All right. Welcome, everyone, to Jefferies 2026 Global Healthcare Conference. My name is Roger Song, Senior Analyst, cover SMID-cap Biotech. It is my great pleasure to have the next fireside chat with Nuvalent. We have CEO Jim Porter, and then Alex, CFO. Welcome. Thanks, Roger. Sincere appreciation for including us, for you and the Jefferies team in the healthcare conference, and we're excited to be here. Excellent. All right. Jim, I know I always start with that. You give us the state of our Nuvalent. You have a lot going on. You achieve a lot since the inception and IPO, and then also you have a lot upcoming. Give us a couple of minutes. Brief background. We're about an eight-year-old company. We just passed our eighth anniversary. We have built a company with an expertise in chemistry, structure-based drug design. I myself am a chemist. We focus on validated biology, so we take the target risk out of the equation, and we partner with physicians, try to learn from them. The folks that have developed the earlier generation inhibitors, what do they see as the needs of the patients they treat? What are the limitations of those therapy? We try to solve that through innovative chemistry. We've made a lot of progress building the company, and maybe Alex can share some of the milestones. Sure, yeah. Made a lot of progress, and we're now preparing for two launches this year. We have an upcoming PDUFA for zidesamtinib in September, and then neladalkib in November, and the team's made a lot of progress to prepare for launch there. Additional milestones include, we're planning to submit TKI-naive data to the FDA to support line extension into TKI-naive ROS1 in the second half of the year. We're continuing to enroll the phase III ALKAZAR study, and then beyond the two lead programs, continuing to progress our HER2 program in non-small cell lung cancer, and we are planning to disclose our fourth program by year-end as well. Excellent. All right. We just right off the press from ASCO. Honestly, Jim, I've been talking with the investors since ASCO because the stock moving, we just had a couple conversation with your team as well, last night dinner is also very engaging. Maybe today's conversation still put this conversation into the public make sure the broader audience also know your view on the ASCO situation. Honestly, I was a little bit surprised how Nuvalent stock will move upon the ASCO readouts, honestly, your own data looks fantastic again. Some of the competitor data, maybe people have some confusion or interpretation. Maybe before I ask a detailed question, what is your reaction or comments on the overall stock? ASCO was huge for us. If I zoom out, eight years ago, we were working with the leaders in the ALK and ROS1 space. Same folks that developed lorlatinib and actually were authors of this weekend's lorlatinib CROWN update. They laid out how they expected the landscape to evolve. This was 2018. This is when lorlatinib was yet to be approved. They said, "Let's paint the picture for you. Lorlatinib will eventually get approved in the second line and then front line. It will be a debate, even though it works better in front line patients, it will be a debate of whether they should choose alectinib, which is well-tolerated and can drive durable responses, or you can choose lorlatinib, which has the potential to drive more durable responses, but brings added toxicity that makes it very difficult for physicians to manage to keep patients on treatment, and for patients to keep doing their lives," right? It has significant cognitive issues that could impact their daily activities, whether being a professional, being a parent. It's something that the physicians would struggle with. Here we are eight years later, and this program has gone exactly according to plan. That doesn't happen in oncology drug development. Usually, there's a lot of twists and turns, and you have to adapt your strategy. This one's gone exactly how the physicians outlined for us. They said, "What you need to do is you need to solve for broadly covering ALK mutations. You need excellent brain penetration, and importantly, you need to design a compound that does not hit the off targets that are driving these toxicities with lorlatinib," right? We are building a chemistry company, and we said, "Okay, that seems like the right chemistry problem for us to take on." Neladalkib is the first and only drug that can do that. It has activity broadly against ALK mutations, both single and compound mutations. It has excellent CNS penetrance. Importantly, it's very selective for ALK, so it doesn't hit those off targets that lead to these challenges that the patients experience on the other therapies. What we learned is that our drug works when patients have already taken the subsequent lines of treatment, alectinib or lorlatinib, nothing else works there. Our drug is active there. We have breakthrough designation there. When the patients have ALK-driven disease, we can drive durable responses there. We see 17.6 month duration response in patients that have already taken lorlatinib. That's double what lorlatinib can do in a second line setting. These are patients that have already failed lorlatinib. The durability is going the opposite direction. It truly speaks to the attributes of the compound we have. We also showed that we can drive durable responses in a second line setting where they yet to take lorlatinib. We see 2.5x to 3x the durability of lorlatinib in the comparable patient population of patients that progressed on alectinib. Proof of principle, right? That's showing us exactly what the physician said. If you can keep them on therapy and broadly cover the mutations, you should be able to drive more durable responses. That's what we see in our ALKOVE-1 update. Then the idea was if it can do all those things, it would work better than all the other agents in front line, right? What the CROWN update shows us is that there is a potential to drive years of progression-free survival in these patients, right? lorlatinib update was, okay, it's seven years, so you have to hit progression-free survival. That's amazing because that's the floor for our drug, like neladalkib might be. We don't know what the ceiling is, but a floor of seven years means you could really consider turning this type of disease into a chronic treatment, which should be the goal for any cancer drug developer. It's a game changer for patients, and also would represent a compelling commercial opportunity. What are the counter theses? What is the counterargument of why this could be a challenge for neladalkib? We'll start with one. lorlatinib has become the new global standard of care, that some of the academics will favor it because they're going to try to get better durability for their patients. What those same academics will tell you is that most physicians will not, particularly in the community, presents significant patient management challenges. Even today, five years after lorlatinib's first-line approval, it's still not the global standard of care. alectinib is. That's because many physicians prefer that drug over lorlatinib because of the safety challenges, and alectinib works really well. There's about 23% of the patients on alectinib that have seven years progression-free survival. It also works really well for patients, just maybe not statistically better than a drug like lorlatinib. Physicians will tell you that 38% of the patients come off lorlatinib in the first two years. That's not a small number. That's a large amount of patients. That's clearly not meeting the need for all ALK patients, right? That's something that neladalkib has potential to solve for, right? Another counter thesis is, patients aren't progressing with ALK mutations on lorlatinib. That's simply not true. There's no data to support that thesis. There were 83 patients that discontinued lorlatinib in that seven-year CROWN update. Pfizer disclosed they had data on 17 of those patients. On 17 of those 83 patients, obviously a small number, it can be really challenging to understand why those patients progress, right? We know this from our own experience in our trials. It's difficult to get patient access to patients that might be progressing. The samples that you do get, you have disease heterogeneity, you have sample heterogeneity, and you also just have challenges in the analytics of such an assay. It's really hard to understand what the reason were those patients were progressing and, in those 17 patients, they didn't see an ALK mutation, but we can tell from our own data, patients progress on lorlatinib. They have ALK mutations, and they respond to neladalkib, and they do quite well. Patients that progress on lorlatinib where we can identify a mutation, they also respond to neladalkib and do quite well. I can assure you, they probably have ALK-driven disease because our drug wouldn't work otherwise. This speaks to the challenge of understanding the analytics of does a patient have an oncogenic driver or not. Another thesis is it's going to be very difficult for us to enroll the phase III ALKAZAR trial. I think our ALKAZAR study team would beg to differ. This trial is going incredibly well. Our phase II ALKOVE-1 study was a 250-patient study, and we enrolled about 800 patients, and we did it in about 13 months. It's one of the fastest, if not the fastest enrolling oncology trial in the history of our industry, right? It is, for our team, just an honor and a privilege to work on a program like that where there's so much demand for this differentiated agent. It's really not about us, it's about the patients that are craving for this. We collaborate closely with these patient advocacy groups. They love the profile neladalkib. Our ALKAZAR trial is going incredibly well, exactly according to plan, and you might have noticed that we just received Priority Review last week for a PDUFA date in November this year. A prerequisite for an Accelerated Approval is that the confirmatory study must be substantially enrolled, right? If we don't have this trial substantially enrolled by November this year, there is no Accelerated Approval. We obviously understand that, and the FDA understands where that trial is at, and we feel like we're going to be on track to have that trial substantially enrolled by the end of this year. Non-issue there. Last thing I wanted to point out is there's a thesis that although lorlatinib can be managed with dose reductions. If you just use a lower dose with lorlatinib, then you can manage the toxicities. There are no data that support that thesis, right? The physicians, you can see them, they did a great job on the podium presenting both the neladalkib and the lorlatinib data and explaining the trade-off decisions they have to make. Even Dr. Mok, who obviously a leader in this space, presented the seven-year update for lorlatinib and said, "I don't use this dose. I use a lower dose." That tells you the crux of the issue is physicians have that tough decision. What do we do with this drug? We know it has the potential to drive more durable responses, but it's less tolerated. Well, what if you didn't have to make those treatment trade-off decisions? That's what you would have with neladalkib. You have the potential to drive durability without the safety, and that's why folks are so excited about this program. We think the update actually very much aligned with our program strategy, and we're pretty emboldened by it. Excellent. Okay. You already touched a lot of the thesis out there and addressed eloquently. Maybe we talk about your own data first, and then we move on to the more spicy talk about the CROWN and then other research to you. One thing people picking up is the Doctor on the stage and on the podium say it's modest efficacy on the durability and PFS for the second plus line. How would you comment on that? Honestly, I disagree, but just how you think about it? There are a couple things I'll point out. Fastest enrolling oncology trial in the history of our industry. I think physicians and patients would beg to differ with that conclusion. There's a reason that they're all going into their trial, and it's not because we have great personalities. It's that the outcomes they're seeing with neladalkib. What did we learn from the ALKOVE-1 study? For patients that have progressed through both alectinib and lorlatinib, and in many cases, other therapies, chemotherapy, other TKIs, we can still drive durable responses. Right? If the patient has ALK-driven disease, beyond all those other therapies, we believe we're the only solution for those patients. That's because we designed our drug to work there. We do not aspire to be only a fourth or fifth or sixth or seventh-line ALK drug. Right? That's not the goal for this program. We happen to be a drug that has the potential to work for those patients. You can imagine, in that late stage, those diseases could be heterogeneous, very difficult patient population to treat. For those patients that have ALK-driven disease, we are driving durable responses. In fact, the median duration of response was about a year and a half. For a third, fourth, fifth-line drug with a duration of response of a year and a half, I'm not aware of many oncology drugs that are even in that zip code. I think the physicians and patients that have been involved with this study that have had great outcomes with neladalkib would beg to differ that this is modest activity. I think this was game-changing activity for those patients. The trial wasn't just about third, fourth, fifth-line patients. We also had a cohort of patients that just received alectinib. They have yet to receive lorlatinib. There, the data really tells a different story. We can actually drive incredibly durable responses. We're seeing about 60% of the patients still in response at a year and a half. We see about a 15-month median progression-free survival in that patient population. This is 2x-3x what lorlatinib can do in a similar patient population. If we are impressed by lorlatinib durability in frontline, we are doubling or tripling the PFS of lorlatinib in second line, right, in the same patient population. That speaks to what the attributes are of neladalkib, and if you portend what that might look like in the frontline, again, we don't really know where the ceiling is, and that's a great thing for patients. Yeah, totally agree. By the way, you do have the preliminary data from the first line as well. That it is absolutely early, but looking just everyone responding, and they're very durable. Yeah. It's an early look, but the right experiment there really is the ALKAZAR experiment. It's the comparing our drug to today's standard of care, alectinib, in a randomized fashion, and we're excited about that program. All right. Maybe just a couple detailed points related to the CROWNs. By the way, I saw you two years ago at ASCO after the CROWN five-year data. It was impressive, the narrative will still be the CNS tox, dose reduction, dose intensity, and the early progressor. I don't think this seven-year really change anything, but I think probably the different presenter and then different environment there. One thing you mentioned early on, the first point is the standard of care for first-line. Can you give us some your understanding, because you talk with a lot of community doc. I think you told us last night is it's not necessarily Dana-Farber or Memorial Sloan Kettering, it is more about those broad community doc, and then they have a high volume. How do they use or how afraid of use lorlatinib, and that's U.S. only? How about globally? Alectinib versus lorlatinib into the frontline use. Yeah. This really comes down to. Actually, this came up on the podium at ASCO with the physicians on the panel. I remember Dr. Mok saying, "I have to have tough discussions with my patients. I can tell them statistically you might fare better on one therapy, but you may also have a job where that therapy's going to significantly impact your ability to do your job. You might have to drive your kids to activities, and you might not be able to do that on this therapy." Right? That's an awful position for a patient to be in and a really challenging position for a physician to make those treatment trade-off decisions. For that reason, they have to pick and choose who are the patients that might be right for lorlatinib. Well, imagine you have only the upside of the durability without the downside of these cognitive issues, right? That's the vision for this program, right? It puts us in a position that if we can realize that profile, we could be the option that sort of removes the doubt, right, for why a physician might want to consider neladalkib for frontline patients. In the community, those are physicians that are typically would have less experience with lorlatinib in clinical studies, so less experience managing through those toxicities. What we've heard loud and clear is when that drug got into the community setting, it first gets approved in the previously treated setting. It doesn't work particularly well in the previously treated setting, and the physician, the experience from the community is, "Okay, here's this drug for patients. It doesn't work particularly well for previously treated patients, and it brings on significant toxicities that oncologists aren't necessarily used to. They're not used to managing depression, suicidal ideation, patients that are too dizzy to walk across the room or drive or work. They're not used to managing severe speech effects and mood disorders, right? These are things that could be really challenging for a patient, obviously, but also just for the physician to do where alectinib, the alternative option, is generally considered to be well-tolerated. That's why in the community, it's largely stayed as that predominant care. The academics, they're always going to fight to get the best possible durability for their patients, and some of them have chosen lorlatinib. We understand that. We get it. Also, some of those same physicians are huge champions for our program. In fact, some of the drivers of lorlatinib are chairing our phase III ALKAZAR protocol because they believe this is a potentially practice-changing study that could solve for what the needs that they're looking for their patients. How about globally? Globally, it's the same. I think that globally, the alectinib has always been the standard of care since it was approved frontline several years ago. lorlatinib, in the academic settings in some of those hospitals, will get some traction. Again, five years after its frontline approval, it still hasn't surpassed alectinib. It's not like it's going to flip a switch. I had so many discussions two years ago at ASCO, the five-year CROWN update, which was quite a buzzy update, and everyone said, "Well, this must be it for alectinib." Two years later, it's still the global standard of care. Nothing really changed this much from our perspective, and I presume it will continue on that slope. Got it. Seems the enrollment from ALKAZAR first-line treatment, investor was trying to build some thesis there, so become a catalyst. You are now not officially guiding, but you say you will have some updates related to the enrollment. I know we know the PDUFA date is in November. You say FDA definitely are looking for substantial enrollment for the trial before they can give you approval. How much we should expect the enrollment updates, in terms of the timing and then substantially? Sure. Yeah. We recognize there's a lot of interest in enrollment of ALKAZAR, we are likely to provide updates in the future, whether that's an interim update or we share once the study is fully enrolled, kind of to be determined. More to come there. As Jim mentioned, we're on track for the PDUFA in November, and there's the requirement that for Accelerated Approval, that the study is substantially enrolled. We feel confident about the plan there. Excellent. In terms of the readout from the ALKAZAR first line, obviously, it's depending on the enrollment, also depending on the event rate. A lorlatinib arm, nothing really changed, right? Nothing we learned anything new. For your ALK, how should we think about this, you put that lorlatinib as the floor of the event or the activity there. I believe it's more the event happened in the first two years, that's not really changed. Also, you mentioned earlier into the on-target, off-target mutation. We do believe most of the lorlatinib early progressors still are driven by the ALK-related mutation. Yeah. The data availability is where we hear lots of questions from folks about helping them understand when this important trial will read out. It's a randomized phase III. It's 450 patients. It's a progression-free survival as an endpoint by blinded independent central review. It's a pretty cookie-cutter study. There's nothing flashy about this study. Four other ALK trials have run the same type of study, just with a different comparator, same endpoint, same design. What we're really aided by is that we can look at those other studies, and we can look at the data from those other therapies. How did those drugs perform in those studies in the same patient population, in a frontline advanced metastatic patient? From that, we can see that alectinib has roughly about a two-year progression-free survival. We can model out how fast those events would happen in our trial. We can also look at what the progression-free survival was in the lorlatinib study. If we believe our drug works the same as lorlatinib, meaning same activity, we can map that out. Now, we happen to believe it works better than lorlatinib. Our data, we think, clearly supports that. Say it works exactly the same. We can model where the events from the neladalkib arm would come and where the events from alectinib would come. That helps us get to a date that we predict at somewhere in 2029. Now, to be clear, that's not a guidance. That is a guess, right? Because three different things influence it. It's the enrollment rate, the event rate, and the stats. The enrollment, we think, will go really well. We have modeled a standard enrollment rate, basically the enrollment rate that the other ALK trials went. That's what entered that assumption. The event rate is out of our control. How fast does the disease get worse for these patients, right? That's something we can't predict when that happens. We can just model what happened with alectinib. If we model that out, it gets us to the end of 2029. Could it come faster than that? It could. Could it be right around there? It might. It could be much slower than that. We just don't know. Excellent. All right. Good. I think we should move on from ALK. You do have the catalyst upcoming in terms of approval from both second-plus line ROS1 and ALK, the launch afterwards. You also were still waiting for the first-line ROS1 pivotal readout, the filing, you say second half. In terms of those two potential approval in the launching second-plus line, I've been telling investor, I think this can be an underappreciated catalyst because the notion for the promise, the notion of Nuvalent can increase the market opportunity is to prolong the duration on treatment. Second line, the same thing. You compare to the current drug is way better. How you think about the launch trajectory for those second-plus line, how much reach through can put that into the first line? I know first line HK is probably the crown jewel here. Yeah. One of the comments I heard recently is, we've obviously had a lot of updates, but in the very near term, lack of catalyst. I was sort of stunned by the comment. We're about to launch two therapies. Should the FDA approve zidesamtinib, we have a PDUFA date of September. Should the FDA approve neladalkib, we have a PDUFA date of November. We have a full commercial team in place. It is incredibly exciting. We have been doing the work. The original business plan was we want to be able to discover, develop, and ultimately deliver new therapies. From my perspective, that's what a sustainable biotech company does. You need to do all three phases well. I think we've proven we know how to discover drugs, right? The company existed on paper only eight years ago, and we're talking about two PDUFA dates this year. Sort of a record as far as our industry, as far as I know. I think we've proven we know how to develop drugs. We have two of the fastest enrolling oncology trials in our history, the industry's history. I think that speaks to we know what we're doing on the development side. I would like Nuvalent to be known as excellent in the phase III as well, delivery. For the last two years, we've been building our commercial organization, and that means building relationships in the community. That is where in the U.S., about 70% of the patients are treated, right? It's not the physicians that are running our trials. These are the community physicians where patients in their community go to their local doctor, and they receive their treatment. We've been building those relationships and understanding how we can best partner with those folks to deliver these drugs to the patients that need them. It's been a great experience for me personally, just to be partner with our team, to go out to these sites, meet these folks, understand what drives their businesses, what are the decision-making factors that matter to them, and how can Nuvalent best position and best partner with them to deliver our therapies. One of the most rewarding things I've heard in those conversations is, many of those physicians already knew who we were. They didn't know who we were because our website, they didn't know who we were because we have good media. They knew who we were because the patients themselves were talking to them about when do we get neladalkib, when do we get zidesamtinib? What is remarkable about these diseases is the patients themselves. They are an online community. They are globally connected. They all talk to each other. When we started this company and we started on these programs, we went and built relationships with the patient advocacy groups. Wonderful people. Just a privilege for us to collaborate with them. They are the reason that we have the fastest enrolling trials. They are excited because they helped us develop these drugs that can impact their community. In their community where these patients are treated, they are talking to their physicians about these drugs that are coming. I think that sets us up really well for these launches, right? That we have now four ahead of us. Pre-treated ROS1, pre-treated ALK, frontline ROS1, frontline ALK. It is an incredibly exciting time for Nuvalent. I am thrilled about it. Great. Don't want to put you on spot, as the investor usually, for smaller biotech company to launch the drug, that's a sure CC is forming, right? On the other side, it seems you are very confident that you do see the profile is significantly better. How would you guide to the investor community, maybe early, but at least qualitatively, you would say that you think this is with a lot of the pent-up demand and then also the profile can drive a relatively quick launch? Yeah. As we've talked about, the enrollment in the studies has been robust, as well as the expanded access programs that we have in place. We see a lot of tailwinds in terms of these launches and, as Jim mentioned, patients are asking for these therapies, physicians have had good experiences for their patients. We're really excited. We haven't put any expectations or formal guidance out there, but more to come as we get closer. Yeah. I think, yesterday you must already ask about the four Q kind of a consensus number. We're going to fine tune our model and as it get closer, and then you probably will give us a little bit more guidance as well. We're thinking about the long term, Roger. We've got four launches, and we're not just doing it in the U.S. We are building a global biotech company. A couple of weeks ago, our first international hire, who our Chief International Officer, going to lead our international organization. Very few companies in our industry ever have this opportunity, and we have it right in front of us, and I'm pumped about it. Excellent. Thank you, Jim. Thanks, Alex. Thank you everyone watching and listening.