Good afternoon, everyone. Welcome to Jefferies Global Healthcare Conference. My name is Roger Song, one of the senior analysts covering SMID-cap biotech in the US. It's my pleasure to welcome, Nuvalent, CEO Jim and the CFO Alex, to join me for the fireside chat for the next 25 minutes. So welcome.
Thanks so much, Roger. It's a pleasure to be at the Jefferies conference, and I really appreciate the opportunity. Thank you.
Excellent. All right, so maybe we can, since we just off the ASCO a couple of days ago, I met you there. So, you know, understanding Nuvalent did not have data presenting at ASCO, but we have quite a few updates from the ALK and the ROS 1 non-small cell lung space. Tell us a little bit, how do you think of this ASCO, have some research in Nuvalent, and then we can go to the each one. But, you know, start from the top line, and then we can go into the each one and how you interpret the research.
Sure, sure. So, you know, ASCO is obviously a great conference for the field oncology and lots of learnings from the space. A lot of exciting advancements across, you know, many different targets. Of course, we're interested in and rooting on the others in this space to make progress for patients. So, with respect to our programs, we're our main two programs are fALKused on ALK and ROS1 non-small cell lung cancer. We maybe speak about the landscape in ALK. There's five approved therapies, but you can really think about in two buckets. The first line, patients receive alectinib, and the only drug that works beyond alectinib is lorlatinib. Patients progress on lorlatinib, nothing works.
So, when we started these programs, we were working with physicians that helped us understand the landscape and the space, and what we need to do to solve for that, for the medical needs of patients that they treat. So starting in third line, where nothing works, we're trying to design compounds that hit compound mutations to work post alectinib, lorlatinib. In second line, we're trying to design a drug that can hit single resistance mutations, have excellent brain penetrance, importantly, avoid an off-target called TRK, which is related to, to ALK. And that's been a limitation of lorlatinib in second line because it has a narrow index for inhibiting ALK versus TRK and leads to dose-limiting toxicities that, physicians prefer to avoid. And then for frontline, alectinib is the standard of care.
Most physicians would tell you lorlatinib is the most active drug in the ALK space because it covers ALK mutations. However, based on the inhibition of TRK, it leads to a broad spectrum of CNS toxicities, and that's been the main reason most physicians have not supplanted alectinib with lorlatinib in the frontline. So, in this space, you know, one of the developments was lorlatinib presented further data in frontline and, you know, it's continuation of what's already been known about this drug, is that the drug is active in frontline patients. I think the 5-year survival of PFS readout was greater than 60%, which is obviously great for patients.
You know, alectinib is also a good drug in this space, and, you know, I think some physicians, particularly at the major medical institutions, have been telling us that they're learning to manage through the toxicities of the neurotoxicities. They have more experience with lorlatinib, and they like to use that drug up front 'cause it is the most active drug. But they would also tell you that majority of physicians do not, and alectinib we expect to remain the standard of care. And we think we have designed a drug that potentially could address each line of therapy here. A drug that's active beyond alectinib, lorlatinib, we've shown that in our phase one data. We've shown a profile where we're potentially have activity beyond lorlatinib with patients with either single mutations and compound mutations and avoiding that off-target TRK safety profile.
That's a good second-line option, and if we have a drug that's as active as lorlatinib without the neurotoxicity, I think it speaks well to what we might be able to do in a frontline development strategy. So that's our path going forward there. In the ROS1 space, there's a lot of exciting compounds there as well. The standard of care is crizotinib. That's most physicians will go to that in the frontline. Limitations of crizotinib are limited brain penetrance and emergence of ROS1 resistance mutations. There's been other drugs developed in this space that go after either one or both of those different needs, either CNS penetrance or ROS1 resistance mutations. What's in common with many of these drugs is they often hit off-target TRK inhibition, which leads to those same challenges with lorlatinib.
And most physicians have given us guidance that what they really want to see in the ROS1 space is a drug that can do three things: hit ROS1 resistance mutations, be a CNS penetrant, and importantly, avoid off-targets like TRK that are dose-limiting, so they can keep patients on therapy and drive deeper, more durable responses. And zidesamtinib, our drug, it's in phase 2 clinical studies, does indeed do just that. So, you know, there are a few updates from other ROS1 drugs that are in that class with dual TRK ROS, and I think the data have been consistent in what's been previously reported.
Yeah. I would say this ASCO is literally validating the design of your molecule, try to address all the kind of limitations so far in terms of the CNS penetrant, AE, and dial out the AE, and then addressing the mutations. Everything just validated in those kind of earlier generation of the compound. They may be able to address some, but not all. But, you know, the 520 and the 655 try to address all of them.
Yeah, and I think that really speaks to what—when we formed the company, is we want to listen to the physicians that knew the most about this space, that they have developed the earlier generation inhibitors. And, you know, drug discovery and development, you learn from the literature. You learn from what's come before you, and the physicians are at the front lines of that. They help us understand, you know, what they see as the limitations of those therapies and where could we potentially do better. And we're a company that's fALKused on an expertise in chemistry, and we try to bring innovative chemistry to solve for those problems that have been identified with those earlier generation compounds.
Yeah. Understanding you design the drug is starting from, you always need to have a starting point. You start from later line after earlier generation. Data looks pretty solid. We can talk about that in a moment. Eventually, you're gonna move your compound into the earlier line. This ASCO, you know, we have the five-year CROWN data from the lorlatinib, and seems very potent, very active, but, you know, they still have the CNS AE, and a lot of physician is worried about that. So, and the ROS1 in the same vein, so they have some new generation potentially can be used earlier line or approval, and then, but still, they have some kind of a drawback, and you try to address. Maybe just give us a high level, how do you think about the front line kind of a setting for ALK versus the ROS1?
How do you think of this really changing or at all? And then, you know, we can move on to your data.
Yeah. So, so for ALK, I think what's gonna be required is showing that your drug is, is a better option than patients that take alectinib, which is the current standard of care. Patients progress on alectinib for two reasons. They can either develop ALK resistance mutations, and the types of mutations that are seen beyond alectinib ALKcur in about 50% incidence, or they can progress with CNS disease. Now, lorlatinib has some coverage of ALK resistance mutations and has excellent CNS penetrance, and, you know, has shown in the front line that it actually does delay, you know, on-target acquired resistance, which I think is very encouraging for the, the proof of principle. The, the challenge there is, though, that it also inhibits TRK, and the, the safety challenges have been somewhat limiting in physicians moving that to the front line.
So, you know, we've known what we wanted to do for our front line strategy for a while now. It's the good precedent in this space that, you know, randomized phase III trials have been done in the ALK-positive non-small cell lung cancer space. They've all been roughly about 300 patients. They've all taken about 2.5-3 years from start of enrollment to, you know, the line extension approval from regulators. And, you know, they've all been randomized 1:1 with the PFS endpoint, and we're not gonna try to reinvent the wheel here. We know what the standard of care is. We think we have a better drug, and we're gonna try to go prove that. So that's our strategy. Lorlatinib ran against the previous standard of care, crizotinib.
That no longer is an option for us. We obviously will be looking at what is the current standard of care. So we'll tell you more about our strategy. You wanna speak to that?
Yeah.
Sure.
Yeah, we can talk about that.
In terms of the data updates?
Yeah. Yeah.
Yeah, yeah. I'll share how we're thinking about the data. So we'll be at a medical meeting in the second half of this year for the updates for both ROS1 and ALK. We think, you know, for both programs, we've already told you the punchline, but we understand that key areas of fALKus are gonna be follow-up, durability, and so we're planning to provide updates on those areas from the phase I studies. The phase II portions of each of the studies are ongoing. Enrollment's been going well. The decision to include any data from the phase II portions of each study will be data-driven, and it'll be based on enrollment and timelines to pivotal data. So, you know, more info to come on that as we get closer.
Got it. And then, so maybe stay on the second half, this medical meeting update. It will be mostly fALKused on the phase I, this kind of, the previous, you know, enrolled at phase I portion. How much data should we expect from that? I understand the durability and the follow-up, and then will that be considered as, like, a mature data, maybe, you know, towards the late stage of data, you're now gonna share with us more, and next time we'll be fALKused on the phase II?
Sure, yeah. So, in terms of how much data to expect, we haven't guided on specific patient numbers or anything like that, but, for our ROS1 program, we started the phase II study in September of last year. For our ALK program, we just started the, phase II program, or transitioned to the phase II program in February of this year. The data cut for our ALK program was in, August of last year. We continued to enroll in phase I up until the phase II transition.
Yeah.
Similarly, for ROS1, we started, or we enrolled from, or the data cut was in August of 2022-
Twenty two.
and continued to enroll through the-
Up until the phase II.
That's right.
Mm-hmm. Got it. Okay, good. You know, we definitely look forward to this update because-
Mm-hmm.
You know, previous data absolutely very, very exciting, and we just need the bigger N and the longer follow-up and to see the durability and the more kind of substance of the data. And then I think, Alex, you mentioned you will data-driven decision to how you will disclose the phase II pivotal interim data. So how should we think about how you're gonna make the decision, and then what has been built in your protALKol, given this is a pivotal? You don't wanna, you know, compromise the
Sure
... the integrity of the study to get approval.
Sure, yeah. So I just reiterate what I said. It'll be driven, you know, data-driven based on how enrollment's going and the timelines to pivotal data, and maybe you wanna talk about the protALKol.
Yeah, yeah. I mean, I think that there's responsible drug development. Certainly, you're not going to, you know, mess around with pivotal data sets too much, but I think our team is very experienced in understanding, you know, what opportunities could or could not exist with presenting interim data. And as Alex mentioned, we think we've already showed folks that the drug meets each of the key area of the target product profile. It's just a matter of, you know, can we show—should we show more data? Everyone likes more. With respect to phase II, yeah, if we're very advanced in enrollment, we, you know, that would impact how we're thinking about sharing updates or how close we are to pivotal readouts. So, we don't like to get ahead of ourselves here.
We always react to what the data tells us to do, and so we're not yet ready to guide on the specifics, but other than we are expecting a data update in the second half.
Okay, good.
Yeah.
And understanding the second half or by the end of the year, you also have another major update for us is the first-line ALK strategy. You know, we have been talking about this lorlatinib new data, and obviously, it seems the alectinib will continue to be the first-line standard of care. So any updates from there, any updated thoughts on your first-line ALK strategy, and then how and when you will give us some update on that strategy?
Yeah. So when we started this program, we sort of knew exactly what we wanted to do, and honestly, like, what's... You know, often in drug development, it doesn't work out this way. It's something where you have a plan, and your plan change as data evolves and strategies evolve. And it hasn't been the case here. This is actually going exactly according to plan. You know, alectinib standard of care, lorlatinib looked like more active, but maybe more toxic. But you know, as the data continues to emerge, that's how it played out, and 655 was designed to address the limitations of both. And so we know what we want to do for phase—for a frontline strategy. We've known what we want to do for a while.
It was a matter of a couple things. We wanted to make sure we generate data first. We thought it was naive to go to physicians and say: Help us design this phase 3 trial, without showing them any clinical data. So as of ALKtober of last year, we had that clinical data in hand, and 655 met each of the key areas of a target product profile. So we feel like we have more firm ground to talk to investigators about, is this the right strategy? And then I also think from a. We needed a dose, and we aligned on the dose earlier this year, and when we started phase 2, so we know we have that box checked.
And then it's about making sure that if you're doing any pivotal study, it's good clinical development practice to align with regulators on the protALKol, right? So you don't want to figure out later on that they don't like the study after you've already run it. So you want to get the buy-in upfront, and so we're in the prALKess of doing that, and when—as we do those things and as we get more clarity on and alignment, we're going to share with the world, like, what the strategy is. But, again, I don't think it's super complicated here. It's pretty straightforward, based on precedent. Show your drug is better than the standard of care, and that's what we're going to try to do.
Yeah. Yeah, certainly. And then just a reminder, this will be a global trial to support a global registration, and how you're going to harmonize the, you know, US, Europe, maybe rest of the world in terms of the comparator as the first-line choice?
Yeah. I think alectinib is the standard of care globally, so, that, that helps. You know, and we, yes, of course, we would be doing a global study. In fact, our current ALKOVE-1, phase II, and our ARROS-1, phase II, are global studies as well. We're conducting those studies across US, Europe, Asia, Australia, engagement with, you know, excellent physicians around the world to develop these in all geographies, and we will, of course, do the same with our phase III study.
Mm-hmm. Got it. Got it. Yeah, so, maybe, another key topics that I know investors are also very keen on is, the potential commercialization. Because, you know, you cannot run the phase III by yourself, but eventually maybe you want to partner with people, for the commercialization. Given, particularly on the ALK side, you know, first line going to take a few years to run. How should we think about the timing of the potential partner? Particularly, how comfortable that your potential partner going to let you to run the phase III, versus they want to, you know, take a lead on the phase III program?
Sure, yeah. So, I think, you know, we're in a great position as a company. We have runway into 2027. We have a lot of optionality as a company. We're anticipating at least one approval within that timeframe. We do get asked, you know, as you mentioned, like, do we need a partner to run the phase III study? And the answer to that is no. We have a team that's experienced in designing and executing on these types of studies. We actually think the study is pretty straightforward, and the team's been thinking about it for a long time. And we also have the capital, and this is built into our current plan.
Where we do think a partner could potentially add value is as we think about global commercialization, getting these, you know, drugs to the most patients possible. We do think there's opportunity to leverage a partner there, specifically as we think about commercialization outside of the US.
Mm. Got it. Let me drill down a little bit on the, the runway, the runway guidance versus your, you know, first-line ALK strategy. It's going to take a few years, and your current cash is towards the 2027.
Yeah.
How should we think about this? Understanding you have a multiple inflection point ahead of you, right?
Sure.
So you have the pivotal data, you're going to approval, so a lot of things going to happen. I believe, you know, investor, even in this room, they're willing to fund you if you want to do on your own. But just dynamic-wise and how you think about, you know, partner early on versus later, understanding you don't need to find a partner to run the phase three?
Sure, yeah. So, you're right. You know, the study's gonna take a few years. We think it's well worth doing, and, you know, as I mentioned, it is built into our current runway. I won't commit that it's-- the study is fully funded within our current-
Yeah
runway. It would require additional capital. As you mentioned, we have a lot of catalysts coming up, and so I think we do have a lot of optionality, and we brought on a head of BD late last year, who's exploring, you know, exactly what the strategy is for the partnership, and what the timeline would be.
Okay, good. We do have a few minutes, and I do want to touch on your earlier pipeline because probably most of the people you talk to is the fALKus on the ROS and the ALK, given we have the time. And, you know, we talk about the HER2 and the NVL-330 and how—what—first of all, what's the, what's the target product profile you try to do? Because we understand pretty clearly about ALK and the ROS.
Yeah.
What is the HER2, and then what's the kind of a timeline look like for that program?
Yeah, I'll touch on the strategy, and Alex can talk about the timing. You know, I think the audience and certainly you, Roger, understand HER2 as a target. This is a you know, a well-validated target for the last couple of decades. There's been lots of drug development against HER2. You know, within HER2 lung cancer, specifically, the driver is HER2 exon 20 insertions, and some of the other HER2 drugs have been tried to repurpose for, you know, HER2 lung cancer. Well, it turns out they have a narrow index for inhibiting exon 20 HER2 versus wild type EGFR. It's known if you inhibit wild type EGFR, you get skin toxicities, you get GI toxicities.
So those drugs that were repurposed had pretty dismal outcomes, you know, poor response rates, poor durability, and, you know, physician feedback was, you know, you should try to solve for that through innovative chemistry. Try to come up with a compound with a wide index for HER2 exon 20 versus wild-type EGFR, and that way, you'd be able to hit the target hard, keep the patients on therapy, hopefully, had to drive deep and durable responses. In addition, because it's lung cancer, unfortunately, patients with lung cancer often get brain metastases. So you need to have excellent brain penetration, which is also a chemistry problem and one with types of problems we like to work on. And so NVL-330 is our solution.
We presented this data in ALKtober of 2022 back at the Triple Meeting, where it said that, you know, very indeed a very wide window for HER2 exon 20 versus wild type and excellent brain penetration. And you wanna talk about the guidance here?
Sure, yeah. So, we're excited. We'll initiate the study this year.
Mm-hmm.
We'll let you know when we're there, and we'll talk a little bit more about the study design at that point.
Mm-hmm. Yeah. Okay, good. So, we didn't talk about that, but I wanna, you know, bring this up, is the you do have this kind of a secret sauce, can figure out the chemistry, medicinal chemistry, and then you figure out a lot of things even pharma spend years cannot figure out. So tell us about your platform and how's the chemistry team and, and, how investor can give you the credit in terms of maybe you can figure out something else which is not fully addressed right now, given, you know, not saying the ALK, ROS, and HER2 is not big enough, but just thinking about additional upside can surprise people, from your platform.
Sure, sure. That's, I love the question. Yeah, so, the company's six years old, and we were a company on paper six years ago. We had nothing. We didn't in-license anything. I'm a chemist by training. The founder is a chemist. We pride ourselves on being very good at chemistry, and we often get asked, "Do you have better chemists than anywhere else?" Like, no, of course not. There's great scientists everywhere, and, I would never, claim to be better or, or compare myself or, or the team to... I can tell you our team's excellent, but judge us by the data, right? Judge us by what we put forward as, as programs. I think you can see the high-quality compounds that we've generated.
You know, what we're not talking to you about is the compounds that we deprioritized-
Mm
... the compounds that we did not meet the bar the physicians set out for us. I think what characterizes our team is the discipline, right? The discipline for, you know, what the physicians see the needs of the patients, and have we met them? If we have not truly met them, we don't talk to you about them 'cause they don't go forward, right? They, they get put on the shelf. I think our ALK and ROS1 and our HER2 program went-- we think we've met that bar, and those are the programs we talk about. We are, you know, building the company based on those principles. Each of those three programs, they were all discovered when we were a 12-person stealth company back by 2021.
So no one had ever heard of us by then, but we did our discovery work on those three molecules as a small core unit. Everything we've worked on since, we don't talk about, and the reason we don't talk about is that we don't tell you what the solut-- we don't tell you what the problem is until we have the solution, right? So we're still working on the solutions for those other programs. We're really excited about them. There are things that, again, are informed by physicians, and they, we work collaborative with them-- collaboratively with them and understand from their perspective, what should we solve for? And then which ones are tractable from chemistry standpoint.
We often get asked, you know, "When's the next one gonna get nominated?" And again, we don't know, because drug discovery science does not work on a timeline, right? We couldn't predict when it's gonna happen, but, you know, we like our chances based on the execution we've had thus far as a company. You know, within 6 years, taking, you know, 3 programs, nominating 3 novel drug candidates, taking their first two through preliminary proof of concept, including breakthrough designation and into pivotal studies, and the third about to go into the clinic. So I like the track record. I'm extremely proud of the team and the progress we've made, and I like our chances for, you know, you know, future programs as well.
Like, you know, it's still experiment, and I'd rather not talk about it until we have the solution.
Excellent. One thing very clear, you're well informed by the physician community, what's that real unmet need, and that you have a, you know, the chemistry team can figure the-
Mm
... figure out. Okay, good. I think we're on top of the 30 minutes. Anything else we haven't touched, but you wanna highlight for us?
No, I don't think so. I think we, we covered a lot. You know, we're, we're excited about what we're doing, and we appreciate the opportunity to be here.
Excellent. Great. Thanks, Jim. Thanks, Alex.
Thanks, Roger.
Thank you.
Yeah.
Thank you, everyone.