Relay Therapeutics Conference Call: Initial Clinical Data for Zovegalisib in Vascular Anomalies

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 Rehmer, Chief Corporate Development Officer at Relay

Therapeutics. Sir, you may begin. Thank you, Operator, and 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 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 and therefore you should not put undue reliance upon them. These statements are subject to numerous risks and uncertainties that could cause excellent results differently from what we expect. I refer you to our SCC filings and on our website for discussion of risk factors. The forward-looking statements in this presentation speak only as of the original date of this presentation. We undertake no obligation to update or revise any of these statements. I'm joined today by Sanjeev Patel, our CEO, and Dom Bertram, our president of R&D. And now I would like to turn the call over to Sanjeev.

Thank you, Pete, for the introduction, and thank you for all of you joining the conference call this morning. Today we'll share further data on our lead program, Zorvigalicib, Zorvega for short, our pan-mutant selective PI2K alpha 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, We're as a company where 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 3 trial in early 2027 with our novel-novel selective-selective combination of Zorvega and a termocycline. But 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 a potential change, a step change in efficacy with Zovega versus what is currently being used as the standard of care, alpelosib. Our initial clinical data shows a 60% volumetric response rate with Zovega versus the 10% to 30% that has been seen in other clinical trials and assessments with Alpelosib. We saw at the 300 milligram BID dose of Zorvega, 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 milligram BID dose of Zovega, we saw a 29% volumetric response rate. We see all of these responses deepen over time, as you will see in the spider block later, where we show that each patient's response deepened between 12 and 24 weeks. And post-data cutoff, we saw this tangibly manifested as we saw an additional response from a 100 milligram 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 milligram BID dose. Based on all of this initial data, we believe we have a very favorable profile versus the current therapies, as 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. And so, as we said, this is a potential step change in efficacy with Zorvega. All of this is seen at a level of tolerability that compares very favorably with the existing treatment option alpelesin. Across all doses, we saw initial rates of grade 3 plus toxicities in Zorvega at 15% versus 70% for alpelesin. If we just look at combining the 100 milligram and the 300 milligram BID doses of Zorvega, we see that common adverse events associated with wild-type PI3K alpha 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 Zorvega expansion cohorts, and we're taking forward the 300 milligram BID dose, which, as we said, today we report 100% volumetric response rate in this data cut, and we believe also has a very competitive safety profile. And the dose just below this, a 400 milligrams once-daily dose, the once-daily dose is equivalent in PK to a 200 milligram 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 and $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. And so if you just assume that 2,000 to 3,000 patients on chronic treatment, that calculates to about a sales opportunity of a billion dollars. And remember that we believe there are 25,000 addressable patients in the U.S. So 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 Berkson, to provide an overview of vascular anomalies, an overview of the trial we're running, and obviously share the excellent data that we're showing today. Thank you. Thanks, Sanjeev.

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. And they share common genetics, of which PI3K-alpha, PIC3CA 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 of isolated, accessible lesions. And 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. So, vagalysis is the only mutant-selective PI3K-alpha 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, PI3K-related overgrowth spectrum, and LM, lymphatic malformations. PROS, with 5,000 to 10,000 patients, with as many as half likely to seek a systemic treatment for their condition, and LMs, with approximately 65,000 patients, with about a quarter likely to seek systemic treatment. That leads, as Sanjeev pointed out, to approximately 25,000 addressable patients in the U.S. alone. Last year, we opened the REINSPIRE trial of Zovega and vascular anomalies. We leveraged nearly 250 patients' worth of experience for Zovega and oncology patients across the doses we would be studying in ReInspire to proceed immediately to randomized dose finding in adults and adolescents with vascular anomalies. In the first part of the study, we randomized patients across three doses of Zovega, 400 milligrams twice daily, which is our recommended phase three dose in combination with flubestrant and breast cancer, 300 milligrams twice daily, and 100 milligrams twice daily. and adults and adolescents age 12 and older. The trial is open to patients with PIC3CA mutated vascular anomalies, including all subtypes of PROS, lymphatic malformations, and PIC3CA mutated venous malformations. Patients with any PI3K mutation can be enrolled on the study, and patients with PROS or LMs without a documented PI3K mutation were also allowed to enroll given and the high prevalence of PI3K mutations in these diseases. The objective of part one was to evaluate the safety, tolerability, and efficacy of Zovega in patients with PI3K-driven VAs. And 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 ISPA conference, we are sharing initial clinical data with a cutoff date of April 15, 2026, including the initial efficacy data from 20 part one patients who have reached their first 12-week MRI scan, and safety data on 32 patients who have received Sovega, 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 two-thirds of patients aged 18 or older, and one-third of patients aged 12 to 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 alpelosib, with some of these patients discontinuing alpelesib only days before signing consent for our trial. And 72% of patients had previously been treated with sirolimus or alpelesib 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 milligram BID cohort being pre-diabetic at study entry. The pharmacokinetics of Zovega and 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 PIC3CA inhibition for the 400 milligram dose, over 80 percent for the 300 milligram dose, and approximately 60 percent for the 100 milligram dose. Across the 20 patients who had reached their 12-week MRI scan at the time of data cutoff, 12 patients, or 60 percent, achieved the 20 percent reduction in lesion volume to be considered a volumetric response. The response rate for the 300 milligram dose was 100 percent. For the 100 milligram dose, and it was 29 percent. But as Sanjeev mentioned, post-data cutoff, we saw an additional response from a 100 milligram 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 percent across all doses and 43 percent at the 100 milligram 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 pro subtypes and lymphatic malformations, across all PI3K mutations, including in patients with no documented PI3K mutation, in patients previously treated with delpelisib, serolimus, 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 and 400 milligram 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 milligram dose who have not yet achieved a response, but show deepening of volume reduction at subsequent scans and are ongoing treatment in the study with one of those patients, as we've mentioned, converting to a volumetric response after data cop. 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 IADRSS pain scale, which is the investigator's assessment of pain in patients who were report pain at baseline. Across all three measures of clinical benefit, and across every dose, patients experienced improvements in symptoms with continued Zovega treatment, with symptom scores at week 20 showing continued improvement relative to week 12. And 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 Zavega shown today was higher than what has been reported for either Alpelisib and either the EPIC-P1 or EPIC-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. An 80% response rate in patients with kinase domain MPI3K 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 were naive to systemic therapy at 62 and 57% respectively. Similar response rates in patients older than 18, 64%, and younger than 18, 50%. And this coincided with the vast majority of patients reporting an improvement in symptom Shifting to safety, Zovega 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 1s, typically occurring within the first month or so of therapy, then resolving. Other common AEs were fatigue, nausea, diarrhea, and decreased appetite, all low-grade. We only observed two grade three plus AEs at the 300 milligram BID dose, one case of hypokalemia in a patient who is taking a potassium wasting diuretic, and one case of hypertension in a patient who entered the study with existing grade two hypertension. And there was only one event of grade three hyperglycemia seen across the study in a prediabetic patient treated at the 400 milligram BID dose. was otherwise low-grade and typically only seen in the first cycle, and a majority of the grade II hyperglycemia seen at the 300 milligram BID dose was in patients pre-diabetic at baseline, of whom many had recently been treated with alcalacin. We did not see other AEs frequently observed with non-selective PI3K inhibitors, including rash or stomatitis. This initial safety profile allowed for patients to maintain a consistent dose intensity and a low rate of dose reductions. Across the 100 milligram and 300 milligram 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 milligram BID dose, but as shown in the efficacy data, this dose is a higher dose than is needed to achieve maximal efficacy for Zovega in these patients. And importantly, all patients remain on study with no discontinuations for any reason across all those 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 EPIC-P1 trial was a compassionate use study and did not have prospective collection of routine safety, and the EPIC-P2 trial used a 125 milligram dose of alpelicib, which is half the label dose, and not the dose that's currently being assessed in the ongoing EPIC-P4 trial. The most robust recent safety data we have for alpelicib at exposures similar to those achieved at the 250 milligram PROS dose came from the EPIC-P5 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 in Zovega to date compare favorably to any trial of Valpelacib, and we believe represents a profile that could support chronic use in vascular anomalies, again, with no reported raster stomatitis, which are traditionally challenging AEs for the PI3K inhibitor class. I will now share some patient vignettes that highlight the potential for Zovega 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 PIC3CA, Q546K. He has not previously been treated with systemic therapy. He has involvement at the entire left leg with a baseline target lesion of over 18 liters. He was randomized to the 100 milligram BID dose of Zovega. The patient experienced rapid symptomatic relief soon after starting Zovega, 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 liter reduction in this very large target lesion. He remains on the 100 milligram BID dose, now in his 35th week of treatment. He's tolerated Zovega well and has not required any dose interruptions or modifications. And 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. And 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 close subtype of PROS. His lesion has a helical domain mutation in PIC3CA, E542K. The patient was previously treated with both sirolimus and alpelicib. He has chest lesions resulting in both pain and difficulty breathing. He was randomized to the 300-milligram BID dose of Zovega. 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, and the patient is tolerating Zovega well and remains on treatment at the 300-milligram BID dose at week 32 with no dose modifications. The last vignette shows the potential for Zovega 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 alpelicin. The patient did not respond to sirolimus and discontinued due to adverse effects. The patient had some symptomatic improvement of alpelicin, 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-milligram BID dose of Zovega. 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 Zovega very well and remains on treatment at the 300-milligram BID dose at week 24 with no dose interruptions or reductions. The 100-milligram BID dose of Zovega 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 milligram 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 milligram BID dose of Zavega with 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. Therefore, we've decided to move into dose expansion with two doses of Zovega, the 300 milligram BID dose, and then an intermediate dose between 100 and 300 milligram BID. It's a 400 milligram once daily dose. And we believe this could show meaningfully better efficacy than a 250 milligram dose of alcalacid, meaningfully better tolerability than a 250 milligram dose of alcalacid with the convenience of a once daily regimen for chronic disease. 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 to 11, and once two dose levels are cleared in those 6 to 11-year-old patients, we'll open the 2 to 5-year-old cohort. I'll now pass it over to Pete to wrap on. 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 ESMOTAT disclosure, front-line breast cancer with our recent triplet data disclosure, and now today with these promising initial data and BAs, we've been able to do just that. We saw meaningfully differentiated initial activity and tolerability in VAs as compared to alpilisib at the very first dose level. And across doses, response rates and symptomatic improvements that we've seen that have not been previously reported by other agents. And we see this activity regardless of mutation type, prior treatment, and most importantly, these early data support our hypothesis that Zovega is active across VA subtypes showing and lymphatic malformations, three out of four LN patients are in response, and our two deepest responses are coming from LN patients. There are about 65,000 LN PIC3CA 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 frontline breast cancer, we will provide a regulatory update for the end of the year and remain on track for a first half of 27 phase three start. We'll also likely give a phase one, two triplet data update in the first half of 2027. And 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 to 2029, and 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 outcomes, in addition to continued data readouts from the Phase 1-2 triplet study and initial NRAS data. With that, I will now open it up to Q&A and hand it back to the operator.

Thank you. To ask a question, please press star 1-1 on your telephone and wait for your name to be announced. And to withdraw your question, please press star 1-1 again. And our first question is going to come from Akash Tiwari with Jeffries. 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 and the milligram BID dose. Did patients on 400 have more dose interruptions or are there any differences in baseline characteristics? And then just one on your subtype data, you're seeing pretty strong early activity in LM, 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? And then as you think about the initial accelerated approval package, is your base case assumption still a pooled PROS LM Invenious filing? And what specifically would the FDA need to see from a consistency of benefit standpoint across the subtype to support a broader label?

Thanks, Amy, for the questions. I'll get Don to take the first one on the 300, 400 milligram question.

Yeah, so I think, Amy, as you hypothesized at the 400 milligram 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. But given that we are already essentially maxing out our benefit by every metric that we can look at at the 300 milligram dose. We feel the 400 milligram dose is clearly super therapeutic and have made the decision, you know, 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 said from the beginning, we believe that the disease biology here is going to 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 Alpelisiv has accelerated approval on the PROS side, and both Alpelisiv and Cirolimus 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. And 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 PIC3CA mutation and 80 plus percent of LNs. In venous malformations, you're going to need a genetic test to direct therapy because there the frequency of PIC3CA mutations is about 20 to 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 going to 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 data set to de-risk the fact that we believe so VAGA is going to be efficacious in both of those subtypes and therefore unlocking the large commercial opportunity there. So thanks for your questions, Amy.

Thanks so much. Thank you. And the next, our next question will come from Yaron Werber with

TDECO and your line's open. Great. Thanks so much and congrats on really terrific data that is much, much better than expected. So I have a couple of questions. The first one is actually two. So you had four patients that have data out to 24 weeks old responders. They're all improved. They improved actually further when you go to 36 weeks. I mean, they're getting to one of them at negative 61 and the other one has an 85 percent reduction. And then there's three other patients. Two of them are week 24 and they're essentially on the cusp of responders they're at the 100 BID they're both of them are 19 and a half 19 eight would you expect those to respond when you do the third scan and then 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 macro cystic and mixed cystic malformation so obviously a lot more topical sort of a different market than what you're targeting but they're talking about accelerated approval based on 40 patients how does fact how does that factor into your timeline and your thinking for accelerated approval thank

you thanks for the questions you are maybe on the kind of kinetics question obviously you can see from the spider plots that the 300 milligram BID dose So you see, you know, very rapid declines in lesion size. And obviously, all of the responses that we had at 300 milligrams all happened at the 12 weeks, and then they deepened. And so you see this kind of profound responses. And just to note, you know, the responses we have, we have multiple now over 50% reduction. We saw in the alpalacib data the kind of biggest responses they had were in the kind of 45% response rate. So 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 milligram BID dose, obviously you're seeing there the kinetics slightly different. We are seeing these patients kind of hovering just below the 20% threshold, as well as seeing some responders. And then, 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 minus 35% at the 24-week scan. So there, the kinetics seem to be kind of smoother declines over time. And so 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 milligram dose, you know, we believe at 100% response rate, you're seeing profound responses very early. And then the other dose, you're seeing a kind of smoother, more kind of balanced responses over time. And I think patients will want different things, and treating physicians will want different And 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. So I think we're very excited about what we're seeing. In terms of the Protara question, Mary, Pete, you can comment on whether 40 patients is going to be enough.

Yeah, I mean, look, it's obviously all these things are interesting precedents, right? So a policy was approved off, accelerated approval off of 37 patients. The Protara data set is 40 patients. The Pelvella data set that they're filing on also kind of in that ballpark. Like, you know, we need to generate 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. But like you call out, these are different modalities and address different needs in different patient populations, especially on the sclerotherapy front. that's a local therapy that is not long-term effective. You can see multiple R vignettes. These patients, unfortunately, have to go through multiple rounds of sclerotherapy. You can only address lesion by lesion, and there's some lesions that are just not accessible for sclerotherapy. But, you know, another good tool in the toolkit for physicians and patients. But, you know, we're excited to be bringing forward a therapy that actually goes after of the root cause of the disease here and can treat it systemically.

Thank you. And our next question will come from Bradley Conino 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-MIG-BID oncology dose? And then 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?

Maybe I'll start the first one and hand it over to Don. I think at the 300 milligram BID dose, so the 100% volumetric response rate, and 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. And so as you go above that, you're just seeing greater tolerability challenges. And so we don't think there's any room for us to go higher than 300 million, or any need for us to go higher than the 300. And that's why you're seeing us explore in the expansion cohorts 300 BID and then one below that 400 once a day. So just to be clear, that's slightly confusing because that's the equivalent to 200 milligrams BID in terms of PK. because we have a very flat PK profile. And so we've seen that in the oncology side and that PK has been validated. And so we do not believe that there is any reason to go higher than 300 milligrams. And we believe that that has a safety profile and an efficacy profile that is gonna be very hard to beat.

And therefore that's why we took it forward. And in fact, as we look across all of our metrics of efficacy, we feel we max out efficacy somewhere between 100 and 300, right? There's nothing we can look at that says going above 300 gets you additional benefit. We're clearly active at 100. So we're actually exploring this intermediate dose because it's possible that you could actually max out efficacy below 300 milligram BID. And in fact, we project that the 400 milligram once daily dose will give us exposure that lies right on top of the 80 percent inhibition line from PI3K alpha. And I think it will be very interesting. Again, this is the first experiment that's ever really been able to assess the relationship between target inhibition and efficacy, and I think it will be very interesting to assess whether you can even go lower and max out the efficacy. So that's why we've opened up this additional cohort.

But remember, we've seen 11% response rate in for our policy for 12 weeks, and so we're seeing 100% at a 300 milligram BID dose. That gives us the confidence to say that I think we're hitting the efficacy of RID. In terms of the cash runway, as you know, we have $642 million of cash at the end of Q1, and that gives us enough runway to generate the VA's 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 a modest amount more cash to make sure that we can get the vascular anomalies trial to registrational data, and I think as we've seen from some of these questions, we don't believe that's going to be a large amount, and cancer patient numbers here we're talking here are also very modest, and then to fund our frontline trial to the point where we have registrational data sets of both second-line breast cancer and the vascular anomalies, and bring forward our NRAS program to having some early clinical data. So, we think that it's a modest amount of money that we will need, but that will give us runway towards some very significant catalysts. Two registrational data sets and another early-stage data set from our NRAS program. And 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. So 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. And 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 useful will play out here? Thank you.

Yeah, thanks, Alvin. The ultimate treatment goal here is to get the 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. So I think that the way we will think about it in the early stages of launch are helping the undertreated and underdiagnosed adult population really expand the market meaningfully there, in addition to penetrating deeply the pediatric population. And so those would be the two approaches, and I think that's the type of kinetics we'd

see early on in March.

Thank you. And 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 question. Could you speak to the trajectory of lesion reductions in those patients that were dose-reduced? And then any commentary, and 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?

Thanks.

No, I'm still...

Yeah, so, I mean, I think, as we've discussed a little bit already, at the 400 milligram 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. But those patients remain ongoing at a lower dose. And, you know, I think we'll continue to track those patients over time, but their lesions are still shrinking, even with a 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. And in general, I think what we're seeing is we're seeing broad changes in the MRI across the spectrum of lesion types. So, 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, you actually start seeing, 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. So, 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 Sobega. Thanks.

Thank you. And the next question will come from Andrew Behrens with Leering 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 for access? We've heard from some of the Metacorp docs that it can be very difficult logistically. Is there any way to offset that or help with that requirement? And then the second is a strategic question, another strategic question for Sanjeev, 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 SMITCAP biotech than breast cancer.

Maybe, Pete, you 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, and then market access conversations. Clearly, a genetic test is not necessary to direct treatment for both pros and LMs, and I think that will be the position we take. We have multiple patients in this data set with unknown mutation types that came on study without a genetic test, and we're seeing clear clinical benefit. So I think that will be the way we approach it, and we'll continue to work with some of 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 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 going to 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 to 30 centers. And so in terms of the commercial model, it is very manageable. And as you said, the market size here is very significant. So it is a very kind of sweet spot for a small biotech to commercialize. And so today's data significantly de-risked that opportunity and will move very rapidly towards trying to get to an accelerated approval and generate revenues. But it doesn't change the fact on the breast cancer side, it's still as attractive. We see Capi Vercertib in the second line moving towards a billion dollars worth of run rate. And they've done that very rapidly. And obviously, we know it's going to share a voice market. And if we can show that we could almost double their median PFS, companies like Menorini have shown that you can very successfully commercialize as a small company in breast cancer, especially in the U.S. And so, you know, walking away from over a billion dollars of revenue in the near term is not something that we want to do. And 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 background. I spent 10 years commercializing therapies, and so I'm excited about going out and winning in both. And then on the other side of this, you see a frontline trial that will also be there. And so that is a huge opportunity. I mean, you can see it from the CDK 4-6 sales that are out there in the tens of billions. So 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. And then I think in the long term, we could really change the kind of revenue trajectory of our company in the front line. So we think all three are manageable and

we're looking forward to executing all three. Thank you. And our next question will come from Sylvan Turkin with Citizens. Your line is open. Yeah, 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 would the, how you see this treatment regimen evolve? Would there be eventually maybe treatment-free windows, you know, considering you have such fast onset responses, could patients cycle on and off drug?

And then a second question is, is the response rate tied to the baseline lesion volume?

So, meaning, do larger lesions respond just as well as small regions?

Thank you. Yeah, so I think we can take them one at a time. So, on the

lesion volume, maybe, Don, you can take that one. Yeah, so 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 response with a large lesion versus

a small lesion. And then in terms of the cycling, I mean, this is a comment that we hear clinically that people are cycling on and off alpalosib. And is it because of the fact that, you know, they're getting better? And the answer is no. It's because of the toxicity. Patients do not want to tolerate it. You know, we were here at the DSO Conference in Philadelphia. We're talking to patient advocates. It's very clear that that is the challenge for patients, which is the toxicity. And so I think what Zorvega 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. And now we know that you need to put pressure on the PI3K inhibition constantly. If you stop, the lesions will recur. And so I do think it allows us for the first time to allow patients to potentially have a chronic solution here. And as we talked about earlier, the different kinetics of the doses is very interesting and allows flexibility for prescribers. Obviously, that 300 milligram, you're seeing 100% response rate, and you're seeing very rapid and deep responses. And that may be what prescribers want. On the other side, you're seeing at 100 milligrams, you know, very much an EE profile that is very, very manageable. We're not seeing any grade 3 toxicity. We're not seeing any hyperglycemia. And so that could be what some other patients want. And so 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. And so we're very excited by taking it forward.

Thank you. And the next question will come from Matthew Beegler with OPCO. Your line is open.

Hey, guys, thanks for the question. I just had a clarification on the patients with unknown PIC3CA status. Is it just that they weren't tested for, or is there, you know, a downstream AKT or maybe P10 overactivation, or just like anything else that would explain the activity that you showed there? because there was at least a few patients that did have a nice volumetric response with that.

Yeah, so, you know, I think the patients with unknown status reflects two challenges with testing these patients. One is accessing tissue for performing the diagnostic test and the lesions. It's not medically feasible to be able to access the tissue, or it's, you know, challenging to access the tissue. And then 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. So, a lot of those oncology diagnostics don't necessarily have the necessary sensitivity to be able to pick up these mutations. So, 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 PIC3CA mutation. We don't think that these patients have downstream mutations, AKT, P10. We think, again, in LMs, the vast majority of patients are driven by PIC3CA. So, I think, you know, these patients in whom we're seeing benefit are PIC3CA-driven anomalies, and it's largely technical or medical reasons why you don't have a detectable mutation.

Thank you. And the next question is going to come from Boris Peeker with Jones Trading. Your line is open.

Great. Thanks for squeezing me in. I just wanted to do a 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? And also just understanding the timing of these dose reductions. Were they typically at the start of therapy or maybe scattered throughout the observation period?

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. Now we have much more now in the triplet. And so as we kind of started out this program last year, the ability to share that safety data both as regulators and with prescribers was critical for us to launch this and go at the pace that we have. And I make that point because I know that we'll get a lot of competitive questions going forwards 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, and the threshold for folks to try these new therapies, the first in humans, is very high. And so maybe with that, I'll hand it over to Dr.

Yeah. So the reductions, we saw more reductions at 300 than we did at 100. We only had a single patient with a modification at 100. The patient who had some low-grade nausea decreased from 100 BID to 75 BID, but then actually came right back to 100 BID and continues to be treated at 100 BID. At the 300 BID dose, when we have had reductions, it's generally been relatively early in the course of therapy, and 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.

Thank you. That does conclude our Q&A session. I will now turn the call back over to Sanjeev 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 going to go over to the ISWA conference now and share the data with physicians, patient advocates, and make sure that we can rapidly enroll these expansion cohorts as possible, sort of 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.