Welcome back to the 46th annual TD Cowen healthcare conference. I'm Marc Frahm from the TD Cowen Biotech team. We're really happy to have with us the, for the next session, the team here from Nuvalent. We've got Jim Porter, CEO, and Alex Balcom, CFO. Maybe to start off with, Jim, you want to just kind of give a high-level status update on Nuvalent, and what you think, the key kind of value creation milestones for shareholders will be over the next 12-24 months or so? Sure. Thanks, Marc, and thanks to TD Cowen for the opportunity to participate in the Healthcare Conference. A pleasure to be here. I'll start at a very high level. Nuvalent is about to hit its eighth anniversary as a company. Eighth birthday coming up, made a lot of progress in building the company. The foundation, it's a deep expertise in chemistry, structure-based drug design. We focus on validated biology, validated kinase targets, and we partner with physicians to understand from their perspective what are the limitations of the therapies that they've developed, what are the needs of the patients they treat. Made a lot of progress building the company, sets us up to have a really exciting year, and maybe Alex, can you walk through some of the near-term milestones? Yeah. Thanks, Jim. Exciting year ahead. We've made a lot of progress on our on-target 2026 operating plan, line of sight to first potential approval this year. We laid out our milestones at the beginning of the year. For ROS1, the FDA has accepted our NDA for zidesamtinib in TKI-pretreated ROS1 non-small cell lung cancer, and we have a PDUFA date of September 18th. Our commercial readiness efforts are well underway to support, you know, a potential launch later this year. We've also guided that we'll submit data to FDA to support potential line expansion in TKI-naive ROS1. That's in the second half of the year. For our ALK program, we have completed the pre-NDA meeting with the FDA. We're planning to submit the NDA for previously treated ALK non-small cell lung cancer in the first half of the year. We're on track to do that. We're continuing to enroll the ALKAZAR, the phase III study for TKI-naive ALK. Beyond the two lead programs, we're continuing to progress our HER2 HEROEX-1 study. It's a phase I-A/I-B study. We've also guided to disclosing another development candidate by the end of the year. All right. Thanks for that overview. Maybe we'll start with the ALK inhibitor, Neladalkib, which is being, as you said, being submitted to the FDA, you know, right around now, for the TKI-experienced patient. Can you just review the indication statement you're seeking, particularly relative to, you know, how specific it may or may not be as to how many TKIs or what TKIs you need to have seen before being able to get access to Neladalkib? In brief, it's for, we wanted to develop a drug for all previously treated patients, and we're submitting all of our previously treated data with a goal for that indication. Just a background here, there are other approved therapies for ALK non-small cell lung cancer patients. We've partnered with physicians to understand from their perspective, what are we solving for? What are the needs of those patients? Most patients in front line receive the standard of care alectinib. When they progress on alectinib, they have ALK mutations or CNS disease. The only drug that works in that setting is a drug called lorlatinib. The reason it works, it has some coverage of ALK mutations and excellent CNS penetrance. When they progress on lorlatinib, nothing works in that setting. We wanted to make a drug for third-line patients that have taken sequential alectinib and lorlatinib therapy where nothing else works. Our drug has shown deep durable responses in that setting. We wanted a drug that works better than lorlatinib in the second-line setting. Lorlatinib has a seven to nine month duration of response in that setting. We thought you could do better by hitting the ALK mutations harder, hitting broad set of ALK mutations, both single and compound mutations, therefore those patients wouldn't progress with ALK-driven disease. Neladalkib is the first and only drug that has that profile, and we've seen deep durable responses beyond lorlatinib and deep durable responses in that second-line setting where lorlatinib comes up short. We submitted all that data for a previously treated indication. I think there's a pretty long list of regulatory precedent for that kind of third-line setting. Yeah ... for those types of indication statements with single arm data. What do you look to as a good example of something that is akin to what you're asking for in that more second-line setting where there is an option, on a cross-trial basis, you think you have a much better option? I hear you, Marc. Third-line setting we have Breakthrough. It couldn't be more straightforward. Obviously, we have to prove that to the FDA with strong data. In that second-line setting, you're right, there is an approved therapy. The argument we're making is this therapy is coming up short. It's coming up short because it's difficult to hit these ALK mutations because this particular compound hits off target that's dose limiting, and that dose-limiting toxicity doesn't allow you to hit the mutations hard enough. That's why we can see these durable responses. You know, if I look across the oncology landscape, there are some examples. One that comes to mind is in the CLL space. You know, Venetoclax got a previously treated indication when other drugs had already shown a previously treated CLL indication. That's one that comes off the top of my mind just based on the prior experience that I've had in this industry, but I'd have to go back and look for others. Okay. What is the regulatory strategy for kind of that same setting, outside the United States? Is that really gonna wait for what we will get to in a minute, the first-line randomized data? Yeah. We think there's an opportunity to pursue registration for both of our programs, Neladalkib and zidesamtinib outside the U.S. I can tell you the trials enrolled incredibly well outside the U.S. Expanded access, which is going great all over the world, not just in the U.S., in other countries. There's a clear medical need in that setting, and we think we have drugs that address that need, and we will pursue registration strategies outside the U.S. We've yet to guide on the specific timing of which. Regulatory with the types of data you have right now. That's correct. Not waiting for that randomized trial? That's correct. These trials were designed to support global registration. This is a little more U.S.-centric question, but, you know, how should investors think about pricing? Are the other ALK inhibitors, I guess maybe most importantly lorlatinib a good comp for how we should think about it? You know, given kind of what you're arguing of, you know, how this is a superior drug we should think about superior, you know, premium pricing to those. I think it's a little premature to comment on our, you know, specific pricing strategy. You know, as you mentioned, there are comps for the other drugs that have been approved, so we'll look at those as benchmarks. Then, you know, of course, consider the profile of our drug as well as, you know, market access, and we will look to share more details in the future. Okay. It's starting to get to the kind of market sizing. How big is the second-line plus ALK market currently in your, in your mind? The drugs in the ALK space in previously treated patients do not necessarily work well in that setting. What today's market is not necessarily a good proxy of what the market could become in the ALK space if you can drive durable responses in that setting, which was always the goal for the Neladalkib program. As of last year's sales, I think, lorlatinib has been growing up to about $1 billion. Most of that growth has, I think, probably come from some maybe some through new front line use. The previously treated ALK market overall, we think was in that $500 million-$700 million range. We think there's an opportunity to grow that by driving more durable responses. Okay. Maybe that's starting to hit that growth, and you noted that you have some of that is coming from some growth penetration in the first line market. What do you view as the kind of current mix today of lorlatinib versus alectinib use in the first line? Kind of what's that trajectory been like in recent years and where do you think it's headed? Yeah. The reason we started this program is we were talking to physicians that had developed all the other ALK drugs, including alectinib and lorlatinib. What they told us is that, you know, lorlatinib is a more active drug. Physicians will want to use it, but the majority will not because of the CNS toxicity that's associated with the off-target inhibition of TRK with lorlatinib. That's largely held up that alectinib today still is the global standard of care for ALK non-small cell lung cancer. Now, in the academic setting, many of those physicians that we collaborate very closely with, they recognize the positive attributes of lorlatinib, meaning a better chance of driving more durable responses for those patients. They're gonna try to figure out a way to get patients onto lorlatinib earlier if the patient can tolerate it. Unfortunately, many patients cannot tolerate it, we'll look for ways to do that, either by lowering the dose or looking for other mechanisms so the patients can actually tolerate the therapy. They also are the first to admit that most oncologists will not do that, particularly in the community setting, that physicians recognize this as typically younger patient population that's has careers, has families, and, you know, taking a drug that's CNS toxic is a little bit more challenging for that patient population. They wanna still live their lives. I think that's why alectinib has remained largely the standard of care globally. I think that will continue to shift a little bit. We do not think it will eventually become all lorlatinib because, you know, of the challenges we mentioned. Okay. Given some of that dynamic you're talking about of you mean the academic docs are a little more comfortable managing the side effects or are a little more eager to deal with that hassle to make sure they get every ounce of efficacy they can. You know, there's some investor fear that that will impact enrollment because those are obviously academic centers are the places that you tend to enroll your pivotal clinical trials. Maybe speak to what enthusiasm are you seeing so far for the phase 3 in first line for enrollment, given that there's only an alectinib controller? Yeah. Alectinib is a phenomenal drug. We're not offering a, you know, an inferior standard of care here. This is something that is the global standard of care for ALK non-small cell lung cancer patients. We've consulted physicians globally on what is the right comparator for this particular study and very, very comfortable with the decision, both with physician feedback as well as regulator feedback, that this is the right study to do. This trial is going exactly according to plan. We are rolling it across 160 sites across North America, Europe, Asia, Latin America. It's going according to plan. We think it's gonna enroll well. I think that even those physicians that recognize that there may be some advantages for lorlatinib treatment in front line. They also recognize the data that, you know, 38% of the patients are not on lorlatinib at two years, even in that five-year CROWN update, right? It's for patients that can tolerate lorlatinib, it could work well. Many of the patients cannot tolerate lorlatinib, so it's not the best option for all. There's a clear opportunity in a, with a drug like Neladalkib where you could have the potential to drive that durability without the safety challenges. That could really be a practice-changing study, and I think physicians recognize that, and they want to actually be part of that practice-changing study for the ALK-positive non-small cell lung cancer patient community. Okay. You know, on those lines also, you know, we've seen in his pre-FDA life and at times in his FDA life, Vinay Prasad make some heavy criticisms of drugs for either in some cases, not running randomized trials. Obviously, you are now. Even in the randomized trials, not necessarily using what in his view is the latest or most advanced therapy or most effective therapy as the comparator arm. I guess when have you most recently kind of confirmed that the trial design is appropriate, is it with this administration versus prior administrations at the FDA? We have an NDA under review and a second NDA we're about to submit. There is pretty much constant communication with the FDA across all aspects of our program, you know, around the right overall development strategy and registration strategy. We very much believe we have the right plan in place. Let me just say a little bit more about that, though. Alectinib is the global standard of care. No other drug has ever shown a benefit over alectinib, ever. In some of the other examples you might be pointing out, it might have been, okay, the standard of care changed because another drug proved it was better than that drug. That has not happened in the ALK non-small cell lung cancer space. We are the only drug that's going up against alectinib in a randomized fashion, showing that we're a better drug than the global standard of care. I think we're doing exactly what regulators often determine as, you know, the way to go here. Okay. How far into enrollment of that first-line trial do you think you need to be in order to kind of support accelerated approval? I assume what you expect to result from that, the filing that's going on. The FDA expectations typically are substantial enrollment. There is no number that they define as substantial enrollment. It's going to be based on that specific indication, the overall trial, the trial design, et cetera. I'm yet to guide on what a specific number other than we believe we will be substantially enrolled at the time of the any such decision. Okay. How should investors think about when you might complete enrollment in the first-line trial? Are the historical first-line randomized trials good comparators for how to think about monthly enrollment rates? You know, is there a lot better diagnosis and more enthusiasm for this drug that's going to lead to much higher? We think enrollment's going to go really well. I'll put some metrics out there. Our ALKOVE-1 study, we had planned to enroll about 250 patients. We enrolled 781 patients. It is the fastest enrolling small molecule oncology trial in the history of our industry. I'm not aware of anything even close to it. That's a pretty good sign, right? That is something that, you know, really gives our team a lot of enthusiasm because it's a reminder that we're doing something right. That is not because the Nuvalent team is very good at execution. They happen to be very good at execution, this is because investigator enthusiasm and collaboration with the patient advocacy groups were very informed in this space. I communicate pretty closely with these, particularly with the ALK-positive patient advocacy community and compliment them. They are the reason that we have the fastest enrolling oncology trial in the history of our industry. A true privilege to collaborate with them. I think some of that's going to carry over to our frontline study for this potentially practice-changing study. That being said, if you just go by standard enrollment rates, meaning what has been done with other trials in the space, the lorlatinib CROWN study, the alectinib ALEX study, the brigatinib ALTA study, you can get to a timeline that's pretty much consistent what we put on ClinicalTrials.gov, right. Standard enrollment rate, standard event rate gives us data somewhere in that 2029 timeframe. Could be faster, could be slower. It really depends on enrollment rate, event rate, and the actual stats we're using in the study. That's, that's good for the next question, which is many of those other ALK trials have, and just lung cancer more broadly, have included interim efficacy analyses. Should we expect kind of a similar statistical approach for ALKAZAR? Yeah. We haven't discussed the specific stats plan for this study, including whether or not there is an interim analysis. What I can say is that, you know, other trials in this space have both included and not included interim analysis. Lorlatinib's CROWN study did include one at 54% data maturity. Brigatinib's ALTA study had two interim analysis. IA 1 was at 33% data maturity. It was positive, but the FDA told them to keep going, until they got to IA 2 at 54% data maturity, where they did indeed stop the trial with, you know, FDA endorsement. we can learn from that, and we designed our study accordingly. You know, we haven't gotten into the specifics of what the stats are for our particular study. Ultimately, when we see the data, obviously the portion of the market that is continuing to use alectinib, it's very easy to interpret if you achieve statistical significance in it and have a good safety profile on a relative basis. For the portion of the market that is using lorlatinib first line, what do you think you need to show from a, whether it's a hazard ratio or a PFS delta, I don't know, what do you think is the best way to come to convince those physicians that they should give up on the added efficacy that they believe is there with lorlatinib to move to your product? I just mentioned we ran the ALKOVE-1 study in previously treated patients where there are six other approved therapies. We had the fastest enrolling oncology trial in the history of our industry. I think physicians and patients are already excited and convinced about neladalkib's profile, right? They have the opportunity to go on some of those other therapies, they're going on neladalkib. What I can tell you in collaboration with the patient communities that we've been working with the last several years, many of them are actually scared of lorlatinib. They understand the upside potential of that particular drug, but for drugs that inhibit TRK in the CNS that cause these CNS toxicities, they see the impact that can have on a patient and their patients, you know, living their life. A comment we receive often from the patient communities is, you know, what can we be doing to help you move faster? Because we really want neladalkib to be an option for us should we progress on a drug like alectinib or brigatinib. We're doing what we can to get the drug approved. I think that portends well that if we are able to be the first and only drug to demonstrate a statistically significant benefit over the standard of care alectinib, and we're the drug that works behind lorlatinib and better than lorlatinib in second line and does not have these safety challenges, I would put the question back to you, why would you ever choose to use lorlatinib as a, as opposed to neladalkib? What reason is there? I can't come up with one. Well, luckily, I don't have to answer questions. maybe we're starting to work our way through the time window. maybe we'll switch for a minute to ROS1, where obviously you are under FDA review. I would say investors are often pretty dismissive of the market size and the market opportunity here in ROS1. What do you think they're missing and why you think you have much higher expectations for what the market could be? You know, the reason we started this program years ago is that we were talking to physicians that had developed the other ROS1 drugs. At the time, crizotinib was the only approved therapy. There were other dual TRK ROS1 drugs in development. The physicians said those drugs are likely to get approved, they're unlikely to get uptake because, you know, there's some of the same challenges we just discussed with lorlatinib, you know, off-target toxicities. What they're looking for is a drug that can hit the ROS1 mutations, the ROS1 fusion, as well as the ROS1 mutations that happen beyond crizotinib, have excellent CNS penetrance 'cause crizotinib is not a highly brain-penetrant drug. Importantly, be selective for ROS1, don't hit these off targets that are dose-limiting. Zidesamtinib is the first and only drug that has this profile. Our trial, you know, This trial, we planned to enroll about 250 patients. We enrolled 540. Again, these things don't happen in oncology drug development. You don't double the enrollment of your studies ever. We, we did. We did because there was a medical need, and physicians and patients were excited about this differentiated profile. The questions used to come to the company of, "How are you going to find these patients?" You know, this is a rare indication. "How are you going to find these patients? How are you going to enroll your studies?" We doubled the enrollment. It's one of the fastest enrolling oncology trials ever. It's because we have what we think is the right profile for these, you know, for these patients. I think that portends well as we start thinking about the commercial launch. There's clearly a medical need that's not being met by the other agents. It comes to the data. What we do see in our data that's really intriguing. In previously treated patients that have already taken crizotinib and entrectinib, 93% of the patients are still in response at a year-and-a-half landmark. There are not too many oncology drugs I'm aware of in the frontline setting that have that kind of durability. We are seeing that in the second line setting. It really speaks to why ROS1, same goes for ALK, is a very interesting driver. The tumors are highly dependent on ROS1 and ALK signaling. If you can broadly cover mutations and CNS disease, which are the two key drivers of disease progression, and you can keep the patients on therapy, that is the formula to drive durable responses. If we can see that kind of durability across all lines of treatment is what we're seeing right now, then you have the opportunity to take what is today's ROS1 market and grow it. Grow it by keeping patients on therapy longer, creating more time on therapy leads to a larger commercial opportunity. We could foresee a world in which today's ROS1 market, which is in that $500 million range, it grows to something closer to what today's ALK market is, you know, $2.5+ billion, right? Just by keeping patients on therapy across all lines of therapy. zidesamtinib has that profile. The other drugs that have launched here, they do not have that profile. Right? We think there's a clear opportunity in front of us. Okay. As you just detailed that, you know, that you have managed to enroll hundreds of ROS1 patients, across the various formal trial cohorts as well as the EAP. Just, maybe first is what proportion of those patients are located in the U.S. and are actually subject to this review versus, later regulatory action? In the ARROS-1 study, I think 42% of the patients were in North America. EAP, we haven't guided to what the breakdown was other than you can imagine it. It's, it's enrolling well everywhere. We haven't guided to the specific breakdown. Probably you can assume something similar to what the trial execution was. If and when you're approved, what is the plan with those patients that are on trials in EAP? Are you planning to try to, you know, transition to commercial product as soon as possible, or do you think you want to keep them on more trial settings for long periods of time post approval to get some of that more long-term data? The patients that are on the ARROS-1 study, they would stay on the study, and we'd continue to follow those patients. For the EAP, you know, the patients that are being treated in the U.S., the expectation would be that those patients, you know, could convert to commercial drug upon approval. Okay. How many patients are in the EAP total? We haven't shared, that level of detail. What we've said is that we have, you know, treated over 700 ROS1 patients, and we've also disclosed that in the ARROS-1 study, we've enrolled, I think, 539. You want to walk through kind of the size and scope of the commercial organization that you need to build to be ready for that approval? You know, how much of that is in place today, and for the other parts, what does that cadence look like? Yeah. We've made a lot of progress building the team, we've, you know, assembled a team that's experienced in oncology and lung cancer, and we have, you know, folks across marketing, market access, commercial operations, as well as sales. We haven't disclosed, you know, for our sales force specifically what that number is, but can learn from, you know, the other launches in this space. Those teams have been in, like, the 40-60 rep range. You know, of course, we also have synergies with, you know, two potential near-term launches, we can look to leverage that as well. The approval right now that you're seeking is in that second-line plus setting. There is a cohort of first-line patients maturing. I think you've talked about needing something around 12 months of follow-up for them, which should happen in the summer, early summer, if I'm not mistaken. How quickly can you turn around and get that into the FDA? Is there a chance that that is done, is actually done as an amendment to the ongoing review, or does it need to be its own dedicated review? There are various mechanisms that companies can employ with this type of arrangement. Rather wait to when we execute and to describe the approach we're gonna take. What we're just guiding to at this point is that we are very comfortable that we will have the appropriate amount of follow-up for the naive patients to submit in the second half of this year. Second half of this year also happens to be our PDUFA date. We have a plan, and once we execute that plan, we'll be sure to share what it was. If it is open to you to, you know, where you would cause a scenario, 'cause obviously, if you gave them the first-line data, that'd probably be ruled as a major amendment to the second line. I agree with that. Yep. ... filing. Yep. Is that a good outcome for Nuvalent if you pushed out any approval by, say, three months but then got a broader label, or would you rather get on the market quickly and lay line and maybe it takes another six months or nine months to get to first line? Yeah. We had a trial that planned to enroll 250. We enrolled 540, and our expanded access is enrolled like crazy. There is a medical need, and we need to get the drug approved as fast as possible. That's why we cut the data earlier for previously treated patients, right? We didn't want to wait for the naive data. We cut it earlier to get the drug approved as fast as possible. We also think, you know, obviously the goal to help patients. We also think that there's a compelling commercial opportunity, right, in previously treated patients that they need better options. The other drugs don't work as well there. Our drug does work really well there. We want to get that drug to patients as fast as possible. Yeah, we're not looking to delay anything. We're running up on time, but there is a third agent in the clinic, your HER2 inhibitor NVL-330. What is the kind of value proposition of that agent versus some of the other most, you know, recently approved even under the commissioner's Priority Review Voucher? Yeah ... agent in that space? Yep. I'll boil it down to simple. Like, our priority is lung cancer. In lung cancer, the needs are HER2 exon 20 inhibition compared to wild-type EGFR, which is skin toxicity, GI toxicity are the dose-limiting toxicities there, and CNS penetrance. The drug that most recently got approved, it has one of those things. It has the selectivity index for exon 20 versus wild type. It doesn't have excellent CNS penetrance in our assays, and we think there's a clear opportunity to differentiate. If you go to the lung cancer space, earlier generation drugs across all different indications that get approved that don't have good brain penetrance get supplanted by ones that do. Beyond that, this is a broad opportunity that we can consider in HER2-driven cancers. The longer these patients that are on other HER2 targeting agents across tumor types, HER2 ADCs across tumor types, the longer they stay alive, the more likely they're going to get disease that spreads to the brain. What better to combine it with than a small molecule, highly brain penetrant, well-tolerated, broadly HER2 targeting, mutating targeting drug like NVL-330? We have that profile. Okay. What is triggering to kind of making disclosures around... The trial's been going on for a while. What do you need to kind of prove and demonstrate before you'd be ready to show data, and is that likely to be a 26 event or is that too aggressive? Yeah. We haven't guided to the timing just yet, but we're taking the same approach as we have with our other programs, following the data and wanna ensure, you know, we can tell a meaningful story about what we're learning. As Jim mentioned, you know, the initial focus is non-small cell lung cancer, but this is, you know, a program that is more broad and we could take many other places. What will be interesting and what we're interested to learn is, more about the profile of the program and where we could potentially take it. More to come in the future. Unfortunately, we're out of time, we're gonna have to cut it off there. Thanks, Jim and Alex, for joining, as well as.