Good day, ladies and gentlemen. Welcome to Relay Therapeutics Vascular Anomalies Update Call. 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 morning, everyone. Thanks for joining us. We are very excited to share our initial vascular anomalies data with you today. 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, 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 and expected therapeutic and clinical benefits of our product candidates, potential of our platform and our product candidates for progress, timing and execution of our clinical trials. Such forward-looking statements are not guarantees of future performance. 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 and on our website for discussion of risk factors. 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. I'm joined today by Sanjiv Patel, our CEO, and Don Bergstrom, our President of R&D. Now I would like to turn the call over to Sanjiv. Thank you, Pete, for the introduction. Thank you for all of you joining the conference call this morning. Today, we'll share further data on our lead program, zovegalisib, zovega, for short, our pan-mutant selective PI3Kα inhibitor, which has the potential to address three very large commercial opportunities. The first of these is second-line hormone receptor-positive, HER2-negative metastatic breast cancer, where as a company, we're laser-focused on executing our pivotal trial, ReDiscover-2, which is recruiting patients globally as we speak. The second of these very large opportunities is first-line hormone receptor-positive, HER2-negative metastatic breast cancer, where we plan to initiate, subject to regulatory feedback, a frontline phase III trial in early 2027 with our novel selective combination of zovegalisib and atirmociclib. Today, our focus is on announcing the initial data on the third of these very large commercial opportunities, vascular anomalies. While the data is early, we believe it shows the step change in efficacy with zovegalisib versus what is currently being used as the standard of care, alpelisib. Our initial clinical data shows a 60% volumetric response rate with zovegalisib versus the 10%-30% that has been seen in other clinical trials and assessments with alpelisib. We saw at the 300 mg BID dose of zovegalisib a 100% volumetric response rate. We believe this to show the full potential of what a mutant selective inhibitor can do in these vascular anomaly patients and believe this leaves very little room for improvement of our volumetric response rate for anyone that will come behind us. At a 100 mg BID dose of zovegalisib, we saw a 29% volumetric response rate. We see all of these responses deepen over time, as you will see in the spider plot later, where we show that each patient's response deepened between 12 and 24 weeks. Post-data cutoff, we saw this tangibly manifested as we saw an additional response from a 100 mg BID patient who converted from stable disease at the 12-week scan to an unconfirmed volumetric response at their 24-week scan. Taking this into account, our volumetric response rate overall across all doses becomes 65% and 43% at the 100 mg BID dose. Based on all of this initial data, we believe we have a very favorable profile versus the current therapies. We see robust initial response rates across different doses, different types of vascular anomaly, different mutation types, different levels of pretreatment, and different baseline lesion volume sizes. In addition to the volumetric reductions we saw, patients saw symptomatic benefit, with 89% of the patients treated by their physicians were assessed to have a clinical improvement of their symptoms at week 12. As we said, this is a potential step change in efficacy with zovegalisib. All of this is seen at a level of tolerability that compares very favorably with the existing treatment option, alpelisib. Across all doses, we saw initial rates of Grade 3 + toxicities of zovegalisib at 15% versus 70% for alpelisib. If we just look at combining the 100 mg and the 300 mg BID doses of zovegalisib, we see that common adverse events associated with wild-type PI3Kα inhibition were low grade, manageable, and reversible. No rash or stomatitis of any grade was observed. No Grade 3 hyperglycemia or diarrhea was observed, and there have been no discontinuations to date due to AEs, and all patients currently remain on therapy. Given all of this, we're excited to open multiple zovegalisib expansion cohorts, and we're taking forward the 300 mg BID dose. Which, as we said today, we report a 100% volumetric response rate in this data cut, and we believe also has a very competitive safety profile. A dose just below this, a 400 mg once daily dose. The once daily dose is equivalent in PK to a 200 mg BID dose. Both doses will allow us to further explore the target profile and generate clinical data that's needed to move forward this important program towards a potential approval and serve a very large patient population. Note that the expected TAM of this opportunity is somewhere between $6 billion-$8 billion in the U.S. alone. This assumption is driven on our base of that there are 25,000 addressable patients in the U.S. and a pricing assumption similar to existing treatment options available, which is around $400,000 a year. If you just assume that 2,000 patients-3,000 patients on chronic treatment, that calculates to about a sales opportunity of a billion dollars. Remember that we believe there are 25,000 addressable patients in the U.S. I think all of this explains why we're very excited about sharing the data today, and we're very excited about the large market opportunity that this provides. I'll turn it over to our President of R&D, Don Bergstrom, to provide an overview of vascular anomalies, an overview of the trial we're running, and obviously share the excellent data that we're sharing today. Thank you. Thanks, Sanjiv. Vascular anomalies is an umbrella term for a variety of conditions with a wide range of clinical presentations. There are many separately named syndromes and conditions that fall into this category. Their commonality is that they consist of malformed vasculature and in some cases other surrounding tissue types. They share common genetics, of which PI3Kα, PIK3CA gene, is among the most common driving mutations in vascular anomalies where patients seek medical therapy. Current treatment options today leave large unmet medical needs, as local treatments like surgery and topical ointments can only treat symptoms or of isolated accessible lesions. Non-selective systemic treatment options carry a toxicity burden that is unsuitable for chronic use and severely limits the ability to inhibit the disease-driving mutation. zovegalisib is the only mutant-selective PI3Kα inhibitor currently in clinical trials for patients with PIK3CA-driven vascular anomalies. Its mutant selectivity allows for greater target coverage while maintaining tolerability, which we believe could lead to improved efficacy. It may also be suitable for chronic treatment, which is important as this disease is known to recur once treatment is paused. Across all of these subtypes, there are roughly 170,000 patients living with PIK3CA-driven vascular anomalies in the U.S. Because of the size and concentration of PIK3CA mutations within the subgroups, the initial focus of our programs is in PROS, PIK3CA-Related Overgrowth Spectrum, and LMs, Lymphatic Malformations. PROS, with 5,000 patients-10,000 patients, with as many as half likely to seek systemic treatment for their condition, and LMs, with approximately 65,000 patients, with about a quarter likely to seek systemic treatment. That leads, as Sanjiv pointed out, to approximately 25,000 addressable patients in the U.S. alone. Last year, we opened the ReInspire trial of zovegalisib and vascular anomalies. We leveraged nearly 250 patients' worth of experience for zovegalisib in oncology patients across the doses we would be studying in ReInspire to proceed immediately to randomize dose finding in adults and adolescents with vascular anomalies. In the first part of the study, we randomized patients across three doses of zovegalisib, 400 mg twice daily, which is our recommended phase III dose in combination with fulvestrant in breast cancer, 300 mg twice daily, and 100 mg twice daily in adults and adolescents aged 12 and older. The trial is open to patients with PIK3CA mutated vascular anomalies, including all subtypes of PROS, lymphatic malformations, and PIK3CA mutated venous malformations. Patients with any PI3K mutation can be enrolled on the study. Patients with PROS or LMs without a documented PI3K mutation were also allowed to enroll given the high prevalence of PI3K mutations in these diseases. The objective of Part 1 was to evaluate the safety, tolerability, and efficacy of zovegalisib in patients with PI3K-driven VAs. For the first time for a PI3K inhibitor in this field, to understand the relationship between target coverage, safety, and efficacy, with the goal of optimizing a treatment regimen for these patients. Efficacy is assessed in the trial by measuring change in disease lesion volume by MRI scans performed every 12 weeks, read by a blinded independent central review, and by investigator and patient-reported changes in disease symptoms. Here at the ISSVA Conference, we are sharing initial clinical data with a cutoff date of April 15th, 2026, including the initial efficacy data from 20- Part 1 patients who have reached their first 12-week MRI scan, and safety data on 32 patients who have received zovegalisib, including the 12 patients who have not yet reached their 12-week MRI scan. As expected, the patient population consisted primarily of patients with PROS, representing 69% of the patient population. 25% of patients have lymphatic malformations, and 6% of patients have venous malformations. The median age of the population was about 25 years old, with 2/3 of patients aged 18 or older and 1/3 of patients aged 12- 17. Half of patients had a non-kinase domain PI3K mutation, 31% a kinase domain mutation, and 19% had no documented PI3K mutation at study entry. A quarter of patients were pre-diabetic at study entry. Most of these patients had previously been treated with alpelisib, with some of these patients discontinuing alpelisib only days before signing consent for our trial. 72% of patients had previously been treated with sirolimus or alpelisib as prior systemic therapy for their disease. Baseline characteristics were generally balanced across the three- dose cohorts. Although in the small sample size, there were some imbalances, including over half of the 300 mg BID cohort being pre-diabetic at study entry. The pharmacokinetics of zovegalisib in vascular anomalies patients was as expected based on our experience in solid tumor oncology patients with a very flat PK profile and low peak-to-trough ratios. With the three doses achieving the levels of target coverage we projected, about 90% mutant PIK3CA inhibition for the 400 mg dose, over 80% for the 300 mg dose, and approximately 60% for the 100 mg dose. Across the 20 patients who had reached their 12-week MRI scan at the time of data cutoff, 12 patients or 60% achieved the 20% reduction in lesion volume to be considered a volumetric response. The response rate for the 300 mg dose was 100%. For the 100 mg dose, it was 29%. As Sanjiv mentioned, post-data cutoff, we saw an additional response from a 100 mg BID patient who converted from stable disease to an unconfirmed volumetric response at their 24-week scan. Taking this into account, the VRR overall becomes 65% across all doses and 43% at the 100 mg BID dose. Even at this early time point, a response rate like this, as well as the depth of responses, has not been seen with non-selective inhibitors. As you can see on the waterfall plot, responses were observed across all three doses, across PROS subtypes and lymphatic malformations, across all PI3K mutations, including in patients with no documented PI3K mutation. In patients previously treated with alpelisib, sirolimus, or both agents, and were independent of baseline lesion volume, including responses in patients with baseline lesions with a volume of several liters. The spider plots of change in lesion volume highlight the rapid and deep onset of response seen, especially at the 300 mg and 400 mg doses, and also show that responding patients who have had a subsequent scan at 24 and 36 weeks, the responses are not only maintained but are deepening. These plots also highlight the three patients at the 100 mg dose who have not yet achieved a response but show deepening of volume reduction at subsequent scans or in our ongoing treatment in the study with one of those patients, as we've mentioned, converting to a volumetric response after data cutoff. While the lesion volume measured by MRI is the regulatory endpoint in vascular anomalies, symptomatic improvement, as assessed by the investigator and the patient, is a major goal of therapeutic intervention. Patients at all doses showed improvement in symptoms, whether assessed by IGIC, which is the investigator's assessment of the patient's general symptom burden, PGIC, which is the patient's assessment of overall symptom burden, or, iADRS pain scale, which is the investigator's assessment of pain in patients who report pain at baseline. Across all three measures of clinical benefit and across every dose, patients experienced improvements in symptoms with continued zovegalisib treatment, with symptom scores at week 20 showing continued improvement relative to week 12. Impressively, 89% of patients showed improvement by investigator assessment, and 79% of patients achieved improvement as assessed by patient assessment. The initial response rate for any dose of zovegalisib shown today was higher than what has been reported for either alpelisib in either the EPIK-P1 or EPIK-P2 at any time points. We saw the same response rate of 60% in patients with a diagnosis of PROS versus a diagnosis other than PROS. 80% response rate in patients with kinase domain PI3K mutations, 55% in non-kinase domain mutations, and 50% in patients without a documented mutation. We've also seen comparable response rates in patients with prior alpelisib or sirolimus therapy or naïve to systemic therapy at 62% and 57% respectively. Similar response rates in patients older than 18, 64%, and younger than 18, 50%. This coincided with the vast majority of patients reporting an improvement in symptom burden. Shifting to safety, zovegalisib was generally well-tolerated across all three doses, with most TRAEs reported as Grade 1 or Grade 2. The most common AE was headache, all Grade 1, typically occurring within the first month or so of therapy, resolving. Other common AEs were fatigue, nausea, diarrhea, and decreased appetite, all low-grade. We only observed two Grade 3 + AEs at the 300 mg BID dose, one case of hypokalemia in a patient who was taking a potassium-wasting diuretic, and one case of hypertension in a patient who entered the study with existing Grade 2 hypertension. There was only one event of Grade 3 hyperglycemia seen across the study in a pre-diabetic patient treated at the 400 mg BID dose. Hyperglycemia was otherwise low-grade and typically only seen in the first cycle, and a majority of the Grade 2 hyperglycemia seen at the 300 mg BID dose was in patients pre-diabetic at baseline, of whom many had recently been treated with alpelisib. We did not see other AEs frequently observed with non-selective PI3K inhibitors, including rash or stomatitis. This initial safety profile allows for patients to maintain a consistent dose intensity and a low rate of dose reductions. Across the 100 mg and 300 mg BID doses, the median dose intensity was greater than 99% and fewer than a quarter of patients required a dose reduction. The rate of dose reduction was higher at the 400 mg BID dose. As shown in the efficacy data, this dose is a higher dose than is needed to achieve maximal efficacy for zovegalisib in these patients. Importantly, all patients remain on study with no discontinuations for any reason across all dose levels. At a high level, we are seeing clear differentiation compared to alpelisib with this initial data. It is challenging to make a direct comparison to the safety profile of alpelisib in VAs as the EPIK-P1 trial was a compassionate use study and did not have prospective collection of routine safety. The EPIK-P2 trial used a 125 mg dose of alpelisib, which is half the label dose and not the dose that's currently being assessed in the ongoing EPIK-P4 trial. The most robust recent safety data we have for alpelisib at exposures similar to those achieved at the 250 mg PROS dose came from the EPIK-B5 trial in breast cancer, where 71% of patients had a Grade 3 or higher AE. The overall rate of Grade 3 or higher AEs observed with zovegalisib to date compare favorably to any trial of alpelisib, and we believe represents a profile that could support chronic use in vascular anomalies. With no reported rash or stomatitis, which are traditionally challenging AEs for the PI3K inhibitor class. I will now share some patient vignettes that highlight the potential for zovegalisib to benefit patients with VAs, noting that these vignettes may not be representative of all patient experiences. The first vignette is a 44-year-old patient with a KTS subtype of PROS. His lesion has a non-kinase domain mutation in PIK3CA Q546K. He has not previously been treated with systemic therapy. He has involvement of the entire left leg with a baseline target lesion of over 18 L. He was randomized to the 100 mg BID dose of zovegalisib. The patient experienced rapid symptomatic relief soon after starting zovegalisib, rated as much improved on the IGIC instrument at week 24. Of note, this patient does not meet the threshold for a volumetric response, but at week 24 had a 19.75% reduction in his lesion volume, reflecting a 3.6 L reduction in this very large target lesion. He remains on the 100 mg BID dose, now in his 35th week of treatment. He has tolerated zovegalisib well and has not required any dose interruptions or modifications. We were particularly excited to hear from the investigator treating this patient that prior to starting treatment, he couldn't walk further than from the front door to his car. Within two weeks of starting therapy, he was able to walk around the block. The next vignette I will share is from a 12-year-old patient with a CLOVES subtype of PROS. His lesion has a helical domain mutation in PIK3CA E542K. The patient was previously treated with both sirolimus and alpelisib. He has chest lesions resulting in both pain and difficulty breathing. He was randomized to the 300 mg BID dose of zovegalisib. At the 12-week scan, the patient achieved a volumetric response with 49% decrease in his target lesions, which deepened to a 55% decrease at week 24. This was accompanied by improvement in symptoms rated as much improved by the investigator at week 24. The patient is tolerating zovegalisib well and remains on treatment at the 300 mg BID dose at week 32 with no dose modifications. The last vignette shows the potential for zovegalisib in VAs outside of PROS. This is a 42-year-old female with a facial lymphatic malformation. Her lesion has a helical domain mutation, E545K. The patient was previously treated with both sirolimus and alpelisib. The patient did not respond to sirolimus and discontinued due to adverse effects. The patient had some symptomatic improvement with alpelisib, but also discontinued due to AEs. The facial lesion has resulted in ear pain, oral pain, and jaw pain at baseline, and the patient was randomized to the 300 mg BID dose of zovegalisib. At the 12-week scan, the patient achieved a volumetric response with 31% decrease in their target lesion, which deepened to a 53% decrease at week 24. This was accompanied by improvement in symptoms rated as much improved by the investigator at week 24, and improvement in ear pain and oral pain, both rated as much improved. The patient is tolerating zovegalisib very well and remains on treatment at the 300 mg BID dose at week 24 with no dose interruptions or reductions. The 100 mg BID dose of zovegalisib with a 43% volumetric response rate demonstrates an initial profile that at already just 12 weeks shows a dramatically greater volumetric response from what alpelisib data has shown at 250 mg BID at any time point, with what we believe to have a markedly improved safety profile with no Grade 3 or higher AEs, no hyperglycemia, rash, or stomatitis, and broad symptomatic improvement as reported by both patients and investigators. The 300 mg BID dose of zovegalisib with a 100% volumetric response rate shows an initial profile with what we believe to show the full potential of what a mutant-selective PI3K inhibitor can achieve in vascular anomalies. With a low rate of Grade 3 or higher AEs, no Grade 3 hyperglycemia, Grade 2 hyperglycemia primarily in pre-diabetic patients, no rash or stomatitis, and broad symptomatic improvement as reported by both patients and investigators with all patients still ongoing. We've decided to move into dose expansion with two doses of zovegalisib, the 300 mg BID dose, and then an intermediate dose between 100 mg-300 mg BID. It's a 400 mg once daily dose. We believe this could show meaningfully better efficacy than a 250 mg dose of alpelisib, meaningfully better tolerability than a 250 mg dose of alpelisib, with the convenience of a once daily regimen for chronic use. Patients are currently enrolling at these two doses in our expansion cohorts. Zooming out a bit further on the development and regulatory path, given the existing precedents in this space, we believe the accelerated approval pathway may be available to us, pending additional data maturation and feedback from regulatory authorities. Additionally, weight-based dose escalation is ongoing in pediatric patients aged 6-11. Once two dose levels are cleared in those 6-11-year-old patients, we'll open the 2-5-year-olds cohort. I'll now pass it over to Pete to wrap up. Thanks, Don. Clearly, these are very exciting times here at Relay. We started the year with the goal of making three meaningful disclosures against three very large market opportunities. Second-line breast cancer with our ESMO TAT disclosure, front-line breast cancer with our recent triplet data disclosure, now today with these promising initial data in VAs, we've been able to do just that. We saw meaningfully differentiated initial activity and tolerability in VAs as compared to alpelisib at the very first dose level. Across doses, response rates and symptomatic improvements that we've seen that have not been previously reported by other agents. We see this activity regardless of mutation type, prior treatment, and most importantly, the early data support our hypothesis that zovegalisib is active across VA subtypes, showing in lymphatic malformations three out of four LM patients are in response, and our two deepest responses are coming from LM patients. There are about 65,000 LM PIK3CA mutated patients in the U.S. We believe approximately 15,000 of these patients could be addressable with a well-tolerated and effective chronic systemic therapy. Moving forward with the development ongoing against these three pillars of value creation, we believe we are entering an extended period of consistent updates. First, in second-line breast cancer, by the end of this year, we believe we will be able to give an update on when we should reach full enrollment for ReDiscover-2. In front-line breast cancer, we will provide a regulatory update for the end of the year and remain on track for a first half of 2027 phase III start. We'll also likely give a phase I-phase II triplet data update in the first half of 2027. In vascular anomalies, we plan to give a regulatory and data update by the end of this year. As you can see, we have a robust set of updates planned over the next 12 months. We have $642 million in cash, which gets us multiple clear data catalysts into 2029, only incrementally more capital would be necessary to get through registrational data and early commercial launch in both breast cancer and vascular anomalies, pending data and regulatory actions. In addition to continued data readouts from the phase I-phase II triplet study and initial unwrap data. With that, I'll now open it up to Q&A and hand it back to the Operator. 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. Our first question is going to come from Akash Tewari with Jefferies. Your line is now open. Hey, this is [Amy] on for Akash. Congrats on the great data. Just two from us. How should we think about the dose response between the 300 mg and the 400 mg BID dose? Did patients on 400 mg have more dose interruptions, or are there any differences in baseline characteristics? Just one on your subtype data. You're seeing pretty strong early activity in LMs, no responses in venous yet. How are you thinking about that venous population? Is that just more heterogeneous, or do you think that could, you know, deepen over time? As you think about the initial accelerated approval package, is your base case assumption still a pooled PROS LMs in venous filing? What specifically would the FDA need to see from a consistency of benefit, standpoint across the subtypes to support a broader label? Thanks, Amy, for the questions. I'll get Don to take the first one on the 300 mg, 400 mg question. I think, Amy, as you, as you hypothesized, at the 400 mg dose, we did have some patients who required dose interruption, which compromised their dose intensity and led to not achieving a response at that first 12-week scan. They do all remain on therapy, and could certainly, as you see in the spider plots, have deepening of response that get them to a response over time. Given that we are already essentially maxing out our benefit by every metric that we can look at at the 300 mg dose, we feel the 400 mg dose is clearly supra therapeutic and have made the decision not to pursue bringing that forward into our expansion cohorts. On the second question on the venous malformations, maybe Pete you can take that one. Yeah. As we've said from the beginning, we believe that the disease biology here is gonna be consistent across these subtypes. We've now demonstrated very clearly across two of the subtypes that we are seeing consistency of benefit. Not surprising, the enrollment in this stage of the study is weighted towards PROS and LMs. That's where alpelisib has accelerated approval on the PROS side, and both alpelisib and sirolimus have had a history of use, off-label use in the LM patients. We believe the venous enrollment will come over time, and we do believe that we should see benefit there consistent with the other two subtypes. In terms of accelerated approval and how we think about pooling these studies, these patient populations, the current study continues to be open to PROS, LMs, and venous malformation patients. The difference between some of these subtypes is venous or LMs and PROS can be prescribed therapy without a genetic test because you have 100% of patients with PROS having a PIK3CA mutation and 80%+ of LMs. In venous malformations, you're gonna need a genetic test to direct therapy because there, the frequency of PIK3CA mutation's about 20%-30%. As to exactly how many of these three get pooled in an initial filing, that'll be subject of conversations with the regulatory authorities, but we are gonna continue to enroll all three subtypes. We think the strength of this early efficacy certainly sets us up well to contemplate the accelerated approval pathway, and that'll be the topic of conversation with the regulators later this year. I think the final point to note there is obviously the PROS and the LMs form the bulk of the addressable patient population, and I think we've gone a long way in today's dataset to de-risk the fact that we believe zovegalisib is gonna be efficacious in both of those subtypes and therefore unlocking the large commercial opportunity there. Thanks for your question, Amy. Awesome. Thanks so much. Thank you. The next question will come from Yaron Werber with TD Cowen, and your line's open. Great. Thanks so much and congrats on really terrific data that is much, much better than expected. I have a couple of questions. The first one is actually two. You had four patients that have data out to 24 weeks, all responders. They all improved. They improved actually further when you go to 36 weeks. I mean, they're getting to one of them at - 61% and the other one has an 85% reduction. There's three other patients, two of them are at week 24, and they're essentially on the cusp of responders. They're at the 100 mg BID. Both of them are at 19.5, 19.8. Would you expect those to respond when you do the third scan? My second question is Protara announced that they are going to file based on 40 patients for accelerated approval. Obviously, a different therapeutic. It's injected into macrocystic and mixed cystic malformation, so obviously a lot more topical. It's sort of a different market than what you're targeting. They're talking about accelerated approval based on 40 patients. How does that factor into your timeline and your thinking for accelerated approval? Thank you. Thanks for the question, Yaron. Maybe on the kind of kinetics question, obviously you can see from the spider plots that the 300 mg BID dose, you see, you know, very rapid declines in lesion size. Obviously all of the responses that we had at 300 mg all happened at the 12 weeks, and then they deepened. You see this kind of profound responses. Just to note, you know, the responses we have, we have multiple now over 50% reduction. We saw in the alpelisib data, the kind of biggest responses they had were in the kind of 45% response rate. One of the things is not just the response rate, but it's actually the profound depth of response that we're seeing. In terms of the kind of 100 mg BID dose, obviously you're seeing there the kinetics are slightly different. You know, we are seeing these patients kind of hovering just below the 20% threshold, as well as seeing some responders. As we said, post the data cut, we saw one of those that were hovering around 18%-19%, converted from 18% or 19% at the 12-week scan to -35% at the 24-week scan. There, the kinetics seem to be kind of smoother, declines over time. I think what we're excited about is just the profile and the flexibility that allows treating physicians. You know, one side on the 300 mg dose, you know, we believe at a 100% response rate, you're seeing profound responses very early. The other dose, you're seeing a kind of smoother, more kind of balanced responses over time. I think patients will want different things and treating physicians will want different things. I think the doses that we have here basically cater to everything. At one end, you're seeing profound efficacy. At the other end, you're seeing a tolerability profile that suits itself to lifelong dosing. I think we're very excited about what we're seeing. In terms of the Protara question, maybe Pete you can comment on whether 40 patients is gonna be enough. I mean, look, it's obviously all these things are interesting precedents, right? alpelisib was approved off accelerated approval off of 37 patients. The Protara dataset is 40 patients. The Palvella, the dataset that they're filing on also kind of in that ballpark. You know, We need to generate our further data on our own and go have our own regulatory interactions, but these are obviously interesting precedents, and it goes to show what can happen when you have profound efficacy like we've been able to demonstrate today. Like you call out, these are different modalities and address different needs in different patient populations, especially the, on the sclerotherapy front. That's a local therapy that is not long-term effective. You can see multiple of our vignettes. These patients unfortunately have to go through multiple rounds of sclerotherapy. You can only address lesion by lesion, and there are some lesions that are just not accessible for sclerotherapy. You know, another good tool in the toolkit for physicians and patients. You know, we're excited to be bringing forward a therapy that actually goes after the root cause of the disease here and can treat it systemically. Thank you. Our next question will come from Bradley Canino with Guggenheim. Your line is open. Hey, good morning. Great data and great progress with the trial. Can we just double-click on the prior question with some more details about how you believe whether you are or are leaving efficacy on the table by not bringing forward the 400 mg BID oncology dose? Second, you talked about cash runway, but what about incremental cash needs going forward to contemplate the full development of vascular anomalies here with the plan and the frontline breast cancer study you plan to start next year? Thank you. All right. Maybe I'll start the first one and hand it over to Don. I think at the 300 mg BID dose, at a 100% volumetric response rate, we're seeing, you know, 80%, close to 90% of patients seeing symptomatic benefit. We believe there is no further efficacy left on the table. As you go above that, you're just seeing greater tolerability challenges. We don't think there's any room for us to go higher than 300 mg or any need for us to go higher than the 300 mg. That's why you're seeing us explore in the expansion cohorts, 300 mg BID, and then one below that, 400 mg once a day. Just to be clear, that's slightly confusing because that's the equivalent to 200 mg, BID in terms of PK, because we have a very flat PK profile. We've seen that in the oncology side, and that PK has been validated. We do not believe that there is any reason to go higher than 300 mg, and we believe that that has a safety profile and an efficacy profile that is gonna be very hard to beat. Therefore, that's why we took it forward. Yeah. In fact, as we look across all of our metrics of efficacy, we feel we max out efficacy somewhere between 100 mg and 300 mg, right? There's nothing we can look at that says going above 300 mg gets you additional benefit. We're clearly active at 100 mg, so we're actually exploring this intermediate dose because it's possible that you could actually max out efficacy below 300 mg BID. In fact, we project that the 400 mg once daily dose will give us exposure that lies right on top of the 80% inhibition line for mutant PI3Kα. I think it'll be very interesting. Again, this is the first experiment that's ever really been able to assess the relationship between target inhibition and efficacy. I think it will be very interesting to assess whether you can even go lower and max out the efficacy. That's why we've opened up this additional cohort. Remember, we've seen 11% response rate in zovegalisib at 12 weeks, we're seeing 100% at a 300 mg BID dose. That gives us the confidence to say that I think we're hitting the efficacy hard here. In terms of the cash runway, as you know, we have $642 million of cash at the end of Q1, that gives us enough runway to generate the VAs data that we've just seen, take our second line breast cancer trial towards registrational data, to move forward our general operating expenses and running our research team. We will need, you know, a modest amount more cash to make sure that we can get the vascular anomalies trial to registrational data. I think as we've seen through some of these questions, we don't believe that's gonna be a large amount. To fund our frontline trial, to the point where we have registrational datasets of both second-line breast cancer and the vascular anomalies and bring forward our NRAS program to having some early clinical data. We think that it's a modest amount of money that we will need, that will give us runway towards some very significant catalysts. Two registrational datasets and another early-stage dataset from our NRAS program. That should give us a cost of capital at that point that is significantly better than it is today and also give us significant options to raise financing at that point using things like debt or royalty. We feel like we're in a very strong position on the cash front, and any money that we do need to raise will be modest. Thank you. Our next question will come from Salveen Richter with Goldman Sachs. Your line is open. Good morning. Could you speak to the eligible populations within PROS and LMs and, essentially on the demand side, how to think about where use will play out here? Thank you. Thanks, Salveen. The ultimate treatment goal here is to get to patients as early in their life as possible, where the disease has not gotten too severe and initiate treatment then and stay on treatment chronically for the rest of their lives. Today, there's an adult prevalent population that is probably underdiagnosed and undertreated. That will certainly be a near-term opportunity for us as you think about the early commercial launch, in addition to continuing to build education and awareness around the use of systemic therapy as early in childhood as possible. I think the way we will think about it in the early stages of launch are helping the undertreated and underdiagnosed adult population and really expand the market meaningfully there, in addition to penetrating deeply the pediatric population. Those would be the two approaches, and I think that's the type of kinetics we would see early on in launch. Thank you. The next question will come from Sean McCutcheon with Raymond James. Your line is open. Hey, guys. Congrats on the data, and thanks for the questions. Could you speak to the trajectory of lesion reductions in those patients that were dose-reduced? Any commentary, in as much as you have this degree of granularity, on the composition of lesions for patients in the study, you know, fatty, fibrotic, and any commentary on robustness of response data to that end? Thanks. I don't know. I mean, I think, as we've discussed a little bit already, at the 400 mg BID dose in that first 12 weeks, we did have patients who had, I think, critically longer dose interruptions, right? Which, you know, compromised the ability probably to see a first scan response. Those patients remain ongoing at a lower dose, and, you know, I think we'll continue to track those patients over time. Their lesions are still shrinking even with the compromised intensity in the first cycle. In terms of lesion composition, these are complex lesions. I think you could see from our vignettes, the nature of the lesions with vascular components, fluid components, fibrotic components, fatty components. In general, I think what we're seeing is, we're seeing broad changes in the MRI across the spectrum of lesion types. You know, you clearly see the reduction in the lesions in terms of the size, but you can also, for some of the more tortuous veins and tortuous vessels that are a hallmark of some of these diseases, in some of the scans, you actually start seeing, you know, this qualitative, of course, but you start seeing, you know, correction of those tortuous vessels. I think, you know, it gives us encouragement that we're not just shrinking lesions, but by actually hitting the underlying biology of the disease, we're actually modifying the disease with zovegalisib. Thanks. Thank you. The next question will come from Andrew Berens with Leerink Partners. Your line is open. Hi. Thanks, and congrats on the data. Obviously, better than we had anticipated. The first one I guess is on, is there any way to remove PI3K testing as part of the payer requirements to access? We've heard from some of the MedOnc docs that can be very difficult logistically. Is there any way to offset that or help with that requirement? The second is a strategic question, another strategic question for Sanjiv. Just wondering on how you see this opportunity versus breast cancer. Would you consider divesting or monetizing breast cancer and using the funds to focus on this? Because it certainly seems more bite-sized for a mid-cap biotech than breast cancer. Maybe Pete can take the first one. Yeah. Look, I think the best thing we can do is to generate the strongest data possible as we move into regulatory conversations, potential filing, market access conversations. Clearly, a genetic test is not necessary to direct treatment for both PROS and LMs. I think that'll be the position we take. We have multiple patients in this dataset with unknown mutation types or not. They came on study without a genetic test, we're seeing clear clinical benefit. I think that'll be the way we approach it. We'll continue to work with some of the commercial providers on making sure that the access and availability of genetic tests when needed are up to the technical standards to be able to be useful in this patient population. In terms of the strategic question, I mean, it's an interesting one, and we think about a lot, and I think we just see it in a slightly different way. I mean, your point is very valid in that this is gonna be a commercial opportunity that is very manageable. As you know, there are only a small number of centers in each country. In the U.S., there's kind of 20 centers- 30 centers. In terms of the commercial model, it is very manageable. For obviously you said, the market size here is very significant, so it is, you know, a very kind of sweet spot for a small biotech to commercialize. Today's data is, you know, significantly de-risked that opportunity, and we'll move, you know, very rapidly towards trying to get to an accelerated approval and generate revenues. It doesn't change the fact on the breast cancer side, it's still as attractive. We see capivasertib in the second line moving towards a billion dollars worth of run rate, and they've done that very rapidly. Obviously, we know it's a gonna share of voice marketing. If we can show that we could almost double their median PFS, companies like Menarini have shown that you can very successfully commercialize as a small company in breast cancer, especially in the U.S. You know, walking away from over a billion dollars of revenue in the near term is not something that we want to do. Given the balance sheet that we have, I think we have the opportunity to do it. My own background is I come from a commercial way background. I spent 10 years commercializing therapies, I'm excited about going out and winning in both. On the other side of this, you see a frontline trial that will also be there. That is a huge opportunity. I mean, those, you can see it from the CDK4/6 sales that are out there in the tens of billions. We feel that we have three very large opportunities. We obviously today have de-risked one. We're very excited about commercializing in the second line and think it's very manageable. I think in the long term, we could really change the kind of revenue trajectory of our company in the frontline. We think all three are manageable, and we're looking forward to executing all three. Thank you. Our next question will come from Silvan Türkcan with Citizens. Your line is open. Good morning, and congrats on this very strong data, and thanks for taking my question. My first question is maybe big picture. I know it's very early here, but how you see this treatment regimen evolve? Would there be eventually maybe treatment-free windows? You know, considering you have such fast onset of responses, could patients cycle on and off drug? A second question is the response rate tied to the baseline lesion volume? Meaning, do larger lesions respond just as well as small lesions? Thank you. Yeah. I think we can take them one at a time. On the lesion volume, maybe, Don, you can take that one. Yeah. On the lesion volume, you know, we've done several cuts of baseline lesion volume versus response rate and don't see significant differences between the probability of achieving a response with a large lesion versus a small lesion. In terms of the cycling, I mean, this is a comment that we hear clinically, that people are cycling on and off alpelisib. Is it because of the fact that, you know, they're getting better? The answer is no. It's because of the toxicity. Patients do not want to tolerate it. You know, we were here at the ESA Conference in Philadelphia. We're talking to patient advocates. It's very clear that that is the challenge for patients, which is the toxicity. I think what zovegalisib allows us to do and what you see is in the data is that for the first time, maybe there is a potential for a chronic therapy that allows patients to stay on therapy chronically. We know that you need to put pressure on the PI3K inhibition constantly. If you stop, the lesions will recur. I do think it allows us for the first time to allow patients to potentially have a chronic solution here. As we talked about earlier, the different kinetics of the doses is very interesting. It allows flexibility for prescribers. Obviously, in that 300 mg, you're seeing a 100% response rate, and you're seeing very rapid and deep responses. That may be what prescribers want. On the other side, you're seeing at 100 mg, you know, very much a AE profile that is very manageable. We're not seeing any Grade 3 toxicity. We're not seeing any hyperglycemia. That could be what some other patients want. I think what we're seeing here for the first time is profound efficacy or profound safety that will allow us to be the kind of solution for everyone here. We're very excited about taking it forward. Thank you. The next question will come from Matthew Biegler with OPCO. Your line is open. Hey, guys. Thanks for the question. I just had a clarification on the patients with unknown PIK3CA status. Is it just that they weren't tested for, or is there, you know, a downstream AKT or maybe PTEN overactivation or just like anything else that would explain the activity that you showed there? There was at least a few patients that did have a nice volumetric response with that. Thank you. Yeah. You know, I think the patients with unknown status reflects two challenges with testing these patients. One is accessing tissue for performing the diagnostic tests. Some of the lesions, it's not medically feasible to be able to access the tissue, or it's, you know, challenging to access the tissue. The other is the sensitivity question. This is a disease of somatic mosaicism. The variant allele fractions are not as high as what you see in, you know, solid tumors. A lot of those oncology diagnostics don't have the necessary sensitivity to be able to pick up these mutations. We have patients who either haven't been tested because of the challenges of getting tissue or have been tested, and the diagnostic sensitivity of the assay has not been able to detect the PIK3CA mutation. We don't think that these patients have downstream mutations, AKT/PTEN. We think, again, in LMs, the vast majority of patients are driven by PIK3CA. I think, you know, these patients in whom we're seeing benefit are PIK3CA-driven anomalies, and it's largely technical or medical reasons why you don't have a detectable mutation. Thank you. The next question is gonna come from Boris Peaker with JonesTrading. Your line is open. Great. Thanks for squeezing me in. Just wanted to question on safety. You mentioned that 23% of patients had dose reductions. I just want to understand, were these primarily at the 300 mg BID or at 100 mg? Also just understanding the timing of these dose reductions, were they typically at the start of therapy or maybe scattered throughout the observation periods? Thanks for the question. Maybe before I hand it over to Don, I'll just make one point around the fact that obviously we have a lot of information around safety that came from our extensive experience in oncology. We now have several hundred patients' worth of data in the doublet. We have you know, much more now in the triplet. As we kind of started out this program last year, the ability to share that safety data both with regulators and with prescribers was critical for us to launch this and go at the pace that we have. I make that point because I know that we'll get a lot of competitive questions going forward and not to underestimate the inherent advantage of having such an extensive multi-year database of entering this field. Because remember, this is a very different field from oncology, the threshold for folks to try these new therapies, the first in human, is very high. Maybe with that, I'll hand it over to Don. Yeah. The reductions, we saw more reductions at 300 mg than we did at 100 mg. We only had a single patient with a modification at 100 mg. The patient who had some low-grade nausea decreased from 100 mg BID to 75 mg BID, actually came right back to 100 mg BID and continues to be treated at 100 mg BID. At the 300 mg BID dose when we have had reductions, it's generally been relatively early in the course of therapy. We've been able to, you know, successfully be able to manage those reductions, still being able to maintain good dose intensity and still being able to achieve the 100% volumetric response rate. Thanks. Great. Thanks Great. Thanks for taking my question. Thank you. That does conclude our Q&A session. I will now turn the call back over to Sanjiv for closing remarks. Thanks for attending the conference call this morning, and hopefully, you believe the data is just as exciting as we do. We're gonna go over to the ISSVA Conference now and share the data with physicians, patient advocates, and make sure that we can rapidly enroll these expansion cohorts as possible, talk to the regulator and hopefully, get this therapy to patients that need it as rapidly as possible. Thank you. This concludes today's conference call. Thank you for participating, and you may now disconnect.