Good day, ladies and gentlemen, welcome to the Relay Therapeutics Corporate update call, RLY-2608 data presentation at AACR annual meeting. As a reminder, this conference call is being recorded. I would now like to introduce your host for today's conference, Mr. Pete Rahmer, Chief Corporate Development Officer at Relay Therapeutics. Sir, you may begin. Thank you, operator, good afternoon, everyone. You can access the press release from today, the slides we are reviewing, and a replay of this call by going to the investor relations section of our website. As a reminder, during this call, Relay Therapeutics 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, objectives, the expected therapeutic and clinical benefits of our product candidates, the potential of our platform and our candidates in progress and timing and execution of our clinical 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 our SEC filings available at sec.gov or on our website for discussion of the risk factors that could cause our actual results to differ materially from those discussed here today. The forward-looking statements in this presentation speak only to as of the original date of this presentation, and we undertake no obligation to update them or revise any of these statements. Today on the call with me are Sanjiv Patel, our President and CEO, and Don Bergstrom, our President of R&D. And with that, I'll turn the call over to Sanjiv. Thank you, Pete. Thank you for those joining the call today. As you know, we shared this morning first in human data for RLY-2608 at the AACR meeting. As we previously stated, our unequivocal goal for this program is to deliver a step change in efficacy for patients with PI3Kα mutations. The data presented today are clearly a promising first step in delivering against our goal. These data show we've been able to meet or exceed the target PK/PD threshold while dialing down the primary off-target toxicities associated with this class, namely hyperglycemia, rash, and diarrhea. This starts to demonstrate that selective inhibition of PI3Kα mutant, which has long eluded our industry, can be achieved with RLY-2608. These data also show early antitumor activity across a broad range of PI3Kα mutations and doses, highlighted by a confirmed partial response in a breast cancer patient with 12 prior lines of treatment on RLY-2608 monotherapy. These data showed the clinical proof of mechanism, which is what we'd hoped to achieve with this initial disclosure. With the favorable exposures we can reach and the emerging differentiated tolerability profile we've shown today, we will now move forward in the second half of this year an open expansion cohort to drive towards interpretable efficacy data. In addition to this, we will continue to advance our next PI3Kα inhibitor, RLY-5836, as well as our CDK2 inhibitor and our ERα degrader into the clinic. We look forward to building a robust business with a broad range of assets over the coming years that can address the broad opportunity in front of us. We believe this is a very important day for patients with PI3Kα mutant tumors. Before Don takes you through the details of the data, let's summarize how we got here. When we were launched in 2016, we were one of the first of a new breed of biotech sitting at the intersection of leading-edge computational and experimental technologies with the goal of making medicine both more efficiently and more effectively. We were initially focused on creating small molecules against clinically and genetically validated drivers of disease in oncology. Over these last seven years, through our constant execution focus, we've shown that we can repeatedly design new molecules in-house, progress them into clinical development, and validate our platform and approach through clinical data. As depicted on slide four, our Dynamo platform consists of an integration of complementary emerging techniques and technologies spread right across both the computational and experimental disciplines, all knitted together by our experienced scientists. Our goal is to create therapies with exquisite selectivity for disease-driving proteins that we're studying. This selectivity allows for greater target inhibition without being limited by off-target toxicities. All of this was exemplified at last fall's ESMO meeting when we shared early clinical data for our FGFR2 inhibitor, RLY-4008. We believe this relationship can be generalized across our portfolio. By deploying our platform and strategy, we now have a broad range of precision medicine programs that you can see on slide five. We've moved from focusing only on small molecule inhibitors to now having degraders and chaperones in our platform. We've also expanded from oncology to pursuing programs in genetic disease, and we previously announced we have three clinical assets. Today I'm excited to announce that our fourth clinical program, RLY-5836, has also entered the clinic. All four of these clinical programs have been entirely created in-house by our team and platform. As highlighted on slide six, today's focus is our growing breast cancer business, and it's all anchored around our franchise of PI3Kα mutant-selective molecules that have emerged from our unparalleled knowledge of this target. The first of these programs is RLY-2608, following its creation, we continued our investment in research and early development for this target. Our clinical experience will help inform the best approaches for maximally addressing this broad opportunity and how best to deploy our broad franchise of programs. As shown on slide seven, globally, there continues to be a significant unmet need in breast cancer, with 196,000 new HR+/ HER2- breast cancer patients being diagnosed each year in the U.S. alone. Specifically, there remain limited treatment operations for metastatic breast cancer in patients who've already been exposed to CDK4/6 inhibitors, with progression-free survival in the second line of best available therapies flattering with around seven months. PI3Kα alterations are an important therapeutic target that could address this and over time become effective in earlier lines of therapy. Moving to slide eight. PI3Kα mutations are the most common kinase mutation across solid tumors. There are about 100,000 breast cancer patients with a PI3Kα mutation in the U.S. annually, which clearly represents a significant therapeutic opportunity. Oncogenic alterations occur right across the gene, with mutations in the helical and kinase domains being the most common. The relative size of this opportunity is larger than for mutations in genes such as EGFR and ALK, which have created multi-billion dollar commercial therapeutic franchises. Normal tissue PI3Kα regulates glucose homeostasis. Approved and late-stage non-selective inhibitors such as alpelisib and inavolisib inhibit normal tissue PI3Kα, and clearly this disrupts glucose homeostasis. The lack of selectivity of these agents also leads to additional toxicities such as rash and diarrhea. All of these off-target toxicities mean that today there remains a high unmet medical need for mutant selective inhibitors and a significant commercial opportunity for us to address. You can see on slide nine, as a result of the current approved therapy's lack of PI3Kα selectivity, target inhibition is limited by high rates of treatment interruption, dose reduction, and discontinuation due to toxicities. The efficacy of the approved and late-stage therapies is also quite limited. Our goal in developing RLY-2608, which is the first allosteric mutant isoform selective inhibitor of PI3Kα, was to try and address these limitations. Moving to slide 10. To do this, we started by solving the first full length structure of PI3Kα in complex with its regulatory subunits for both wild type and mutated forms of the protein. We used these data to perform long timescale in silico molecular dynamic simulations to identify potential drugable differences in the proteins. We found a novel drugable allosteric pocket in the mutant protein that we thought could provide us an opportunity to develop a pan-mutant selective allosteric inhibitor. We believe these insights are unparalleled in the field and culminated in the discovery of RLY-2608. Moving to slide 11. We'll now take a look at RLY-2608's development in more detail. Slide 12 highlights the biochemical data validating RLY-2608's unique mechanism of action. As you can see, it selectively targets mutant PI3Kα, in contrast to the orthosteric inhibitors that potently target both mutant and wild type. The kinome plot further shows RLY-2608's exquisite selectivity right across the PI3K family, as well as in fact the entire kinome. On slide 13, you can see further validation of RLY-2608's mechanism in mouse breast cancer models. The graphs show RLY-2608's robust dose-dependent efficacy in both helical and kinase models, and that RLY-2608 has little or no impact on glucose homeostasis at efficacious doses. In contrast, at doses required for efficacy, which are actually not clinically achievable, the orthosteric inhibitors significantly disrupt glucose homeostasis. As you can see on slide 14, RLY-2608 selectivity for mutant PI3Kα has been demonstrated in preclinical models. Meaningful target coverage and inhibition of the pathway does not lead to off-target toxicities, including most notably glucose dysregulation. All of this ultimately demonstrates tumor regressions in preclinical models. Moving to slide 15, we highlight our initial objective for today's disclosure, which is to demonstrate clinical proof of mechanism. This is similar to the focus of our first disclosure for our FGFR2 inhibitor, RLY-4008. What this translates to is showing early and initial PK and PD data that support the fact that we can engage the target at or above levels associated with efficacy in preclinical models. It also translates into showing early safety and tolerability data to show that we can avoid key off-target toxicities at these high levels of target inhibition. This is exactly the data that we'll show you today. Moving forward, the goal of future disclosures is to generate data that will allow us to further evaluate the potential efficacy profile of RLY-2608. Moving to slide 16. Our unequivocal goal for this program is to deliver a step change in efficacy for patients with PI3Kα mutations. The data presented at the AACR meeting today are a first step in delivering against this goal by demonstrating selective targeting of mutant PI3Kα. These data show we can achieve selective mutant PI3Kα target inhibition above the IC80 threshold associated with efficacy in preclinical models. We can do this with limited observed impact on glucose homeostasis and no Grade 3 hyperglycemia being observed. All of this clearly speaks to the fact that RLY-2608 is selective over wild type. This selectivity translates into an overall favorable safety profile. Adverse effects are low grade and generally well-tolerated with no DLT or adverse events leading to treatment discontinuation. At therapeutically active doses, we observed low rates of rash, diarrhea, and most notably hyperglycemia. All of this translates into a potential greater dose intensity for RLY-2608. This is manifested in early anti-tumor activity that we observe across a range of doses and across a range of PI3Kα mutations. All of this, as you know, has also been confirmed with our partial response being observed in a heavily pre-treated breast cancer patient that was on RLY-2608 monotherapy. The totality of these early clinical data start to demonstrate our goal, which is to show clinical proof of mechanism for this program. We look forward to opening expansion cohorts and generating robust and surgical efficacy data. All of this, we believe, brings us a step closer to potentially realizing our goal of developing a medicine that could provide a step change in efficacy for patients. Now I'll hand it over to Don Bergstrom to walk us through the data in more detail. Thank you, Sanjiv. Starting on slide 17, ReDiscover is a dose escalation, dose expansion study with key objectives to define the maximum tolerated dose and recommended phase II dose, PK and anti-tumor activity of RLY-2608 alone and in combination with fulvestrant. The monotherapy arm focuses on PI3Kα mutant solid tumor patients, including breast cancer patients not eligible for the combination arm. The combination arm focuses on HR+/ HER2- breast cancer patients treated with prior CDK4/6 and endocrine therapies. Today, we'll present initial results of the dose escalation portions, both of which still are ongoing and open to enrollment. The cutoff date for the data in the presentation was March 9th, 2023. As shown on slide 18, 12 dose levels on a continuous daily dosing schedule were examined in these dose escalations using a Bayesian Optimal Interval design, with additional accrual permitted to cohorts declared tolerable. Across both arms, maximum tolerated dose was not reached, with no DLTs observed. Dose escalation and cohort enrichment continue to define the recommended dose or doses to take into cohort expansions. Slide 19 summarizes the study population. 42 patients with PI3Kα mutations were enrolled, with 19 treated on the monotherapy arm and 23 treated on the breast cancer combination arm. Both populations had significant prior therapy. In the monotherapy arm, the median number of prior regimens in the metastatic setting was four, with the majority of patients treated with prior chemotherapy or an antibody-drug conjugate. This arm included a broad diversity of solid tumors, predominantly tumor types not predicted to be sensitive to single-agent PI3Kα inhibition. In the combination arm, all patients were treated with prior endocrine therapy and a CDK4/6 inhibitor per protocol. About half the patients in the combination arm had two or more prior systemic therapies for metastatic disease, and about 1/4 of patients received prior chemotherapy or an ADC in the metastatic setting, including patients treated with trastuzumab deruxtecan. While the protocol prohibited prior treatment with a PI3Kα inhibitor, 17% of patients were previously treated with an mTOR or AKT inhibitor. Also note that while the protocol required good glucose control at baseline, enrollment was open to patients at risk of prediabetes, and more than 1/4 of enrolled patients had a BMI greater than 30. On slide 20, we show the molecular demography of the 42 enrolled patients. A wide spectrum of oncogenic PIK3CA mutations were detected, reflecting the published prevalence of mutations of PI3K in solid tumors. Most commonly seen were mutations in the helical and kinase domains, and five of the 42 patients had two or more detectable PIK3CA mutations. Slide 21 shows RLY-2608 pharmacokinetics for both study arms, with dose levels depicted on the left of the Y-axis. The upper dashed line in both plots indicates the exposure associated with 80% inhibition of pAKT and associated monotherapy efficacy of RLY-2608 in preclinical models. Note favorable PK was observed across both arms, with dose-dependent increase in exposure and low peak-to-trough fluctuation across dose levels. At trough concentration, the 400 mg monotherapy dose achieved the predicted efficacious exposure associated with 80% inhibition of phospho-AKT, as shown in the left panel. The 600 mg and 800 mg combination doses achieved continuous 80% inhibition of phospho-AKT for the duration of the dosing interval, as shown on the right panel. Moving to slide 22. To assess pathway suppression with patient samples, we developed an ex vivo pharmacodynamic assay using plasma samples collected at trough from each patient to assess suppression of phospho-AKT in PIK3CA mutant cancer cells. This graph shows the relationship between RLY-2608 at a trough PK draw and the extent of phospho-AKT inhibition measured at that time point. As shown in the graph, across dose levels, nearly all patients achieved at least 50% pAKT suppression in the trough plasma sample. pAKT suppression was concentration-dependent, with robust 80% suppression at concentrations achieved by 400 mg BID monotherapy and 600 mg and 800 mg BID in combination with fulvestrant. On slide 23, you can see that glucose homeostasis was generally preserved across all dose levels evaluated in the ReDiscover trial, with a low rate of Grade 1 or 2 hyperglycemia and no observed Grade 3 hyperglycemia across all 42 patients. On slide 24, we show glucose levels versus time for the dose cohorts that exceed 80% inhibition of phospho-AKT continuously over the dosing interval. The data represent the mean per cohort plus or minus standard deviation. Across these predicted efficacious dose levels, glucose levels remain largely within the normal range. Modest glucose elevation was observed in some patients, but this was readily managed with oral anti-hyperglycemic agents. No patient required insulin or experienced Grade 3 or higher glucose elevation. These data, together with the PK/PD data, show that RLY-2608 has minimal to no impact on glucose homeostasis at exposures in the predicted therapeutic dose range. This supports mutant selective targeting of PI3Kα by RLY-2608. On slide 25, we show the therapeutic potential of mutant selective PI3Kα inhibition. The vignette shows radiographic response in a heavily pretreated woman who received RLY-2608 monotherapy at the 400 mg BID dose. She had received 12 prior lines of therapy for her metastatic disease, including Enhertu. As shown in the baseline scan on the left, the patient had high disease burden with multiple liver metastases. After four weeks of therapy, marked reductions of greater than 90% were observed for both detectable PIK3CA mutations as well as ESR1 mutant ctDNAs, as depicted in the middle panel. Subsequently, the patient achieved a partial response per RECIST, with 36% tumor reduction at the first radiographic assessment, as shown on the right. This response was subsequently confirmed after the data cut-off. The patient experienced no hyperglycemia or other adverse events due to study treatment, demonstrating mutant selective inhibition of PI3Kα by RLY-2608. She currently remains on treatment. Of note, the overall monotherapy experience included only four patients from the indications we will focus on for our expansion cohorts, two head and neck patients and two breast cancer patients with more than one PI3Kα mutation. Of these four patients, only one was treated at a dose that met our target exposure threshold, and that was the patient who achieved a confirmed PR. On slide 26, you see radiographic tumor regression and RECIST assessment for all breast cancer patients with measurable disease. The patients on the far right is the partial response highlighted in the previous slide. Overall, 56% of measurable patients had radiographic tumor reduction with stable disease or partial response per RECIST criteria, with 11 of 16 patients ongoing on RLY-2608. Regressions were observed across doses in PI3Kα genotypes, including patients with helical domain mutations, kinase domain mutations, and other PI3Kα mutations. Moving to slide 27. Declines in mutant PIK3CA ctDNA are an indicator of pharmacodynamic inhibition of mutant PI3Kα. The graphs show PIK3CA ctDNA levels at baseline and after 28 days of treatment with RLY-2608. Declines in PIK3CA mutant ctDNAs were observed in most patients and occurred with both monotherapy and combination therapy. As emphasized by the abstract discussant, Dr. Fabrice André, when referring to the pharmacodynamic mechanism of RLY-2608, this is evidence that, in his words, "The drug works." The swim lane plot on slide 28 shows duration of exposure and response for all RECIST evaluable breast cancer patients. 19 out of 27 patients shown here remain on study. Overall, the median duration of follow-up at the time of data cut was 16 weeks, with a range of four to 44 weeks, including a number of patients treated at doses below the target exposure threshold who have remained on treatment for more than six months. Moving to slide 29. This is the overall safety profile for RLY-2608, showing all treatment emergent adverse events occurring at greater than a 15% frequency across both monotherapy and combination therapy cohorts and all doses. There are no dose-limiting toxicities, AEs leading to discontinuation or Grade 4 or 5 AEs. The majority of AEs were Grade 1 or 2, manageable and reversible. Of note, the overall rate of hyperglycemia was low, and there was no Grade 3 or worse hyperglycemia. Slide 30 shows a comparable distribution of AEs for RLY-2608 monotherapy on the left and combination therapy in the middle panel. The right panel shows AEs for the 17 patients who received doses that exceeded the target exposure for 2608, associated with sustained 80% inhibition of mutant PI3Kα. Of note, the overall rate of AEs in the target exposure population is largely reflective of the overall safety profile, including low rates of hyperglycemia, diarrhea, and rash, and no Grade 3 events for these three key toxicities of non-selective inhibitors. Moving to slide 31. In the SOLAR-1 trial of alpelisib, the three AEs that most commonly led to treatment discontinuation were hyperglycemia, diarrhea, and rash. Toxicities such as these were treatment limiting, as 25% of patients discontinued therapy due to AEs. High rates of hyperglycemia, diarrhea, and rash, including Grade 3 or worse events have been observed for the non-mutant selective PI3Kα inhibitors alpelisib and inavolisib. Capivasertib, a pan-AKT inhibitor, demonstrates lower rates of hyperglycemia, but still demonstrates high rates of diarrhea and rash, including Grade 3 or worse events, despite being administered on an intermittent four days on, three days off schedule. In contrast, as you can see on slide 32, RLY-2608 shows a low rate of the three AEs most commonly leading to treatment discontinuation for alpelisib, including in the 17 patients who exceed the target exposure of RLY-2608. This toxicity profile in these data translates to a low rate of dose interruptions or reductions due to AEs and no treatment discontinuations due to AEs. Dose intensity is preserved with median dose intensity greater than 98% of the planned dose. Moving to slide 33. In summary, as emphasized earlier today at the AACR meeting from both Dr. Varkaris and Dr. André, RLY-2608 has favorable PK/PD that provides robust target inhibition, including sustained inhibition of mutant PI3Kα at 80% or greater, with limited observed impact on glucose homeostasis. We believe this initial clinical data has shown a favorable and differentiated safety profile consistent with mutant and isoform selective PI3K inhibition, which could enable treatment of broader patient populations and combinations that cannot be achieved with non-mutant selective inhibitors. RLY-2608 shows encouraging antitumor activity across PIK3CA genotypes and HR+/ HER2- breast cancer. Together, we believe these proof of mechanism results demonstrate that RLY-2608 is the first allosteric pan-mutant and isoform selective PI3Kα inhibitor to enter the clinic. Moving to slide 34. ReDiscover dose escalation continues to define go-forward doses for the planned monotherapy and combination therapy dose expansions, which we expect to begin in the second half of 2023. Moving to the next program in our breast cancer franchise on slide 35. Our commitment to ensure that we deliver the best therapeutic solution for patients with PI3Kα-mutated cancers is manifested by our decision in 2021 to bring RLY-5836 into development prior to seeing clinical data with RLY-2608. I am pleased to say that the first-in-human trial of RLY-5836 has started. As you can see on slide 36, the design of the RLY-5836 trial is similar to the RLY-2608 ReDiscover trial. With that, I will now hand it over to Pete to wrap up. Thanks, Don. RLY-2608 exists as part of a broader portfolio of breast cancer assets that we are advancing with the aspiration to bring about a step change in treatment of breast cancer. The data we shared today validate the potential advantages of highly selective inhibition of validated breast cancer targets that lies at the heart of our breast cancer portfolio. As we transition to enrolling the expansion cohorts of patients in RLY-2608 later this year, the goal is to demonstrate that this clinical profile translates into interpretable efficacy and a differentiated long-term safety profile relative to non-selected PI3Kα inhibitors. We continue to build on the foundation laid by RLY-2608 with RLY-5836, our second pan-mutant selective PI3Kα inhibitor now in clinical development. Our selective CDK2 inhibitor, RLY-2139, which is on track for entry into the clinic in 2024. Lastly, our oral bifunctional ER degrader on track for choosing a development candidate nomination sometime this year. Our efforts against breast cancer targets continue with other undisclosed research stage programs. As you can see on slide 38, we have a robust precision medicine pipeline with more than 13 active programs that continues to progress as planned and has the potential to address hundreds of thousands of patients annually in the U.S. alone. We believe the data presented today continue to validate our approach. The more we do, the better we get. Lastly, moving to slide 39. A key theme throughout the remainder of 2023 will be continued clinical execution, particularly with our lead clinical programs. For RLY-2608, we will continue initial dose escalation with a goal of starting dose expansion in the second half of the year. As we mentioned earlier, we just initiated the RLY-5836 first-in-human study. We will make additional clinical data disclosures in 2024 from either one or both of the pan-mutant selected PI3Kα inhibitor programs. We have two key anticipated milestones for RLY-4008 in the second half of 2023. First is the full enrollment of our pivotal cohort in FGFR2 fusion-positive cholangiocarcinoma, and then we will show initial clinical data from the ongoing non-cholangiocarcinoma expansion cohorts. With today's data, we continue to make progress toward our goal of delivering life-changing medicines to patients. We have an execution-focused team, sufficient capital, and emerging track record to deliver on all of these milestones, and we look forward to updating you on our progress over the year. Before we turn the call over to the operator for questions, I'd like to ask, all the folks asking questions to please limit to just one question per person. Operator? Thank you. If you'd like to ask a question, please press star one one. If your question has been answered and you'd like to remove yourself from the queue, please press star one one again. Our first question comes from Salveen Richter with Goldman Sachs. Your line is open. Good morning. good afternoon. Thanks for taking my question. Just maybe here on what you can do to optimize efficacy as the target engagement curve suggests that higher doses may not drive benefit, and you're sitting at kind of 600 mg and 800 mg BID where we see PI3K inhibition plateauing at about 80%. Yes. I mean, maybe Don, you wanna just take that one? I think the number one thing we need to optimize efficacy is more time and experience at a given dose. Efficacy in this patient population takes time to establish whether it's measured by response rate, where for alpelisib in the phase I-B trial with fulvestrant, the median time to response was four months, or measured by clinical benefit rate, which is a six-month endpoint. I think we anticipate that we are seeing the degree of target inhibition that's been associated preclinically with seeing robust antitumor efficacy. We're seeing strong PD as manifested by the clearance of ctDNA, especially at the doses that we project to be in our efficacious range. In early scans, we're seeing evidence of tumor shrinkage, and we anticipate we just need to have more time and experience to be able to see those responses potentially continue, as well as to be able to estimate a clinical benefit rate, which ultimately I think will be our signpost as we're looking towards PFS, which is the ultimate registration endpoint in this patient population. I think six out of seven of those 600 mg patients still remain on therapy. I think for us it's the question is now moving forward with a greater number of patients and a greater duration of follow-up. I think all the things that we wanted to achieve, which is engaging the target, doing it with a cleaner safety profile, we've been able to achieve. I think we look forward to opening the expansion cohort and getting the data. Thank you. Thank you. Our next question comes from Brad Canino with Stifel. Your line is open. Hi. Congrats on achieving the intended product profile here. On the dose management, you know, I'm really struck by the lack of dose reductions, but most of the 800 mg BID patients are eight weeks or less of treatment here at this data cut. My question is, how does that compare to the alpelisib experience? Do you see the majority of the alpelisib reductions within the first two months? Are we going to need to wait to see a longer follow-up to have confidence that you're avoiding that with RLY-2608? Thank you. Maybe, Don, you can just talk about the emergence of when the adverse effects emerge. I think the experience with alpelisib, and I'll back up and say, you know, I think the primary AE, again, that led to reduction of alpelisib and deintensification of dosing was hyperglycemia. The onset of hyperglycemia in alpelisib is quite rapid, certainly within the first cycle, frequently within the first two weeks of dosing. I think the fact that now we have a number of patients treated at the 800 mg dose that have been treated, you know, past that two to four-week threshold, and we're getting more experience without seeing the onset of the hyperglycemia, is reassuring, that as we continue to get experience with the 600 mg and 800 mg dose, we'll be able to maintain the dose intensity that we've seen to date. I'll also point out that, you know, by far the vast majority of the AEs that we've seen across the profile for RLY-2608 have been Grade 1 AEs. They've not been clinically significant and they've not impacted the ability to manage dose intensity and manage dosing of the patients. Thank you. Thank you. Our next question comes from Jason Gerberry with Bank of America. Your line is open. Hey, guys. Thanks for taking my questions, or question, singular. In the past, you guys have talked about a goal of getting to IC50 or lower coverage with the wild type coverage. I didn't see that update. Maybe it's just inferred from the low rates of adverse events. Just curious if you can comment on the exposure to the wild type. Ultimately, you know, how should we think about prioritization of RLY-5836 after this data? Is it purely a hedge in the event of some unforeseeable idiosyncratic talks or is there anything more you'd add to that? Thanks. I mean, great question. Maybe I'll take the first of the questions, singular. RLY-5836, I think as you know, when we shared that we had the program last summer, it was all around providing, you know, the best available treatment to patients. You know, we didn't know what would happen when you put a medicine. Apparently you do see idiosyncratic things. RLY-5836 has a different chemical structure, slightly different PK profile. It will, as we announced on the call today, it is in the clinic now. We'll have both in the clinic for a period of time. We'll make the choice on which to take forward. The IRA, as you know, provides us with an interesting opportunity to actually take both forward if we had to, split the indications. I think there is today our need for RLY-5836 being the proof of mechanism that we have on RLY-2608 has probably gone down, the need for it. There is just this one thing around the IRA which actually require us to take both forward in a certain situation. If maybe with that, I'll bring it back to the first question around on the IC50. We didn't explicitly show IC50 data, but our goal using IC50 was using that as a threshold above which we were concerned we could run into wild-type PI3Kα toxicity. I think with the tolerability profile that we've shown, with low rates of hyperglycemia, diarrhea, and rash, and then again, generally across all AEs, largely Grade 1 AEs, is consistent with us, you know, being in the range we want it to be for minimizing the either wild-type PI3Kα-related toxicity or toxicity related to other isoforms or family members. Got it. All right. Thanks. Thank you. Our next question comes from Yaron Werber with Cowen. Your line is open. Yeah. Hi. Thanks for taking a question. I got sort of interrelated two questions. I guess the first one, how much higher do you foresee going in terms of the dose escalation? Secondly, when you do look at the, I think it's slide 26 at the measurable disease slide, the 16 patients, it looks like one arm actually crosses the 30, and that's not the mono, the combo, but it wasn't considered a PR. Did they just not get scanned, or can you give us expand on that? Thank you. Maybe, Don, you just take that. Yeah. Yeah. That was a patient who, again, consistent with the notion that responses come late for this mechanism in this patient population. This was a patient who had the cycle six scan, approximately 24 weeks into therapy, had shrinkage of target lesions down below 30% response. Unfortunately, at that scan, the patient did have detection of a new non-target lesion. A new lesion, which defines that scan not as a response but as a PD. Given the reduction in the tumor lesions that the patient had, the investigators felt strongly that this patient was responding from therapy, and this patient does continue on treatment with RLY-2608. Maybe, Pete, you want to take the question on how much dose escalation? Yeah. I think you highlight a good point, Yaron, which is we have a clear and discernible range of doses that hit the target profile of what we're looking to achieve. We will continue to dose escalate just to understand the full breadth of potential exposures and knowing that we're nowhere near having hit a DLT or an MTD. Generally speaking, you know, anything from the 400 mg BID to 800 mg BID look like clearly potential dose or doses to contemplate taking forward into expansion. Maybe, Don, you just comment on the kind of dose intensity that we're looking for. Yeah. I think, you know, Yaron, as we, as we go through looking at doses and selecting doses to take forward, one of the key things we'll be looking at is the ability to maintain dose intensity chronically. We've been able to show at the doses we've evaluated so far, we maintain 98% dose intensity. The reason why that's significant is, as we mentioned earlier, with alpelisib, you see significant challenges with maintaining dose intensity. The average dose that's actually administered for alpelisib, the median dose that's actually administered is about 250 mg daily compared to 300 mg daily dose that is the label dose. There is actually an analysis of the SOLAR-1 data that looked at PFS as a function of whether patients were able to stay above that median dose of 250 or so milligrams or whether they're below that median dose. There was a numerically significant difference in PFS for patients who were able to maintain dose intensity with alpelisib. Our goal as we choose a dose for RLY-2608 is to choose a dose where we can not only hit PI3Kα hard as we are already, but maintain the type of favorable tolerability that allows you to maintain dose intensity. I think based on that precedent experience with alpelisib, if you can maintain dose intensity, that should translate into superior progression-free survival. Are you planning on dose escalating further up, or you're just planning on expanding the current doses? Thank you. We can continue to dose escalate, and we do anticipate looking at higher doses, and we'll look at the totality of the data as we choose which dose or doses to take forward into expansion cohorts in the second half of this year. Thank you. Our next question comes from Michael Schmidt with Guggenheim Securities. Your line is open. Hey, thanks for taking my question. Is there something going on with the potential drug-drug interaction with fulvestrant? I'm just asking because you're reaching the IC80 in the monotherapy at 400 mg, but you seems like you have to go a bit higher to 600 mg or 800 mg for the combination. You know, is there a signal perhaps? You know, what would that mean for, you know, achieving higher exposures if you go higher in dose? Michael, I think, you know, as we presented the data, we presented based on what we've observed in the data set that we have to date. We did see that in the 400 mg monotherapy, we were exceeding that 80% threshold. That being said, the numbers are still small for both monotherapy and combination cohorts. We entered into the study, we have no a priori hypothesis for a mechanism-based pharmacokinetic interaction between fulvestrant and RLY-2608. We need to get more data to understand whether there truly is you know, lower exposure in the fulvestrant combination. We've, you know, continued the dose escalation of both monotherapy and combination therapy, and they are decoupled from each other, so we're not limited by the monotherapy experience for how we can dose in combination. We will choose the best doses to go forward. One could imagine there could be different monotherapy or combination doses in the scenario where there were two interactions. Again, we need to have more experience to be able to know whether that's the case. I will point out that the experience we've had so far has suggested that even in the monotherapy dosing at 400 mg, the patient who achieved the PR was actually the 400 mg monotherapy patient who had the lowest exposure amongst that four-patient cohort. You know, I think the data supports that, you know, at the 400 mg mono, we're hitting the target hard, and we anticipate with more time and experience, we'll evaluate whether 400 mg combo shows similar profile. Thank you. Our next question comes from Eric Joseph with JP Morgan. Your line is open. Hi, guys. Thanks for taking the question. There was talk in the discussion section this morning about the level of phospho-AKT suppression that could correlate with response and, you know, some data corroborating 80% as a, as a, as a threshold, lining up nicely with your data. I just wonder whether or really how comparable that analysis would be to the ex vivo PD work you're showing here today. Whether you have opportunity to kind of look at phospho-AKT response kind of side by side with alpelisib in your analysis, and also whether you're looking at other effectors downstream. Yeah. Yeah. As a marker of suppression, perhaps like 4EBP1. Thanks. We have been focusing primarily at this point, Eric, on phospho-AKT. You know, I think with additional time, we can build out the translational program and look at some other markers. I think what we are very reassured about at this point is the agreement that we've had between our projected pharmacokinetic level to achieve 80% inhibition and what we see in the readout in the ex vivo assay. As we were running the preclinical experiments with RLY-2608, we're able to show that, at drug levels that were around the level of about 4,000 ng/mL, in the mouse, that was associated with, you know, deep phospho-AKT inhibition on the order of close to 80% in tumor and associated with anti-tumor regression or regression in the mouse animal models. I think what we've now shown as we've gone into the clinic is we achieved that same level of drug concentration on the order of about 4,000 ng/mL. Now in the ex vivo assay, we see that we are at about 80% phospho-AKT inhibition, so very close to what we would have projected based on the mouse experience. We're seeing that in the context of robust impact on circulating tumor DNAs and then ultimately tumor regression, including the PR. Thank you. Our next question comes from Akash Tewari with Jefferies. Your line is open. Thanks so much. In slide 22, when you measured, kind of to that similar point, when you measured, pAKT inhibition in those patients, any color on what time points those measurements occurred? Were you explicitly able to track potential reactivation of other downstream effector pathways over time? I guess more broadly speaking, how concerned is the team that maybe wild type inhibition for PI3Kα may be necessary to confer efficacy, given we've seen with some of the other PI3Kαs responses even when they're hitting kind of the IC60 or IC70 range? Thank you. Yeah. On that slide you mentioned, slide 22, all of the dots there are trough measurements. These are measurements that were taken immediately before a patient was administered a dose. Because what we really wanted to show was that at the lowest level of PI3K inhibition, we're still exceeding 80%. Each patient can have more than one dot in this graph, because these time points are taken over the course of treatment, at cycle one, day 15, and then at the beginning of each cycle for subsequent cycles at a trough. We're collecting multiple measurements per patient. In terms of the question of wild type, the requirement for wild type PI3Kα inhibition, we've seen nothing in our preclinical experience that would suggest that we need to hit wild type PI3Kα to be able to see activity. We've looked at molecules that have a range of selectivity for mutant PI3Kα over wild type PI3Kα. The driver of anti-tumor response over the course of xenograft models that we've run, you know, for longer than a month, has been to show that it's how hard you hit the mutant PI3Kα that ultimately dictates whether a tumor is going to regress. I think that, you know, again, is supported by the clinical data, including the patient we showed today with a response. That was a patient with very large tumor burden. As you can see on the scans, multiple lesions with the PI3K mutation. We're able to go in, we're able to drive significant debulking of that patient. As Dr. Varkaris indicated, it was associated with not only radiographic improvement, but clinical improvement in that patient as well. We were able to do it in a setting where there was no AEs recorded, including no hyperglycemia. It would suggest that we really had minimal wild-type PI3Kα inhibition in that patient with a marked tumor response. Thank you. Our next question comes from Peter Lawson with Barclays. Your line is open. Great. Thank you so much. I guess the question I've really got is just around what you wanna see from RLY-5836 versus RLY-2608. I mean, is that deeper responses? Is it similar agent activity or a better combination activity? Or do you expect to see some kind of patient segmentation occurring between the two molecules? Thank you. Thanks for the question. Maybe I'll hand it over to Pete, maybe you can take that one. I know we touched on it a little bit before around, you know, today, RLY-2608, the data that we show probably gives us great confidence that we can take it forward. You know. Yeah. I don't think there's much more to say other than we don't see any problem that we need solving with RLY-2608 by RLY-5836. The initial intention, as we alluded to earlier, was one of protecting against idiosyncratic tox. That's been largely dispelled today. I think in the context of now just extra conservatism on continued observations clinically with RLY-2608, but also that of the IRA gives us the ability to maintain flexibility for an extended period of time to and observe both of them clinically before we make decisions as to what to do with both programs. Today was definitely the first day in which we gained a lot of comfort by these data that RLY-2608 may be the ultimate answer we need to finally address the shortcomings that for patients with PI3Kα mutations. Yeah. I mean, the two things that were clear from the data is that, you know, it's clearly selective, and then the pan-mutant coverage that is seen. Again, those were the two clear questions for us that needed answering, and now we're gonna go off and get the clear efficacy data that I think these patients require. Gotcha. Okay. Thank you so much. Thank you. Our next question comes from Matthew Biegler with Oppenheimer. Your line is open. Oh, hey there. Thanks for the question. Are we sure fulvestrant's the best combination partner for RLY-2608? I think the discussion mentioned pairing it with an AKT inhibitor like capivasertib. I'm just kind of curious, given your safety, if that's something you're considering. Thanks. I mean, I think given the safety profile that we have now, it is potentially combinable with a broad range of assets. That's been one of the challenges in this treatment paradigm, is just the lack of ability to combine these agents on top of each other. I think our agents should help with that. Maybe, Don, you can comment further. Yeah. I think, you know, at this point in the development of RLY-2608, and as we were starting the first in-human trial, for the patient population that we're initially addressing following treatment with the CDK4/6 inhibitor, fulvestrant is the sort of default standard of care combination partner at this point. That really drove the choice of fulvestrant in this trial. That being said, a number of our patients in the combination arm had already had prior fulvestrant. A number of the patients in the combination arm, and in the monotherapy arm had ESR1 mutations. You know, I think those are, you know, the types of profiles that would suggest potentially you could consider, over the life cycle of RLY-2608, combining with newer generation, estrogen receptor targeting agents, especially agents that would have activity against ESR1 mutations. As Sanjiv Patel highlighted, the profile of RLY-2608 is a profile that should be very combinable with other therapies. We have our own portfolio of assets that we are bringing forward to combine with RLY-2608, including RLY-2139, our selective CDK2 inhibitor. We feel the profile that we've demonstrated today is a profile that should be more combinable with CDK4/6 inhibitor therapy for moving into earlier line treatment in the front line metastatic and adjuvant setting. There's the potential to consider other types of rational combinations, of which AKT could be an example. The profile that we've been able to demonstrate today is now uniquely for PI3K -targeting agent, leaving any of these options available to us. Thanks, Don. Thank you. Our next question comes from Dane Leone with Raymond James. Your line is open. All right. Thank you for taking the questions. I'll try and wrap one, I guess, semi-complicated one together for you. Just to be clear in terms of your messaging on what you hope to accomplish with RLY-2608 in the remainder of the year, is it correct interpretation that you'll have or be choosing an RP2D for the expansion cohorts in the back half of the year, which would imply maybe you could give us another clinical update and especially maybe more follow-up at the higher 800 mg BID dose level. You know, within that framework, have you actually started dosing any patients above 800 mg BID at this moment, or already? Your commentary kind of implies you might have, but, it'd be good to clarify that statement. Thank you. Dane, thanks for the question. You're right that our goal would be to initiate expansion cohorts before the end of this year, so in the second half. Then we've also guided to sharing additional data from either RLY-2608 or RLY-5836 sometime in 2024. As we progress through the rest of this year, we'll get clearer as to when in 2024 that might come. Yes, we do intend to explore doses above 800 mg. That effort is ongoing. Okay. I guess, I mean, is there another update on this data set this year, perhaps? No, not ruling it out, just saying our guidance is 2024. If we generate data that is clear and interpretable against either next steps or, against the profile of the molecule different than what we've shown people today, we'll remain, you know, we'll remain committed to get that data into the hands of the public as quick as we can. As we sit here today, knowing what we have in front of us and with the goal of this next update to make sure that we can get some more definitive clarity and interpretability around efficacy specifically, our best guidance is 2024. If I could sneak in a very quick question. Some people just asked if there was any difference in glucose management for patients in the 400 mg BID monotherapy cohort. I think people are just eyeballing your chart and wondering why there might not be a dose response on glucose concentration at 400 mg BID monotherapy versus the two lower dose cohorts preceding it. Thank you. No, no, there's no difference in glucose management. The, you know, I think consistent with experience with other agents, the strongest predictor of somebody potentially having any excursion here is what their risk is for glucose metabolism dysregulation at baseline. I think generally what you're seeing rather than dose dependence is, what is the baseline metabolic status, BMI, HbA1c, and other variables. Thank you for the clarification. Appreciate it. Thank you. Our last question comes from Silvan Türkcan with JMP Securities. Your line is open. Well, thank you for taking my question. Congrats on the presentation. I have a question. If you could maybe quantify or comment on the dynamics of tumor burden reduction in these patients per dose. Do you see any faster reductions with, you know, the higher doses, the 600 mg, 800 mg BID versus, you know, some of the lower doses? That'd be helpful. Thank you. Yeah, I think it's, Silvan, it's still largely too early to make any conclusions. Although I will point out just looking at, you know, the experience in some of the double mutant patients, of course, our response within the double mutant patient at 400 mg BID was the only double mutant patient we treated at an active dose, and we did see a first scan response there, but the experience is still quite early. Just to point back to the prior alpelisib experience that, you know, responses with that agent in a comparable patient population are slower with this mechanism. You know, time to response median was about four months. There were some patients that didn't respond until almost two years into therapy. It is a later event. Thank you. Thank you. Ladies and gentlemen, this does conclude the program. You may now disconnect. Everyone, enjoy the rest of your day.