Okay, great. Well, good afternoon, everyone, and welcome once again to the 46th annual TD Cowen Healthcare Conference. I'm Yaron Werber from the TD Cowen Biotech team. It's a great pleasure to moderate the next fireside chat with Relay Therapeutics. With us today, we have Sanjiv Patel, President and CEO. To his left, Peter Rahmer, Chief Corporate Development Officer. To his left, Don Bergstrom, President of R&D, and with us today, Jaena Han as well from our team. I think we have a few slides to go through, and then we'll actually start the presentation thereafter and Q&A on vascular malformations, which is a new and important new area, and then we'll talk about breast cancer. Excellent. Well, thank you, Yaron. Thank you to Cowen for the invitation. We're excited to talk about the exciting year ahead that we have. It's been set up because over the last few years we've built a foundation. As you know, we've all lived through tumultuous times, we made some very deliberate choices as a company to get through those so that we could focus all of our precious capital on advancing zovegalisib, which is our PI3K mutant selective molecule. To do that, we obviously focused our research organization, we staggered the entry of our preclinical programs that focused on NRAS and Fabry, and we outlicensed what was at the time our most advanced clinical program, lirafugratinib. All of that extended that cash runway into 2029 and allowed us to focus our effort in three very large clinical areas. 2nd line, hormone receptor-positive, HER2-negative breast cancer, 1st line, metastatic hormone receptor HER2-negative breast cancer, and then PI3Kα- driven vascular anomalies. All of these are very large commercial opportunities, and our goal with the capital and resources we have over the coming years is to deliver these medicines to patients and make sure that we can meet these unmet needs. Over the coming year, we're gonna share three different datasets that will hopefully de-risk meaningfully these three opportunities in the minds of our stakeholders, including our investors. Let me go through those three disclosures that we hope to make. The 1st one will come in our 2nd-line metastatic breast cancer area at ESMO TAT in Paris in two weeks' time. Up- to- date, we've shared data from our 600 mg BID fasted cohorts, which have shown a PFS over 10 months and a response rate close to 40%. As you know, a couple of years ago, we did a food effect study, we wanted to dose our pivotal trial using food. We selected a equivalent PK dose, 400 mg BID fed. The data from this disclosure will come from 57 patients who have had 400 mg BID fed as their dose. The same dose that we'll use in our phase III pivotal trial, ReDiscover-2. The goal would be that it would show consistency with the data that we've already shown and meaningfully de-risk our phase III trial. On that note, we're kinda heads down executing, we're enrolling across the world, and we're very happy with how things are going. In our frontline approach, what we'll share this year is hopefully the design of our trial, as we think about how to penetrate this very large market and the go-forward regimen that we hope to use. In the new area that we'll talk a lot about, I'm sure today, around vascular anomalies, where there is an agent with accelerated approval, where they've shown 27% response rate, in their accelerated approval, in their kind of failed confirmatory trial, they showed an 11% response rate at 12 or 14 or 16 weeks, I think 16 weeks. What we'll show is 20 patients' worth of data at the 12-week efficacy endpoint. What we hope to show is meaningful differentiation from that. Hopefully, that will provide proof of concept for this mechanism, and then hopefully then we'll be able to share next steps. The goal of the year is to meaningfully de-risk all three of these very large commercial opportunities and then for us to continue our journey towards getting these medicines to patients. With that, maybe I'll turn it over to Q&A. I'll start us off. Clearly vascular malformations or vascular anomalies are really coming into focus for you guys this year. Let's kind of zoom out a little bit. In Q1, you started your phase II ReInspire study, Q1 of last year. Yep. You started your ReInspire study of zovegalisib in adults and children with vascular malformations. Could you provide an overview of kind of this indication as a whole and why vascular malformations should be amenable to treatment with a PI3Kα inhibitor? Yeah. I mean, maybe I'll start, maybe Pete, you could take over. Obviously, the condition is driven by PI3Kα mutations. We've seen proof of concept with the non-selective PI3Kα inhibitor, alpelisib, and then the non-selective kinase inhibitor sirolimus in these patients. We know that if you can inhibit this pathway, you do see responses. What we've been able to show in breast cancer is if you can mutantly selectively inhibit the pathway, try to reduce some of the off-target toxicities, you can achieve greater target coverage, and we see meaningfully increased PFS. We hope to see the same thing here in vascular anomalies to see meaningfully differentiated response rates. That's why we feel very confident that this is an area that we can be successful in. That'd be great to add. Yeah. I think that covers it. Among vascular anomalies, we have three kind of key subtypes. We have the PI3K-related overgrowth spectrum, lymphatic malformations, and venous malformations, as well as cerebral or cavernous malformations. Are there differences between these subtypes and how sensitive they are to PI3Kα inhibition? We don't think so. I mean, obviously, we have to run the experiment. There hasn't been, you know, robust datasets produced with the molecules that we have, and so we'll run the experiment. We think a priority there is not How do you expect enrollment of between these kinds of subsets in your phase II study? Yeah. In the ongoing phase I/II study ReInspire, in the initial data disclosure, we imagine the bulk of the patients will be PROS patients. They tend to be the most severe patients, because that's where you have alpelisib with accelerated approval, those patients are actively seeking treatment and are discussing systemic treatment options with their physicians. Over time, we think that we'll, well, one, we'll have some lymphatic malformations and venous malformations in the study, over time, the distribution will probably grow. Right. If we zoom out a bit, you said that, PROS is the most kind of common. In general, overall, what's the prevalence of VM, and what% of that would be, these PROS patients? Yeah. It's a great question. At the highest level, there's about 170,000 PIK3CA-driven vascular anomaly patients in the United States on a prevalence basis. If you narrow down to the three subtypes that are most likely to be in our study over time, which is PROS, LMs, and VMs, that's about 100,000 patients. 5,000-10,000 of them are PROS, 60,000-65,000 are lymphatic malformations, you know, about 20,000-25,000 in the venous malformations. We think of that 100,000 of that cumulative, those three subtypes, we think about 25,000 of them would seek chronic systemic therapy to treat their disease. You can think of that to correlate with the severity spectrum of these patients. We believe that today, based off of, you know, the understanding what's driving uptake of both alpelisib in PROS and then off-label and then sirolimus use, you know, you're sitting at about 25% of those three populations seeking systemic treatment. The goal would be to present a therapeutic intervention option like zovegalisib that could expand that patient population over time. Right. If we just double-click on kind of standard of care, you've mentioned alpelisib and sirolimus. Kind of what options do patients have, and what does the typical patient journey look like? You wanna take it, Don? As Pete mentioned, there's really a continuum of severity in these patients. These are largely congenital disorders. Patients are born with them, frequently diagnosed in childhood. Patients with quite severe manifestations, so who have either large lesions or multi-tissue lesions, those are the more severe cases. They tend to be picked up a little bit earlier. These are the patients who were referred into these centers of excellence, multidisciplinary centers of excellence, of which there are, you know, roughly 30 or so in the U.S., usually children's hospitals. You know, they will undergo a number of either procedures, so they could have surgery, they can have sclerotherapy. Essentially, when you have toxins injected into the lesion, you know, other types of interventional radiology procedures. Eventually, a large proportion of these more severely impacted patients will look for systemic therapy because the local therapies, whether it be surgery or sclerotherapy, both, you know, eventually in multifocal disease, you can't control the disease anymore. Invariably, after either an excision or after sclerotherapy, the lesions will grow back, right? These are patients frequently who will end up looking for systemic therapy. There are patients with less severe disease who, you know, especially may present with skin disease, frequently will be seen by dermatology, frequently may go years with misdiagnosis until eventually, you know, they'll see somebody who will put the pieces together. Really, the disease is quite heterogeneous in terms of the way it presents, and quite heterogeneous in terms of the experience patients have through their diagnosis and treatment. Right. Then can you remind us what you've disclosed so far on the trial design for phase I /II ReInspire, kind of in terms of target enrollment, primary endpoint, what doses you're evaluating, et cetera? Yes. Don, want to take that? Yeah. When we started the ReInspire trial, we were able to leverage the fact that we had treated at that point about 200-300 solid tumor oncology patients with zovegalisib. Consequently, we had a good idea what the safety profile looked like as a function of dose. As we started ReInspire, we didn't have to go through sequential dose escalation in the new patient population. We're able to open randomized dose optimization in patients 12 years and older, where we are randomizing patients across 3 different dose levels of zovegalisib, with the top dose level being 400 mg BID fed, which is our oncology recommended phase III dose. We're looking at two doses below that, 300 mg BID and 100 mg BID. These are all biologically active doses that sort of span the range of target coverage. We'll have 45 patients who are randomized one to one to one across those three doses, so 15 total. Once we finish that part of the study, can move into cohort expansion, so in the same patient population. Now with what we learn from the dose randomization, we can move forward with either a single recommended phase II dose or a couple of recommended phase II doses. And we'll continue enrolling in a single arm fashion there with an ORR endpoint. We feel that there's still the potential opportunity, given the fact that there are no approved therapies for these patients to have an accelerated approval path forward. We'll obviously need to talk to health authorities, but it's possible that the data we generate in these single-arm cohort expansions could be used to support an accelerated approval application. At the same time, as I mentioned, this is a congenital disease, so everything I mentioned is for patients 12 and older. We have recently opened dose escalation in patients between 6 years old and 11 years old. That will be weight-based dosing. We'll initially dose patients at a dose that we think should give us exposure comparable to what you see at the 100 mg BID in the adolescent and adult patients. With time, we have the option of opening as well a two to five-year-old cohort. Right. Even though ORR is kind of the primary endpoint for potential accelerated approval, when you think about vascular anomalies as a whole, what do you think is the most clinically relevant thing? Are we looking just at ORR? Is it DOR, PFS? Then kind of what is the bar that you want to meet here? Do you wanna just be better than VIJOICE was in their pivotal trial? Do you wanna be better than their failed confirmatory? What are you looking for here? Give it to you. The precedent to regulatory endpoint here is ORR. It's measured by volumetric MRI. What the FDA has looked for a few different times here is, these patients generally are scanned about every 12 weeks, and they're looking for your confirmed objective response rate, 20% reduction or greater by volumetric MRI in a confirmed response. The bar in EPIK-P2 was to exclude 15% in the lower bound of the 97.5% confidence interval. That is at least the currently defined regulatory hurdle. I think our Like you said, the bookends of the best that our policy has done to date is 17% in their failed confirmatory study, 27% in their accelerated approval study, which to remind everyone, was retrospective chart review of 37 patients treated on compassionate use. By no means a traditional clinical study. In their failed confirmatory study, the response rate at the most comparable time point that we'll be able to show in our initial data was 11%. Ultimately, we wanna show a profile that's an approvable drug. You know, it's clearly we wanna beat the 11% and ultimately over time, wanna make sure that we have a dataset that could clear the regulatory hurdle. Right. Then on the safety side, what kind of profile do you think would be acceptable given that kind of these vascular anomalies are benign? Yeah. I mean, I'll start and then Don. I mean, I think, you know, you characterize, we all characterize these types of lesions as non-cancerous or benign, but the symptom involvement and the burden of the disease on the patients is far from benign. The safety and tolerability will be extremely important because the goal is to treat these patients chronically starting in childhood. It'll be a critical component of how we assess what dose to ultimately bring forward, but we're also going to make sure that we are choosing a dose that has the best risk-benefit profile to allow patients and physicians to make their best treatment decisions. The... You know, as folks that are rare, you know, understand rare diseases, there's commonly a lot of decisions being made by physicians and patients around dose. Like if you look at any of the old sirolimus studies, there's constant moving around of the dose being used in those patients. We'll kind of put all those factors together. We definitely want a safe and tolerable drug that can be dosed chronically, but also one that offers the maximal benefit for patients over time. If you see a similar profile to kind of what you've seen in breast cancer with single-digit rates of grade 3 hyperglycemia or stomatitis, do you think that's good enough for vascular anomalies? I think it's really just gonna come down to the risk-benefit profile. Like what kind of response rate are you gonna get for that kind of tolerability profile? You know, the totality of data will tell us, you know, what the best trade-off is gonna be. Makes sense. Also how might zovegalisib be differentiated from Palvella's QTORIN rapamycin, which is also in development for lymphatic malformations and venous malformations? Yeah. That whole team has done an amazing job of bringing forth another option for patients that have no options today. We definitely applaud all their efforts and are rooting for them to get that drug registered and bring another option forward for patients. We don't think that these patient populations, the one that they're pursuing and the one that we are pursuing, are gonna have that much overlap. Yeah, their drug is obviously a, it's a topical, so it can only treat, you know, topical cutaneous lesions. And as their KOL has described it's called going after the microcystic lymphatic malformations. Those are lesions that are cutaneous and of 2 cm or less. I think there's a lot of these patients. There's a lot of unmet medical need. We believe that the bulk of the patients that we'll be seeing are gonna be of either mixed or macrocystic presentation. We don't think that the patient populations are going to overlap that much. Great. I'll pass it on to Yaron to cover breast cancer. Great. As you mentioned, a TAT, we're gonna see the data from the 400 mg BID 57 patients. If I recall correctly, previously, we've also seen sort of a 50s patient number at a 600 mg. That's right. Once a day, non-fed. Is the data gonna be long enough to look at PFS? Yes. What about and I assume on response rates as well? Absolutely, yeah. We should be both, you know, presenting both ORR and PFS. It sounds like we can read between the lines that you're comfortable with the data, and they're probably gonna be fairly comparable. Our goal is to show consistency between the two different cohorts. I think we've been public to say that both cohorts were shared with the FDA, and that totality of the data was part of the granting of the breakthrough designated designation that we got in January. In terms of maybe more data that we can expect this year, it sounds like you're saying this year we'll get, I imagine both the CDK4 combo with the Tyrmo and the CDK4/6 combo and a phase III trial design. Is that sort of fair? I think our goal is to share data of specifically for the go-forward regimen. What more data we share at the time, we'll decide 'cause obviously it's gonna be a lot of information to get over. We're gonna need to share, you know, all the relevant benchmarks in the second line, the data, the regimen that we go forward, the frontline trial design, the next steps. We just wanna make sure that, you know, whenever we put out a disclosure, it is easy to digest. We'll see when we put it all together, we'll see what else we'll share. We'll definitely share that. You know, as you think about a, what would make sense and would be innovative in frontline, I imagine there's an opportunity potentially to think more in the CDK4 axis as opposed to the CDK4/6. You could do a combination, I presume, with either one, depending on, you know, tolerability and things like that. Would it make more sense to advance a CDK4 forward? That could be actually a good in combination with a PI3, it sort of evens the risks of CDK4 path to market, depending on how their own data shakes out. I think the premise of a frontline regimen has been the path has been blazed by the INAVO120 trial. It showed that if you add a PI3K inhibitor to a CDK4/6, an AI in the frontline, you add significant efficacy. The challenge in that regimen is the tolerability. The point you make is exactly the right one, which is this is about showing a tolerable profile. This isn't about proving the efficacy. That's already been proven. Between the three triplets that we run, our goal is to try and figure out which is the one that is going to be tolerable for patients to take for, you know, 3+ years. The premise of having a CDK4 selective and a PI3Kα mutant selective together, the premise would be that would be the most tolerable. Obviously, we have to let the experiment play out. When you're thinking about what would be the challenges to that kind of a regimen? I guess the one thing that comes to mind is if the CDK4 head-to-head against the CDK4/6 fails, how does that impact your ability then to get that regimen approved? Yeah. you know, I think obviously there's an ongoing trial of atirmociclib in the frontline doublet versus doublet, the Four Light- 3 trial. I think if we were to move forward with atirmociclib, we'd be looking at a slightly different hypothesis, right? The CDK on the efficacy side would not necessarily need to be superior to the existing CDK4/6 regimens for efficacy. We'd be looking at our, you know, triplet being superior. The success of that approach does not necessarily hinge on the success of the Four Light- 3 trial. Now, there are questions about what the contribution of parts would be. We think that recent FDA guidance that came out last year for the development of these types of novel agents and looking at contribution of parts would be consistent with potentially using Four Light- 3 data to support that. In a 1,000-patient trial, you would anticipate that you'd see on the order of about 200 patients who would be PIK3CA mutated that would receive atirmociclib that could potentially be used to support the contribution of components. All of this, if we were to go that route, would require us to work through with the authorities. Right. You can potentially use the data that Pfizer's generating and get access to that data. That would be consistent with recent guidance, yeah. Any questions from the audience? Maybe, an update to your ReDiscover-2 study, going head-to-head against TRUQAP, both in combination with fulvestrant. Any sense how far along are you on enrollment wise? Yeah. As Sanjiv hit at the top in his remarks, we're very happy with the progress being made thus far. We are open globally now and enrolling patients. We're not currently guiding to full enrollment or top-line data. I think once we have all sites open globally and have a good handle on what the enrollment rate is with all sites open, we'll probably endeavor to try to give some kind of target date to full enrollment. Not quite there yet, but very happy with how the trial is rolling out globally. There's been a lot of questions over the years on the Scorpion compound 478. Now that we've seen its profile a little bit more, can you maybe remind us of your relative efficacy in all mutations and in a kinase mutation and tolerability relative to 478? Yeah. I mean, I think obviously we've done this one to death over the years. The monotherapy data I think started out strong and then deteriorated. Obviously we've never really focused on that. We don't see that as the focus. We saw immediately for us to focus on the doublet with fulvestrant, where we showed 39% response rate. I think their latest data update was in the 20s. In the triplet, I think they showed some very early data where again, they were below what they saw in the doublet. I think on the efficacy front, I think we put out a bar, which no one has beaten yet, and no one has really even come close to. I think on the tolerability profile, there's some questions on the compound. Sure that they'll work through them, obviously you still see, a very short follow-up, significant grade three, grade four liver function abnormalities. So that really the question to answer on that compound is what is the dose gonna be, and then what's the tolerability profile gonna be. I think we look forward to seeing the long-term follow-up data where we can really do head-to-head comparisons and really come to a conclusion on, you know, what really is this compound. In phase III, they're still doing some dose finding in combination with CDK4/6s, right? That's right. Yeah. What, what was the reason for that? I mean, I think they obviously moved very, very fast, as is their way and as is their ability, the size of a company that Lilly can do. I do think there is a significant question around what is the dose. I do think that that's the fundamental is, you know, what's the tolerability profile gonna look like, and what's the balance between tolerability and efficacy. As you know, these patients are gonna be on the frontline on this regimen for 3+ years. As we've said right at the beginning of this, tolerability is what matters here, and that's critical. We'll spend time making sure that we've got the right frontline regimen, and I'm sure they'll do the same. There's We've been getting questions from Celcuity's data is expected to have the phase III VIKTORIA-1 data. It sounds like it's gonna be late this quarter or early next quarter or so. They've shown 9.3 months as a triplet in in the PI3Kα wild- type, and now we're waiting for the PI3Kα mutant data. Can you remind us what they've said in the past on their PFS? You know, we think it was a very small sample. You know, what do you think about that triple overall, just given the lack of convenience? They've not shown any robust data from their phase I/II study at that dose and regimen. I think they had a bullet in a presentation that said they had 11 patients that were CDK4/6 experienced, treated at that dose and regimen, and they said that that was a 19-month median PFS. That would obviously be a very compelling PFS if that held up in a randomized controlled phase III trial. As you highlight, this is a three-drug regimen where gedatolisib is administered three weeks on, one week off intravenously, and then it's combined with palbociclib, so CDK4/6 retreatment. It's combined with endocrine therapy, fulvestrant. Steroid mouthwash. There's prophylaxis steroids and prophylaxis antihistamines. It quickly accumulates to a five-plus drug regimen. In the second-line setting, these metastatic patients are living very active lives, it's gonna be a very challenging regimen regardless of the PFS in true second-line patients. The mechanism of the molecule is a multi-targeted drug hitting multiple pathways. The safety profile from the VIKTORIA-1 study in the wild-type patients looks a lot like an mTOR inhibitor. All we know is that we have a lot of data in an mTOR inhibitor in breast cancer that with everolimus does worse in mutant patients than it does in wild-type patients. At the end of the day, you need to see the experiment play out, but we don't believe in any outcome that it is truly a long-term competitive threat to our regimen in second-line patients. Great. Any maybe final question from the audience? Or maybe final question for you. What about doing a PI3 and SERD combo? Can I take that? Yeah. I mean, I think it completely makes sense. You know, one of the things that we've been doing over the recent past is looking for the SERD space to settle out. I think we're starting to see that happen. Last piece we'll see fall, or one of the last pieces we'll see fall coming up imminently is gonna be the persevERA trial. You know, I think this is an avenue we definitely, I think, could go into in the future. Arnie should have asked the question, should it be a combo with the SERD?