Our next session of the Piper Sandler Healthcare Conference. My name is Kelsey Goodwin. I'm one of the senior analysts here. With me, I'm thrilled to be joined by the Nuvalent team. We have CEO Jim Porter, CFO Alex Balcom. Welcome, and thanks for joining us today.
Thanks, Kelsey. Thanks to the Piper team. Pleasure to be here.
Great. Let's start, for those less familiar, with just a quick, high-level, one to two-minute summary of Nuvalent and where we stand heading into 2026.
Sure. So we are a company that's about seven years old. We are the foundation of the company. It's a deep expertise in chemistry, structure-based drug design. We focus on validated biology, so specifically kinase targets. There's over 100 approved kinase inhibitors. So we de-risk the discovery and development phase by focusing on validated biology. And then we partner with physicians to understand, from their perspective, what are the needs of the patients they treat? What are the limitations of those therapies? We try to use innovative chemistry to solve for it. So in about seven years, we made a lot of progress in building the company. And maybe Alex can talk through some of the recent highlights.
Sure. Yeah. So over the past two years, our progress has been guided by our OnTarget 2026 operating plan. And that lays out the path to our first potential approval in 2026. And so as part of that, we've laid out some ambitious 2025 milestones, including delivering on two pivotal data sets for both our ROS1 and ALK programs, as well as NDA submission for TKI pretreated ROS1. We also recently announced that NDA was accepted. And then initiating the phase 3 ALCAZAR study for frontline ALK. And then continuing to progress our HER2 non-small cell lung cancer program through development. And so we're looking forward to our first potential approval in 2026, as well as providing further updates on the pipeline in the future. Great. We'll start with ALK, since that's where investors typically focus.
Starting there, and based on what we know today with existing programs, how do you think about the ALK non-small cell lung cancer market opportunity?
Yeah. So there's actually six approved therapies, and that can seem complex and crowded. How do you navigate that? We talked to physicians. They break it down into a pretty simple concept, where it's really just two lines of options for patients. Newly diagnosed patients are often treated with alectinib as the standard of care. When they progress on alectinib, the only drug that works is lorlatinib. And when they progress on lorlatinib, nothing works. And our idea was, let's solve first for that third-line patient population. Those patients, they progress on lorlatinib due to inefficient coverage of ALK mutations. So we designed a solution to address that. But we don't want to just be the third-line option. We want to be an option for all ALK patients. In second line, lorlatinib, we believe, is limited. It's limited because it can't hit those mutations hard enough.
If we can hit them harder, we should be able to drive more durable responses. And eventually, we want to get to frontline. And we already know from physicians lorlatinib is a more active drug than alectinib. The reason it doesn't get used in frontline as much is because it hits an off-target that's dose-limiting. We designed a solution that does not hit that off-target, so we can hit the mutations harder and eventually replace alectinib as the standard of care. So we have demonstrated now data in that second-line and third-line setting that shows we can drive deep, durable responses, significantly more durable than lorlatinib. And in third line, where nothing works, we have durable responses. And we have an ongoing phase 3 trial comparing our drug to the standard of care alectinib.
The market opportunity, to your question, today's market is about $2 billion-$2.5 billion for ALK non-small cell lung cancer. We're not looking to capture a portion of that market. We're looking to grow that market. We think we can drive durable responses in any line of treatment, and in doing so, you can imagine more time on therapy means a larger market opportunity.
Understood. And as you alluded to, you presented the pivotal ALK phase 1 data just a few weeks ago. Maybe just walk us through the highlights there and what you think stands out that really helps narrate that story right there, that this is best in class.
Yeah. There are two themes for the data update. The first was just on enrollment. We have treated 1,000 patients with NVL-655, and the trial just started a couple of years ago. The phase 1/2 is one of the fastest, if not the fastest, enrolling oncology small molecule trial ever in our industry, and that's pretty humbling to work on a program like that. Typically, things make you think you're doing something right. The company's super excited to be involved in such a thing. Between the phase 1/2 and the ongoing expanded access program, over 1,000 patients treated, and that's the majority of just in the last year and a half. The second theme was around durability, so we are seeing durable responses no matter the line of treatment. In that third-line patient population that's taken lorlatinib, we see an 18-month duration of response.
That's double the durability of lorlatinib beyond lorlatinib, and that just does not happen in oncology drug development. Typically, in subsequent lines of treatment, the duration of response will get worse and worse. Ours improved by 2x compared to the previous line of treatment, which clearly speaks to the attributes of NVL-655. In second-line patients where lorlatinib is the standard of care, we are seeing deep, durable responses significantly longer than what lorlatinib can deliver in that setting, and we think with that combined update, that second-line data and that third-line data, we're in a good position to use that data to guide regulatory discussions around a broader previously treated ALK indication.
On that durability topic, I guess, obviously, that is the key differentiator or one of the key differentiators. How should we think about that maturing over time, over 2x lorlatinib, post-lorlatinib? How should we think about it in second line?
Yeah. So what we saw is for patients that have taken previously treated ALK, sorry, previously treated ALK patients that have yet to take lorlatinib, we saw a 46% response rate in the 63 patients in that cohort. The duration of response, 60% of the patients were still in response at a year and a half landmark. So haven't even hit the median. For patients that have only taken one prior ALK TKI, alectinib or brigatinib, there are actually 46 of those patients. The response rate was 48%. The duration of response was even higher. It was 70-something% at that year and a half landmark. That kind of durability in that second-line setting, it's remarkable. It's alectinib-like durability beyond alectinib. And again, that doesn't happen in oncology drug development. It really speaks to why this is such an interesting cancer target.
The tumors are so dependent on ALK signaling. If you can broadly cover those ALK mutations, that is the formula to drive these deep, durable responses. We're seeing that with NVL-655.
Understood. And one thing that's unique, obviously, about Nuvalent is you've always kind of partnered and worked hand in hand with the patient support groups and the foundations. That's something you don't hear often with these companies. Maybe just tell us what you think that brings to the table that your competitors don't have.
The first thing it brings is just an incredible enthusiasm within the company. All of us in this industry want to work to try to help make an impact for patients. That's why we all, whatever we do in this industry, your ultimate goal is to make an impact for patients. So to be so personally connected with the patient communities that have these diseases, it's incredibly exciting and inspiring and rewarding for our team. We just had our annual patient advocacy event just a couple of weeks ago where 14 patients spent the day with the entire Nuvalent team. Coolest day of my career, for sure. So the other advantages it brings is you can see from the enrollment of our studies. We have one of the fastest enrolling oncology studies ever in our industry.
Our ROS1 program, we used to get asked, "How are you going to find these patients?" We just enrolled 540 of them in just a few years. And I think largely due to the collaborations we have with the patient advocacy communities. And I think that sets us up quite well when we think about the commercial setting because these patients are advocating for better options, for new options for their diseases. You can imagine if you're launching the drugs and the patients are advocating for your therapies, that can only help on your commercializing these therapies.
Great. And maybe quickly before we get to regulatory strategy, on the safety profile, very clean from a CNS perspective, that being kind of a key differentiator. If you have to squint and find something, it seems like we could look at liver enzyme elevations. Maybe just walk us through what you've seen there. And then from a non-small cell lung cancer doc perspective, how comfortable and used to treating these AEs are they?
Yeah. So most kinase inhibitors have transaminases elevations. All the approved ALK therapies have transaminases elevations. So it's something common with lung cancer docs because they're treating patients with these other kinase inhibitors. They're used to managing this. They typically show up as generally they're asymptomatic lab abnormalities. So the patient doesn't experience something. It's more in their blood work. You're seeing these transaminases elevations. They're transient. They happen early in the treatment. They typically don't recur. They're managed by either interrupted dose and that it will resolve, or sometimes it just resolves on its own. Sometimes you reduce the dose. It resolves. Doesn't recur. We think we clearly have a handle on that. Really, what helps support that argument is you can look at the enrollment and durability. It's clearly not impacting the patient, the physician interest in using NVL-655, as well as the outcomes the patients are experiencing.
Understood. And then from a regulatory strategy and the timeline for getting this program to market, maybe just remind us what you've said and also what gives you confidence in approvability on a single-arm trial.
Sure. Yeah. I can take the timing piece first. So what we've said is we look forward to discussing these data with the FDA in a pre-NDA meeting. And then we are also planning to present the full data set at a future medical meeting. So we'll provide more updates in the future on timing.
Okay. Understood. And in terms of just to confirm, you haven't met with the FDA yet, and you will tell us at some point with some guidance?
Yeah. We will provide updates in the future.
Understood. Shifting to the frontline ALK trial, how is enrollment in ALCAZAR going, if you can comment? And maybe if you can't, high level, are you seeing similar demand to what we just spoke about with the fastest oncology trial to be enrolled? Are we seeing that same level transition from phase 1, 2 into ALCAZAR?
So I think in short, the trial's going exactly according to plan. We have an experienced team that knows how to run these types of studies. We're in study startup mode. So we're getting a lot of sites open across the world. There's going to be 160-plus sites across North America, Europe, Asia, and Latin America. I think there's broad enthusiasm from the investigators on this potentially practice-changing study. There's broad enthusiasm from the patient communities that are sort of going to keep pushing patients towards trying to get new options for their community. I think it's going to enroll quite well, but we've given no specific guidance on enrollment updates.
Okay. Understood. In terms of the timing of it, obviously, it's a more active control arm. How do you think about timing? I know not guiding towards a specific time, but how do you think about that?
Three things influence that availability. One is the enrollment rate, which we just talked about. We think we'll go fast. The second, probably the most important, is the event rate. And that is how fast the events happen, we would hope, on the control arm, alectinib. Alectinib is a good drug. It has a couple of years of progression-free survival. So it's not something you can't make that happen faster. So that is likely to be the gating factor. And then we often get asked, "What about, can you share the specific stats assumptions? Does the trial include an IA, blah, blah, blah?" We don't get into the stats of our studies. We do have to put a line in the sand on ClinicalTrials.gov of expected data availability. We put that as second half of 2029. That's just an estimate based on the various factors we just discussed.
Could be faster. Could be slower. Could be exactly that. But as we get more clarity around those variables as they're progressing, there will be opportunities in the future to guide some more specific timing.
Understood. In terms of the evolving frontline market opportunity, obviously, we saw CROWN last year. And post the data, even though a lot of investors think that lorlatinib has become a standard of care in frontline, the sales data doesn't necessarily reflect that. And sometimes we hear that the lorlatinib safety profile, it's not that bad. So maybe just could you speak to what are kind of the key toxicities? What do you hear when you talk to physicians and patients of why lorlatinib is not gaining that frontline traction? What about the safety profile specifically stands out?
Yeah. We talked earlier about the relationship our company has with the patients. I can say one of the most common things we hear from the patients is they're scared of lorlatinib. Imagine being in the prime of your life, 30, 40, 50 years old. You have family milestones. You have your parent. You're a professional. You have a job. And you're told this drug might drive a durable response, but you have a greater than 50% chance of having significant cognitive issues. You're too dizzy to drive or work. You could have sleep disorders, mood disorders, speech effects. That's a scary thing for anyone, especially a young professional or a parent. And they're scared to go on lorlatinib. And I don't blame them. That was the reason we came up with this profile.
They were guided by the physicians because they wanted an option that could drive these types of durable responses without having these neurocognitive issues. NVL-655 has that profile. And that's why I think our trials have enrolled so well.
Understood. Okay. Shifting gears to zidesamtinib, your ROS1 program. So as Alex mentioned, the NDA was recently accepted. The program has BTD designation, was submitted into the RTOR pathway, but was accepted with the standard review timing. I guess maybe what commentary do you have there? Any thoughts around why that was the case?
We started this program three years ago, and we just found out our NDA was accepted. We were pumped, so huge milestone for our team. Our ROS1 team is cruising, and we're excited about it. When the FDA guides to or gives you an NDA acceptance letter and they say it's going to be standard review, there's no additional insights. That's the decision, and we're happy with it. We'll do whatever we can at Nuvalent to get the drug approved as fast as possible. We view our relationship with the FDA as a collaboration. We always take any interactions with them super seriously, and as fast as they can go on getting this drug approved, they're going to get everything from Nuvalent to enable that.
Understood. In terms of the dynamics of starting with the TKI pretreated and then eventually wanting the label to be agnostic with the TKI naive included, are there any dynamics in terms of the timing of when you could start the naive filing if the pretreated is under review? Maybe just walk through that.
Sure, so just to orient you, there's four approved ROS1 therapies. Each one of them were approved off a single-arm phase 2 study, and they all were given full approval. That's pretty interesting. Full approval, single-arm phase 2. We ran the same exact strategy. Now, for each of those four, they were approved with 12 months of follow-up post-response. We saw there was an opportunity for previously treated ROS1. Our drug works quite well for those patients. We designed it to work well for those patients. We're seeing incredibly durable responses in that setting. We have breakthrough designation in that setting, so we went to the FDA and said, "We want to cut the data earlier for previously treated patients," and we aligned on a six-month data cutoff, got that alignment. That's what we did. That was the update this year. We presented the data back in June.
It was at the presidential symposium at WCLC in September, and we just announced that the NDA submission has been accepted, so the TKI naive cohort, we had shared a preliminary update of the first 35 patients back in June, and we basically showed the drug is active. It's an 89% response rate. It has a high intracranial CR rate. None of the other ROS1 drugs have anything like that. The responses are trending durably. 96% of the patients are in response at a year. It's got all the attributes that we would want to see for zidesamtinib, but it was only the first 35 patients. As of June, we had already enrolled 104 patients in that study. That's more than we believe we need for TKI naive, but we just don't have enough follow-up. We want to keep following those patients.
So we haven't guided to what that specific strategy would be other than we're going to work with the FDA on, again, the precedent has been 12 months. We cut it earlier for previously treated for six months. We'll keep following these naive patients. As that data matures, we'll work with the regulators on alignment on that particular submission strategy. Once we have that alignment, we'll share what it is.
Understood. In terms of the competitive landscape there in ROS1, maybe just walk us through kind of how the newcomers' launches have gone and what you think has driven the fact that crizotinib has kind of yet to be dethroned?
Yeah, and so when we started the program, we worked with all the physicians that developed all those drugs. And what they said is, "Although crizotinib is a good drug, it has a year and a half duration of response. Patients will progress with ROS1 mutations or they'll progress with CNS disease." Crizotinib, it's a repurposed drug. It's not a ROS1 inhibitor. It hit other targets. It happened to have ROS1 activity. So we said, "We want a solution for ROS1 patients specifically. You got to hit the fusions. You got to hit the mutations. You got to get into the brain. Treat patients with brain mets because they have lung cancer." Lung cancer, unfortunately, spreads to the brain. And importantly, the other drugs that have tried to do this, they all hit another off-target. That off-target is dose limiting, causes these neurocognitive events. Try to avoid that.
You're a chemistry company. Can you come up with an innovative chemistry solution? zidesamtinib is the first and only drug that has that profile, and you can see how the trial's enrolled. You can see that in all of our data. Physicians are excited about this differentiated profile. We can drive deep durable responses no matter the line of treatment, so they had told us the other drugs are unlikely to launch well. Physicians will try them in the community setting, but due to the neurocognitive issues, they're unlikely to keep using them. They'll go back to crizotinib, and that turned out to be true. Other drugs like entrectinib were approved and repotrectinib. They didn't have necessarily the greatest launches because I think the community docs didn't want to manage these neurocognitive issues for their patients and stuck with crizotinib, a drug that works reasonably well.
There's a newer entry as well. This drug, in addition to maybe has some of the less neurocognitive events, has other off-target events. And I think that could be dose limiting. I think zidesamtinib profile is clearly differentiated from all those other drugs, and we're excited to bring it forward.
Great, and so seven years since you started the company and about to bring two drugs to market within the next 12 or so months, how have you been building out your commercial presence, and how do you think about commercialization?
Sure. Yeah, so that's a big focus for the team. We brought on our head of commercial at the beginning of last year. He's been focused on building out the commercial and field teams as well as engaging with key prescribers, sites of care, healthcare decision-makers, and so at this point, our commercial readiness efforts are well underway.
Okay. Understood. In terms of how you think about potential for a partnership, do you think that's necessary? Are you set up to do it by yourself?
Yeah. So our goal is to build a fully integrated company, and we're in a great position to do that. We have the team and the capital to continue to execute. So there is potential to leverage a strategic partner as we think about XUS. But where we sit today, we have a lot of optionality, and maybe you want to share your thoughts as well, Jim.
Yeah. I mean, we just completed a recent financing as well. And we have two drugs that can drive durable responses across any line of treatment. We have everything we need to build the next great global biotech company. And what an opportunity. That doesn't come that easily in our industry. So we feel incredibly fortunate. And if the right partner shows up, obviously, and they share our vision for the tremendous value that these drugs can deliver to patients, then we'll obviously listen to that. But it's press the gas down, build the next great global biotech company. And that's just an incredible opportunity for our team.
Yeah. That's great. Okay. With our last one minute, let's touch briefly on your HER2 program, NVL-330. Where does this stand? How might it be differentiated? Kind of a tall ask. We got 50 seconds.
Yeah. I got it. HER2 development, there's lots of history in this space. HER2 lung cancer, a little bit different. The driver is exon 20 insertion. The key is hit exon 20 with a wide index for wild-type EGFR, which is dose limiting. That's skin toxicities, GI toxicities. 330 has that. Another drug, zongertinib, also has this. Just got approved. The problem here is with lung cancer, patients get brain mets. You need excellent brain penetration. 330 has that. The other drug, zongertinib, not highly brain penetrant. So there's a clear path forward in lung cancer. But then consider beyond lung cancer, all the HER2 drug developments across all these different tumor types, what would be nice to combine with those other ADCs, antibodies, etc., a highly brain-penetrant HER2 drug that's well tolerated, that broadly covers HER2 mutations. 330 has that as well.
Perfect. And with that, right on time, thank you guys so much for joining us.
Thanks, Kelsey.
Thanks, everyone in the audience.