My name is Akash Tiwari, I am a farm and biotech analyst here and we have the Arvinas management team. John, I'm gonna hand it off to you for some. I think you have some slides you want to present and then we'll get started with the Q& A.
Yeah. Thanks for being here. I thought I'd start just by setting the scene around Arvinas and giving a little bit of background of where we are today. Forward looking statements. Arvinas is focused on protein degradation. We were the first company in this space, founded in 2013 by Craig Crews at Yale University. Through the last several years we've hit a number of firsts for the technology and the platform. First to get INDs and programs, first to get into phase I, first into phase II, and most recently the first company in the space to get a PROTAC all the way through pivotal trials with positive data. It's been a world leader in the space of protein degradation since its beginning.
You can see protein degradation as a kind of almost like standard technology used across a number of different companies in big pharma. The reason for that are the benefits you get with protein degraders. I put some of them here, the most specific being the elimination of the protein through hijacking the cell's natural protein degradation system. Very different from inhibition which is occupancy driven. Any protein that sits in a scaffold, if you get rid of the targeted protein from that scaffold, it can also impact signaling. You get a very profound effect. PROTACs are catalytic or iterative. Once the protein is dropped at the proteasome, the PROTAC is released and you can do multiple rounds of degradation. Again very uniquely different from an inhibitor. Of course we make compounds orally bioavailable.
You get broad tissue distribution so you act back very much like a normal small molecule. You can have mutant or wild type specificity and because the small molecules are slightly larger than average small molecules, but small molecules nonetheless, manufacturing and routes of synthesis are just normal. Great benefits for PROTACs in general. We're starting to see that in the clinic, not just from Arvinas, but many other companies. The benefits in oncology, we believe you can see the ability of a PROTAC to overcome evolving resistance mechanisms. We're able to target classically undruggable targets as well. We've made almost all of PROTACs orally bioavailable. On the neurodegeneration side, really excitingly, we've made PROTACs that are blood brain barrier penetrant. You don't have to worry about IM, IV, or intrathecal dosing in those spaces.
We also see biodistribution into deep brain regions and that's encouraged us as we move forward with our neuroscience portfolio. This is the portfolio we have today. It has been dominated very recently by vepdegestrant, our ER degrader, which is in partnership with Pfizer. A 50/50 co-development, co-commercialization. We just had our pivotal trial data over the weekend at ASCO and I'll touch on that for a second. We have a number of trials that are ongoing in the first phase I, phase II and we can discuss what's happening with the Pfizer collaboration shortly. Behind that we have a number of programs that we're very excited about. ARV-393, our BCL6 degrader, our first in the B-cell lymphoma space.
In neuroscience we have a LRRK2 degrader, ARV-102, we have just finished the SAD/MAD in healthy volunteers and we also have a cohort in Parkinson's disease patients. ARV-806, a KRAS G12D degrader, just passed its IND and will be in the clinic very shortly. Behind that we have two other programs not named here that have just become clinical candidates and should be in the clinic in about a year. Of course, I do not want to forget the AR degrader luxdegolutamide, which we out-licensed to Novartis last year and that seems to be progressing very well by all accounts. Just touching on vep, as I said, we had our pivotal data. It is clear that further treatment options are needed for the 20,000 patients in a second line setting that appear every year.
The VERITAC-2 results show that we have a five month median PFS in the ESR1 mutant group and that gave a robust 2.9 month improvement over fulvestrant. Fulvestrant is an IM injection, PROTAC is an oral drug and it added this 2.9 month increase in PFS. Now, we believe that novel mechanism of action differentiates it from other targeting therapies and that novel mechanism of action also looks good in terms of its safety tolerability. We're on track with Pfizer to submit the NDA very shortly and keep moving forward with submissions in the rest of the world and planning for, if approved, planning for a launch in 2026. These are some of the key events that are coming up this year, as I mentioned, we've already had the VERITAC-2 data. The NDA is imminent with 102.
We'll have data from our SED cohort in the second half of this year. We'll be initiating the phase I MED cohort with PD, with PD patients in the second half. With the BCL6, we'll have preclinical combination data with our ARV-393 and present the initial phase I data in the second half of this year as well. Finally, with 806, initiating that phase I trial very shortly. We're in a very strong capital position, just under $1 billion cash on hand and a runway into second half of 2028. The next several months will be a really important transition point for the company as we move this next cohort of programs forward into the clinic and beyond. Thank you.
Alrighty. So, you know, let's start with maybe the Pfizer partnership, strategically where you are and how to think about this because, you know, the way I think we kind of see it right now you have the serious data, it's going to be hard to implement in a real world setting. You know, getting the ctDNA measured all the time. I don't know if there's any other place in a first line setting right now where I can feel reasonably confident that, you know, a SERD is going to work because it's obviously standard care is really difficult. So I'd love for your team, what areas outside of the ESR1 in kind of a late line setting are you interested in exploring with vepdeg? Is it second line in combination with CDK4/6, which I think could be interesting, or a tirmo? Is it in an adjuvant setting?
Where do you feel like there is some white space here?
Yeah. So talking about the deal with Pfizer initially, when we, when you did that, when we did that deal in 2021, we were focused on a platform of adjuvant first line combination with palbociclib and then the second line monotherapy study. Things evolved over the last few years and now we're left in a situation where it's only a second line monotherapy. From one point of view, that's not as much value as we initially thought, either for us or for Pfizer. There's an opportunity for us to look at that collaboration and see whether or not there's a way forward where one of the companies gets more economic value out of vep. That's one piece which is ongoing, which is the evolving relationship with Pfizer and seeing if we can change that collaboration. The second piece no one can talk to as well.
Clearly we believe vep has an opportunity still in the second line space. It's a second line monotherapy. We've got a number of nice data points in the second line setting. In combination, we saw that with Palbociclib, we showed some data last year with abemaciclib. We've got an ongoing study with atirmociclib in the second line and Pfizer just added it to a CAT6 study in the second line. There is a set of data either already or coming out that should explore and exemplify vep's ability to be combined well in a second line setting. Above and beyond that, the first line I think is an area where vep could work. I think there is a kind of a relative disbelief right now that can you work against wild type? The second line data showed that maybe you couldn't.
Of course, in the first line setting we believe patients there have tumors that have wild type that is endocrine sensitive. So a drug like vep should work. The real test of that, I think one of the first tests will be the data that comes out from Roche on giredestrant. That's in a first line study, that's a SERD that we think our compound looks much better than. If you saw good positive data from that study, that would encourage vep to be put into that first line setting. Having said all that, we're very cognizant of the fact of what the market is telling us in terms of where our stock price is. We are very focused on making sure that vep gets the right value going forward and the right positioning, either with Pfizer or us or somewhere else.
I do think there's a significant opportunity for the development of vepdegestrant, and maybe, Noah, broadly, you can talk to that.
Sure. Thanks, John. And thanks for the question, Akash. I think you heard from John. We have belief that in the adjuvant setting and in the first line setting, in that case combination with CDK4/6 is which is standard of care, there's no reason to think this drug that degrades estrogen receptor as well as mutant estrogen receptor should be able to have a role. Now, we as a small company are not going to run such a registration program. The idea right now is, you know, and I think it was summarized to just run as many practice informing studies as we can. Yeah, and that's where we stand. We have, we'll have more mature data for the ABEMA combination. We'll have a first disclosure of an atirmo combination at some point.
Eventually we'll have some Cat 6 data and we'll see things were evolved eventually possibly for PI3- kinase combinations.
Got it. By the way, John, you mentioned something that's very provocative, which was it could be the nuance of endocrine sensitive and then wild type and non wild type and there might be a nuance between that which I want to hit on in a bit. Let's just stick on the Pfizer partnership. You know, here's the way I kind of see it. Pfizer has a huge breast cancer franchise. This is a plug and play drug for them. It goes straight to the bottom line. Right. I would not be surprised. You have, I would say, less diarrhea than the Radius drug. I think you have similar data when it comes to efficacy that you could have this quickly become, let's say, a $500 million, a $700 million opportunity. You're splitting that in half.
That's a big deal for a company with, you know, with your longer term ambitions. Here's kind of my thought process. Number one, there's two card flips. You don't have that CDK4 data, which I think is a huge deal because again that might inform what's going on in a second line setting. Number two is your NDA filing and frankly number three is the Cat 6 combo data. What's the rush on renegotiating anything with Pfizer until you have some of those card flags? Do you think that there could be a change in the Pfizer partnership? You mentioned that pretty openly here. Is that decision going to be made before let's say CDK4 data or NDA submission?
Yeah, I mean I think Pfizer have made their decisions pretty clearly. The ones that didn't want to go forward with either the two. Phase III is the second line combo with the CDK4 or the first line combo with the atirmociclib . They've been great partners. We really like working with them. We disagree with the decision on the first line. I think vep would have had a really good chance of showing activity in that first line setting. They’ve clearly stated they no longer want to develop vep. I think when they made the decision not to go into first line, whatever level of value driver vep had plummeted. And whatever ranking they did in their portfolio assessment, that may have been up at the top 10, but then it drops maybe to the bottom 10. I think that's just the reality that I don't think they're.
I don't think they'll be interested in developing it further. With that in mind, we still think there's an opportunity for it to be developed, not necessarily by us, but if Pfizer don't want to do it, then there could be a conclusion where maybe we get the compound back. We'll see what happens with the discussions that we have with Pfizer. Nothing's been decided yet, but that may be an outcome.
Okay, and let's just go near term. Do you have an OS trend and enough data with your monotherapy ESR1 data to file right now? I just want to make sure that.
Yeah, our filing is imminent.
Okay, got it.
Imminent.
Now, it kind of sounds like you're talking about three scenarios. You guys proceed forward 50/50 collab, which is the current base. Case number two, the Pfizer partnership remains, but it's, let's say, 30-70, where the economics are in favor of Pfizer. To your point, you're not carrying on the development costs. The interesting thing there is it doesn't sound like they want to develop anything further. Why wouldn't I would rather actually just say 50/50, and then them not develop anything if we're going to be purely financial. The third scenario is you get it back and you're going to go look for a partner. I can't help but think that if the answer is number three, that you would have a good degree of confidence that there is a strategic ready to go. I will ask that question.
How c onfident are you that there is strategic interest for vepdeg? You were just at ASCO. I'm sure you were talking with a lot of people about that phase III data set. Can you talk to us about, you know, generally speaking, what's the feedback you've gotten?
Sure. Yeah. I do not want to get ahead of any kind of potential negotiations for something that has not been cited yet. Clearly, when the data was presented, what was really great, having had, to be honest, two or three months of fairly negative feedback from investors, was this flow of incredible positivity.
We're depressed people sometimes.
Yeah. We got a lot of really nice positive stuff coming from the KOLs who looked at the data, were very excited about it, saw the potential for the best-in-class opportunity, saw the tolerability aspect of that being extremely positive. Yeah, you could look and you could quibble about efficacy, but you line them up, the three compounds together, we certainly showed the best PFS difference to fulvestrant. We have really great tolerability, I believe, and ideally will show durability as well over the piece. I think other companies, when they get that flow of positivity coming from KOLs, I think they will be interested if we're in that situation.
Okay, let's maybe just on second line. This has been the kind of the bizarre thing. It's like Pfizer makes an announcement, they're going in first line before you have data in the CDK4 combo. Now it's like they're not moving forward it and they still don't have data in the CDK4 combo. That to me boggles my mind. In our discussions I'm actually quite excited to see what that signal looks like because my belief is CDK4 is actually hitting the target meaningfully more than even the bias. CDK4/6 is. Couple points. Number one, that seems like a very important data point that's coming up and that should be in Q3. Can you help us understand how many patients you have?
Because I remember, Noah, you were mentioning at San Antonio when we were talking that that trial actually got expanded as late as the fall from Pfizer. So how many patients, what's the durability? What are we going to know from a response rate perspective? What are we going to know from CBR and PFS and what's the milieu of first line, second line plus patients in that study?
There are no first line patients in the study. It's all second line plus. There are about 50 patients in the study at two different dose levels of the CDK4. We completed enrollment early in the year. You can extrapolate from there.
Okay. If you were to say again, I go back to Pfizer's own public comments and this is where it gets a little confusing. Their oncology day a year and a half ago, they said it will be an efficacy based decision to move forward with the atirmo-vepdeg combo. I am sure with I know what you're going to say, which is you're not going to have enough long enough follow up on PFS or CBR. To me, the only thing you're going to have is potentially response rates. We go back to San Antonio last year or two years ago where you guys were showing a 43% response rate, which was unprecedented in kind of that second line setting.
When we think about response rate bars that we should be thinking about with the assumption that CDK4 is hitting that target much more potently than let's say abem or Kisqali, what would get you excited? The second question I'd ask is, is that open label data? Is that data that Pfizer already has?
Right now or so we haven't even seen data cut recently. I don't want to go into more details than that. The decision was really based. I mean, I'm not sure where that was coming from, the characterization of it being efficacy based, it was principally safety based because it's. We're making a decision in second line about whether we wanted to go in first line. We dropped the notion of going ahead with palbo because we saw that we had a safe combination, atirmo and vepdeg, and early signals that we have kind of activity.
Sure.
There is nothing to update since then really. We will have more mature data at some point. I cannot even guide you to when it would be shared, but those would be the data that we could look at for a combination.
Are you a believer on CDK4 as a class? Because, you know, it's interesting, Lilly, I think they made a bet which is interesting. PIK3CA to their credit is the only thing that's actually worked in a first line setting so far. So I do think that's an underappreciated target. Third jury still out. They're trying adjuvant. And then Serena is, I feel like, kind of the best you can do in terms of the hybrid scenario. So CDK4s are really the other bet. Right. So are you, how do you think those CDK4 AI data sets are going to play out? Is there going to be a safety benefit that will translate to an efficacy signal? Is it because you're having more continuous efficacy that you're going to have a durability benefit? What's the angle then? Number two, you see Novartis, they're working on their own.
Roche, they got their asset from Regor. Beijing has data right now. Are those the people we should be thinking about as potential strategics who would be interested in something like vepdeg?
Just to address the interest in CDK4, we were interested. That's why it was a candidate for first line treatment. We were all in then. Pfizer leaned in, losing confidence about the role of a SERD or PROTAC in the first line, and they did not want to proceed. We maintain our enthusiasm. It's odd because here we are, we're enthusiastic about vepdeg, and the plan was to combine it with their drug atirmo. Whether they've lost confidence in atirmo or not, I can't comment about. I don't think so. But, I mean, you would have to address it.
Yeah. The only thing it would be obvious in that setting is the fact that they moved their, they had an atirmo phase III that was moved to phase II.
Right. That was the second line.
One second.
Right.
Yeah.
Yeah. So I would say that's the clinical perspective. We have conviction in the company that CDK4 could play an important role. As for who potential, you know, that's getting ahead of ourselves. Who potential partners are.
Yeah, got it. Okay, understood. Now. I think some investors will say, man, when I was talking with Arvinas two months ago, it was like, look, just forget about vepdeg. Right? To a certain extent in this market, sometimes people are like, I'd rather just refresh the story. Maybe I'm interested in LRRK2. Maybe I'm interested in the AR degrader. Some, you know, confusion is often, sometimes an issue. How do you. You guys are very cognizant of what your shareholders want too. It's something you care about. Like, how do you balance the potential of, hey, you might get vepdeg back. I think people.
What I think what people would want to understand is like, okay, what is Arvinas committed to spend up to then exploring a partnership so that there's not like this consistent spend on a program that maybe we don't know what the next steps are. How do we, how would we understand.
In the kind of hypothetic scenario of us getting the compound back, we clearly are committed with Pfizer to do the submission. The U.S. one is, I see, is imminent. There are others in the rest of the world that are fairly advanced. I think those would be, to the point of submission, ready. I think we'd be doing the work, the finalized work to get launch ready. That would be a relatively minimal amount of money, $25 million, probably less, to get that piece done. There would also be the unwind of VERITAC-2 . There are a lot of patients still on drug, which is fabulous for the patients, but when you're unwinding, it still costs a lot of money. That will also be part of our costs over the next, I don't know, eight, nine months to a year.
If we got the compound back, what we'd be doing immediately is trying to find either a partner who wants to take it forward in terms of development but also launch or a straight out license to get that value that way. What we want to do is get the compound to the point where it's been submitted in the relevant markets or submission ready for those markets and it's launch ready. It kind of
Sounds like all. In sub- $100 million. Is that probably fair to say?
Yes, definitely sub- $100 million. Yeah. I mean the biggest driving cost is the wind down of VERITAC.
Maybe sub- 50 all in.
Yeah, I mean it's not going to be 100.
That helps someone. No, that's huge. Yeah. Like I just think having a number, a range is really helpful for investors.
It's not in one year. I mean, that's.
Yeah.
VERITAC- 2 is going to take a
50/50 partnerships. What are your thoughts on them going forward?
We'll probably not do another one for a while.
Okay.
The great thing about that deal in 2021 when you look back on it, first of all, it was an exciting deal. We got $1 billion up front. 50/50 co-development. It was adjuvant first line combo, second line model. Really gave you and has a really great sense of how we could build the company. We also had the androgen degrader as well. You could imagine a scenario where we had those vep launches plus the ER launch as well. Things change and the reality is 50/50 on an adjuvant study is a pretty gigantic amount of money. 50/50 on a first line study is pretty gigantic. The only way you could do that is actually have the success of data and the excitement of investors to keep putting money in. Of course that did not happen.
There's a risk that comes along with the 50/50 co-development. I think in the current environment, doing deals where the economics are maybe less favorable but you have risk mitigation in terms of your cost is a far better thing to do.
85/ 15/70 something.
Yeah, something is not 50/50.
Right.
The learning's pretty useful because here we are right now with a pipeline where we have our patients enrolling in a BCL6 study that's going to play a significant role in the treatment of non-Hodgkin's lymphoma. Yeah, we have, we're on the verge of enrolling patients in our KRAS G12D dose escalation where we will be the second degrader to go into patients. We have differentiation from inhibitors and degraders based on our preclinical data. We're dosing patients with Parkinson's disease for our LRRK2. That obviously has enormous opportunities in very large studies. The learnings from this past experience will probably inform that since we have a first or best in class drug there as well.
Understood.
Noah's correct. I mean the company, if we resolve the vep issue, drive value in some way, the company has a chance to reset itself back to being a phase I, early phase II company with those three assets with two pretty quickly behind it. That is five clinical bets in phase I going into phase II with a restructured company with vep and the overhang of vep fully resolved.
Again, I know we're dealing in hypotheticals, but let's indulge ourselves. You think about outright giving away vepdeg, but again you get cash in return and you go back into a phase I company and you think about comps. The obvious comp is the Radius deal. I think that was like, what, $700 million-$800 million, quote quote, am I wrong? That is a significant cash payment. To be clear, what were you buying? A basically ESR1 mutant launch and they quickly, you know, are getting to kind of like $500 million-$700 million in sales. That is the pitch. My guess would be now you're splitting that market. I'm sure you have a sense that you're going to get more share. Is it fair to say if an outright sale of that would be in that kind of $300 million-$500 million range?
We don't want to speculate again, we don't have the asset that's taking the hypotheticals quite far. All we know is that the market in the second line could be much bigger than it currently is. I think Orserdu has actually done a really good job of carving out significant market for itself, probably addressing only a third of the patient population. So the market could be $1.5 billion-$2 billion. They're the only one playing in there in that space, apart from obviously fulvestrant. We'll see what happens with elacestrant and I think vep with its profile could actually take a significant position in that second line s ailing.
interesting now and again. I think some of this is just, you know, clarity is really helpful. Right, so you've got LRRK2, BCL6, KRAS G12D. I don't know, like non-Hodgkin's lymphoma really takes super long to run these studies and get like a clinical definitive answer of whether it's good or not. BCL6, there's players there, there's players in KRAS,
There's only one player in BCL6 and they're sharing data at EHA in a few weeks that shows a 80% response rate.
Yeah, right. No, that's fair. The standard of care is also like in the 1990s. Here's my, here's kind of my point. The question for you guys, and this is what an investor is going to say, is like, Akash, when is the money-making catalyst for Arvinas where it's going to have something that's going to show not just proof of concept but some efficacy in a clinical population that people can say this can have the potential to be best in class. Right. When you, can we just walk through for LRRK2, BCL6, and KRAS. When do you think those inflection points are? And then, I'll give you an even harder question, the spend associated to maybe get to that time point.
For LRRK2 there are a few key inflection points that we have to pass through. We have to complete our long term tasks which will happen at the end of the year.
Okay.
That allows us to dose patients for more than a month and right now we continue to collect data in Parkinson's disease patients as we move into the MAD this summer, which so far has demonstrated to us that we engage the target with our orally bioavailable brain penetrant PROTAC, the only one that exists in the market today and that we're degrading LRRK2. We will repeat, we will demonstrate this and the downstream markers of inflammation and neuronal death that we will suppress. We will do that over the course of the second half of the year. Next year there's some startup of phase II studies that can be informative and we can go into that when we have more time. When it comes to KRAS G12D, I said that the start of that study is imminent.
We will demonstrate whether or not we have differentiated activity after several cohorts in a small expansion that's going to happen by the sometime next year.
End o f 2026 would be back after 2026.
I think that's fair. BCL6, there are really two plays with that. We have in our study, we're enrolling patients that have AITL, so a T- cell lymphoma. That's a differentiation from the competitor in the space that's only focused on B- cell malignancies. We're obviously also focused on that. We'll look at whether or not there's an accelerated approval path. If we demonstrate the right benefit risk in that patient population, and there will be data shared next year that will be more substantial in that population. We'll have just some dose escalation updates at the end of this year. Next year, think of it as an expansion cohort that can be reported out as well next year at some point, and that's true for B cell lymphoma as well.
Where we're headed in B-cell lymphoma is to start, you know, the end of this year, early next year, a combination with bispecifics, which we think is the enormous opportunity. Right.
As bispecifics can play a role in second and third line relapsed refractory B- cell lymphomas, we would be adding on top of that, and we've demonstrated great preclinical activity. The goal is to start generating that clinical data, which may be next year.
Already EGFR degraders or something.
That's not in our.
Okay,
Not in our plan currently. The key is by the end of 2027, all of these data sets are moving. At the end of 2026, all of these data sets, you'll have some meaningful and interim data along the way.
Okay, and is it fair to say cash on hand could still be around $750 million? Is that fair to say
Right now?
No, no. As in by that point, obviously.
Depending what happens with vep, there could be another restructuring of. Right.
Or higher, potentially
Or lower. Yeah. We'll still be in a pretty good position by the end of next year.
Understood. I know these are tough conversations, but I really do appreciate the clarity and honestly, this is great for investors. Thanks so much. Really.
Thank you. Thank you.