Conference Transcript - RLAY 2026-09-08

Eva Fortea, Analyst — Wells Fargo

Perfect. So welcome to our next session of our Wells Fargo Healthcare Conference. I'm Eva Fortea, one of the biotech analysts here. And we have with us Imogen, Chief Operating Officer, and Pete, Chief Corporate Development Officer of Relay Therapeutics.

Pete Wehmer, Other

Thanks for having us. Yeah, great to be here.

Eva Fortea, Analyst — Wells Fargo

Awesome. So maybe we can start with, you know, kind of lay of the land, past 12 months, next 12 months. What's, you know, up for Relay?

Pete Wehmer, Other

Yeah. Thanks again for having us. Great to be here. Great way to kick off the fall season. So over the next 12 months, you know, coming off a very exciting first nine months of the year for us, made a number of disclosures across both vascular anomalies and breast cancer. We're able to fortify the balance sheet. And now as we look forward, we're really moving into the next leg of growth here as we start preparing to become a commercial company. And I think a lot of that will be underpinned by additional disclosures and clarity on the regulatory path forward in both breast cancer and VAs. Specifically, we've guided two regulatory updates for both frontline breast cancer phase three trial, which we intend to start early next year. And so we'll go have a regulatory interaction before the end of this year and report back out on how that goes similarly with vascular anomalies that program is going quite well and quite fast from a development perspective and so we'll have a conversation with the agency on a potential accelerated approval path before the end of the year and report back out on that and then from a data perspective we will share additional vascular anomalies data before the end of the year, and we will share additional phase one to triplet data in the first half of next year. So it continues to be a very robust set of months for us before we get to the end of the year, and then moving our way quickly towards registration readouts in both breast cancer and vascular anomalies.

Eva Fortea, Analyst — Wells Fargo

Nice. So lots of stuff to talk about today. Maybe you can start with the breast cancer side of the story. Maybe you can, you know, give us a quick overview of the data we've seen so far for Zovega in breast cancer. And what are key differentiators, especially in this very competitive landscape?

Speaker 1

Yeah, so the sort of, we'll start with the second line, because that's where we've got our current phase three running. The goal with Zovega when we set out was really to try and design a drug that was very specific and did not have the limitations of the generations that came before it and so avoided some of the off-target toxicity. And so we went after the second line breast cancer population first because that was the biggest unmet need and the place where it made sense to start. What we were able to show, and Pete alluded to this earlier this year, we showed our Fed data, we showed that we had an 11-month PFS, which was really exciting because it avoided some of the off-target toxicity, had a much cleaner profile, and it delivered against this promise of if you could have a better tolerability profile, you should be able to extend the efficacy. And so that compares really nicely to CAPI for CERTIBs, five and a half months in a post-CDK four six setting so we're really excited about that and that's what gave us confidence to launch our second line phase three which we started last year then earlier this year we showed we showed data from a median third line population in the triplet setting also that Pete alluded to and that looked really compelling both from an early efficacy perspective we showed an ORR of 44% there. But more importantly, we wanted to show that from a combinability perspective, it would be a really nice tolerable regimen for patients in the frontline and could compete well with the existing standard of care.

Eva Fortea, Analyst — Wells Fargo

Got it. So maybe starting with the Rediscover 2 phase 3 study, just in terms of enrollment, I mean, is it tracking line expectations and how should we think about timeline to read out?

Speaker 1

Yeah. I mean, I think this is probably one of the most important priorities for us as a company right now it's um it's and it's going really well it's a very compelling study for physicians and patients given that you are taking zoe vega plus full veteran versus cappy cappy the market leader right now versus full veteran it's the enrollment people are very excited about it and enrollment's going well as pete mentioned will guide at the end of the year before the end of the year as to when last patient in will be but right now we're feeling really good about it and we think that we will do very well compared to the benchmarks that we've seen for similarly sized studies.

Eva Fortea, Analyst — Wells Fargo

Should we expect an impact on this study given you know the recent focus on the first line?

Pete Wehmer, Other

No not at all I think for us it's it's one of the key priorities as I mentioned it's really important in terms of the patient population there's a lot of excitement and we will have a completely separate team working on standing up a front line the front line study and it's kind of nice the as this study will reach full enrollment and you're then just collecting events that is you know well in contrast we'll have the front line phase three trial getting up and we can have the team focusing on shifting and focusing on enrollment into that study on a global basis will leverage a lot of the same we'll use distinct teams internally but it will leverage a lot of the global infrastructure

Eva Fortea, Analyst — Wells Fargo

we put in place to be able to execute against rediscover too got it you mentioned cappy as the control arm but we've seen recent data from one of your competitors get a taller sip that looks very compelling do you think this sets a new bar or are you still thinking as cappy as the bar to beat?

Speaker 1

We still see CAPI as the bar to beat. I think, you know, we get it, get it all the SIP came out with an 11 month PFS in their data in PIC3CA muted patients at ASCO. We think that when, when you look at the weekly IV, that's just such, it's going to be so onerous for patients in this setting. It's going to be a very hard, it's tough, especially as you think about our own efficacy sitting at 11 months, if you compare a weekly IV versus an oral option, people are going to want to go for the oral option. So I think it's an exciting drug in the wild type setting where there are limited options, but for PIK3CA mutated patients, I think we can do better.

Pete Wehmer, Other

I think the dynamic that happened between PCRE and Trucap in the setting tell us everything we need to know to that question you had peak ray with about a six month meeting PFS based off of the phase three trial that led to approval but was encumbered by safety and tolerability issues namely grade three plus hyperglycemia but also rash, stomatitis, GI toxicities and where TRUCAP actually had a nominally smaller medium progression free survival of five and a half months but just had a slight trading off and side effects with numerically lower grade 3 hyperglycemia and has now become the market leader in the space. So I think it really tells you that the tolerance safety tolerability profile is paramount for these patients especially in the second-line setting and I think that direct comparison between us and really any other regimen that's available today favors Zovega quite a bit here.

Eva Fortea, Analyst — Wells Fargo

Got it. So maybe can you just remind us a little bit on how Zovega's tox profile compare and how are you thinking about the market opportunity in terms of the second line?

Pete Wehmer, Other

Yeah, on the tolerability profile, we've seen improvements across the board. We have no stomatitis rash to speak of in our AE table for the second line patients. Our grade 3 hyperglycemia rate remains in the low single digits across over 100 patients treated at this exposure. And so, you know, in the context of whether it's getotelicib or capivacertib or alpelicib, you see that in the case of capi, there's a high degree of stomatitis, rash, and diarrhea. In the case of get it to listen, you need three or four different concomitant therapies just to keep the grade 3 stomatitis in check and the rash. And so I don't think, you know, we're seeing, one, we don't need concomitant therapies to prophylactically treat these side effects. And two, the overall absolute rates that we're seeing are much more favorable compared to these other issues.

Eva Fortea, Analyst — Wells Fargo

Got it. so maybe talking a little bit about the first line opportunity in earlier this year you selected a thermal as the silicate four of choice uh for the combination you know where are you at in terms of you know regulatory conversations and how do you think about the path forward in the first line so as as pete mentioned we've guided towards coming back with regulatory feedback before the end of the year.

Speaker 1

That being said, what we're envisioning is a reasonably straightforward design. So our goal is to go after the endocrine-sensitive patient population with a study that largely emulates Pfizer's forlite 3 study of a termocyclib in the same patient population. We went after the endocrine-sensitive population because it's the larger portion of the frontline setting. We haven't ruled out going into endocrine resistant patients but I think as we thought about what made sense for our initial move that that was the most compelling thing to do we're still thinking about whether or not to add a small contribution of parts on to the study and whether or not we add in a term O plus AI to help us ex-US with inside the US the FDA has been pretty clear that we could reference for like three but I think outside of the US it will be helpful to have at least a small contribution of parts arm um so our goal is to to set that study up to get it to get it designed and approved and then hopefully be ready to launch in the first half of next year

Eva Fortea, Analyst — Wells Fargo

early part of 27 got it and in terms of durability i mean follow-up was quite short from the one that we've seen so far for the triplet but how should we be thinking about you know next update how much data and durability are we going to get?

Pete Wehmer, Other

Yeah, I think the biggest thing that we're looking at in the phase 1-2 data in the initial update and in subsequent updates will continue to be the safety and tolerability of the regimen. That is going to be the best indicator of eventual durability because we already have good analog data from Anavalisib in the front line. So the The ANAVA-120 study was anabolisib, a non-selective inhibitor, plus palbo, plus flivestrin versus palbo and flivestrin in endocrine-resistant patients. And in that trial, they had to have a very favorable metabolic profile of the patients in order to keep the hyperglycemia at bay. But the efficacy was quite profound. you saw a doubling of the PFS in that patient population which tells you that when you add a pathway inhibitor to these patients in the frontline you're going to get a dramatic prolonging of progression free survival and the real key question is when you contemplate the frontline endocrine sensitive population where you could be treating these patients for upwards of three years can you put together a regimen that is tolerable enough to stay on for three years. And so in the phase one, two data that we continue to generate, of course, we'll continue to report on response rate. And eventually, if we get enough data maturity, we can look at progression-free survival in that setting. But the key metric we'll continue to look at is the safety and tolerability of that regimen.

Eva Fortea, Analyst — Wells Fargo

Got it. Are there any safety events that we should expect to accumulate over time versus seeing them at the beginning?

Pete Wehmer, Other

I think, you know, when you treat any patient population over the course of three years, you're going to, especially one where the median age, it's a metastatic cancer population in the median age, it's somewhere in the neighborhood of 60 years old, you're going to see accumulation of certain AEs. I think most of the AEs that we have seen thus far with Zovega do tend to be early on, tend to be low grade. Some of them are reversible. They all appear to be exceedingly manageable. I think in the context of combining with a CDK pathway inhibitor, the one addition you're definitely going to see is neutropenia. That is a class AE that we've seen across the CDK class of therapies. It looks like in the previous termocycloid data that the grade 3-4 neutropenia tends to be a little bit less than what you see with palbo, abema, or ribo. And just the general tolerability of that agent versus the incumbent CDK4-6s seems to be better than what we've seen historically.

Eva Fortea, Analyst — Wells Fargo

Got it. And you also showed in the early data that it seems like there was higher exposure, like a 2.5 increase exposure for Zovega. Is there any risk in dose selection for the phase three? How should we be thinking about that?

Speaker 1

No, we don't think so. We feel pretty confident in the exposure that we've seen and in the dose that we intend to move forward. We know that we do have an exposure, a DDI, with a termocyclib, but we don't see dramatic differences in interpatient variability or something like that. So it's a very manageable, predictable exposure increase. So we feel confident moving forward with our RP3D.

Eva Fortea, Analyst — Wells Fargo

Got it. And maybe in terms of control arm, I mean, the landscape is rapidly changing. Do you foresee any, you know, unexpected issues with your, you know, trial design or anything that could impact the way you're thinking about it?

Speaker 1

I mean, I think today, as we sit here now, the CDK4-6 plus endocrine therapy is very much the standard of care. And so this is the best design that we can design from where we sit today. We will see, there are a number of CDK4s that are in development. We're seeing the rise of some of the oral CERDs. But I think from where we are now, this is the design that makes sense. And this is part of the reason why we wanted to bring a selective PI3K with a selective CDK4 plus the endocrine backbone. because we felt that that was going to be one of the most future-proof designs that we could bring to bear.

Pete Wehmer, Other

And as we think about, you know, the two main questions you're trying to answer there is, do global regulators, will global regulators view it as a regulatory standard of care? And I think we can definitively say for the next five years or so that that question is going to remain yes. And then is it a study that physicians on a global basis will want to enroll to? And I think, again, the answer to that question is yes, you're offering CDK4-6 of choice, along with the standard aromatase inhibitor backbone in the endocrine-sensitive population. And the option is to randomize into a treatment arm where you're, as Imogen said, you're offering the selective-selective approach, which, you know, based off of the data we have in hand today and some of the data we've seen from the terminal cyclic thus far, should be a favorable option against the existing standard of care.

Eva Fortea, Analyst — Wells Fargo

Got it. Can you remind us how much data should we expect in the first half of 27 as we get more information about this first-line strategy?

Pete Wehmer, Other

Yeah, we continue to enroll in second-line plus patients with Zovega plus Eterno plus Fulvestrant. We've also enrolled smaller ARMS to look at Zovega plus etermal plus aromatase inhibitor. And we are also trying to enroll or enrolling a smaller portion of patients that are endocrine resistant with the Zovega plus etermal plus philvestrin regimen. The bulk of the patients we'll see being reported out from the phase 1-2 will be this median third plus line of therapies which is why we continue to focus on the safety and tolerability that we're getting out of this this data set got it is there any reason to believe this third line data wouldn't translate well to the first line we've seen this the precedence is that it translates favorably you generally see if you look at the anabalicive experience and then And in smaller captive assertive studies, you tend to see response rate improve by 20% to 30% when you go to second or third line plus patients into the frontline patient population.

Eva Fortea, Analyst — Wells Fargo

Got it. Very helpful. Maybe just last question within the breast cancer space. How are you thinking about prioritizing HER2 positive patients or triple negative?

Speaker 1

I mean, from a biological perspective, it's definitely interesting. I think as a company, where we chose to focus first has been HR-positive, HER2-negative metastatic breast cancer, and I think that remains our focus. Of course, we'll continue to think about these other opportunities, but for now, we're going to focus here because we see it as the biggest opportunity.

Pete Wehmer, Other

And there's also, before we even get into triple negative, you know, one of the settings we think about in HR positive or HER2 negative is the adjuvant setting. So I think there's future opportunities in HR positive or HER2 negative disease. You could contemplate, you know, Roche-Genentech are running combination studies in HER2 positive disease. So there's definitely a broader breast cancer opportunity as we continue to think about ways to expand the utility of Zovega.

Eva Fortea, Analyst — Wells Fargo

Got it. Very helpful. I don't know if there's any questions for the breast cancer side of the story before I move on. No? Okay. Then I'm going to move on to the vascular malformation side of the story. I mean, very exciting data that you've shown. And maybe, you know, can you put some of the data into context of, you know, how does it compare with the other PICC-3 available to date?

Pete Wehmer, Other

Yeah, we came into vascular anomalies with the same hypothesis we had going into breast cancer. You had good, clear clinical proof of concept with a, you know, 20-plus-year-old non-selective inhibitor in alpalosib. And our hypothesis was that with a selective inhibitor, you could push the therapeutic dose intensity, get better efficacy, and that could also come because of the selectivity window, come with a better safety profile. And I think the initial data that we disclosed at ISFA in May really checked all those boxes and then some in certain contexts. And so we started the study in the middle of 2025 and then presented initial data from the dose-randomized portion of the study in May of this year at ISVA. We saw across the dose-randomized patients a 60 percent response rate. And importantly, some of the early indications for patients that have made it out past multiple MRI scans we are seeing deepening of benefit for those patients it's coming with good symptomatic improvement across the board and both investigator and patient reported outcomes and specific when looking at pain which is a common symptom that a lot of these patients have to deal with and so it compares quite favorably to what we've seen with Opelosib to date which has a 20 to 30 percent response rate at the the labeled dose and so here in just our in our dose uh a randomized dose finding uh we're seeing already a 60 response rate at unoptimized doses at an early time point and so i think we are extremely excited about what's to come from a differentiation standpoint for zoeva and vascular anomalies got it and how are you thinking about further dose optimizing and also how should this data translate to the younger cohorts? Yeah, so earlier this year, at ISPO, we announced that we have started the dose expansion portion of this study. We brought both 300 milligrams BID and 400 milligrams once daily into expansion. We're currently prioritizing enrollment in the 400 milligram once daily dose. We think that's a real good sweet spot between 100 milligrams BID, which was extremely well tolerated and was showing similar efficacy, modestly better efficacy to Elpolisib, but dramatically better safety. And then at 300 milligrams twice daily, we saw 100% response rate, and it came with a little bit more tolerability profile, but still better than alpelicib. So this 400 milligrams once daily might end up being a really good balance of safety, tolerability, and efficacy, and lead to meaningful differentiation from both safety and efficacy against alpelicib and ultimately serolimus. And so we're very excited about continuing to roll into the expansions and really confirming a go-forward dose. That's all in the 12 and older population. We also started dose finding in the 6 to 11 population. There, it is a more traditional dose escalation study. And so we're moving through weight-based dosing there. And the goal is to get to a weight-based dose equivalent of roughly 400 milligrams once-daily exposure. And I think ultimately we can get to similar once-daily options in both the 12 and up patients and then in the weight-based dosing in the 6 to 11s. And then ultimately we'll move even lower into the 2 to 5-year-olds once we identify a go-forward dose in 6 to 11s.

Eva Fortea, Analyst — Wells Fargo

Got it. Is the physiology and the dynamics of the disease similar in the older patient population and in the younger? Should we be expecting any differences there?

Pete Wehmer, Other

Biology, we don't really expect any difference or impact on the disease. Clearly, you would like to intervene as early in childhood as possible. These lesions tend to grow with the patients over time. And so if you can intervene early in childhood, you have the opportunity to maybe stave off disease severity as the child gets older. But we have no reason to believe that the impact there in the disease biology is any different in younger patients than older patients.

Eva Fortea, Analyst — Wells Fargo

Got it. And you previously mentioned, you know, some deepening of responses.

Pete Wehmer, Other

During the data cut in May, we didn't have a ton of follow-up. how important is it durability versus you know the responses and the you know quality of life measures that you can get like pain at the beginning that i think durability is going to be critical uh to maintain over time and so yes you in in a handful of patients we were able to to get out to 24 week scans so two scans and we saw in every patient that was in response going into the 24-week scan, we saw a deepening of the response at 24 weeks, and then we also saw sequential improvement of the symptoms over some of the early time points in the study, and so we'll be critically keeping an eye on the ability to maintain response with these patients, and probably equally as important, if not more important, the symptomatic improvement over time.

Eva Fortea, Analyst — Wells Fargo

Got it. were there any type of patients that did better than others that you could, like, point out? And also, what was the status of the PIK3 mutations? If I recall correctly, there was a small subset of patients that didn't really have a PIK3 mutation there.

Pete Wehmer, Other

Yeah, we reported on many different subtypes or different cuts of the data. And with the caveat that in these early disclosures, Once you get into these subcuts, you get into pretty small ends. But we are encouraged to see that regardless of the subset, we're seeing similar activity. So whether it's pros or non-pros disease, whether it's kinase mutation, non-kinase mutation, prior serolimus and l-pelisib or not, we tend to see very similar outcomes from these patients thus far, which was quite encouraging to see. You highlight specifically there are some patients in the study without an undocumented PI3K alpha mutation. The reason for that is we allow that for both PROS and lymphatic malformation patients because those patients can be diagnosed clinically and don't need a genetic test to direct treatment. And because crows patients are 100% PIC3CA mutated and the lymphatic malformation patients are 80 plus percent PIC3CA mutated, we feel comfortable allowing undocumented patients coming into the study because almost certainly they are going to have a PIC3CA mutation. There's sometimes, because the mosaicism of the disease, in order to do a genetic test, you have to take a tissue biopsy of the disease, and that's sometimes not feasible in certain patients. And also, in some patients where you do have a biopsy, they may have very low, very allele frequency of the mutation that may be below the lower limited detection of the diagnostic test being used. So, for instance, our lymphatic malformation patient that we reported on that has the greatest depth of response that in our data set today does not have a documented PIC3CA mutation. Clearly, the patient is PIC3CA mutated. It's just the technical limitations of the diagnostic tests have not detected a PIC3CA mutation.

Eva Fortea, Analyst — Wells Fargo

Got it. And you also mentioned patients that were alpelesib serolimus experience. Were this patient like intolerant? Have they progressed?

Pete Wehmer, Other

The majority of them came off of serolimus or alpelicib due to intolerance of some kind. Or they've plateaued at a level that was unsatisfactory to the patient and the physician. So I think those are the two main reasons we see patients switching to Zovega, is the prospects of getting deeper volumetric reduction, better symptomatic improvement, and that coming with a better safety and tolerability profile.

Eva Fortea, Analyst — Wells Fargo

Got it. And just in terms of washout period, did you have a mandate washout period for patients to enter the study?

Pete Wehmer, Other

Yeah, we have a very standard washout period of three half-lives of the drug. Got it. That happens within a couple of days of L-pelicib. What doesn't happen in those couple of days is complete reconstitution of whatever side effects that those drugs were causing. So we will, because we're being so inclusive in the study, we'll continue to see some of the baggage of having been treated for longer periods of time with serolimus or alpolisib may kind of trickle over into our study. But those patients have such high medical need and will be an important patient population for us that it was worth it from our perspective to make sure we're allowing those patients into the study.

Eva Fortea, Analyst — Wells Fargo

Got it. And you mentioned a lymphatic malformation patient before. What was the split between your PROS patients and your lymphatic malformations patients? And have you seen any difference in terms of how they react to the drug?

Pete Wehmer, Other

Yeah, we're currently seeing roughly 70, 75% PROS patients, 25, 30% lymphatic malformation patients today in the study. not surprising to see this split given that the PROSE patients tend to be as a percentage of patients that are severe. They're a much higher percentage of those patients are severe patients as indicated by the fact that they have some syndromic disease. And then that's the indication where you have Opelosib with accelerated approval. But to date, we've seen no difference in performance of Zavega in either the PROS or lymphatic malformation patients. And as I alluded to, some of our deepest responses have come in the lymphatic malformation patients.

Eva Fortea, Analyst — Wells Fargo

Got it. And you mentioned you are going to be talking to the FDA later this year. I mean, what are the key points that you need to discuss? And is, you know, an accelerated approval path on the table? And how would that look like?

Pete Wehmer, Other

Yeah, so we, the current precedence, there's only one approval in this space. It's a very, in contrast to what Imogen's tackling on the breast cancer side, on the VA side, it's a very nascent disease area with not a lot of precedence. But the one approval we do have is Alpelosiv has accelerated approval in pros based off of a very strange study, which was 37 patients treated under compassionate use, And it was a retrospective chart review of those patients. And so, yes, we do believe accelerated approval should be available or could be available to us. And so what we will propose to the agency is a pooling of pros and lymphatic malformation patients and a single arm accelerated approval path to address both of those patients, both patient populations. And the question will be if they agree with that or if they would like to see those subgroups split out. And then, obviously, what we would also like to get a sense of is the size of that data set required for accelerated approval. So those will be the two key things we're trying to elucidate with the agency.

Eva Fortea, Analyst — Wells Fargo

Got it. So based on the precedent, I mean, how are you thinking about potential timing for this accelerated approval? And also, I mean, it's a little bit more clear for PROS than it is for lymphatic malformations, but do you think you're going to need the same amount of data or you could get away with more data for PROS than lymphatic malformations?

Pete Wehmer, Other

So I'll refrain from getting too specific there until we actually have a conversation with the agency. They're ultimately the ones that have the most say in that. But what we do know, we do know the current regulatory endpoint is exclusion. it's a volumetric response rate endpoint, exclusion of 15% in the lower bound of the confidence interval for your data set. And so with the magnitude of benefit we're seeing today, we don't believe it would require that many patients to be able to achieve that outcome in both pros and lymphatic malformation patients.

Eva Fortea, Analyst — Wells Fargo

Got it. And how are you thinking about the opportunity there? How should we be thinking about, you know, PROS versus lymphatic malformations, and also, you know, what's next for the vascular anomalies program after this?

Pete Wehmer, Other

Yeah, so we think it's a very large opportunity. Just within PROS and lymphatic malformations, you know, there's probably somewhere in the order of magnitude of about 15,000 patients in the U.S. with moderate severe disease that should be addressable with chronic systemic therapy like Zovega. And as a reference point, if you have via joist-like pricing, which is about $36,000 a month, every 2,500 to 3,000 patients would result in a billion dollars in peak sales if you can keep these patients on therapy chronically.

Eva Fortea, Analyst — Wells Fargo

Got it. Okay. What does chronically mean here?

Pete Wehmer, Other

Exactly what it sounds like. You start the patients as early in child as you can and keep them on forever. life got it okay very helpful we're out of time thanks so much for joining us