Good day, ladies and gentlemen, and welcome to Relay Therapeutics Corporate Call, RLY-2608 Corporate Update. As a reminder, this conference call is being recorded. I would now like to introduce your host for today's conference, Mr. Peter Rahmer, Chief Corporate Development Officer at Relay Therapeutics. Sir, you may begin. Thank you, operator, and good morning, everyone. Thanks for joining. We are excited to share these data for RLY-2608 in combination with fulvestrant with you today. You can access the press release from today, the slides we are reviewing, and replay this call by going to the investor relations section of our website. As a reminder, during this call, we will make certain statements that are considered forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including express or implied statements regarding our strategy, business plans and objectives, the expected therapeutic and clinical benefits of our product candidates, and the potential of our platform and our candidate product candidates' progress and timing and execution of our clinical studies trials. Such forward-looking statements are not guarantees of future performance, and therefore you should not put undue reliance upon them. These statements are subject to numerous risks and uncertainties that could cause actual results to differ materially from what we expect. I refer you to the SEC filings on our website for a discussion of the risk factors that could cause our actual results to differ materially from those discussed today. The forward-looking statements in this presentation speak only as of the original date of this presentation. We undertake no obligation to update or revise any of these statements. On today's call with me are Sanjiv Patel, our President and CEO, and Don Bergstrom, President of R&D. We will share data from the RLY-2608 plus fulvestrant doublet arm of the REDISCOVER study in HR-positive, HER2-negative, PI3K alpha-mutated breast cancer. We will also take you through our preliminary plans to initiate a second-line pivotal trial next year and our continued preparation for future first-line studies. I would also like to note that the data we will be sharing today had been submitted for presentation at the San Antonio Breast Cancer Symposium in December and will be shared with the clinical community at that time, pending acceptance. I will now turn the call over to Sanjiv to get started. Thanks, Peter. Before we get into the details, let me summarize today's headline that we're excited to share with you. RLY-2608 has a 9.2-month median progression-free survival in the second-line plus metastatic hormone receptor-positive, HER2-negative setting. This is nearly a four-month improvement in the median PFS relative to capivasertib, which is the regulatory and fast becoming the commercial standard of care in this population. With that said, let's start at the beginning and remind you that PI3K alpha represents a very significant commercial opportunity, spanning three separate sizable pillars, collectively addressing more than 500,000 patients in the U.S. alone across PI3K alpha-driven breast cancer, solid tumors, and vascular malformations. This represents one of the largest unaddressed treatment areas left in the targeted therapeutics. Unfortunately, these markets remain poorly addressed despite several approved therapies, because these non-selective first-generation agents have a high degree of meaningful toxicity, which limits their efficacy and makes it difficult or impossible for them to be combined with other agents. We believe we have addressed these liabilities by using our Dynamo platform to create RLY-2608, the first selective allosteric pan-mutant and isoform selective inhibitor of PI3K alpha. Today, we are showing clinical data with RLY-2608 to support our hypothesis. The doublet arm of the REDISCOVER trial enrolled a heavily pretreated patient population with a significant portion of patients having seen at least two prior lines of therapy and a prior SERD. The selectivity of RLY-2608 continues to be demonstrated with longer follow-up, with RLY-2608 showing limited off-target toxicity. At the recommended Phase II dose, only 25% of patients experienced a Grade 3 treatment-related adverse effect, with no Grade 4 or 5 events seen, and only 1 out of the 64 patients at the recommended Phase II dose having a Grade 3 hyperglycemia event, which of course, is the toxicity that we want to minimize. As a result, RLY-2608 leads to greater target coverage with a 95% dose intensity. This in turn leads to greater efficacy, including, as we've already stated, a 9.2-month median progression-free survival, as well as a 57% clinical benefit rate and a 33% objective response rate. Across all of these measures, we are showing results that are meaningfully higher than anything that's previously been seen in the class. Taken together, these data give us great optimism that 2608 will be able to demonstrate superiority against the newly emerging commercial standard of care, capivasertib, in the second-line pivotal trial. As a next step, we will now take these data to the FDA to gain alignment on dose and pivotal trial design. Our proposal will be that the trial is a superiority trial powered to show a clinically meaningful PFS benefit for 2608 relative to capivasertib in PI3K alpha-mutated, hormone receptor-positive, HER2-negative breast cancer patients that have previously been treated with a CDK 4/6 inhibitor. We are moving forward as quickly as possible and anticipate being ready to begin the pivotal study in 2025, of course, pending regulatory feedback and alignment. There are three distinct significant PI3K alpha opportunities, and we have robust development plans across all three areas. Let me summarize our clinical plans, beginning with breast cancer. As we've already said, next year, we intend to initiate the second-line doublet pivotal trial that we just talked through. We also continue to advance our efforts to demonstrate RLY-2608's first-line potential through our CDK4/6 triplet trial. We're now dosing at biologically active doses of RLY-2608 with ribociclib and fulvestrant, and are on track to identify a dose of RLY-2608 that is combinable with full-dose ribociclib. We plan to share initial safety and tolerability data from this triplet later this year in Q4 and open expansion cohorts in 2025. We also remain on track later this year to initiate a triplet combination with Pfizer's novel selective CDK4. In the second pillar of RLY-2608, genetic disease, our vascular malformations team is pressing ahead and on track to initiate the RLY-2608 trial in vascular malformations in the first quarter of 2025, and in the third pillar, as we mentioned, we have reinitiated monotherapy dose escalation in solid tumors and are pleased with what we've seen so far with PRs across multiple tumor types and mutations, and we're continuing to enroll more patients and collect data and look forward to moving into monotherapy dose expansion soon. As you can see from all of these three pillars and broad execution, we're leaning into our demonstrated precision medicine clinical execution expertise across our multiple PI3K programs. In addition to the large opportunities across the three pillars of RLY-2608, we have a robust portfolio of preclinical programs, all created in-house using our Dynamo platform. Let me highlight the recently disclosed non-inhibitory chaperone that has the potential to serve Fabry's patients and the selective NRAS inhibitor that can serve a broad range of patients with NRAS-driven solid tumors. We remain well-funded with nearly $700 million at the end of the last quarter. However, we continue to make careful capital allocation decisions to focus our dollars and effort on significant medium-term catalysts. To this end, we continue to focus our research footprint and reduce spend to focus on the highest value next-generation targets, and with differentiated data in cholangiocarcinoma and across other fusion tumor types and a positive FDA interaction, we've made the decision to seek a global commercial partner for RLY-4008, lirafugratinib. All of this enables us to focus our capital and execution resources on the near-term value, creating three pillars of RLY-2608, our newly disclosed and soon-to-be in the clinic programs of NRAS and Fabry's, as well as on a small number of high-value early-stage programs. Our current balance sheet will carry us into the second half of 2026, and this assumes that we continue to wholly own all our assets, achieve success on all fronts, and prosecute fully all of our current programs. Given all of these levers, we continue to have plenty of internal options to extend our runway, and this allows us to have great confidence that we can execute the second-line RLY-2608 pivotal trial and get RLY-2608 to patients as rapidly as possible. With that now said, I'll turn it over to Don Bergstrom to take you through the data and our pivotal plans in more detail. Thanks, Sanjiv. Today, we will focus on results from the hormone receptor-positive, HER2-negative breast cancer patients treated with a doublet of fulvestrant, plus RLY-2608 in the ongoing REDISCOVER clinical trial. As Sanjiv mentioned, the trial also continues to enroll solid tumor patients treated with RLY-2608 monotherapy, as well as breast cancer patients treated with the triplet of fulvestrant, plus ribociclib, plus RLY-2608, and we remain on track to initiate dosing of the triplet of fulvestrant, plus Pfizer's investigational CDK4 selective inhibitor, atirmociclib, plus RLY-2608, prior to the end of 2024. To date, more than 200 patients have been treated with RLY-2608 across these three groups. As previously disclosed, the RLY-2608 fulvestrant doublet arm of the trial initially performed dose escalation at doses ranging from 100 mg BID up to 1,000 mg BID of RLY-2608. No MTD was identified, but we opened our first expansion cohort at the 600 mg BID dose as the totality of the data, including PK, PD, safety, and efficacy, suggested this was potentially an optimal dose for the RP2D, and this is the dose level we will focus on today as we present efficacy data for RLY-2608 plus fulvestrant in PIK3CA-mutant, hormone receptor-positive, HER2-negative breast cancer. As would be expected for a patient population enrolled in a Phase 1b clinical trial, patients were heavily pretreated, with half of patients having received two or more prior lines of therapy in the metastatic setting, and over half of patients having been treated with fulvestrant or a novel SERD. Almost two-thirds of patients had visceral metastases. The distribution of PIK3CA mutations reflected the natural distribution of these mutations reported in the literature, and just under half of patients had a kinase domain mutation. And critically, more than one-third of patients had BMI of at least thirty and/or baseline hemoglobin A1c of at least 5.7%. The population we will focus on for Phase III development of 2608 are patients with any PIK3CA mutation, either kinase or non-kinase. And based on our understanding of pathway biology and 2608 mechanism, we will exclude patients with co-occurring PTEN or AKT mutations from the pivotal trial. We treated 52 patients with this genotype at the RP2D of RLY-2608 plus fulvestrant, and observed a median PFS of 9.2 months, with a landmark 6-month PFS of 64% and a 9-month landmark PFS of 60%, which is the longest PFS yet reported for any PI3K pathway agent combined with fulvestrant in patients previously treated with a CDK inhibitor. Additionally, CBR was 57%, which compares favorably to other trials testing fulvestrant plus a PI3K pathway inhibitor in patients previously treated with a CDK4/6 inhibitor, where the CBR has ranged from 37% for alpelisib group C to 48% for inavolisib, Phase Ib arm D. And with the caveat of small n, PFS in second-line patients is trending toward being longer than in third-line patients, as would be expected. We have also assessed objective response rate for the RP2D in patients with measurable disease by RECIST 1.1. Reduction in tumor dimensions has been observed in 73% of patients, and objective responses have been observed in 10 out of 30 patients for an ORR of 33%. This includes two ongoing unconfirmed partial responses as of the data cutoff. Subsequently, one patient has confirmed, and the other remains on treatment in continued response. After the data cutoff, one additional stable disease patient has converted to an unconfirmed partial response and remains on treatment. This patient is not included in the ORR. Tumor regression and objective responses have been observed in both patients with PIK3CA kinase domain mutations and non-kinase domain mutations, consistent with the pan-mutant mechanism of RLY-2608. Comparing this to benchmark data sets for PI3K inhibitors in CDK4/6 experienced patients, this is the highest ORR that has been reported for a PI3K pathway agent in combination with fulvestrant. Additionally, we have observed a complete response in a patient with non-measurable disease, who is therefore not shown on this waterfall chart. Consistent with the observation of clinical activity across PIK3CA mutation subtypes, there was robust clearance of circulating mutant PIK3CA DNA in both kinase and non-kinase patients. Nearly all patients treated with the RP2D showed reductions in ctDNA, with more than half of patients completely clearing the mutant ctDNA line. Given that some efforts to target PI3K in a mutant-selective manner leverage an allosteric pocket that only targets kinase domain mutations, we chose to also perform a subgroup analysis in kinase domain patients. As you can see on the waterfall plot, 2608's efficacy in kinase domain patients was consistent with the activity observed in the overall population of PIK3CA mutated patients, with an observed ORR of 53% and median PFS of 10.3 months. These subgroup data again give us confidence as we prepare to initiate a Phase III superiority trial versus capivasertib in 2025. One of the hallmark toxicities of PI3K pathway-targeted therapies has been hyperglycemia. For 2608, we maintain continuous daily dosing, and greater than a third of the patients on the study had baseline BMI of at least 30 and/or hemoglobin A1c of at least 5.7%. A population shown to be at increased risk of hyperglycemia in the Phase I trial of inavolisib, where patients with this metabolic profile had a 44% rate of Grade 3 plus hyperglycemia, despite metformin prophylaxis in arm F of the inavolisib Phase Ib trial, and we see very little perturbation of glucose levels at the RP2D of 2608, as shown in this graph of mean glucose level versus time for each dose level. In fact, of 64 patients treated with the RP2D, we have observed only a single case of Grade 3 hyperglycemia in a patient receiving concomitant steroids, which is an independent risk factor for hyperglycemia. RLY-2608 plus fulvestrant was well tolerated overall, with only 20% of patients across all dose levels experiencing any Grade 3 TRAE, and only 25% of patients at the 600 mg BID dose experiencing any Grade 3 TRAE. There were no observed Grade 4 or Grade 5 TRAEs. As mentioned earlier, there's only a single case of Grade 3 hyperglycemia at the RP2D, and the majority of hyperglycemia AEs were Grade 1 and required no medical management. TRAE rates were low for AEs commonly seen for the PI3K pathway class, including diarrhea, rash, and stomatitis, with Grade 3 rates for these AEs in the low single digits or zero. The favorable overall tolerability profile is associated with the ability to maintain dose intensity, which is critical for driving long-term clinical benefit. Median dose intensity at the RP2D was 95%. Those interruptions, when they occurred, were brief, and only two out of 64 patients discontinued treatment due to TRAEs. The majority of discontinuations were due to disease progression. The totality of the efficacy and safety data gives us confidence to initiate a randomized pivotal Phase III trial of fulvestrant plus RLY-2608 versus fulvestrant plus capivasertib. This trial will be a superiority trial, powered to show a clinically meaningful PFS benefit for 2608 relative to capivasertib in PIK3CA-mutated, hormone receptor-positive, HER2-negative breast cancer patients previously treated with a CDK4/6 inhibitor. Capivasertib is a relevant regulatory standard of care for these patients, given its recent FDA approval in November 2023, and qualitative feedback from physicians, as well as the dynamics of the capivasertib launch, suggest it is becoming the commercial standard of care as well. We will align with health authorities on trial design and anticipate initiating the pivotal trial in 2025. Earlier this year, we initiated triplet dose escalation of RLY-2608, combined with fulvestrant and ribociclib. ribociclib has become the standard of standard of care CDK4/6 inhibitor for the treatment of newly diagnosed metastatic hormone receptor-positive, HER2-negative breast cancer patients, as it is the only CDK4/6 to have demonstrated survival benefit in this setting. We are encouraged by the progress we have made in dose escalation and are currently administering biologically active doses of RLY-2608 with full label dose of ribociclib. We have observed a favorable interaction of RLY-2608 with ribociclib, meaning that the dose of RLY-2608 will be lower in combination with ribociclib and fulvestrant than the 600 mg dose we have characterized in the fulvestrant doublet. And we are confident that we will be able to identify a dose of RLY-2608 that is combinable with full-dose ribo, and look forward to sharing initial safety and tolerability data from this triplet in the fourth quarter. We also remain on track to initiate dose escalation of RLY-2608 in combination with atirmociclib, Pfizer's investigational selective CDK4 inhibitor, by the end of this year. As you've heard, we are incredibly encouraged by the data we shared today and believe that, coupled with our strong clinical execution and broad RLY-2608 development plans, are very well-positioned for an exciting future with the potential to significantly improve treatment for these patients in both the first and second-line settings. With that, I'll turn it over to Peter to share more on our corporate go-forward strategy. Thank you, Don. As you heard from Sanjiv and Don, we are very excited by these data and the opportunity in front of us. I want to spend a moment putting these data into context as the breast cancer market is dynamic, but one constant is PI3K alpha is the most commonly mutated kinase in cancer and the driver mutation in over 150,000 breast cancer patients each year just in the United States. It has long been a goal of the industry to find a novel, selective inhibitor of this critical driver mutation to serve these patients. Today, we have been the first to demonstrate the impact such an inhibitor could have across second-line patients in the near term, with a clear path and efforts already underway to be able to serve earlier lines of therapy. We believe the profile presented today clearly demonstrates how RLY-2608 can become a backbone therapy for all PI3K alpha-mutated patients across all lines of therapy in breast cancer, regardless of the combination partner, which represents a very significant multibillion-dollar global commercial opportunity and is just one of the three pillars in our PI3K alpha franchise. The confidence is clear when you consider the data just presented in the context of other options for patients today. The selective nature of RLY-2608 leads to a differentiated safety profile compared to other PI3K pathway inhibitors. We have shown an overall low rate of Grade 3 AEs, with very low rate of treatment-related discontinuations due to AE. For the first time, a PI3K pathway inhibitor, we have demonstrated the ability to sustain continuous high-level inhibition of PI3K alpha mutant signaling, while avoiding the high rates of Grade 3 hyperglycemia that have generally limited the class. We've been able to do this in a patient population representative of the typical Western oncology patient population, including patients with high BMI and/or elevated baseline HbA1c. As we look more closely across key AEs that have been an issue for the class, 2608 demonstrated a differentiated safety profile across the board, with low overall rate of any grade hyperglycemia and less than 20% of patients requiring any medical management, and lower rates of diarrhea, rash, and stomatitis. Lastly, when we put the efficacy data in the context of other PI3K pathway inhibitors in this population, it further strengthens our conviction in RLY-2608's differentiation from these first-generation agents. As you can see in these cross-trial comparisons, RLY-2608 has demonstrated the highest PFS, CBR, and ORR ever seen from a pathway inhibitor, despite being in a heavily pretreated Phase Ib population. As such, we are optimistic that we can generate a positive result in a head-to-head clinical trial with capivasertib, which we plan to initiate in 2025. Today's data validate the mechanism and impact of RLY-2608, and further increases our optimism at being able to address the additional large areas in solid tumors outside of breast cancer and vascular malformations. We are moving rapidly to realize RLY-2608's potential across these areas. Today's data also further validate the productivity of our Dynamo platform, which over the past years has continued to evolve its collection of cutting-edge computational and experimental techniques, and successfully prosecute some of the most challenging drug targets known today. We recently announced two new first-in-class programs targeting Fabry and NRAS that have been discovered in-house and are wholly owned. These programs will move into the clinic in the second half of 2025. So combined with our Q1 initiation in vascular malformations, we'll have three new programs entering the clinic next year. This is where you'll see us focus the majority of our time, effort, and capital. Therefore, as Sanjiv mentioned earlier, we have chosen to seek a global commercialization partner for lirafugratinib. Lira has shown differentiated data in cholangiocarcinoma, and the data for fusions outside of CCA continue to be promising. These data will be shown in detail at the upcoming Triple Meeting in October. We use these data sets to have a positive interaction with the FDA, who have recommended that we first file an NDA in CCA based on the existing pivotal data, and then generate additional data and follow-up for a subsequent tumor-agnostic fusion supplemental NDA. Given this will require internal efforts and dollars, we have decided to focus our own effort and money on the large near-term opportunities for 2608 and the other pipeline programs. All of this leaves us with a focused precision medicine portfolio addressing large commercial markets. We have a broad set of catalysts over the next eighteen months. We also have a team and balance sheet that over the last eight years, has shown it can deliver. That said, we remain diligent on how to deploy our team and capital. We'll always retain flexibility to confidently execute the second-line pivotal trial and have multiple strategic levers to extend our cash runway further. In closing, you can see why we are very excited by the data we've shown today and what they could mean for the nearly 500,000 patients in the U.S. alone across PI3K alpha-driven disease. In each of these settings, we believe the planned or ongoing studies will produce meaningful and interpretable efficacy data throughout the next two years. I would also like to recognize and thank the team for their relentless efforts on this challenging target that has taken many years to crack, as well as all of the patients, families, investigators, and center care teams who have participated in this study. As we move all these programs forward, it is going to be an extremely busy next couple of years, and we look forward to updating you on our progress as we go. With that, we'll open up to questions. Operator? Thank you. We will now open the line to questions and ask that you limit it to one question per person. To ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. And the first question comes from Salveen Richter with Goldman Sachs. Your line is open. Good morning. Thanks for taking my question. Could you provide more detail on why you see capivasertib as the comparator for this data and why you'll power against capivasertib instead of alpelisib, and what the limitations are with evaluating RLY-2608, inavolisib and alpelisib in the Phase 3 studies, just given the efficacy data that you've seen versus kind of, you know, on your comparator, as your comparator on Slide 25, just kind of putting that in context for us. Thank you. Thanks, Salveen. We'll hand that one over to Don. Yes, thank you, Salveen. So as we think forward to the planned Phase 3 clinical trial and the timeline we're looking to start the trial, there are two approved standards of care for this patient population, either alpelisib or capivasertib. Inavolisib is still running a Phase 3 trial in this population, and we don't anticipate that it will be an approved agent in the timeline we're looking to start this trial. So as we look at alpelisib versus capivasertib, I'd point out first that the performance of those agents in heavily pretreated patient populations is actually quite similar to each other. In the BYLieve Cohort C of alpelisib in heavily pretreated patients, median PFS was five point six months. For capivasertib in the CAPItello-291 trial in CDK4/6 pretreated patients, median PFS was five and a half months. So I think it's fairly consistent what the benchmark is that we'd be looking to improve upon with 2608 as we move into a pivotal trial. With that being said, as we've solicited feedback from investigators and KOLs, the consistent feedback we've been getting is that capivasertib would be the desired agent to be randomized against, given their preference for treating patients with PI3K mutations with capi versus alpelisib. And I think that is largely consistent with some of the market dynamics since we've seen the launch of capivasertib last November, where we see that commercially, capivasertib is faring with a fairly successful launch. ... And the next question will come from Brad Canino with Stifel. Your line is open. Hi, good morning. Great to see the durability update. Don, you briefly touched on this on the call and caveat at the small end, but can you walk through in more detail any differences you saw in patients who are less heavily pretreated? And really, I'm trying to get your thoughts on how RLY-2608 could perform in a more true second line population, or vice versa, how capivasertib might look in this population that you studied that were half third line plus. Thank you. Thanks for the question, Brad. As we said, obviously, we are in a more heavily pretreated patient population. As you rightly point out, you know, the N is still small, but there are some trends that we can discern. Maybe, Don, you can just detail what we've seen. Yeah, I mean, I'll first, I think, as you alluded to in your question, Brad, just point out that with regard to pretreatment, our patient population is more heavily pretreated than the CAPItello-291 population, on which we base that five and a half month number for capivasertib. I think it's been fairly common, in this space to see that with subsequent, lines of therapy in more heavily pretreated patients, you typically see PFS go down and become shorter. Obviously, there's a precipitous drop off, after first line CDK 4/6 inhibitor therapy, where you go from PFS in the twenties down to PFS in the single digits. And then as patients get into subsequent lines of therapy in the third line plus, typically you see that PFS number continue to drop. I think consistent with what we've seen externally, when we do a subset analysis of PFS by line of therapy in our patient population, the trend is towards second line patients having longer PFS than first line patients, and we see separation of those curves, third line patients. Great. Maybe a quick follow-up, 'cause you had the twelve patients that had the PTEN or AKT mutation. Is that 19% co-mutation rate consistent with the background rate, just as we think about the market opportunity size here? Thank you. Yeah, Brad, this is Peter. No, it is not actually. In larger studies characterizing co-PTEN mutations in the second line, those studies with thousands of patients characterized would suggest a co-mutation rate in the neighborhood of 7% to 10% at most. Thanks again. Our next question will come from Yaron Werber with TD Cowen. Your line is open. Great, thanks for the update and congrats on the data. Maybe just a couple of questions. Number one, can you give us a sense. Next year is gonna be a pretty busy year for you. How fast can you start the Phase 3? Is there any way to pull it into the first half of the year as opposed to the second half of the year? And then secondly, when we look at the pivotal study for Truqap, it's about 355 patients or so. Are you envisioning sort of a similar size study? Thank you. Thanks for the questions, Yaron. I mean, as you know, we're moving as fast as we possibly can. As the data update today is obviously driven by the fact we want to engage the regulator. Maybe I'll ask Peter to comment on just how fast we can go. Yeah, suffice to say, Yaron, we'll move as expeditiously as possible. I think once we're on the other side of interaction with regulators, we can come back and put a little bit of a finer point on the exact timing of that clinical start. But, you know, we want to move fast. And I think it's more likely to be early to middle next year than later next year, but we'll see how it goes on the other side of conferring with regulators on that front. In terms of size, I think, sure, you know, the CAPItello-291 study, the total size of that study is actually approaching 700 patients when you take into account the wild type patients included. So that was a pretty large study. And on par with other all-comers studies you see in the second line setting. I think when you look at probably the best other most closest analog would be INAVO121, the inavolisib plus fulvestrant versus alpelisib plus fulvestrant second line study that started early last year. That study is about 400 patients. So I think study sizes ranging between 400-500 in a genomically identified population in the second line is a fair analog for now until we have a conversation with the regulators and come back with more detail. The next question comes from Peter Lawson with Barclays. Your line is open. Thanks. Thanks Thanks for the question. Thanks for the update today. Just on the Grade 3 hyperglycemia from the one patient, anything you can tell us about the patient and what visits, any way to kind of mitigate that going forwards? Thank you. Yes, absolutely. Yeah, we can, as you remember, it was one out of sixty-four. Maybe, Don, you can talk us through that. Yeah. So this was a patient who was being treated with concomitant steroids. So it was a great patient with brain mets who was on a stable dose of steroids. And of course, the steroid, concomitant steroid use is an independent risk factor for hyperglycemia. But the patient was able to be managed medically. They were able to continue treatment with RLY-2608. And ultimately, at our RPTD, we did not see any dose discontinuations for hyperglycemia. So when we look across the profile, the only one out of 64 Grade 3, and in general, the most of the hyperglycemia we're seeing being medically insignificant and not being needed to be managed in a patient population that included over a third of patients at risk for hyperglycemia. I think we're very encouraged by the hyperglycemia profile we're seeing. As we move forward to the pivotal trial, our intention is to use metabolic inclusion criteria that will be relatively broad and will allow enrollment of patients who are reflective of a Western breast cancer population. Richard, thank you. Then just a follow-up, just around drug-drug interactions. If you-- there's anything we should be thinking about as regards to, combination drugs that you can or can't work with? No, not at this point. I think as I mentioned, with ribociclib specifically, we've seen an interaction that actually works in our favor. So in this case, 2608 is a victim of ribociclib, as opposed to this being a more generalized effect of 2608. And what we anticipate we'll see is to reach the same blood concentration of 2608 that we achieve at the 600 milligram doublet dose with fulvestrant, we'll actually have a lower dose of 2608, which is why we consider it to be favorable. Gotcha. Thanks so much. Congrats. The next question comes from Jason Gerberry with Bank of America. Your line is now open. Hey, guys, this is Chi on for Jason. Thanks for taking our questions and congrats with the update. So, the nine point two months PFS looks impressive relative to capivasertib's five point five months, considering your Phase I trial enrolled more refractory patients than the comparator Phase III trial. But I want to ask, can you help us understand capivasertib's efficacy in PIK3CA altered patients, those without AKT or PTEN mutation, as we compare and contrast your PFS data compared to capivasertib in a more like-for-like genetic alteration footprint, if I may say? And I guess secondarily, could you provide PFS, CBR, and ORR data for the all comer population, including those with the AKT and PTEN mutations? And just one quick follow-up. Given you saw numerically better PFS and CBR rates in the kinase mutation subgroup, are you planning to stratify patients by PIK3CA mutations in your phase III? Thanks so much. Thank you for that multi-part question, Chi. So let me, let me try to pick through them. The five point five months we are citing in terms of the median PFS for capivasertib is in the PIK3CA mutated population. They, they've done one presentation where they isolated PIK3CA only, and that's also at the five and a half month median PFS range for CDK four six pretreated patients. The next part of your question was- Do we have all the numbers? You know, obviously, this is an interim data report as we get to a final Phase I study data output, which we intend to do at full maturity of the Phase I study. We can do a lot of different analyses and subsets. Suffice to say, you know, as we look at the totality of the patient population outside of PTEN and AKT mutations, we see very consistent benefit on a PFS basis across all subsets of data. As you would imagine, you know, given the biological hypothesis that a PI3K pathway inhibitor would not be active or overly active against PTEN mutations and the small number of PTEN mutations we have, we, you know, we see the drug not performing as well as you would imagine in that very small subset of patient population. And look, as you can imagine, in a kind of dose escalation Phase, we included all of the patients to try and move as rapidly as possible to get the kind of safety and tolerability information that we wanted to select a dose, and that's why they're in the trial. Even though we hypothesized it would never be in our pivotal population, and I think you see in some of the kind of mutant selective PI3K alpha trials that are ongoing now, where they're actually excluded from the start of those trials. We thought it was just better to get the information and data. And obviously, as you see now, as we go into the pivotal, we'll cover a very, very large range of mutations. Great. Curious if you're enriching, stratifying patients by PIK3CA mutations in your Phase III, given you see numerically better PFS in the kinase mutation subgroup? Yeah, we see no need to enrich or disqualify any PIK3CA mutation as we think about designing the Phase III. We will run a Phase III study in all PIK3CA mutated patients. We think 2608 is active right across the mutational spectrum of PI3K alpha mutations. Got it. Thank you so much. And the next question comes from Michael Schmidt with Guggenheim Partners. Your line is open. Hey, guys. Good morning. Thanks for taking my questions. And, yeah, congrats on the early data surprise. Did the study include any patients that were pretreated with another PI3 kinase inhibitor or capivasertib? And quick follow-up, obviously makes sense to exclude the PTEN AKT mutations, also based on the signaling and the mechanism of action, obviously, of the drug. But in the planned first line setting, where you would do the triplet combination, would it be possible to include the PTEN AKT patients, in your opinion? I'm just curious. Thank you. ... Thanks, Michael. Maybe Don, maybe you can take both of those. Yeah. So, I'll start with the second question first about PTEN. You know, I think what has been reported in longitudinal studies is that PTEN mutations tend to be acquired with lines of therapy. I think that's, you know, consistent with what Peter just highlighted, with our rate in a heavily pretreated population of PTEN co-mutations being higher than what you'd expect, based on what we see in the databases. And I think we anticipate, as you go into a frontline population, the proportion of patients presenting with a PTEN mutation will likely go down and will likely be a relatively irrelevant patient population, just in terms of overall numbers. So, you know, whether we include them or not, I think is a question still to determine, but I think it's unlikely to be a very significant patient population in frontline patients. With regard to your first question, our inclusion criteria did prohibit treatment with a PI3K pathway inhibitor in prior lines of therapy for inclusion in the REDISCOVER trial. Great. Thank you. The next question comes from Sean McCutcheon with Raymond James. Your line is open. Hi, guys. Thanks for taking the question. Can you speak to the timing of the RECIST responses, and any weighting to responses in patients that were enrolled later in the study, and any differences in disposition that may have been enriched in this subset of patients? Thanks. Yeah, I mean, the timing at our R&D tends to be, you know, relatively rapid, with responses generally seen at the first or second scan. So we're scanning every eight weeks. We're generally seeing the responses in that time window. You know, we do have a number of patients who are ongoing in partial response. You know, as we look at our data and as we look at the PFS number that we've reported today, I think as you dig in and look at our Kaplan-Meier curves, you will see that there are early censored patients. Those censored patients are largely patients who are ongoing, who have not yet had a progression event, and a considerable number of those patients are actually patients with an ongoing partial response, which gives us confidence as we look at this PFS estimate that we reported today, that it will hold up with continued data maturity or potentially even improve. Our next question comes from Billy Smith with JP Morgan. Hi, this is Billy. I'm for Eric. Thanks for taking our question. Quick one, firstly, on the safety profile. I just wondered if there's any sort of cumulative safety effects we saw from this that might have some read-across into a PI3K use in VM? No. Yeah. No, and I think, you know, at this point, we are reporting data where we have sufficiently long follow-up and sufficiently long exposure that we're getting a feel for what the chronic tolerability profile looks like. I think we're very encouraged with the profile and excited to move into the VM population as well, where obviously chronic treatment will be the goal. We look forward to opening that trial Q1 of 2025. Yeah, thanks. And then quickly, just on the pivotal plan, do you anticipate any sort of prophylactic medication needed for hyperglycemia or just... Yeah, I'll leave it at that. No. No. I mean, as you know, I mean, this has been a real challenge for the non-selective inhibitors and very high rates of Grade 3 hyperglycemia, causing, you know, dose discontinuation and lack of efficacy. The hypothesis that we've always had is, if you can create a selective mutant inhibitor, you'd be able to dial out or dial down the toxicity levels, and that's exactly what we've seen. And we will not need any kind of prophylactic treatment or exclusion criteria that we've seen in some of the other studies. Great. Thanks for taking our question. Congrats on the data. The next question comes from Silvan Tuerkcan with Citizens JMP. Your line is now open. Hey, good morning, and congrats on this great update. Could you please contrast your discontinuation rates and dose reduction rates to the other PI3K alpha inhibitors? You know, at a dose intensity of 95%, what does that mean for the combo, for the triplet combo with full dose ribo? Thank you. Yeah, I think as you saw us present on the total modification rate, you know, we compare very favorably to what has been seen with the other non-selective agents in terms of interruptions and reductions, very much in line with first-in-human oncology studies. And most importantly, the treatment-related discontinuations, where we've only seen two in the entirety of the 64 patients treated at 600 milligrams twice daily, compares quite favorably to the over 10% you saw in alpelisib, and we're strongly encouraged with that as we move into the Phase 3 study. With regard to combinability, similarly, you know, I think we've seen an overall safety profile with a low burden of overall toxicity and then a very low burden of PI3K-related AEs. You would expect from the profile we've seen, that you're not going to see significant overlapping toxicity with the CDK4/6 class. And we anticipate we'll be able to maintain a high degree of dose intensity with full dose ribociclib or other combination agents in the CDK4/6 or CDK4 class. Great. Thanks so much. ... And the next question comes from Akash Tewari with Jefferies. Your line is now open. Hey, this is Amy on for Akash. Thanks so much for taking our question. So what is the reason for the 22 patients having non-measurable disease at the recommended Phase II dose? Was it just not enough follow-up? And then an additional one, if we could. Have you conducted any drug-drug interaction studies with 2608 with CYP3A4 inhibitors? Do you expect any dose adjustments in combination with CDK4/6 inhibitors or other combination regimens? Thanks, and we will take both questions separately. And maybe, Peter, maybe you can take the first one and just explain the natural history of breast cancer. Yeah, as most folks are aware, in HR positive, HER2 negative breast cancer, there's a natural distribution of about one-third, two-thirds non-measurable disease to measurable disease. Our patient population very closely mirrors that natural distribution, and so that's the reason for having given that we want to treat the entirety of the HR positive, HER2 negative, PIK3CA alpha mutated breast cancer population. That's why we have a patient population that mirrors the natural distribution of patients here. You know, by definition, you know, just so folks are aware, RECIST 1.1 clearly defines what is measurable and non-measurable, and we follow those criteria closely when reporting data. So we're trying to be as inclusive as we can in the population. And then on the second question- On the drug interaction front, so again, the interaction that I mentioned with ribociclib is an interaction where 2608 is the victim to something that ribociclib is doing that will lead to a lower dose of 2608 to achieve the same exposure that we have at 600 milligrams. It is not CYP-mediated. And as such, we don't anticipate there are CYP-mediated issues for 2608. And again, this is a specific interaction that we're seeing with ribociclib, where 2608 is the victim. Great. Thank you. I see no further questions at this time. I would now like to turn the call back to Sanjiv for closing remarks. Thank you for taking the time this morning. As you know, this has been a long time coming. It's been one of the most difficult drug discovery challenges in the industry. We believe that the data we've showed today shows clearly that we've been able to create a mutant-selective inhibitor that dials out some of the challenging toxicities that have plagued the non-selective inhibitors, and that today we've shown translates into a 9.2-month median PFS, and we're excited now to take RLY-2608 into a pivotal trial in the second line, continuing to push forward in the triplets to try and see if we can get it into earlier lines, open the vascular malformations trial in Q1 of 2025, and then finally to explore tumors outside of breast cancer. So it's an exciting time for the company, and we hope that we look forward to continuing to update you with all the catalysts over the coming year. Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.