Great to see you all. My name is Akash Shawari. I'm a farm and biotech analyst here at Jeffrey's, and I have the pleasure of hosting the Arvinus management team. Randy, why don't I hand it off to you for some intro remarks, and we'll get started.

Sounds good. Thanks. I'll just take a couple minutes. I'll swap you, please. Thanks very much, and I appreciate everybody's time today. Yeah, I thought I'd start off with just a very quick high-level overview before we dive into the Q&A. We're Arvinus. Make pro-tech degraders. I've been around for quite a while now, over 10 years. and had a recent approval, which we'll get into just in a couple minutes. Disclosures are here. We have had a pretty strong history of firsts in the protein degradation space that we're very proud of. I'm going to skip over nearly all of them today, this morning, and go straight to that last one, which is the first ever approval of a protact degrader, which just happened about a month ago. That approval for Vepinu, which is Vepdegastrant, is in ER-positive, HER2-negative breast cancer, advanced breast cancer, with ESR1 mutations. It's the first ever approval for a pro-tech degrader, which we certainly take a lot of pride in. There are a lot of companies that might be the first to have a therapy in a specific indication or area. It's very rare to be part of a company that actually gets to have the first approval of a new therapeutic modality. So that's certainly something that the company has taken a lot of pride in, thanks to the company, our partners at Pfizer on getting that done as well. We also announced in just a very short while later a licensing deal with Rigel, who will be the company that takes that program the last mile to patients. So we're excited about that. It's still under review, but they're raring to go and get that program moving as rapidly as possible. And we're really excited about the potential of Vepinu and really pleased that that will be getting to patients in very short order. I want to spend just a couple of minutes on our pipeline, really in bullet format, and talk a little bit about the strategy that we've outlined really over the past year, and I think in a particularly emphatic way since I took over as CEO just a few months ago. So if we were here a year ago, we were talking about that degustrant, AR, the AR degrader we had that we then licensed to Novartis called lexdigalutamide. But really since then, we've really focused on transitioning the dialogue and how we think about ourselves as a company as not just a company that has an interesting platform that can create a great pipeline, but then looking at that pipeline and saying, what are the right programs for our Venice to take forward. We've right now got four programs in phase one, and what we've been telling people for a while now is we're going to be very careful to make sure that we take forward the programs where it makes sense for our Venice to invest, where we think that we can create differentiated therapies, where we think we can change the paradigm for patients, versus where we think that we might get help from other companies to help us do that. To go through what we have as the pipeline right now, ARV-102 is a LARC-2 degrader. We are planning to develop that for both PSP, a rarer neurodegenerative disorder, and for PD. We have ARV-027, which is a polyglutamine repeat AR degrader that we will use for SBMA or Kennedy's disease and has a potential to be the first disease-modifying therapy in both of those areas, both 102 and 027. ARV-393 is a degrader for BCL-6 in Phase I for hematologic disorders, both B-cell lymphomas and T-cell lymphomas, has the potential to become a standard of care that's oral and chemo-free. Moving to what's coming, ARV-6723 is an HPK1 degrader that will start in the clinic in the second half of this year. That's our first I.O. program. And then, as announced last night and this morning, ARV-806 is our KRAS-G12D degrader, And we announced yesterday that that program will finish its phase one dose escalation, which it's in right now, and then we'll only move forward to future trials if a partner's found to do that. And I think we'll spend some time talking about that this morning, but I really see that as emblematic of what we've said we were going to do, which is focus on where we think the right priorities are for our Venice to invest versus where we think it's the right opportunity for our partner to invest. I'll skip over the pipeline for now that's certainly available and maybe just leave this introductory part with what we see as our milestones that are coming up for each program 102 will have additional biomarker data from its phase one trial later this year and then the main and then also starting a couple of trials this year both a phase 1b and a phase 2 trial both in patients with PSP which will be our first trials in patients with that disease ARV 027 It's in its phase one now. We'll have data in the first half of next year in healthy volunteers. And then on the oncology side, ARV 393 will have its first phase one data in the second half of this year. And 6723 is going to start its phase one trial in the third quarter of this year. And that's where we sit in terms of milestones. We're pleased that we have capital to move these programs forward, get to the next inflection points to really show what our programs can do, and look forward to the rest of the Q&A and discussion about it.

Thank you. And that's, look, I think it's a great starting point because I still remember, you know, the first time you and I talked in your new role as a CEO, that was one of the biggest things that you said was, we are going to be very disciplined. We're going to put yourselves in the analyst seat, the investor's seat, and we want to make sure that there's congruence between what we're doing, what investors want, and what's really prudent also for the company long term and balancing those interests um you know talk about uh the g12b and d and the decision to really say look we're going to develop it to phase one and then after that we're going to look for an external partner um you know and you had alluded that there was going to be kind of a mid-year update what led to that decision are there any hints you can give us about the clinical profile that your program was showing let's say relative to some of the updated data we got from redmed Yeah, absolutely.

And as you said, we've been talking about how we need to prioritize what we are doing and where we can focus. I think the beauty of having a really strong platform is that we can create great programs that reach the clinic. The problem that you then have is a great one, which is that in order to win in any one area, you really need to dive and invest. And so we have to pick where we're going to do that. And for KRAS-G12D, I think you phrased it correctly as what hints can we give you. We're not sharing the data today, so we'll have to be very consistent on this, but the data are competitive. The tolerability is really good. The efficacy is comparable, competitive with what we've seen others do in dose escalations. That's really hard to compare across, but we have a lot of reason to believe that you could take this program forward through its expansions, through combinations, and show that you have something special here. The question is whether we're the right ones to do that, and we decided that we're going to prioritize the other programs where we think our business is better able to do that and allow another company to do that if one is found and and focus on the other programs that I that I just went through understood and uh are there plans uh for your team internally to just give maybe a more broader disclosure about the dose escalation profile that we did see with that absolutely yeah we have we're maintaining the guidance of sharing the phase one escalation data this year so that's still coming um yeah absolutely you'll see it okay and um I guess maybe just lastly on this is this something where we should really be looking at that data and this is gonna be a catalyst for the company it's more hey we're gonna disclose it because we want to be transparent but really we want to shift the focus to LARC 2 or some of the other programs right now and that is really the right way to think about our Venus over the next few years yeah it's very clearly the latter right yeah what we want to focus on that's what that's what we're doing and that's what investors should be focused on is is what's coming up for milestones how are the programs moving along for for So the current other programs that are in the clinic and then in HPK1 that's coming along. So it is very much in the latter category.

Now, maybe hitting on WebDag and Rigel, because the deal did happen. I think that's quite important. Talk to us about how Rigel is thinking about the opportunity in ESR1 mutated patients. And really, what are some comps that you can point to where you can say, like, look, this population, you get very rapid uptake. And, you know, it is getting established into HR-positive breast cancer. So what did Rigel see in your asset that made them pull the trigger here? And how is their commercial strategy maybe going to be unique versus what expectations are?

Yeah, certainly happy to touch on that. And we ran a process there to find a partner. And what we really wanted to find was someone who was enthusiastic about taking that last mile to patients. We talked to quite a number of parties and looked at different ways to structure that deal. And what we really liked about Rigel is that the place it will play in their pipeline, sorry, not in their pipeline, in their bag of commercial products is really strong. As they said in their call after the deal was announced, this could very well be their number one product. So they're thinking a lot about it. They're putting a lot of emphasis into it. In terms of how they'll resource, in terms of expectations, those are all questions I'll defer to Rigel. I think they, as an existing commercial company, have said that they won't have to add a lot of resource to the team to get this launched in a strong way. As I said, they're quite enthusiastic about it. The terms that we have for the deal are quite strong, especially when it comes to the downstream royalties and things like that. It's not a deal where we need to hit super high into the tiers to see value come back to us. we're mostly excited for them to get after it when they get through all the necessary reviews and get it launched, which they've said will be in fairly short order.

Now, maybe hitting on LARC 2, and I'd love to get your take on the Denali data that was recently published. I know it as well, absolutely. And, you know, I think you guys had been very clear that you didn't particularly have high hopes for that program when it came to the design of the study, the population they were running, but there were always going to be trends or potential things that you could see that could maybe indicate that the biology of LARC-2 is having some level of validation. So I'd love to get your take. What should we be paying attention to with that Denali data?

I think you actually summarized our position pretty well there. That was really our expectation. Noah, maybe I could invite you to say a bit more.

So, well, we haven't seen the data yet. We've just heard that the study is negative. The position that we've taken, and I think that has been shared in the scientific community, is that LARC2 is an outstanding target. We know that it's quite relevant for Parkinson's disease on the basis of genetics. For us, it becomes relevant for Parkinson's disease, but also for PSP, because of some interesting biology that's come out over the past few years. All that has happened in the course of this announcement is we've seen that a drug that was not able to achieve, that didn't have the best PK properties and wasn't successfully dosed at a dose level that was really able to move endolysosomal trafficking and neuroinflammation through LARC-2 inhibition, that that drug was unsuccessful so we haven't really invalidated the target we've just you know a shot was taken with the drug that was maybe suboptimal and now we're very focused on what we can do with our drug a drug that is not limited to lark-2 inhibition but is a degrader so it can target the other portions of the molecule that we know are very important in all these aspects of of disease progression for these patients.

And again, I thought it was very helpful with G12D. You guys prospectively talked about the bars that you were looking for. I'd love to get your take, because again, we'll get biomarker data, we'll get early data, but when we do get that full Denali data set, help us define what do you feel like is a clinically meaningful level of LARC2 engagement that you would need to actually drive a downstream benefit? What do you expect to see when Denali shows their data? And are there any trends that you would expect in their clinical data that might be suggestive? Or is your point, it's more of a threshold effect, and if you don't get to that level, you know, we don't expect to see any signal here.

So we've been very consistent in the, with the approach that we'd like to see 50% reduction in the activity of LARC-2. We know that typically patients with Parkinson's disease have twice the level of LARC-2 compared to age-match controls. We know from all kinds of other biological inquiries that this is associated with problems with trafficking pathological proteins. So just hitting that a little bit is not likely to create a clinical benefit. What has gotten us very excited about our data set is that when we presented at ADPD in March, we demonstrated that we easily achieved more than 50% reduction in the LARC-2 expression. It was associated with a dose-dependent reduction starting at about 50% with a reduction in all of these markers of neuroinflammation and then the lysosomal trafficking. So that seems to be, there seems to be a threshold matter at play here, and we look forward to sharing more data at the end of the year.

And I do think it's important to remind folks that we have already seen data, both clinically and preclinically, that we think are showing something different than what a LARC-2 inhibitor As Noah just pointed out, the biomarker data that we showed at ADPD was, you know, achieving knockdown or reduction of disease-relevant biomarkers in a way that the LARC2 inhibitor has never been able to do. And even back in the preclinical studies, in terms of looking at the results of LARC2 inhibition versus degradation, we were seeing things like increased numbers of lysosomes, increased numbers of, you know, increased lysosomal activity, changes in reductions in pathologic tau after treatment with ARV-102 that we could never see with a LARC2 inhibitor. So So I think we've already, we're certainly looking ahead to data. I think it's important to remind that we've already shown some differentiation in the clinic, as Noah just went through, but throughout the program's history.

Understood. Now, you know, so much of this is also like getting the right drug, but also running the right clinical trial. And talk to me about, really, in the Parkinson's population, what are the challenges you have in terms of showing, even if you are engaging with the target, help us frame how long you think a patient would need, you know, a 50% or greater LRRK2 inhibition to actually start to see a downstream impact on clinical symptoms. And is your team running that trial now? And if not, when you do start showing data in Parkinson's, how should we be reading it? And then let's maybe also contrast that with PSP, where again, you potentially get a much faster disease progression.

So I think this is one of the challenges that the Parkinson's disease field faces, and we're sidestepping that by focusing on PSP, a disease that's very dependent on LARC-2, and we've demonstrated, at least from a biomarker standpoint, that we're likely to impact. And I'm going to pivot to PSP for that reason, and it will draw a contrast. So PSP is a rapidly progressive disease. So from the time of diagnosis to death, it's seven years on average for patients. Contrast that with Parkinson's disease, where patients can progress slowly over 30 years. If you can catch PSP early and impact the circuitry in the brain that is responsible for the progression of their disease, you could see that in a reasonable amount of time because it's so rapidly progressive. Parkinson's disease... By the way, define reasonable. A year. A year, okay. Think about Parkinson's disease, a disease that's progressive gradually over 30 years. How much change will you see in one year for a disease-modifying agent? So I think that's... We haven't slayed that dragon yet. That's a challenge for us in the future when we choose to move into Parkinson's, But we think we're making a very wise choice, focusing on PSP, which allows us to really maximize patient selection, tying it into the biology, being able to track it with biomarkers, imaging, and other metrics of motion, oculometrics, and so on. So that's the important contrast we'd want investors to keep in mind. That's very important.

And now, you know, this is Wall Street, and the question everyone asks is, give me a catalyst. And this is where it gets kind of interesting, because I think we've seen examples in some of these rare orphan diseases where even incremental updates, interim updates, versus historical controls can actually end up being quite meaningful. So, Rainey, you're in a setting where, yes, you have to develop these programs, would be you have to tell us in the broader community like hey this is something that really we should be allocating funds to how do you create that catalyst profile with PSP and lay that you know route over the next year or two what should we be paying attention to here yeah I think it's an important question because even PSP is going to be a long-term you know treat for a year sort of disease I think it in the immediate future it's going to come back to biomarkers it's going to be back to what can we and other members of the industry, but especially us, show in terms of how biomarkers can relate to disease progression.

And so that even though the trial that we will ultimately run, at least the first registrational trial, will be based around a rating scale, the PSPRS, what can we do in the meantime to show that the biomarkers we're moving are tied directly to the progression of disease? To Noah's point, that's a lot easier to do in PSP, which progresses over a short term versus a PD which progresses over a longer term. There's a lot of activity in this space, which we expect to be leaders in. Noah mentioned some of the more novel biomarkers that we'll look to. We will certainly get to a point where we're looking at a registrational study, and we'll have to get to the outcome of that for sure. But I think there are development aspects that we can pursue that will help give confidence along the way before you get to that final readout.

And so just to help us understand, you know, that initial kind of more biomarker-focused PSP cohort, how many patients are we talking? What's the dose level, right? I mean, with the G12D, you have five different cohorts. So, again, we can't just look at dose escalation. We have to think about when do you get your target dose. So lay out what that initial development program is in PSP.

Yeah, maybe, Noah, it's helpful to talk through both of the trials that we have planned and obviously pointing out that these are active conversations with the FDA, and so we won't go into tons of detail, but please.

So if we keep our eyes on the goal, the eventual registration trial, which we've guided to, we may be able to start by the end of the year, pending regulatory discussions and so on, would be a study involving a few hundred patients where the primary readout is going to be the PSP rating scale. So that's a rating scale that measures clinical functioning of a patient and is accepted by global health authorities. The study would involve treatment for a year. It involves a few hundred patients. So at some point, we'll offer more guidance, but I guess folks can do the math about what we're shooting for. We've also said that we'd like to start within the U.S. a phase one study that would look at a smaller number of patients and start linking the biomarkers to that PSPRS and maybe some other tools. And that would be able to even generate a readout earlier than the registration trial. So that study, think of 50-plus patients, two dose levels, and compared to placebo, Data would be augmented by external control, placebo control data. And we're looking at biomarkers that become more relevant for PSP. Earlier, biomarkers that we couldn't see in a 28-day study, but that we can see in a study that's three, six months. And this study would be six months. and those a biomarker that folks may recognize would be neurofilament light chain let's say so a measure of neuronal health and then on top of that tools that are looking at like oculometrics and other actigraphy type devices that are looking at patients muscle activity and of course PSPRS for which it will not be at a 50 plus patient study it's not going to be powered, but you can start making the association between the biomarkers and that registration endpoint. Understood.

And do you feel like this could be a 2026 event where, let's say, you start that phase one trial, and maybe we get some biomarker data by the end of the year, or is this more likely 2027? 2027 for the early up.

Yeah, not offering the guidance yet on when we'd see that data, but it's not possible for 2026. Understood.

Now, when do you, looking at the biology, when do you feel like we're going to see this congruence between improvement on biomarkers and then actually improvement on the registrational endpoints, right? What's the time course in PSP where you feel like, you know what, we're going to, we shouldn't, even that early subset of patients start seeing trends in the right reduction, you know, direction on cognitive function?

Well, we designed that study as a six-month treatment study because we believe that's the appropriate time frame where you could start to see those changes.

On the, not just on bipolar?

All these tools, really. Something like neurofilament light chain, it's changing earlier, but you can't see it because the half-life is only, I'm sorry, the half-life is about four months. So it takes some time for that data to present itself. But I think we designed it rationally as a six-month study.

Understood. Now, maybe just hitting on 027, and I feel like that's the product that I'm not sure investors are super familiar with, but, you know, could be a clear point-and-shoot opportunity in a defined market. So, you know, tell us a bit about 027's profile. What gets you excited about its treatment effect in this disease? And how soon could we get, you know, the question is, like, how soon do we know it's real, right? Is this a market where we can get very early validation, you know, with O2-7? Or is this something where we're going to need long, large trials to really see if it's a product or not?

Look, the short, I want to maybe hit the high level first. O2-7 is a program that we rolled out and began a phase one trial just a few months ago. It's for polyglutamine repeat AR, like I mentioned in the opening remarks. and it's a very defined disease and defined patient population so this is absolutely a situation where it's actually an interesting contrast where LARC 2 where certainly the target needs validation we're excited there's a lot of reasons to believe that's the right target to hit but the opportunity there is really dramatic the opportunity for SPMA and to help those patients is also pretty significant right and it's a very well-defined disease maybe Noah can talk bit more about the disease itself as we as we introduce it but we think that by hitting that target which is ar uh which we have a good history of hitting you know it's it's a bit different it's going to be in the muscle uh not in not in tumors like lex degalutamide was doing but we actually think that by degrading polyq ar and muscle which we should be able to show in fairly short order even out of the phase one in healthy volunteers we think that will be a very direct link to modifying disease which is really a space that uh that we we see ourselves as a very strong leader in we don't know of other air degraders that are focused in this area certainly you can always get surprised uh and really not that many other companies that are focused on it so it's we think it is a very clear leadership opportunity for us i would just add that um i in the biotech drug development space a big challenge is you're looking at uh multifactorial diseases very often

We were talking before about Parkinson's, LARC-2 is relevant mechanistically, maybe one of the most relevant markers or targets, but it's not a monogenic disease. On the other hand, SBMA is a monogenic disease. Patients, the way you diagnose it is that they have a series of symptoms and signs, and then you look and see that they have poly-QAR, and now that's SBMA. So the fact that we know that the disease is caused by this particular gene, we have the ability to degrade this gene, which when it accumulates with these glutamine repeats becomes a toxic gene within cells, that positions us from a risk point of view in a very good position. Now, we're running our phase one study in healthy volunteers, but also are adding patients at the end who have SBMA. And we are doing biopsies. So we will be able to demonstrate, if successful, that we are degrading in a dose-dependent manner in the healthy volunteers, the androgen receptor in their muscle, and then prove that we're doing the same thing for poly-QAR. And our drug degrades It's AR as well as poly-QAR, and so there's no reason to think that wouldn't follow through. So we come through at the end of this phase one next year with biopsy-proven, if successful, degradation of AR in the target organ for a monogenic disease. That's very exciting. Now, we've shown pre-clinically that by degrading poly-QAR, we can restore grip strength and endurance in mice. mice aren't people, but it's also not so common that you have a good, you know, indicator of disease and its reversal like this. So we think that we're on track once we prove that we've degraded poly-QAR to look for those clinical benefits. We have to, it's not going to be approved on the ability in all likelihood of grip strength, but there will be an approval if successful on the basis of endurance, like their patients' overall strength, there are very good ways to reach agreement with health authorities on those endpoints. And we think we can start seeing indicators in treatment that maybe it's a year or so, but more to follow as we get further down the line.

So is it fair to say maybe potentially by next year, we might be able to get early signs of clinical activity here?

Well, patients are only being treated for 28 days. That's a short amount of time to reverse a chronic muscle loss in these patients. But I think that we would have the degradation data, have its association in the muscle, have its association with dose, so a dose response. And then we'd want to tie that into clinical data over a longer-term study.

Okay, understood. So maybe lastly for you, Randy, when you think about a lot of cash on the balance sheet still and you have a lot of optionality, how do you think about kind of internal investment into the RVNAS portfolio versus looking externally for partnership opportunities or in-licensing opportunities? I mean, we're seeing certainly with China and academic partnerships that there are, you know, the cost of acquiring interesting drugs has seemed to gone down. And so there is flexibility on your end as well. So given the reprioritization you just had with G12D, how front and center is that discussion with you and the board about external versus internal development?

I would say we are very much focused on internal, right? So we have had a really strong history of creating great programs to put into the clinic. And I'll go back to a point I made at the start, which is we, at least I believe, that in order to compete in every one of these areas, there's going to be competition, right? There are going to be very few opportunities. Perhaps SBMA is the clearest one to have a phase one lead directly into a registrational type study. In most areas, it's going to require multiple approaches. We didn't even talk about our BCL-6 program today, right? But monotherapies, combinations, different indications. So for us, the prioritization is really that in the purest sense, which is to move capital from the programs we think are better for a partner to help take forward to the programs that we're going to invest in heavily. And so we are fortunate to have a strong balance sheet. I want to make sure we keep it that way. But I also want to invest to win in the areas that we do choose to play. So I would say that's the priority.

And just maybe last question. You've got to pick your favorite child sometimes. But if you were to say right now, for investors who's never looked at the Arvina story, and they had a limited amount of intellectual capital in terms of what to dig into, how would you prioritize their diligence? What do you start with in terms of the most important versus, you know, more of the other shots?

Look, ARV-102 is the furthest along and by investor human nature is going to get the most attention. What I think should be not missed, right, is the balance here, right? We have targets like LARC-2, which are less validated, but with a much stronger competitive, you know, market opportunity, opportunity for millions of patients to benefit down the road. And on the other end of the spectrum, we have SBMA, a rarer disease with fewer patients, but with tremendous unmet need and as clear as you can get connection between the target we're hitting and modifying the disease. And I think that having those multiple shots on goal that have different types of profiles is really important for us to continue as a healthy company that is able to use that balance sheet that we have to the best benefit for patients and for our shareholders.

It almost sounds like to me, start with 027, because if you can get a defined market and a clear one there, then we can think about the upside with LARC-2.

I think even though it's the most recently introduced program, for the reason you just said, it's one where the clearest disease-modifying indication could come very clear. Although, again, being said, we didn't talk about BCL-6, which where we'll have phase one data by the end of the year, where, of course, in oncology, we're talking about what can we do in terms of response rates, what can we do in different populations. And with elsewhere in oncology, you do get more of an early read, which always, of course, has to translate later on.

Wonderful conversation. I really do appreciate it. Thanks, everyone. Thank you very much.