Newsfilter article unlocker

Good morning, everyone. I'm so happy to be joined by the management team of Relay Therapeutics on the last day of the Morgan Stanley Healthcare Conference. I am joined here by President and CEO Sanjeev Patel, President of R&D Don Bergstrom, and Chief Corporate Development Officer Pete Ramer. So I'll just read a quick disclaimer. Please visit morgansanley.com slash research disclosures for our research disclaimer. And let's dive right in to the Relay story. Maybe we can start with you, Sanjeev. And sort of what's been, you know, 2026 has been a very eventful time for Relay with data disclosures across both breast cancer and vascular anomalies. So what's sort of been the company's focus over the past few months? So, yes, as you, first of all, thank you for the invitation. And thank you for all of you attending both online and in person today. 2026 has been an eventful year for us, exactly as you said. We've been pushing forward our lead program, Zovega, which is a PI3K-alpha mutant-selective inhibitor across three different indications. The first of those is second-line hormone receptor-positive HER2-negative breast cancer, where in March this year, we showed data using our pivotal dose of 400 milligrams BID that showed a PFS in this population of 11 months. This compares very favorably with the current standard of care capivacertib. And so we're headed down there executing a pivotal trial across the world, and we're very happy with how that's going. And later this year, we'll share an update on when we believe the last patient in will be on that trial. In our first-line hormone receptor-positive HER2-negative breast cancer efforts, we declared in April of this year that we'll use a regimen of Zovega with Pfizer's selective CDK4. This is a really important mechanism because using a selective-selective approach, we believe we can minimize the side effects and maximize the tolerability of this regimen, which has been the challenge in this field. We know that adding a PI3K pathway inhibitor matters because we've seen that from the NAVO data, the challenge has really been the lack of tolerability and the lack of ability of these patients to take this regimen for, you know, up to three to four years. And so using this mutant selective and CDK4 selective approach, we feel very comfortable that we'll be able to provide the regimen that patients actually need. And then in May of this year, we showed data in vascular anomalies, where we showed a very robust volumetric response rate of 60% across the doses that we were using, and that compares, again, very favorably to the current standard of care, Alpalisib. So there, we're very much focused on the dose expansion portion of our study, establishing a dose, and then later this year, we'll do both a data update and a regulatory update on how we believe that we can get this therapy to patients rapidly. So it's been a very eventful year, but it's still an eventful years ahead. What's the next year to come? Absolutely. You mentioned that, you know, in the second-line breast cancer, you had an update from Zoviga earlier this year. Maybe you could talk a little bit about what that data actually showed, and you referenced sort of the competition with the standard of care cap of a certib. Maybe you can kind of profile that a littlebit for us in terms of what you demonstrated. Yeah, and so, as you know this is a very large market, the second line, hormone receptor positive, HER2 negative breast cancer market. And the standard of care has evolved over the last few years. Alpalaciv, which is a non-selective PI2K inhibitor, was approved a few years ago. And unfortunately, commercially, was not that successful because although it showed a PFS in the kind of seven to eight-month range, the tolerability challenges of hyperglycemia, diarrhea, rash, stomatitis, unfortunately mean that patients just cannot stay on this therapy. And so although it's efficacious, it's unfortunately not tolerable. Then we saw the emergence of the AKT inhibitor from AstraZeneca, Capivacertib. Again, this showed actually numerically a lower PFS than Alpalacib, but was perceived to be more tolerable in that it had in its label lower rates of hyperglycemia, but it did have still significant rash. And so this has been launched a couple of years ago and is doing commercially very successful. It's kind of moving towards a billion dollars of run rate in its sales. And it shows that if you could have what is perceived to be a more tolerable regimen, you can definitely be commercially successful to the tune of a billion dollars here. And so the data that we showed earlier this year in this patient population was in second nine and second nine plus patients using our 400 milligrams BID dose of Zovega. And the premise of this program was if you can have a mutant-selective inhibitor in this field, you can dial down the off-target toxicities of diarrhea, rash, hypoglycemia, stomatitis. And that's exactly what we showed, which is low rates of all of these. And that means that you can keep patients on therapy with a greater dose intensity, and that should translate into greater efficacy. And That's exactly What the Data Showed. We showed 11 months of PFS in this patient population, and obviously that compares very favorably to the five and a half months of capivacertib. And so we feel pretty confident now as we run this head-to-head pivotal trial against capivacerib that we could be successful in this patient population and create a very commercially meaningful therapy for patients. And Jeev, can you talk a little bit more about the phase three trial design? What are the key timelines? And then, you know, how you think about Dovega ultimately fitting into the evolving second-line breast cancer landscape. To me, I'll hand that over to Don to talk about the trial design, and maybe then Pete can talk about their landscape. Yeah, so it's a one-to-one randomized trial of fulvestrant plus Zovega versus fulvestrant plus capivacertib. The patients who were enrolling have all previously been treated with endocrine therapy and a CDK4-6 inhibitor. The criteria for enrollment are a little bit tighter than what was used in our phase one program to date. For example, we're not allowing patients to have multiple prior CDK4-6 inhibitors or an ADC, so we are looking to enroll as close as we can to a true second-line patient population. The trial is powered to show clinically meaningful improvement in PFS. We also have OS as a key secondary endpoint. So, as Sanjeev mentioned, we opened the trial in the middle of last year, mid-2025. We're very encouraged with the way enrollment is going. Trials of similar size and a similar population have traditionally enrolled over the course of 30 to 36 months. We just saw upper one in second-line patients. This is the oral SIRD trial. That enrolled in 33 months. So as Sanjeev mentioned, we will have an update at the end of the year on when we think will reach full enrollment. On the landscape in second line PIK3CA mutated patients, there's two pathway inhibitors that have full approval. We've mentioned both of them already. L-alpilacid, marketed as PICRE, could be deserted, marketed true cap. The most recent data from both the assets that we have publicly puts their PFS in the same ballpark of about five and a half months, six months. And so we feel very confident that with the data we have in hand today that Sanjeev has talked through, which is in almost a median third-line patients, that when we move into this phase three trial in more true second-line patience, we'll have the ability to see at least close to a maintaining of the PFS we've seen so far in phase one, two, now across 120 patients. And so, as mentioned, the commercial market today across the class is probably in the neighborhood of about a billion dollars run rate and still growing, which is quite encouraging. And if we can come with a next-generation profile, which we have in hand today and prove that out in a phase three study, we do believe we should be able to rapidly take some of that market share and continue to grow the market. In terms of trial execution, we're very happy with how things are going. We started the trial in mid-2025. Precedent trials for full enrollment take somewhere between 30 and 36 months. We just saw a recent benchmark for a similar size trial in this field taking close to 33 months. So our goal here is to go as fast as we possibly can knowing that these are the benchmarks and try to beat some of them if we can. Okay, great. Thanks to all three of you for laying that out. I want to turn the attention to the first-line opportunity now, and maybe you can spend a moment on the first line landscape and sort of where do you see the remaining unmet need there? Yeah, so in the current landscape and front-line trial, current standard of care for most patients is the combination of endocrine therapy plus a CDK4-6 inhibitor. And what we've seen in retrospective analyses that have been run in a number of the trials testing these frontline regimens is that patients with PI3K mutations tend to have a shorter PFS than the patients who are enrolled who have wild-type PIK3CA. So in the case of ribocyclib, the PFS that was observed for PIK2CA mutant patients in in an endocrine-sensitive population was 19 months versus 31 months for PI3K wild-type population, so about a year difference in PFS. So we feel that the current CDK4-6 doublets are, you know, can be improved upon, especially in PIK3CA mutant patients, and I think that hypothesis was borne out in the results we saw for the ANAPO-120 trial of inovolacib, Roche's non-selective PI3K inhibitor, in an endocrine-resistant subpopulation. So these are patients who had shorter treatment-free interval between their adjuvant therapy and recurrence of metastatic disease. And in that patient population, we saw inovulacib be able, in combination with filvestrant and in palbocyclib to deliver on both PFS and OS in a randomized phase three trial leading to approval. Now, the challenge here is that that was a very heavily selected patient population, both in terms of being an endocrine-resistant patient population. And the patients had to be very, very metabolically fit because of the hyperglycemia profile of anabolicib. So that has translated into limited utilization after the launch just because the physicians that we talked to have a real challenge finding the appropriate patient who's going to be able to handle this regimen. It is the toxicity burden of the regimen when you consider the hyperglycemia, you consider rash, diarrhea. It's a heavy toxicity burden. and patients are taking multiple concomitant medications to actually manage the AEs that are associated with the drug, so it's being used sparingly in very fit patients. Our hypothesis is we know that PIK3CA is a negative prognostic marker in these patients. We know inhibiting mutant PI3 kinase can provide additional benefit, and we want to develop a regimen that has the tolerability profile, as Sanjeev mentioned, that patients It will be able to be used broadly in a general patient population, and patients will be able to tolerate it and stay on therapy, you know, for three years or longer. So along those lines, we really focused on a termocyclib and the triplet of endocrine therapy plus a termocyclib plus a vega as providing that tolerability profile, as we showed in the data disclosure from earlier this year. and we're focusing right now on the design of a randomized trial in endocrine-sensitive patients, so the more common patient population, where we would be testing the triplet of endocrin therapy, in this case an aromatase inhibitor, plus a termocyclic, plus Zovega, versus endocran therapy, aromataze inhibitor plus a CDK4-6 in an investigator's choice. Tom, can you talk a little bit more about the decision to go in the endocrinesensitive population? You know, what's driving that? It sounds like a bigger population, bigger portion of patients. Yeah, so it is commercially the larger opportunity. It's a place where, you know, we have the evidence that shows that the PIK3CA mutant patients don't derive full benefit from current CDK4-6 targeted therapies, so there's clear unmet need there as well. And we're also, you Know, in the ongoing Rediscover2 trial, we are testing Zovegan patients who are post-CDK4-6 inhibitors. So we, you know, with the endocrine-sensitive approach in the front line, and then with the ongoing Rediscover 2 trial in the second line, we envision that we could have labels that will capture, you know, the vast majority of the metastatic PIK3CA mutant breast cancer population. Okay. How do you think physicians will decide between using a PA3K alpha targeting agent in first line versus second line and when to kind of engage that opportunity? Yeah, so I think, you know, that will be the option that treating physicians will have with these two trials that we're running. And, you Know, I think again it's going to come down to the profile that we are building in our front line trial and the opportunity to have this selective, selective regimen for a termocyclib and Zovega that, you know, we feel the overall toxicity burden for patients with the selective-selective approach, with the data we've generated so far, is not meaningfully worse than the existing CDK4-6 doublet therapies with current-generation CDK 4-6 inhibitors. So I think, you now, basically the proposition we'll have is that you can have a, you meaningfully more efficacious frontline therapy with the triplet, with a safety profile that doesn't bring additional burden on patients, will be a very attractive option for physicians. There could be cases where you have patients who are maybe older or frailer where the decision is made to go with a, you know, potentially milder therapy in the frontline and reserve Zavega for second-line patients. But I think, you know, again, what we're looking to do with this development program is really to be able to provide that optionality and to be able to have labels where we can capture, you know, patients where we think that the vast majority of patients with the profile we have would be good candidates for a triplet and frontline. But then for the population who maybe wouldn't be candidates for frontline triplets, there's the option to drive benefit from Zovega in later line two. And when you think about the triplet with the Pfizer drug, what gives you confidence that the drug-drug interaction with the TIRMO will not be an issue in this study? Yeah, I mean, I think there, you know, we have a good mechanistic understanding of what's happening. And what we've seen is that when we co-administer ZoveGA with a termocyclib, a termocyclob actually increases the absorption of Zovega. So we get the same blood exposure to Zovegia in combination with the termo, but with a lower dose than what we have in the doublet. So the doses that we're focusing on that we reported out earlier this year was a 100-milligram BID dose and a 150-milligram BID dosing triplet compared to 400 milligrams BID in the dublet. But this effect is consistent across patients. The interpatient variability is the same in triplet as we see in doublet. So if anything, it's maybe a little bit of a benefit in the sense that it's reduced our dose, and we're not concerned about there being new sources of variability or other complications that could make development more challenging. Just on the point around the termo, I mean, is there any concern around whether a termo is approved or has a positive phase 3 and it's its own first-line study, the 4-Lite-3 study? Yeah, no, I don't think we have a concern. I think what we're looking for in a termо is a tolerable safety profile. The whole premise here is to stack a mutant selective with a CDK4 selective inhibitor to try and minimize the AEs. And so I think what we've seen in the data so far that's in the public domain is exactly that from a termo, and that's what we want to use as our foundation. The 4.3 trial is a trial that is looking at superiority in terms of efficacy versus the standard of care CDK4.6. So in a way, you know, that, whether it is or it isn't, is irrelevant to what we're looking for. We're looking For a tolerable foundation to be the backbone of our regimen. And so our focus is on is a termo a more tolerable mechanism than the CDK4-6, and I think we feel very confident of that. So it's kind of irrespective around whether 4.9.3 is successful or not. Okay. So just looking ahead to next year, you said publicly you'll actually start the Phase 3 in the first line early 2027 pending regulatory feedback. So, you know, anything you've kind of contextualized for investors around the regulatory interaction that may be upcoming for that program or on just the plan for the Phase 3 next year? No, it's just all the dull stuff that goes into making and developing a new medicine. So we're obviously getting all the sites and selections, CROs and dose and putting everything in place and going to the FDA. We don't believe that there's anything specific inside of that than just getting everything clarified. And obviously, we look to start this trial as rapidly as we possibly can. Okay, great, and good luck. Thanks. I want to turn to vascular anomalies and the market opportunity here. How would you kind of size the opportunity and what subpopulations are most useful to consider? Can you hand that to Pete? Yeah, what we've said is the current total addressable market, we believe, is $6 to $8 billion. dollars. What is behind that is in the U.S., there's about 170,000 of these patients with PIC3CA mutations. We don't believe all those would need chronic systemic therapy to address their disease. So we've done some market research and talked to many investigators and physicians that treat these patients. And what that funnels down into is within the subsets that we're currently testing, treating in the trial, which is PIK3CA-related overgrowth spectrum. That's 100% PIK2CA-mutated. Lymphatic malformations is 80-plus percent PIK1CA-mutated, and then venous malformitions, about 20% to 30% PIK4CA- mutated. Across those three subtypes, we think there's about 25,000 addressable patients that could be amenable to chronic systemic therapy to address their disease. We only need to capture a fraction of that to have a very large opportunity for ourselves. So to put that in context, about every 2,500 to 3,000 patients, if you assume the current by-joice pricing of the only drug that has accelerated approval at $36,000 a month, every 2.500 to 2.000 patients would get you a billion dollars of sales. And so we don't need to capture much of that 25,000 to be able to have a blockbuster product here. We do think we're generating the profile that will allow us to capture a good amount of that 25, 000, maybe over time able to grow that 25 000. But I think where a lot of our confidence stems from is that it doesn't take a lot of patience to have really meaningful opportunity here, and the early data we've shown has been dramatically better than what is out there for patients today. Yeah, let's go further into that. The data that you showed earlier this year, maybe you can contextualize what you actually demonstrated versus the standard of care drugs. Yeah, so we brought Sovega into the clinic in vascular anomalies in the spring of 2025. And in just about a year's time of being in the clinic, we were able to show data that is demonstrating superiority on a cross-trial comparison basis to Alpelosib. Alpelossib has accelerated approval just in PROS today, so the small subset of PROS, and their data has shown somewhere between a 20% to 30% volumetric response rate. That's the regulatory endpoint here is volumetic response rate, and a patient is considered to the response if their target lesion has shrank by 20% or greater. So in the case of Alpelicib, their data has shown roughly 20% to 30% volumetric response rate. Our initial data across 20 patients demonstrated a 60% volUM response rate, so a doubling or tripling of what Alpelisib has been able to demonstrate. And most importantly, that comes with a much better tolerability profile than what we know botopelicid today. And so I think these early data exceeded even our expectations. And around the time of the disclosure in May, we opened up expansion cohorts into 300 milligrams BID and 400 milligrams once daily. And we've been prioritizing enrollment into the 400 milligram once daily dose. We think moving to a once daily dosage would be quite a good convenience advantage for these patients that would be on, intended to be on this drug chronically. So very encouraged by the early data. We've guided to showing additional data before the end of the year in addition to a regulatory update. Remain on track to be able to do so. And excited to see how fast we can get Zovega-Licid to the vascular anomalies patients. Okay, great. Maybe just a little bit more about the RE-INSPIRE trial that you're running. And you said there will be an update later this year in vascular anomalies. But maybe talk a little more about that. Maybe talk a bit more a little about the trial design and just the rationale here, what you're hoping to show and what would be sort of viewed as successful. Yeah. So the study, because of our experience in oncology patients, we are able to go into dose randomization to do our dose finding. So we tested three doses in parallel, 100 milligrams BID, 300 milligrams B ID, and then the top dose is 400 milligrams B I D, which is our current second-line oncology dose. We enrolled 32 patients into that dose-randomized portion of the study, and that was focused in patients that are 12 years and older. At the time that we disclosed the data at ISFA in May, 20 of those patients were efficacy-evaluable. These patients get MRIs to evaluate efficacy every 12 weeks. And so by efficacy-valuables, that just means there's only 20 that had made it out to that 12-week point at the time in which we disclosed data at the ISFA. And so, by the time we make a disclosure before the end of the year, all 32 will now be efficacy-evaluable, and we'll probably even have a good number of those patients that have made it out past multiple scans. And so it'll be, within that patient population, a bit more median follow-up than what we had at ISFA. So that was about four months at IS FA, so wherever we do the data cut, there'll be that much more median following-up. So that'll be an encouraging early look at more mature data in this setting. And then in addition to that, we will show our early expansion data, but that'll be smaller end and certainly less follow-up. But nonetheless, with the data we've seen at 100 milligrams BID and 300 milligrams BID, we like the idea of what 400 milligrams Q-day could look like in the context of those two experiences, and it might be the optimal dose to bring forward, but we just have to enroll some more patients there and get some more experience before ultimately calling that a dose. And just thinking a little bit further ahead about the regulatory path for Zovega, what can you take from Alpelacib's regulatory path, and how might it compare for Zvega? Yeah. So, to remind everybody, L-pelicib had a very unusual accelerated approval. So, it was approved off of 37 patients that were treated under compassionate use, and it was a retrospective chart review of those patients. So not a traditional clinical trial by any means, but it really does speak to the level of unmet medical need in these patients, that the FDA would allow such data to warrant accelerated approval there. And so that was 37 patients able to get accelerated approval. Al-Palisad then ran a confirmatory study that failed, and they now went back to the drawing board to run another confirmatory steady that started in the fall of last year. The second confirmatory study they are now running is a single-arm study, 104 patients. Again, that's for full approval. So you have accelerated approval with 37 patients, an ongoing confirmatory study presumably negotiated with the FDA as being appropriate for full approval, single- arm 104 patients, and so as we think about our regulatory path forward. You have a high unmet medical need patient population with a very severe disease and moderate to severe patients, and you have no agents with full approval, no medicines with full approval in those settings. And so we do believe that accelerated approval should be available to us, and that will be the nature of the discussion we go have with the agency before the end of the year. And what we will propose is pooling of pros and lymphatic malformation patients. So far, our data is showing good consistency across those populations. The disease biology is quite similar there. So we'll propose pooling those two together and pursuing accelerated approval inside the ongoing re-inspire study. And so the question really will be, what's the requisite end to warrant accelerated approval? And then what would a confirmatory study look like if we were able to have accelerated approval, Again, we would propose for full approval, we just continue to enroll in a single-arm context inside of Re-Inspire, enroll more patients, and just have more follow-up. And that would be what we propose to be the full approval study. But this is all subject to discussion with the FDA. It may be the decision is to split out pros and LMs, which would be a fine outcome, too. our goal is just to get this as rapidly to patients as we can and get it on the market as fast as possible. That's a really helpful context, Pete. Maybe just one last question on Zoliga before we kind of look more organizationally. What are the pricing considerations for vascular anomalies versus breast cancer for the drug? Yeah, so we have some precedents here, which is helpful. So how Publisib, It's approved in both settings, as I mentioned. Marketed as PICRE in breast cancer, and in breast cancer, it is priced at $25,000 a month. It's marketed as VIJOYS in vascular anomalies, priced at$36,000. Obviously, a bit premature for us to talk about pricing of Zovegalicin, but suffice to say, it's a good precedent to see that you could have a very similar situation that we will find ourselves in, which is the same base API and two separate brands and able to have differentiated pricing inside of these two very different indications. Okay, maybe just last question on your pipeline. I don't want to gloss over the NRAS program, so Relay 8161. Maybe you can just give a quick summary of that program and when we might expect to see some data. Yeah, so NRAS is a very strong oncogenic driver. You see mutations most frequently in melanoma, colorectal cancer, non-small cell lung, thyroid, and some other malignancies. And there are anecdotes of patients with NRAS-driven tumors benefiting from pan-RAS inhibitors, although they don't get complete suppression of the pathway, and there's the toxicities associated with pan-RAF inhibition. Historically, people have tried combinations of downstream signaling nodes, so RAF inhibitors combined with MEK inhibitors, which have had, I would say, moderate efficacy, low to moderate efficacy, and high rates of toxicity. But everything we know preclinically about NRAS suggests it's a very strong driver oncogene. And everything we knew about NRAs in terms of tolerability would suggest that it's largely dispensable in any postnatal organism. So we think if you could have an NRAS-selective inhibitor, you could see very powerful efficacy in NRAS driven tumors, potentially with very clean safety profile. And we were able to use our platform to discover a novel pocket in NRas, then to exploit that to be able to make an NRas selective inhibitor. Very active as a single agent across preclinical models with melanoma, lung cancer, and colorectal cancer. And in non-clinical toxicology studies, almost no toxicity. So the hypotheses are borne out through the preclinicle testing. We brought 8161 into the clinic earlier this year, and we're now testing the hypothesis in humans. Okay, great. Just on sort of your cash balance, I know you completed a raise and now have $911 million of cash at the end of Q2, so you're well-funded into 2029. How are you thinking about just managing cash burn over the next several quarters, particularly as you get into later-stage trials and managing multiple different programs? I mean, as any company that's lived through the last year in biotech, we manage it very tightly. $910 million is precious, and we'll focus the majority of that, obviously, on executing against the three registrational trials that we are focused on running, so the first line, second line, and the VAs. Around that, obviously, we start to think about preparing for commercialization and being ready to commercialize as rapidly as possible as soon as we get the approvals for all three of those indications. And then behind that, honestly, over the last few years, we've significantly reduced our research footprint um but it remains you know very productive uh but it's obviously a much smaller part of our burn than it was uh back in you know 2021 2022. um but you know as you know with 911 million dollars we've got plenty of levers uh to move up and down uh as the programs move at different paces but we're confident that we can execute against um all three initiatives And in the life of this cash balance, we think we can deliver top-line registrational data on the second-line trial and the VA's trial and be significantly through the front-line trail. So we think there's lots of value we can create in this cash window. Maybe just as we wrap up, Sanjeev, anything you want to leave investors with as you think about the next 12 months, what you're most excited for and what they should be focused on? Look, I think we sit now having kind of de-risked a lot of the questions that were sitting out there at the beginning of the year. You know, is there a meaningful opportunity to improve the standard of care in the second line? We believe there is, and we've shown data against that. And now we're kind of rapidly executing towards getting that therapy to patients. And then on the other side, you know, the selective-selective approach, I think, has a, you Know, potential to be very large in a very big market. And then, obviously, opening up an entirely new therapeutic area in vascular anomalies, I think we've done a lot to educate the investor community around that. So I think they're one of the few companies out there that sits with multiple large opportunities with a single asset that's now de-risked. And now it's all about execution. And obviously we have a significant cash balance against that. And so we think that in the life of the next 12 months, we have significant catalysts to generate value for investors. That's great. So Sanjeev, Don, Pete, thank you for joining us. We're really glad to have you here and thanks for all your thoughtful answers. And we're wishing you luck. Thank you. Thank you to the Morgan Stanley team. Thank you for those of you in the presentation today. Thank you