To the Relay Therapeutics team for joining us as our next company presenter at the SVB Annual Healthcare Conference. I'm Jason Gerberry, Leerink Partners biotech analyst. I'm joined by Qi Fang, who's my colleague. We've got on stage with us Don Bergstrom, President, R&D, and Pete Rahmer, Chief Corporate Development Officer. So, gentlemen, thanks, first off, for joining us. Yeah, thanks, Jason. Appreciate you having us. So, quiet first half, but it seems like you guys are going to have a pretty busy second half. Maybe, if you just want to set the stage for some of the updates that you're going to have in second half, because it seems like you're hitting a pivot point where, you know, there was, you know, limited updates, but now second half looks like it'll get busy. Yeah, we would agree with that assessment. So, coming up in the second half, probably the one we will probably spend a decent amount of time talking about is on RLY-2608, our PI3K alpha mutant selective inhibitor. We have that molecule's been in the clinic for a couple of years now. We now have it moving forward into, you know, kind of expansion stage of the study at 600 milligrams twice daily in HR-positive, HER2-negative, PI3K alpha mutated metastatic breast cancer. And there, you know, the questions that we answered early on were around safety and efficacy and showing meaningful differentiation against the existing non-selective inhibitors. And I think the remaining question is more around the on the efficacy side and understanding the comparability against some of the non-selective inhibitors. And especially when you start to think about ahead to the regulatory endpoint, which is progression-free survival, you know, that is just, it's one of those endpoints that it just takes time to generate that data. And we're pretty excited to be able to point to the second half of this year as a point in time when we think we'll have some pretty robust data on to that end against understanding the profile of 2608 when it comes to efficacy and ostensibly the second-line patient population and breast cancer. So that's a key data point that we're looking forward to, and we continue to be very excited about that opportunity. We are even, in the face of that data coming in the back half of the year, starting to put some preparations in place for a potential pivotal study next year. Continue to have a lot of confidence in that program and its ability to drive meaningful change for patients with PIK3CA-mutated breast cancer and beyond. Additionally, with RLY-4008, our FGFR2 inhibitor, we had shown initial tumor agnostic data last fall at the Triple Meeting. And at that time, we said we were pausing regulatory and commercial preparations in cholangiocarcinoma, to allow the tumor agnostic data sets to catch up and so we can kind of understand the profile of the molecule in that setting. And we pointed towards minimizing spend in 2024 against that program, but generating some more mature tumor agnostic data, going to have a conversation with the regulatory authorities about a potential tumor agnostic regulatory path forward. And then in the second half of this year, we'll put those two things together, a data update, some regulatory feedback, and really provide a view of the strategic direction of that program moving forward. And then, just yesterday morning, we put out a press release announcing that we'll be hosting a new program and platform event next month. We had guided last year to showing at least one new program this year. And so that event will be the forum for us to show a couple of new programs. And that, you know, is really quite exciting for us. We continue to have a very productive platform, the Dynamo platform. You know, we were one of the first in this space to really bring together cutting-edge computational and experimental techniques to solve previously unsolvable problems in targeted oncology. We then expanded that to genetic disease. This will be a forum for us to really remind people of how powerful and productive the Dynamo platform has been when it comes to solving very hard problems. These programs that we will talk about will be. The intent is to be able to demonstrate potential either first-in-class or best-in-class profile. It'll be against targets that are known but have had liabilities that have not been solvable through traditional means. We'll be able to identify and articulate a novel approach that the platform has afforded us. When we think about the platform, I think with both FGFR2 and PI3K alpha, you've demonstrated an ability to develop more selective molecules and solve for certain, I guess, those limiting side effects and potentially be able to generate better efficacy. I guess the overlay of that has been things like Project Optimus, IRA, all these different things that have, from a stock perspective, I think made the end market opportunities more challenging, I think, for investors to crystallize what the light at the end of the tunnel looks like. So as you think about, you know, advancing new programs into the clinics, how do you what do you say the learnings from how the market's evolved and how you go about product selection? Yeah, so it's important to remind folks that the platform is not created to solve biology questions. It is created to solve novel insights of how to go after a target once you've chosen a target of interest. And there, the platform has evolved better than we had anticipated in its ability to help us identify novel ways to go after genetically or clinically validated targets, because that's what we choose to point it at today. And therefore, you know, we continue to have a large focus on that target selection part of the process. That is more of a strategic question that we ask at the very beginning of any drug discovery effort. And then once we set our sights on a target of interest, we can then set the platform off to do what it can do, which it has done repeatedly now, which is identifying novel ways to go after these protein targets of interest and helping us identify novel chemical matter to be differentiated for patients in those settings. Yep. Okay. Well, maybe shifting to the PI3K alpha program. And Don, can you just remind us sort of the improvement relative to the existing standard of care on hyperglycemia and some of the early efficacy and maybe how you would define sort of therapeutic benchmarks, right? Because it's a fluid and evolving space from both second line and there's ultimately like looking ahead to front line. Yeah. So, you know, I think when we look at the non-selective PI3K alpha inhibitors, there are three toxicities that are shared across the class that have really been limited, both the doses that patients can be started at as well as the ability for patients to be able to maintain dose intensity. And those are hyperglycemia, diarrhea, and rash. Those are the AEs that most frequently led to discontinuation of alpelisib and its—I mean, of alpelisib and its pivotal trial. So, we hypothesize that with mutant selectivity, we should be able to be superior across these key toxicities. Now, hyperglycemia is one that we see is really critical for physicians and paramount in them thinking about what drug they're going to reach for. They, you know, are grade 1 hyperglycemia, which is a lab abnormality, doesn't require any medical intervention. Grade two typically is met with starting an oral anti-hyperglycemic. I think oncologists have shown that they're largely comfortable with those. Grade three is when patients start requiring injectable insulin, sometimes need hospitalization. I think that's sort of the red line that we've seen that physicians aren't comfortable with and frequently are calling endocrinology consults if they want to keep a patient on a drug or just stopping the drug and moving to something else. Our goal, you know, was really to dial out grade three hyperglycemia. In the early data we've shared to date, we've been able to do that successfully. I think we've also seen lower rates of diarrhea and lower rates of rash. That gives us confidence that the profile that we were able to generate in the lab is translating into a superior safety profile in patients. Now, when we look at these comparisons, it's important to take into consideration who are the patients who are being treated. We have used enrollment criteria in our ongoing trial of 2608 that are relatively broad and relatively reflective of a Western patient population. We can enroll patients who have higher BMI. We can enroll patients who are most likely prediabetic. In the most recent data disclosure that we saw from Roche on their PI3K inhibitor inavolisib, which they disclosed in December at the San Antonio Breast Cancer Symposium, that was an incredibly highly selected patient population that really had strict limits on fasting plasma glucose and hemoglobin A1c that functionally excluded about 50% of a Western population just based on the metabolic criteria alone. So, I think one of the key questions is, as you're benchmarking us, who's our patient population and what's the hyperglycemia number in that patient population? And then when you get to the efficacy side in the post-CDK4/6 setting, at this point, the two most relevant comparators are the two agents that have full approval in the post-CDK4/6 setting. And that's alpelisib and capivasertib. Alpelisib in the real world in patients who, you know, have seen prior fulvestrant, prior CDK4/6, maybe prior chemotherapy. It's been reported by Novartis and others that you're seeing a real-world PFS in the neighborhood of six months. For capivasertib, which is an AKT inhibitor from AstraZeneca that was approved in late 2023 in their phase three trial in the post-CDK4/6 patient population, PFS was five and a half months. I think as we look at the benchmark ultimately for what the approval of an agent that you might run head to head against either of those agents, it's going to be in the neighborhood of 5.5-6 months that you're looking to beat for progression-free survival. Do you think you'll have interpretable PFS? Because I recall, like, last year we met and focus was on CBR and maybe just I guess I don't fully know what the CBR benchmark might be. Yeah. Yeah. So I think at the point that the PFS data are not yet mature, CBR is the relevant endpoint to look at. We anticipate CBR will be most robust when we get into a disclosure in the second half of this year. So, you know, the CBR benchmark for alpelisib in the BYLEEVE population, which is the patient population that was less heavily pretreated than ours is likely to be, was 46%. And capivasertib did not report a CBR, but with a 5.5-month median PFS in post-CDK4/6 patients, you would put that at probably a low 40s for CBR. So I think somewhere in the 40s is what we're looking at for the benchmarks. And what we'll be looking to do is improve on that substantially. With it. Yeah, go ahead. And I think just although we would anticipate we won't have a mature enough data set to show a median PFS point estimate, in addition to the CBR, we can do a six-month landmark PFS analysis against this data set, which becomes very germane when you talk about these benchmarks that have a median PFS of, you know, in and around 5.5-6 months. And so if we can show, you know, a CBR rate that's, you know, meaningfully north of 50% and then a median, a landmark PFS six-month analysis, again, meaningfully north of 50%, and you're talking about, you know, CBR rates in the mid- to low 40s and PFS in 5.5-6 months range, that starts to become. That's why we continue to say that this will be a robust and interpretable data set against those benchmarks. I guess as you think about different therapies that have been sort of limited by these side effects, is the thinking that, you know, when you look at data cuts with those reductions or without, that, you know, being able to avoid these side effects, you can actually generate a step change in efficacy? Or is it more about having something that works comparable but for everyone? Yeah, it's about changing efficacy. I think the strongest proof we have for that is actually in the development of alpelisib itself in the SOLAR-1 trial, which was in patients who are naive to prior CDK4/6. So it's not purely interpretable relative to our data, but still in that trial, they actually did a retrospective analysis based on doing a cut at median dose intensity. So the label dose for alpelisib is 300 milligrams once daily. The median dose intensity was about 250 milligrams. So half the patients actually are getting less than 250 milligrams a day, half more than 250 milligrams. And when you looked at the differential PFS based on dose intensity, the patients who had higher dose intensity did significantly better than the patients with lower dose intensity. So there's clearly efficacy left on the table here. I think with 2608, with dialing out some of these AEs, being able to hit the target harder and being able to maintain dose intensity, we feel we can pick up that efficacy. Stepping back, is the, you know, how do you think about what's the market opportunity that you're truly chasing? If Roche moves into front line, is PI3K alpha, is there still going to be a relevant second line plus subsegment worth further developing that all the way to goal line? Or is this more about validating and then knowing you going into pivotal phase three in front line, say, that that's the worthwhile investment? I mean, sure, we think that even in the face of a potential approval for an inavolisib off the INAVO120 study, that there's still a meaningful size opportunity within the second-line. If you play that out, and the broadest label they would likely be able to get is in that endocrine-resistant patient population in the front-line. And so that's probably 40% or so of the patient population. They then have the hurdle that they didn't actually combine it with the current commercial standard of care, which is ribo and fulvestrant. So you have to convince physicians to use the, like, an inferior combination partner in palbo and fulvestrant. And then you're further restricted in the fact that the data set that they have was highly metabolically selected. Even if they get a broader label in the endocrine-resistant patient population, physicians full well know that, you know, the way they got to that level of PFS was through choosing extremely metabolically fit patients. That's not representative of the Western patient population. If you really take all the cuts that they provided to get to the extremely positive phase 3 study that they ran, it really only represents about 20% of the front line patient population. That's, again, not with the current commercial standard of care combination. I think, you know, it's somewhere in between, you know, 0%-40% of the patients that they would address in the front line patient population. If you presume all of them saw alpelisib in that setting, you still have 60% of the 18,000 PI3K alpha mutated patients in the front line that would be available for, you know, subsequent PI3K alpha inhibitor in the second line setting. I want to get that number right. Because it sounded like you were saying more than half of the patients' second line will be PI3K naive based on the cuts that you just outlined. At least, yes. At least 60%-80% if their label were going to be strictly restricted to what the patient population they ran the phase 3 study in. Yeah. That's something, you know, that we can only speculate on right now. Sure. Sure. Label will reflect that. Yeah. Yeah. Yeah. GDR? Yeah, sure. Speaking of, you know, safety angle with your molecule and perhaps better compatibility with a triplet regimen in the first line setting, you do have a triplet in evaluation right now. Granted, it's phase 1 and it's in the second line plus setting, but you do, I think you're going to get some safety PK data, those escalation data. So, can you talk a little bit about that data set, you know, in second half and how might that inform safety differentiations? More specifically, I guess, compatibility with, you know, CDK4/6 and fulvestrant. Yeah. So as you pointed out, that'll be that triplet started earlier this year. So it's going to be very early dose escalation data, really looking for acute safety and tolerability. And the ultimate goal there is to find a dose of 2608 that can be combined with the full dose of ribociclib. And the one thing that's a little bit easier to evaluate in this context is the other non-selective inhibitors have not been able to establish any dose in combination with ribociclib, which is becoming the first-line standard of care CDK4/6 regimen. And so if we can establish a dose in combination with the full dose of ribociclib, I think that would be a significant win and significant step towards being able to demonstrate that, you know, 2608 truly has the opportunity to become the backbone PIK3CA mutated agent of record for all patients across breast cancer. Do you think you would get to the sort of in a preliminary answer in second half, or do you think that those escalation might keep going? I think we can get to the beginnings of an understanding by the second half. We may still have more work to do on the dose escalation side, but I think we'll have enough to tell us if we're on our way there. So it'd be full dose ribo, full dose fulvestrant, and 600 milligram b.i.d. 2608 would be sort of like the target. I think the ultimate question is, what is that 2608 dose to be combined with those full doses of those other agents? And I think that's the question we're trying to answer in this dose escalation exploration. Would you say the alpelisib phase 3 data as a key benchmark in terms of how you benchmark the safety, or do you think that the phase 1 data should be reviewed in isolation? As you pointed out, that this phase 1 data is good that we're generating is going to be in more of a second-line patient population as opposed to that INAVO120 study was in a front-line patient population. Prior CDK4/6 matters a lot in these patients. Again, when you get into the advanced setting of patients, we're seeing roughly a quarter of them have had either chemotherapy or ADCs. They're 50% or so have seen prior fulvestrant. These are more heavily pretreated patients, and that comes along with it some additional background toxicities in those patients. And also just gets back to the comparability to the INAVO data with regard to the metabolic selection that they did. If you go back to the phase 1B experience with alpelisib, they did have two arms that were palbociclib triplet that were segmented by baseline metabolic status. So they had one arm, those patients were both low hemoglobin A1c, low BMI, and they had another arm that were patients that were either high A1c or high BMI. And they allowed metformin prophylaxis in that second patient population. And even with metformin prophylaxis in that second patient population, again, is more representative of about half of Western patients, they had, I believe, 43% rate of grade 3 hyperglycemia. So, you know, we know that that's an agent that in patients who are less metabolically fit is a very challenging agent to use. You know, I think as we look in our patient populations, which again tend to have broader inclusion criteria, be more representative of a general patient population, the question is going to be, even in these less heavily preselected patients, can we still maintain low rates of significant or severe hyperglycemia? So you have double data coming up second half, triple data coming up second half, and thinking about potential pivotal initiation next year, should we think about the case of update as something perhaps you would bundle the 2608 double and triple data sometime in second half along with maybe some phase three strategy plan, just sort of like thinking ahead in terms of cadence of potential update investment we look forward to? Yeah. So I think from a regulatory standpoint, we have a couple of steps ahead of us in terms of we have not had any regulatory interactions around 2608 data yet to date. And so we have to have one around dose selection at some point, and then we have to have one, as you're alluding to, GDR, on phase 3 trial design. Those are likely to be back half of the year, beginning of next year events. And I don't think we'll have fully been through those by the time we disclose those data sets. All that being said, we can talk a bit more with more interpretable data in hand, you know, the potential phase 3 design elements, knowing that it's probably going to still be contingent upon a conversation with the agency at some point after that. Given the evolving treatment paradigm, now that you have capivasertib and second line and alpelisib coming up in front line, I know it may be too early to tell, but do you have a sense whether you gravitate towards prioritizing front line trial or second line trial? We think there's a very large unmet medical need and an extremely attractive market opportunity in the second line setting. You're talking 14,000-16,000 patients with PIK3CA mutations in that setting. They're pretty underserved today from our perspective with alpelisib, again, sitting in that median PFS range of 6 months. So if we can show a meaningful efficacy difference and a decent degree of probability of success against a potential phase 3 trial in the second line setting, we think there's a lot of value to be generated, again, for patients and a very meaningful market opportunity in the second line setting, all while continuing to generate supportive data that can provide future support for front line phase 3 trial also. I guess last point from me before I turn it back to Jason, Don, is breast cancer is a large opportunity, but also when you look into phase 3, you need to enroll quite a bit of patients, you know? So I'm curious about in terms of capital allocation, do you think you want to go it alone with the phase 3, or are you looking into exploring partnership opportunity? We want to be extremely clear on this point. We have the capital to go stand up and run a phase three trial next year, and we'll do that with this agent and with these data as long as they continue to mature in the direction that they appear to be maturing. We think that that's an extremely valuable opportunity for us as a company and one that we can certainly tackle ourselves if that's what we choose to do. That being said, our obligation is to maximize the value of this asset for patients and shareholders. So if a partnering opportunity avails itself at some point in time in this continuum, we will always evaluate that with a reasonable practicality of, it's just our obligation to maximize the value of the asset. Thanks. Is there a competitive interplay in your view with 2608 and HER2-negative breast and then in HER2, which, you know, is an emerging role on HER2-low and ultra-low segments? Just wondering, you know, I feel like when you talk about breast cancer, they can have a conversation without Enhertu. Yeah, no, it's definitely, I think, has, you know, obviously very successfully expanded the scope of what we think our patients who are appropriate for HER2 targeted therapy. That being said, all of the development to date in the hormone receptor positive, you know, HER2 negative from the application perspective, all of that development has been done in trials with chemotherapy as a comparator. You know, I think we anticipate that data will continue to be strong in those trials. But, you know, the question becomes, who's the relevant patient population? And, you know, in patients who are either newly diagnosed metastatic patients or second line patients, chemotherapy is a small minority of the patients receive chemotherapy, typically patients who have visceral crisis or very rapidly progressing disease and need the rapid debulking that chemotherapy can give. But today, chemotherapy is not the first thing that docs are reaching for this patient population. And I think, you know, our goal as we focus on developing 2608 is to have, you know, an all-oral non-chemotherapy regimen that provides strong efficacy for patients with a good tolerability profile. And I think, you know, with achieving that profile, even with the strength of the data that we've seen so far for Enhertu in HER2-negative patient populations being treated with chemotherapy, those would probably be used for later line patients after receiving a non-chemotherapy regimen. It's very similar to what's played out in some other disease areas where chemotherapy has been a standard of care. And then once you get highly effective and well-tolerated chemotherapy-free regimens that, you know, those typically are used before chemotherapy. Yep. Okay. Maybe in the last 2 minutes, just shifting gears to 4008 and the update in the tumor agnostic setting this second half, maybe, you know, where you're most optimistic that you might see activity based on some of the earlier clinical evaluation in other settings in the. Yeah. So when we showed so to date, the bulk of the development has been in cholangiocarcinoma fusions. We've seen, you know, relatively strong activity there. And then the data we showed outside of cholangiocarcinoma in the fall of last year at the Triple Meeting, you know, the strongest signal we had, not surprisingly, was in non-cholangio fusions. That kind of tends to hold up with the pattern we've seen in fusion oncogenes of the past. And so I think that is where we would expect to see probably the continued strongest signal and the a priori, the most likely tangible opportunity moving forward outside of cholangio is in tumor agnostic fusions. I think that'll be part of the conversation that we would intend to have with the agency in the coming months so that we can put that together with a bit of a data update and kind of holistically be able to talk about the path forward for 4008. How does that compare, you know, because I know that cholangiocarcinoma in and of itself is a niche market, but when you go, say, to a tumor agnostic, you tend to get limited to more of a salvage setting out of the gates. And so maybe just kind of weigh the different sizing of those opportunities and what you're gaining? Yeah. So if you looked at cholangiocarcinoma fusion, FGFR2 fusions in the U.S., it's probably 800-1,000 patients per year in the U.S. If you then expand that out to call it late line tumor agnostic FGFR2 fusions, it probably expands to 3,000-5,000 patients per year in the U.S. So, you know, putting those things together ends up being a pretty interesting opportunity depending on the scope and scale of the data maturation. That 3,000-5,000 is inclusive of cholangiocarcinoma then? No, in addition to that. So probably 6,000 to 7,000 total. You would look at the opportunities probably being the cumulative opportunity for both. Yeah, I think yeah, I think that's the way to think about it. We certainly have our accruing a data set in cholangiocarcinoma that in and alone would have registration ability. Sure. Sure. Okay. Great. I know we're out of time, but thank you, gentlemen, so much for joining us. Thanks for having us again. Appreciate it.