Relay Therapeutics, Inc. ($RLAY)

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, 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 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 [indiscernible] 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 animates progress, timing and execution access. Such forward-looking statements are not guarantees of future performance, and therefore, you should not put undue reliance upon them. These statements are subject to numerous risks and uncertainties that could cause actual results to differ materially from what we expect. I refer you to our SEC filings and on our website for a 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. And now I would like to turn the call over to Sanjiv.

Thank you, Pete, for the introduction, and thank you for all of you joining the conference call listening. Today, we'll share further data on our lead program, zibogolisib, Zovega for short. our pan-mutant selective PI3K alpha inhibitor, which has the potential to address 3 very large commercial opportunities. The first of these is second-line hormone receptor positive HER2-negative metastatic breast cancer whereas a company we're laser-focused on executing our pivotal trial and 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 a novel, novel selective combination of Zovega and [indiscernible]. But today, our focus is on enhancing the initial data on the 1/3 of these very large commercial opportunities, vascular anomalies. While the data is early, we believe it shows a potential change that step change in efficacy with Zovega versus what is currently being used as the standard of care, alpelisib. 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 alpelisib. We saw the 300-milligram BID dose of Zovega, 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 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 plot later, where we show that each patient's response deepened between 12 and 24 weeks. And post data cutoff, we saw is tangibly manifested as we saw an additional response from 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 become 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 Zovega. All of this is seen at a level of tolerability that compares very favorably with the existing treatment option at alpelisib. Across all doses, we saw initial rates of grade 3 plus toxicities at Zovega 15% versus 70% for alpelisib. If we just look at combining the 100-milligram and the 300-milligram BID doses of Zovega, we see the common adverse events associated with wild-type PI3K alpha inhibition were low-grade, manageable and reversible. No rational stomatitis of any grade was observed no grade 3 hypoglycemia or diarrhea was observed, and there have been no discontinuations to date due to [indiscernible] and all patients currently remain on therapy. Given all of this, we're excited to open multiple Zovega 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 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 billion 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 $1 billion. 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 dates 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 and overview of the trial we're running and obviously share the excellent data that we're showing 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, and they share common genetics, of which PI3K alpha Victor CA gene is among the most common driving mutations and 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 nonselective systemic treatment options carry a toxicity burden that is unsuitable for chronic use and severely limits the ability to inhibit the disease driving mutation. [ Sovagelisib ] is the only mutant selective PI3K alpha inhibitor currently in clinical trials for patients with PIK3CA driven vascular anomalies. It's 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 1/4 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 Zovega and vascular anomalies. We leveraged nearly 250 patients worth of experience for Zovega in 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 3 doses of Zovega. 400 milligrams twice daily, which is our recommended Phase II dose in combination with fulvestrant in breast cancer, 300 milligrams twice daily and 100 milligrams 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 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 the high prevalence of PI3K mutations in these diseases. The objective of Part 1 was to evaluate the safety, tolerability and efficacy of Zovega in patients with PI3K driven BAs. 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, and 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 Zovega 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 to 17. Half of patients had a nonkinase domain PI3K mutation, 31% a kinase domain mutation and 19% had no documented PI3K mutation at study entry. 1/4 of patients were prediabetic at study entry. Most of these patients have previously been treated with alpelisib with some of these patients discontinuing alpelisib only days before signing consent for our trial. And 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 3 dose cohorts. Although in the small sample size, there were some imbalances, including over half of the 300-milligram BID cohort being prediabetic at study entry. The pharmacokinetics of Zovega and vascular anomaly 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 3 doses achieving the levels of target coverage we projected, about 90% mutant PIK3CA inhibition for the 400-milligram dose, over 80% for the 300-milligram dose and approximately 60% 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% and achieved a 20% reduction in lesion volume to be considered a volumetric response. The response rate for the 300-milligram dose was 100% and for the 100-milligram dose, and it was 29%. But as Sanjiv 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 BRR overall becomes 65% across and 43% at the 100-milligram BID dose. Even at early time point, a response rate like this as well as the depth of responses has not been seen with nonselective inhibitors. As you can see on the waterfall plot, responses were observed across all 3 doses across PROS subtypes and lymphatic malformations. Across all PI3K mutations, including in patients with no documented PI3K mutation. And patients previously treated with alpelisib [indiscernible] or both agents and were independent of baseline lesion volume, including responses in patients with baseline lesions with a volume of several leaders. Despite our plus of change in lesion volume highlight the rapid and deep onset of response seen, especially at the 300- and 400-milligram doses. [indiscernible] 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 thoughts also highlight the 3 patients at the 100-milligram dose who have not yet achieved a response, but show a deepening of volume reduction at subsequent scans and our ongoing treatment in the study with one of those patients, as we've mentioned, converting to a volumetric response after data com. 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 GIC, which is the investigator's assessment of the patient's general symptom [ Bird, PGIC ] which is the patient's assessment of overall symptom burden our IADS pain scale, which is the investigator's assessment of pain in patients who report pain at baseline. Across all 3 measures of clinical benefit and across every dose, patients experienced improvements and symptoms with continued Zovega treatment with symptom scores at week 20 showing continued improvement relative to 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 Zovega shown today was higher than what has been reported for either alpelisib in either the EPIC T1 or EPIC T2 at any time points. We saw the same response rate of 60% in patients with the diagnosis of PROs versus the diagnosis other than PROIs. An 80% response rate in patients with kinase domain PI3K mutations, 55% nonkinase MA mutations and 50% in patients without a documented mutation, we've also seen comparable response rates in patients with prior alpelisib or sirolimus 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 burden. Shifting to safety. Zovega was generally all tolerated across all 3 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 then resolving. Other common AEs were fatigue, nausea and diarrhea and decreased appetite, all low grade. We only observed Grade 3 plus AEs at the 300-milligram BID dose. One case of hypokalemia in a patient who is taking a potassium wasting diuretic and 1 case of hypertension in a patient who entered the study with existing grade 2 hypertension. And there was only 1 event of Grade 3 hyperglycemia seen across the study in a prediabetic patient treated at the 400-milligram BID dose. Hyperglycemia was otherwise low grade and typically only seen in the first cycle and the majority of the grade I hyperglycemia seen at the 300-milligram BID dose was in patients free diabetic at baseline, of whom many had recently been treated with alpelisib. We did not see other AEs frequently observed with nonselective 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 1/4 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 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 alpelisib with this initial data. It is challenging to make a direct comparison to the safety profile of alpelisib in VAs as the FCTI trial was a compassionate use study and did not have prospective collection of routine safety and the PICP 2 trial used a 125-milligram dose of alpelisib, 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 alpelisib in exposure similar to those achieved at the 250-milligram PROS dose came from the PIC-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 alpelisib and we believe represents a profile that could support chronic use and vascular anomalies, again, with no reported [indiscernible] 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 VA noting that these venues 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, Q-546K. 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 leaders. 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 station does not meet the threshold for a volumetric response. But at week 24 had a 19.75% reduction in this 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 2 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 closed subtype of Pros. His lesion has a helical domain mutation in PIK3CA, E542K.a. 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-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 DAs 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 of balalisib 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 of 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 it already just 12 weeks shows 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 Zovega 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 prediabetic 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 2 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 alpelisib, meaningfully better tolerability than a 250-milligram dose of alpelisib with the convenience of a once-daily regimen for chronic use. Patients are currently enrolling at these 2 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 2 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 up.

Thanks, Tom. Clearly, these are very exciting times here at Relay. We started the year with the goal of making 3 meaningful disclosures against 3 very large market opportunities: second-line breast cancer with our ESMO TAC disclosure, frontline breast cancer with our recent triplet data disclosure. And now today, with these promising initial data in DAs, we've been able to do just that. We saw meaningfully differentiated initial activity and tolerability in BAs as compared to Alpelisib at the very first dose level and across doses, response rates and symptomatic improvements have not been 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 in lymphatic malformations, 3 out of 4 LN patients are in response and our 2 deepest responses are coming from LN patients. There are about 65,000 LN 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 3 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 II. In frontline breast cancer, we will provide a regulatory update for the end of the year and remain on track for our first half of '27 Phase III start. We'll also likely give a Phase I/II 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 2029. And only incrementally more capital would be necessary through registrational data and early commercial launch in both breast cancer and vascular anomalies, pending data and [indiscernible] in addition to continued data readouts from the Phase I/II TRIPLE study and initial NRAS date. With that, I will now open it up to Q&A and hand it back to the operator.

[Operator Instructions] And our first question is going to come from Kash Tiwari with Jefferies.

This is Amy on for Akash. Congrats on the great data. Just 2 from us. How should we think about the dose response between the 300 and the 400-milligram BID dose -- did patients on 400 have more dose interruptions? Or are there any differences in baseline characteristics? And then just 1 on your subtype data. You're seeing pretty strong early activity in LM. No response is invenous yet. How are you thinking about that venous population? Is that just more heterogeneous? Or do you think that could deepen over time? And then as you think about the initial accelerated approval package, is your base case assumption still a pool pros invenous filing? And 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 mean I'll let Don to take the first 1 on the 300, 400-milligram question.

Yes. So I think, Amy, as you hypothesize that 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 slide or 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 not to pursue bringing that forward into our expansion cohorts.

On the second question on the venous metamations, where you can take that.

Yes. As we've 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 2 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 pro side. And both polished Sirolimus have had a history of use off-label use in DL patients. We believe the venous enrollment will come over time. And we do believe that we should see a benefit there consistent with the other 2 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 an LMS and PROs, can be prescribed therapy without a genetic test because you have 100% of patients with Pros having the piece mutation and 80-plus percent of LN. In venous malformations you're going to need a genetic test to direct therapy because there the frequency of PPC mutation is about 20% to 30%. As to exactly how many of these 3 get pooled in an initial filing, that will be subject of conversations with the regulatory authorities. But we are going to continue to enroll all 3 sub-types. We think that the strength of this early efficacy certainly sets us up well to contemplate the accelerated approval pathway and that will 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 got a long way in today's data set to derisk the fact that we believe Savage is going to be efficacious in both of those subtypes, and therefore, unlocking the large commercial opportunity there. Thanks for your question.

And our next question will come from Yaron Werber with TD Cowen.

Congrats on really terrific data that is much, much better than expected. So I have a couple of questions. The first 1 is actually 2 -- so you had 4 patients that have data out to 24 weeks old responders, they 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% reduction. And then there's 3 other patients, 2 of them are at week 24, and they're essentially on the cusp of responders, they're the 100 BID. They are -- both of them are at 19.5, 19.8, 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 that factor into your time line and your thinking for accelerated approval?

Thanks for the question. Maybe on the kind of genetics question. Obviously, you can see from the spider plots that the 300-milligram BID dose, you see 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, 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. 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 are slightly different, but 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 we're hovering around 18%, 19% and converted from 18 and 19 at the 12-week scan to minus 35 at the 24 weeks car. 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. In one side, on the 300-milligram dose, we believe that 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 a lot of different things. 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 Proto question, [indiscernible] Pete can comment on by the 40 patients is going to be enough.

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

And our next question will come from Bradley Canino with Guggenheim.

Great data and great progress for the trial. Can we just double click on the prior question with some more details about how you believe whether you are or leaving efficacy on the table by not bringing forward the 400 mg 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?

All right. Maybe I'll start the first one and hand it over to Don. I think the 300-milligram BID dose, or 100% volumetric response rate, and we're seeing 80% to 90% 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 exploring the expansion cohorts, 300 BID. And then 1 below that, 1 day. So just to be clear, that's slightly confusing because that's the equivalent to 200 milligrams BID in terms of PK, you 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, it is going to be very hard to beat. And therefore, that's why we took it forward to [indiscernible]. 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 as going above $300 gets you additional benefit. We're clearly active in 100. So we're actually exploring this intermediate dose because it's possible that you could actually max out efficacy below 300 milligram. And in fact, we project that the 400-milligram once daily dose will give us exposure that lies right on top of the 80% inhibition line for MIK 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 here 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 at [indiscernible]. 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 VAs data that we've just seen, take our second-line breast cancer trial towards registrational data to move forward 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 set for 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 toward some very significant catalysts, 2 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 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.

And our next question will come from Salveen Richter with Goldman Sachs.

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.

Yes. 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 stay on treatment chronically for the rest of their lives. Today, there is a -- 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 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. And so those would be the 2 approaches. And I think that's the type of kinetics we would see early on in March.

And the next question will come from Sean McCutchen with Raymond James.

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 on the composition of lesions for patients in the study, fatty fibrotic? And any commentary on robustness of response data to that end?

Yes. Yes. 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 compromise the ability probably to see a first scan response, but those patients remain ongoing at a lower dose. And I think we'll continue to track those patients over time, but their lesions are still shrinking. -- even with the compromised intensity in the first cycle. In terms of lesion competition, these are complex lesions. I think you could see from our vignettes the nature of the lesion vascular components, fluid components, fibrotic components, say 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 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 this qualitative, of course, but you start seeing correction of those tortuous vessels. So I think it gives us encouragement that we're not just shrinking lesions, but by actually hitting the underlying biology of the disease or actually modifying the disease with Zovega.

And the next question will come from Andrew Berens with Leering Partners.

Obviously, got 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 Medicor docs that could be very difficult logistically. Is there any way to offset that or help with that requirement? And then the second is a strategic question, other 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 bias for SMid-cap biotech than breast cancer.

Pete, you take the first one.

Yes. Look, I think the best thing we can do is to generate the strongest data possible as we move into regulatory conversations, potential filings and then market access conversations. The -- 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 or not [indiscernible] 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 the -- 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 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 management. As you know, there are only a small number of centers in each country in the U.S., that's kind of 20 to 30 centers. And so in terms of the commercial model, it is very manageable -- and obviously said the market size here is very significant. So it is a very kind of a sweet spot for a small biotech to commercialize. And so today's data significantly derisk that opportunity, and we'll move very rapidly towards trying to get to an accelerated approval and generate revenues. But it doesn't change the fact that our breast gas side is still as attractive. We see capivasertib in the second line moving towards $1 billion worth of run rate, and they've done that very rapidly. And obviously, we know it's going to share of voice marketing. If we can show that we could almost double the 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. And so walking away from over $1 billion 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 way background, I spent 10 years in 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 those -- you can see it from the CDK4/6 sales that are out there in the tens of billions. So we feel that we have 3 very large opportunities. We obviously today of derisked 1. We're very excited about commercializing in the second line. I 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 3 are manageable, and we look forward to executing all 3.

And our next question will come from Silvan Turkcan with Citizens.

Congrats on this very strong data -- my first question is maybe big picture. I know it's very early here, but how would the how you see this treatment regimen involved? Would there be eventually maybe treatment-free windows, considering you have such fast onset of responses, could patients cycle on and off drug. And then the second question is, is the response rate tied to the baseline lesion volume, so meaning 2 larger lesions responses as well as small regions.

Yes. So I think we can take them one at a time. So on the lesion volume, maybe Don, you can take that one.

Yes. So on the lesion volume, 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 alpelisib, and this is because of the fact that they're getting better. And the answer is no. It's because of the toxicity. Patients do not want to tolerate it. We were here at DS conference in Philadelphia. We're talking to the patient advocates it's very clear that, that is the challenge for patients, which is the toxicity. And so I think what Zovega 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 occur. 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. It allows flexibility for prescribers. Obviously, that 300 milligram, you're seeing a 100% response rate and you're seeing very rapid and deep responses. And that may be what prescribers what. On the other side, you're seeing the 100 milligrams, 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 were -- and so I think what we're seeing here for the first time is profound efficacy or prefinance safety that will allow us to be the kind of solution for everyone here. And so we're very excited about taking it forward.

And the next question will come from Matthew Biegler with OPCO.

I just had a clarification on the patients with unknown PIK3CA status. Is it just that they weren't tested for -- or is there a downstream AKT or maybe P10 over activation? 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.

Yes. So I think the patients with unknown status reflects 2 challenges with testing these patients. One is accessing tissue for performing the diagnostics as some of the lesions. It's not medically feasible, to be able to access the tissue or it's 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 solid tumors. So a lot of those oncology diagnostics don't 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 has 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 mutation VACATP10. We think, again, in LMS, the vast majority of patients are driven by PICC. So I think these patients in whom we're seeing benefit or picture ACA-driven anomalies, and it's largely technical or medical reasons why you don't have a detectable mutation.

The next question is going to come from Boris Peaker with Jones Trading.

Great. I just wanted to question on safety. You mentioned that 23% of patients had dose reductions. I just want to understand what these primarily at the 300 mg BID at 100 meg 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 day to both the regulated and with prescribers was quicker 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 forward and not to underestimate the inherent advantage of having such an extensive multiyear database of entering this field. because remember, this is a very different feel from oncology and the threshold for folks to try these new therapies are sourced in human is very high. And so might, I'll hand it over to Don.

Yes. So the directions, we saw more reductions at 300 than we did at 100. We only had a single patient with a modification in a patient who had some low-grade nausea, decreased from 100 BID to 75 BID, but then actually came right back to 100 BID. It 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 successfully be able to manage those reductions. -- still being able to maintain the 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 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 going to go over to the SA conference now and share the data with physicians, patient advocates and make sure that we can rapidly enroll these expansion cohorts as possible solve to the regulator and hopefully get this therapy to the 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.