expenses were $34.1 million in the fourth quarter, compared to $27 million for the same period of 2023.
Andrew: The increase of $7.1 million was primarily due to developing our commercial operations of $2.6 million, personnel and infrastructure related costs of $2.2 million, and professional fees of $1.8 million.
Andrew: G&A expenses were $165.4 million for the year compared to $100.3 million in the prior year.
Andrew: Research and development expenses were $83.3 million in the fourth quarter compared to $95.2 million for the same period of 2023.
Andrew: The decrease of $11.9 million was driven by a net decrease of $9.9 million in external expenses primarily related to the out-licensing of ARV 766.
Andrew: For the year ended December 31st, 2024, R&D expenses were $348.2 million compared to $379.7 million for the prior year.
Andrew: We are well capitalized as we move into 2025 with the potential for an exciting milestone-rich year beginning with our first phase 3 top-line results expected later this quarter for VeriTech 2.
Andrew: For ARV-102, our first degrader targeting neurological disease, the presentation of first in human data in April is another important milestone for the company.
Andrew: 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.
Andrew: We also look forward to sharing data from the Phase I study of our BCL6 degrader ARV393 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. John?
John Houston: 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 3 VERITAC-2 trial and advance our promising pipeline of protein degraders.
John Houston: As we prepare for our first phase 3 data readout, the first ever for a ProTag, the excitement here at Ardvinas is palpable.
John Houston: I want to thank our dedicated team for working tirelessly and enthusiastically to bring this potential new medicine to patients.
John Houston: 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 today without their collective efforts.
John Houston: I also want to thank our shareholders for 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&A portion of our call. Jeff?
Jeff Boyle: 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 VERITEC-2 trial or providing additional guidance on our expectations for data at this time. So with that, operator, will you please open up the queue?
Speaker Change: Thank you. As a reminder if you would like to ask a question please press star one on your telephone. We also ask that you please wait for your name and company to be announced before you proceed with your question. One moment while we compile the Q&A roster.
Speaker Change: Our first question today will come from the line of Derek Ortella of Wells Fargo. Your line is open.
Derek Ortella: Hey, good morning, and thanks for taking the questions. Just one, in terms of just the TACTVU cohorts that you'll be reading out this year,
Speaker Change: Think about the cadence of that data across, you know, different medical meetings and ultimately are you waiting for that data to really decide on the second line, you know, CDK4-6 combo. Thanks.
Speaker Change: Thanks, Derek. I'll hand over directly to Noah and he can answer that.
so those agents include
a CDK-7 inhibitor, ribocyclib.
Speaker Change: combination. Those data continue to mature. We haven't shared information for the other two yet.
Speaker Change: We haven't offered guidance about when we will share the specific updates of these, but the hope is that, you know, as data mature, we can be sharing more. As to the question about whether or not...
This will determine the choice of...
Speaker Change: CDK4-6 inhibitor that's combined with ZepDeg. We think at this point we've established that ZepDeg combines very nicely with Palbo and combines with Abemacyclib.
Speaker Change: 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 detail on that right now, but we hope that we can give updates in the next few months.
Speaker Change: Understood. And if I can squeeze one more on LARC2, just in terms of what you plan to share for the SAD, I guess, you know, what level of degradation, you know, do you find to be therapeutic in kind of the preclinical setting and how will that translate to the human setting? Thanks.
Speaker Change: Yeah, Angela, do you want to answer that question? Certainly, thanks for the question, Derek. So, based on preclinical data that's been published by
you know, many others.
showing that 50% reduction of the
Protein
Speaker Change: is disease-modifying in certain contexts including in the context of alpha-synucleinopathies as well as tauopathies.
Speaker Change: So those data are published. In addition, Human Genetics guide us, more recently, omics studies that.
relate to single-cell LRRK2?
Speaker Change: expression levels in the brain, in particular in microglia, that show that there's two-fold elevation in LRK2 expression in microglia, and this has been confirmed in iPSC-derived cells from Parkinson's disease patients.
Speaker Change: where there's overexpression of LRK2 in idiopathic Parkinson's disease. So, you know, we believe that we stand the best chance of testing the LRK2 hypothesis by reducing LRK2 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.
Speaker Change: And our next question will be coming from the line of Jonathan Miller of Evercore. Your line is open.
Jonathan Miller: Hi guys, thanks so much for taking my question. I guess since we just had a question on the phase 3 and the second line gating factors, I'll ask on 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 Attack2K 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.
Yeah, great question.
and Laura. Thank you. Thank you.
Thanks, John. So, thanks for the question, John.
Jonathan Miller: Overall, you know, as we've shared, we plan to combine VEPT-EGG with the termocyclib in the first line.
Jonathan Miller: And this is based on the totality of evidence that we have in which we've assessed what we could do with the termocyclib from an earlier data set in which we were looking at two different doses of the termo combined with PEPTEG-200.
and are now in the expansion part of that.
Jonathan Miller: and also reflecting back on PalboCyclib, how we did in our combination there. These were, you know, where we're looking in later line settings, but also in the first line setting. And overall...
Jonathan Miller: recognizing how there's a shift in the use of CDK4-6s in first line and palbocyclob is being used much, much less.
Jonathan Miller: and we see a great opportunity for a terminal in the future. As for what's gating, 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. We do not feel that we need at least six months of data to have this conversation with the health authorities.
Speaker Change: Great. And maybe if I can squeeze one more. I know you're not answering questions about Veritek 2, but could you talk to commercial preparations beyond what we assume is going to be a wonderful readout in a couple of weeks? How is your commercial prep going and what do you think ramp there needs to be to be ready for a launch?
Speaker Change: Yeah, clearly we've been focused on building the initial runway for a commercial organization. We have that in place.
all the other aspects of
Speaker Change: The different components for a launch are getting in place as well. As you know, we'll be launching with Pfizer.
Speaker Change: and we'll be the U.S. lead, so a significant amount of planning related to that. So, yeah, I'm very pleased with the progress getting made by the team and we're in good shape.
Thanks very much.
Thank you. One moment for the next question.
Speaker Change: And our next question will be coming from the line of Lee Waseck of Cantor. Your line is open.
Hey, good morning team and thanks for taking our questions.
Speaker Change: I wonder if you can just comment on VARI-Tag2, if it has any weight 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.
Speaker Change: Noah, do you want to at least talk about that part, about the potential influence?
Thank you.
Speaker Change: 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.
Speaker Change: I probably can't go into more details like that. We're in the process of going through, you know, our health authority preparation and discussion and also, you know, just continuing to evaluate maturity of data in the second line setting.
Speaker Change: Clearly very excited about seeing our first neuroscience neurodegenerative program moving forward.
Speaker Change: and we are well-placed to take LARC2 Degrader to a significant stage of development. We'll see in the future how the progress of the compound is, whether 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 and getting it to a significant milestone.
Thank you.
Thank you. One moment for the next question.
Speaker Change: And our next question will come from the line of Akash Tiwari of Jaffrey.
You're on. Thanks.
Akash Tiwari: Thanks so much. So, Faiz just previously mentioned that the decision to progress the Webdeck 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 to give an early take on CFS? And if not,
Akash Tiwari: What do you think response rate should be for both the first line and second line settings for your go-forward dose? And then on Veritech2, this isn't a timing question, but how concerned are you that a six-month prior ET requirement is not sufficient?
Speaker Change: to remove E.T. fast progressors and what percent of fast progressors you expect in your study versus what we saw with Lily. Thank you.
Thank you.
Speaker Change: For the second half of that question, again as we said at the beginning, we won't be answering any questions related to Veritac II. First half of the question...
Speaker Change: in terms of how much efficacy and safety data we'll be looking at.
It's, you know, decisions about going into first line.
Speaker Change: are mostly safety-driven. There's a, you know, we'll be looking at efficacy as well, but safety is the dominant deciding factor.
Speaker Change: second line plus setting from the phase one programs that we've that we've run.
Speaker Change: So mostly now it's just discussing whether or not the dose that we recommend is going to be acceptable with health authorities and, you know, continue 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.
Speaker Change: The next question will be coming from the Lana Tazine Lamott of Bank of America. Your line is open.
Speaker Change: Okay, I think that's me. So, maybe I have a couple of questions. The first one is on
metastatic breast cancer.
Speaker Change: What data do you think you'll need to show to give confidence to KOLs on the profile of that group?
and the termo.
Speaker Change: Just considering that, historically, they will have had a lot more experience with the other CDK inhibitors, like Ribo and Palbo, for example. And then I have a follow-up. Okay.
Noah?
Thanks. Yeah, thank you for the question.
Speaker Change: 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, you know, the hazard ratio that's being targeted.
Speaker Change: the other features of the statistical plan, but in general terms
Speaker Change: All the feedback we get is that investigators would want to see more than...
Speaker Change: you know, 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
Speaker Change: a generic competition a few years from today when when Palbo is generic and so if you view the the first line
Speaker Change: CDK-4-6 plus AI combination as delivering somewhere between 24 and 28 months of medium PFS, you'd want to see something in that range, five, six months better, to know that you have something special.
Speaker Change: Okay, got it. And then if I could ask a question on your KRAS degrader. Can you talk about how you think it might be differentiated given that this G1-2 degrader space is pretty competitive? You've got other companies like Astellas in the clinic and what would you want to see in order to move it forward?
Speaker Change: the Astellus molecule. We know we're 40-fold more potent than that Astellus degrader. It is encouraging that the Astellus degrader did show some efficacy at the higher doses, but was, you know, I think discontinued for issues.
due to safety.
based on the data that we've generated.
Speaker Change: We do believe that, in terms of the inhibitors in the G12D space, that we're very competitive.
in terms of a ternary complex, so very different.
Speaker Change: than an inhibitor, the degrader binds both. And we know that we're more potent in inhibiting cell proliferation and inducing cell death.
Speaker Change: We also disrupt the scaffolding functions that are known for G12D-K-RAS.
Speaker Change: and we have the potential for distinct and non-overlapping resistance mechanisms that we can impact.
Speaker Change: with G12 date. And beyond that we have some very compelling data in terms of some of the neoantigen profiles that we're producing that we know inhibitors do not.
Speaker Change: to, you know, to address efficacy before those come into play.
Great question, thank you.
Thank you. One moment for the next question.
and John Houston. Thank you. Thank you.
Speaker Change: The next question will be coming from the line of Deborah Oconda of Troost. Your line is open.
Deborah Oconda: Thank you so much for taking my question. My first question is on ARV393. Can you talk a little bit about...
Deborah Oconda: enrollment status for this program and whether there's any focus on a particular subset of NHL patients.
Speaker Change: And given the profile of the target, where do you think this might fit into the landscape, you know, with other targets like BTKs or BCL2?
Thank you.
and I have a follow-up.
Thank you.
That's a great question. Thanks for that.
Speaker Change: 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
Speaker Change: in terms of how this drug may differentiate itself. Well, first of all, it's differentiated in the sense that there are no BCL-6 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.
Speaker Change: 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.
Speaker Change: We view what you would see there is a lot of potential combinations that can open up the door to this, you know, orthogonal approach.
towards anti-lymphoma activity.
Speaker Change: One of the things that we're working out is to what degree do you need...
Speaker Change: 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 hasn't really demonstrated pre-clinically and in our top studies, evidence of real hematopoietic toxicity.
Speaker Change: 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, you know, anti-CD20 therapy, whether it's a single, you know, an antibody therapy, or if it's bispecifics.
Speaker Change: So lots of paths we can follow and the first step obviously is generating data about a maximum tolerated dose and then moving on to combinability.
Speaker Change: around the chief commercial officer leaving right before a key readout and potentially in a year or so before potential commercial rollout. Can you talk a little bit about it and help alleviate investor concerns about this? Thank you.
Speaker Change: Yeah, absolutely. Yes, our Chief Commercial Officer John Northcott, he had to leave, unfortunately, because of personal reasons, which I can't get into. Luckily for us, and us also through great planning, we had a second-in-line, highly experienced executive, Alex Santini, who has been able to step into the breach as our interim Chief Commercial Officer, and he's absolutely superb.
Speaker Change: So I can honestly say we haven't missed a beat. Alex has continued the game plan that was laid out by John, and the team's progressing really well. So it was unfortunate, but because we had such a great depth
Speaker Change: in terms of the leadership team there would be able to move on really quite easily.
Thank you so much.
Thank you. One moment for the next question.
Speaker Change: And our next question will be coming from the line of Jeet Murkidji of BTIG. Your line is open.
Jeet Murkidji: 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 102 later this year and are there any biomarkers you'd be looking for that would translate to functional improvements in these patients and I have a follow-up. Thank you.
Speaker Change: Thank you. Noah, let's start with you and then we can go to Angela. Yeah.
So...
just to put us on the same page.
Speaker Change: The first step is to demonstrate or to share what we've demonstrated in Healthy Volunteers and so this involves
Speaker Change: our understanding of PK PD, so understanding how dosing leads to, you know, what PK properties can be tracked in the periphery, but also in the central nervous system, you know, by virtue of what we see of drug in the CSF.
Speaker Change: And then, of course, there's PD, so what's happening to LARC2, again, in the periphery and, more importantly, in the CSF.
Speaker Change: And so we expect the first glimpse of those data at the Alzheimer's Disease Parkinson's Disease Conference.
Speaker Change: 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.
Speaker Change: And then we would next move to MADD 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, you know, and conference schedule, we hope we can share some update that would be at least sad, but we'll have to see how...
Speaker Change: how much data we can accumulate by the appropriate conference later in the year.
we've been able to conduct a discovery effort.
Speaker Change: around biomarkers that we think are LRRK2 driven based on published
Speaker Change: Parkinson's Disease Progression Initiative from the Michael J. Fox Foundation. So, you know, we're encouraged by our non-clinical data that suggests that we can move neuroinflammation endpoints as well as
Speaker Change: lysosome function endpoints. So it's promising and so we await getting toward the MAD portion of Parkinson's disease studies to assess this.
Speaker Change: Understood, that's helpful. And maybe a Veritac 2 question if you just wouldn't mind. You said you'd present full results at a medical conference. Would any abstract embargo rules potentially limit what you could say as part of a top line press release? Thanks.
Speaker Change: Yes, I think there would be, and we'll get more information as we get past that next stage.
Thank you. One moment for the next question.
Speaker Change: And our next question will be coming from the line of Brad Pacino of CIFL. Your line is open.
Good morning.
Speaker Change: Listening to the large pharma earnings, we should expect frontline phase 3 oral SIRT trials in combination with the CDK4-6 inhibitors from Roche and AstraZeneca this year. That's right around the time you and Pfizer will be kicking off the frontline VEP CDK4. How will Arvinas think about these results of the studies as they pertain to your frontline plan? Thank you.
Speaker Change: Yeah, thanks Brad. Yeah, obviously we're going to be very interested in the datasets coming from both those companies. Noah, do you want to say anything about additional to that?
Speaker Change: Sure, so thanks Brad. I guess the question can be will this impact
Speaker Change: standard of care and the feeling is that with the study
Speaker Change: That's going to launch this year and take less than a couple of years to enroll.
Speaker Change: It's not going to have, it's not likely to have impact on our ability, you know, on the operational feasibility of a study in any way. So, if anything, it's kind of just
Speaker Change: I guess the, you know, create some excitement in this area if there are some positive results.
Speaker Change: We also recognize at the end of the day that pro-tax are very different than CERDs because of our targeted degradation. So, whatever we see, we can, you know, our hope and...
Speaker Change: and expectation would be that we can see something stronger from a prototype.
Speaker Change: So, we're looking with anticipation, but recognize that it just creates opportunity.
Thank you.
Thank you. One moment for the next question.
Speaker Change: And our next question will be coming from the line of Sudan, Logan Nathan of Stevens. Your line is open.
Logan Nathan: Hi, good morning, and thank you for taking my questions here. And my first one will be on etiromyciclis, you know, in regards to that first line combination you're playing with, Deb Degg. You know, I think etiromyciclis is uniquely characterized, you know, by like a 20-fold and 4-fold increase in selectivity for CDK4 over CDK6, which I believe that probably helps with the neutropenia or any hematologic toxicities that may...
Logan Nathan: have showed up with like palsycyclic potentially, but here's to how you view the glucose metabolism component for CDK-4 involvement in that.
Logan Nathan: and how that may play out in the safety profile. And just even just your very, you know, broad view on, you know, what makes a PR myciclid in your view better, you know, than a polymyciclid, ribomyciclid or any of the other CDK46 inhibitors out there. And I can follow up.
Thanks Sudan, Noah. Sure, thanks.
And so you had mentioned specifically the neutropenia.
Logan Nathan: Just as a general observation, we don't really view VEPTEC as having a neutropenia liability. There was some neutropenia or increased neutropenia, which is really a palbo liability that was observed in combination with palbo.
Logan Nathan: And, you know, since then, we've shared data, probably enough to give a very strong glimpse of safety for an abema combination, and there was no signal of anything like this. So when it comes to DDIs,
Logan Nathan: That whole concept is fading away, and that may have been, you know, particular to Palbo's toxicity. In terms of what to expect in first line, well, we should note that a termo combined with AIs
Logan Nathan: is already a phase 3 study that that Pfizer has announced so you can see that listed on clinicaltrials.gov.
Logan Nathan: 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.
Logan Nathan: So in our case, we've now been dosing patients with VEPTA-Ganitermo in collaboration with Pfizer. We've been seeing a really attractive safety and early glimpse of efficacy look fine.
Logan Nathan: So 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.
Speaker Change: Great. No, I appreciate the insight there. And my second one is in regards to the BCL60 greater ARV393, could you share your perspective on the potential efficacy and utilization of the PROTAC technology, you know, in comparison to Bristol-Myers Squibb's BMS986458, I believe, which employs the ligand-directed degradation for B-cell malignancies. And if your strategy has evolved or changed in response to any preliminary data that...
Logan Nathan: You know, BMS has provided up to this point, but they're a bit greater.
Logan Nathan: Yeah, nice question. Yeah, 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 degrader is designed using our technology, our insights.
Logan Nathan: We have to see how that looks going forward, but it's difficult to mention anything about the BMS degrader because we haven't seen much in the way of 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.
Speaker Change: And our next question will be coming from the line of Ted Tintoff of Piper Sandler. Your line is open.
Speaker Change: Great. Thanks for taking the question, everyone. I'm 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 with
Speaker Change: How are you guys seeing sort of a, like with the CERDs and the CDK4-6 up front in first line, how are you seeing the second line treatment paradigm changing ahead of VEPDEG monotherapy data in VeriTec2 data? Thanks.
Speaker Change: Thanks, Ted. Great question. I'll hand it straight over to Noah. Okay. Hi, Ted. So, thanks for the question.
Noah: So certainly there are changes in the treatment landscape and, you know, 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 Abema so and Palbo's use is fading there. So the question is what happens is is their use of cdk4-6 after cdk4-6?
There's
Noah: Some, it's still limited, but in the second-line setting, you would think that there would be much less use of Ribo, and the data outside of our experience with
Noah: combining PALBO and VEFTEG, there aren't great data out there for PALBO 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 CDK4-6
Noah: So where 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.
Noah: And that's having some impact. You've obviously seen some exciting data, and we know there are phase three program that's been kicked off for cat six in the second line setting. So this is ...
You know, and that's combined with fulvestrant.
Noah: There's a term mode that's combined with fulvestrin. So there are a bunch of.
Noah: 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.
Noah: with VapDag in this setting, and, you know, it'll be up to physicians in the end whether they want to be using Fulvestrant or they'd be wanting to use an oral agent.
Noah: in those types of settings and, you know, the data will probably support, will just in the end help to support whatever decision they make.
Speaker Change: Okay, great. That's really helpful. I appreciate that color. I'm looking for data from the rest of the pipeline, too.
Thanks, Ted.
Thank you.
Thank you. One moment for the next question.
Speaker Change: And the next question will be coming from the line of Ellie Murrell of UBS. Your line is open.
Ellie Murrell: Hey guys, thanks for squeezing me in. Just in terms of the front-line setting for VEPDEG, how are you thinking about potential enrichment strategies for patients who might be more responsive to an oral CERD, 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.
Thanks, Ellie. Oh, sorry, I'll just let me have it.
Speaker Change: So, yes, so Ellie in the first line we are not likely to be taking all comers in our study
Ellie Murrell: So, there are obviously some patients that have progressed rapidly in the adjuvant setting when they've been exposed to AIs.
Ellie Murrell: And, you know, standard of care now in these patients would be a CDK-4, 6-inhibitor plus fulvestrant.
Ellie Murrell: 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-1 wild-type as well as ESR-1 mutant.
Ellie Murrell: and so therefore should work very well in a broad population.
Ellie Murrell: 95% 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
Ellie Murrell: prevent the evolution of ESR-1 mutant clones by effectively suppressing any clone that would develop because we'd degrade that as well.
Ellie Murrell: You know, 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. You know, I'm happy to discuss that offline with you some more if you have some good ideas.
and John Houston. Thank you. Thank you.
Speaker Change: Thanks. And then just a follow-up, maybe just a broader strategic question. There's been a lot of focus on stat six as a target for degraders.
Speaker Change: 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?
Speaker Change: 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?
Speaker Change: Yeah, clearly our focus over the last several years, as you know, has been oncology and neuroscience. There's been elements of immuno-oncology that has brought in elements of immunology as well.
Speaker Change: So we're always aware of potential targets that we believe a degrader 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 and it will continue to be that for the foreseeable future.
Speaker Change: In terms of our approach to moving a target forward, it's very dependent on what the starting points are. Clearly, we have abilities to move the PROTAC design forward fairly rapidly.
Speaker Change: To get to that point, though, you need good starting points 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, we can move a program forward relatively fast.
because of our insight and know-how to apply the technology.
Speaker Change: 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? Yeah, I just wanted to add, you know, that was great, John, I just wanted to add some of the learnings that we've had over the past, you know, 13 years.
that have been built into our platform technologies.
Speaker Change: where we iteratively learn from some of the pharmacokinetic, pharmacodynamic properties that we have.
Speaker Change: and our molecules that lead to more rapid designs and accelerated movement through our pipeline. So you know
Speaker Change: With the constraints that John just defined, you know, of course, building out our ligand capabilities is core to where we're focused now to tackle some of these under-drugged targets. And then just a point about the...
the Immunology Indications course.
Speaker Change: You know, we are looking at some of our assets and some immune indications.
Speaker Change: BCL6 may play a role in innate immune disorders like MS and other disorders. So pre-clinically...
Speaker Change: We're evaluating, and so we're keeping an eye open there as well as LRRK2 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.
Speaker Change: at least in preclinical studies. So I think there's a lot of opportunity and a lot of potential in our pipeline.
Understood. Thanks.
Check.
Thank you. One moment for the next question.
Speaker Change: And the next question will be coming from the line of Paul Joy of GS, your line is open.
Paul Joy: Hi, thanks and good morning. Thanks for taking our questions. I had just a couple quick ones on ARV393. Can you maybe just comment on, you know, what you'd like to see from your initial clinical data and patients that's coming up later this year to think about potential expansion into the post-stem cell population or maybe other subpopulations such as the elderly who are traditionally too fragile for
Paul Joy: standard of care such as RCHOP. And second, can you just confirm if that initial phase 1 data will either be at EHA or ASH? Any clarity there would be great. Thank you.
Okay, thanks Paul. Noah here.
Paul Joy: Well, we're not giving guidance as to when we're presenting this. It's it's a bit far off so and obviously we're also still enrolling patients in this phase one.
in terms of
I'm trying to go back, did you say something about...
Some of the
Speaker Change: stem cell? Can you just repeat that? Post stem cell? Yeah, post transplant populations. Yeah, or elderly populations who are traditionally too fragile for RCHOP.
Yeah.
So these, you know, that gets into what's the...
Speaker Change: You know that gets into study design issues and opportunities so
Speaker Change: We recognize that there are opportunities, there are limitations for RCHOP in large B-cell lymphoma. I'm sorry, we recognize that RCHOP in large B-cell lymphoma may cure 50% of patients up front.
and so it's a preferred treatment. You also see
policy being used with
Speaker Change: chip in this population increase. So that's become more of a standard of care.
Speaker Change: Yet there are patients that can't be addressed with those treatment options.
Speaker Change: 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 a combination with...
Speaker Change: with anti-CD20 therapy, that would be a thought of how to bring this forward.
but overall where we'd be looking at
Speaker Change: 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 medical need, but those patients also have very severe disease or rapid progressors and are a challenging population to look at as your first indication. So it depends on the data that we continue to accumulate in our phase one.
Speaker Change: I think there's some inevitability to combinability or to combining our 393 with other agents, whether it's an anti-CD20 therapy, a bispecific, or other agents in these advanced late-line settings.
Speaker Change: as a start and then obviously moving to combinations in second line and even hopefully first line.
Speaker Change: And then if I could just add to that, 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 ARV393 performs in that setting specifically. So I think, you know.
More to come.
Okay, great. Thank you.
Thank you. One moment for the next question, please.
Speaker Change: And the next question is coming from the line of Michael Schmidt of Guggenheim. Your line is open.
Michael Schmidt: Hi, good morning. I'm sorry. A couple more on WebDagastrand. Are you planning to present any of the VeriTag 3 lead-in data with Parbow this year and are there any learnings in terms of efficacy from that experience that
Michael Schmidt: can perhaps be applied to the design of the planned Phase III study with a thermocyclip.
Michael Schmidt: And then for Veritech2, as we are trying to contextualize Lilly's EMBR3 data from last December, perhaps relative to the post-Monarch data from ASCEL, what is your base case assumption for PFS in the full vestibular control arm in ITT?
and he is a one mutant subset for Ploetz.
and Ari. Thanks so much.
Thanks, Michael.
Michael Schmidt: Yeah, in relation to our SLI, at some point, we haven't guided, we'll be sharing that data. Clearly we've moved to the point where a termocyclib is the combination partner of choice in our first-line setting. So in terms of having informed that decision, it was probably lower ranking in terms of the decision-making.
a big goal.
through the SLI Plus.
Michael Schmidt: the data we've seen with the Aeternal WebDAG combo. So we're very happy with that decision making, but at some point, once we get past this next big data set, we'll be talking about when the next data sets will come out, and potentially including that SLI.
Michael Schmidt: Again, the question related to Veritac, we're really not answering any questions, as we said at the beginning, related to Veritac and I know that's a very frustrating scenario for the people on this call, but you understand we're so close to the data set and once that data set comes out, all questions will be answered.
and John Houston. Thank you. Thank you.
Thank you.
Michael Schmidt: Thank you. This does conclude the Q&A session for today. I would now like to turn the call back over to John Houston for closing remarks. Please go ahead.
Michael Schmidt: 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.
Michael Schmidt: Thank you all for joining today's conference call, you may now disconnect.
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