All right, good afternoon, everyone. Thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Ulz, one of the biotech analysts here, and it's my pleasure to introduce the team from Nuvalent, including Jim Porter, CEO, and Alex Balcom, CFO. Just a reminder, the format for today is a fireside chat, so if you'd like to ask a question, you know, please raise your hand, and we'll address your question in our discussion. Before we get started, I just need to read a quick disclaimer. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative.
With that, you know, Jim and Alex, thanks for joining us today, and maybe I can turn it over to Jim, if you wanna just make some quick introductory comments, and then we can go into Q&A.
Yeah, I just wanna say thank you, Mike, for the opportunity and for Morgan Stanley, the opportunity for the conference. We're excited to be here and looking forward to sharing more about, you know, the progress we're making at building Nuvalent.
Yep, sounds good. May we just start with a sort of platform, you know, strategy question? You know, obviously, precision oncology, maybe you can talk about some of your unique capabilities, you know, how that has translated into your early success now twice. We're waiting for the third, so
Sure, sure. Yeah, well, the company is about six and a half years old. We're based in Cambridge, Mass. The focus is, as you pointed out, precision oncology. The foundation of the company is a deep expertise in chemistry and structure-based drug design. We focus on clinically proven kinase targets, and the rationale there, there's 80 plus kinase inhibitors approved, so we know these mechanisms work, and we try to bring innovative chemistry to solve for the needs of patients. And to understand what those needs are, from the outset of the company, we formed relationships with physicians that have developed the earlier generation kinase inhibitors, understand from their perspective, what are the limitations of those therapies? What are the needs of the patients that they treat?
And we try to solve for them through innovative chemistry, and, you know, just in, you know, just a few short years, we've, you know, built the company up to where we have two clinical proof of concept datasets in our parallel lead programs targeting ROS1 and ALK non-small cell lung cancer. Both those programs we've received breakthrough designation by the FDA. Both are in phase II pivotal studies, and we have a third program in clinical development and a robust discovery pipeline behind that.
Maybe you can touch on some of the key challenges with existing kinase inhibitors.
Yeah, sure. Yeah, so we. Our approach is really guided by the physicians, learning from them, and, you know, the areas they pointed out, in particular, programs that we're interested in, you know, kinase inhibitors often work well. They drive durable responses, but patients can become resistant, and their disease will progress. So the immediate need is solving for those resistance mutations that have emerged beyond earlier-generation therapies. Those patients don't have options, so we try to come up with solutions that can address those specific resistance mutations. The other need, often the earlier-generation kinase inhibitors, they hit other off targets, and those other off targets don't necessarily help with the, you know, treating the disease, but hitting that off target could lead to off-target adverse events or safety challenges.
The feedback from the physicians was, "You know, we-- if you're gonna make a next-generation inhibitor, we'd like to avoid those specific off targets-
Mm-hmm.
'Cause they're driving dose-limiting toxicities in our patients. If you had more selective inhibitors, you can keep the patient on therapy longer, you can hit the target harder, drive deeper, more durable responses. And that's how you would open up a best-in-class therapy approach, where you can move up the treatment paradigm, make options for all patients with that given disease. So it's a pretty simple strategy. The really unique aspects is listening to the physicians and using the innovative chemistry to try to solve for it.
Yeah. Yeah, it's a simple but effective strategy.
Sure, sure.
Maybe just on resistance, you know, obviously, you kind of know what some of the resistance mutations are, but is there any way to sort of think ahead and kind of prevent, you know, other potential resistance mutations that could emerge in the future?
Yeah, this is really one of the advantages. Great question. It's one of the advantages of working in a space that's so well precedented and validated, it's we can learn from the literature.
Yeah.
As I mentioned before, there's eighty-plus kinase inhibitors that have been approved over the last two decades. There's so much learning from the literature.
Mm-hmm
Of what, you know, what are the limitations of the other therapies in this space? What are the types of resistance mutations that are likely to emerge beyond specific therapies? What are the, across a range of different indications? And quite frankly, there are learnings that we applied to our approach of not only let's solve for the ones that have been identified, but the ones that might be identified.
Yeah.
And, you know, that's helped guide our approach and our drug discovery efforts.
You talked about sort of three programs you're moving forward, but you also have an active discovery. You know, maybe just at a high level, how do you sort of determine, you know, where you started with the first two and now the third, and then, you know, where do you go in the future?
Yeah. So, you know, we only really talked through our, or discussed externally, the three lead programs targeting ROS1, ALK, and HER2 non-small cell lung cancer. A lot of learnings across each one of them 'cause they're all within lung cancer.
Yeah
Working with many of the same physicians, many of the same sites, and the discovery approaches mirrored each other as well.
Yeah.
But the approach is really anchored in understanding from the physicians where the needs are and where the chemistry takes us.
Mm-hmm.
We're not necessarily a lung cancer company.
Yeah.
Like, we'll go wherever the chemistry and the needs take us. And, you know, those three programs I mentioned, those were all discovered when we were a stealth company back by 2021 , right?
Mm-hmm.
We were a twelve-person stealth company. We were working on these three targets, and we solved them. Everything we've been working on since, in discovery research, we have yet to disclose.
Yep.
The reason being, we like to make sure we have the solution before we discuss the problem.
Yep, yep.
We often get asked when we will nominate the next development candidate, and the answer is we don't know.
Yep.
'Cause discovery doesn't work on a timeline. We have to figure it out, but you know, based on the past successes, you know, we hope to be successful with these other programs we're working on too. And there's a whole range of programs across a variety of different oncology indications that we're working on.
Yep, and just in terms of prioritizing, you know, your sort of lead programs versus discovery programs. You know, you now have three. Is adding a fourth into the mix? Does that kind of make spread you too thin, for example? Or just how do you think about that?
Not worried about that.
Okay.
I'm not worried about that at all. We have an outstanding team that's very passionate and dedicated towards driving these programs forward. I think someone's a little.
Somebody's typing.
That's a test fire alarm, I guess. [audio distortion]
Sweet.
Sorry for that interruption.
No problem.
If you lost your train of thought, I know.
No problem, no problem. Yeah, so the question was, you know, could we take on more? Absolutely.
Yep.
You know, I think we have a team that's very skilled at, you know, pushing these programs forward, and you know, with the discovery efforts are already ongoing, if we have another development candidate, we will develop it.
Yep. And just how do you think about read-through from your earlier programs to maybe some of these earlier pipeline programs? You know, obviously, you've had some success. You sort of applied a similar sort of strategy in lung, as you suggested. You know, are there similar strategies in the early-stage pipeline? Are there different strategies? You know, just-
Yeah. You know, it's. There's certainly learnings from one program to another. I will tell you that, you know, all discovery research problems are unique.
Yep.
Past success does not predict future success.
Yep.
But it can guide, it can help. You know, there's learnings that we can take on to our other programs. But, you know, all drug discovery challenges, I think, are unique, and they present their own unique challenges, and it requires, you know, skilled, talented researchers to try to solve them.
Yep. Great. Maybe we can switch to your lead program, your ALK inhibitor. Maybe just talk about the current treatment landscape and where the unmet need is, and kind of the things you've done to sort of solve for those.
Sure, sure. So there's five approved therapies in the ALK space, so, number of options for patients, and the obvious question is, "Why, why, why a sixth? Why you needing a sixth?" And you can really think about it pretty simply in two buckets. You know, when patients are newly diagnosed in the advanced metastatic setting, they receive alectinib. That is the standard of care. When patients progress on alectinib, the only drug is that really works in this setting is lorlatinib. And when patients progress on lorlatinib, nothing works. There's no option for those patients. And the physicians urged us to go try to solve for that immediate need. There's no option for patients. These patients present with ALK mutations, something called single and compound mutations. None of the available therapies work there. That became our immediate challenge, to try to solve for that.
But with each of our programs, we're looking not just to address the immediate need, but how do you make a best-in-class therapy? And of those other therapies I mentioned, most physicians would tell you lorlatinib is the most active ALK drug. But it gets the second-line use as opposed to the front line because it hits a specific off-target, and that off-target can drive CNS toxicities, and those CNS toxicities are things that physicians and patients were looking to avoid. So if we could make, you know, a drug that avoids that specific off-target, that has the other favorable attributes lorlatinib has, meaning good coverage of ALK mutations, CNS penetrance, then we would have a better second-line drug than lorlatinib, and we would have a better front-line drug than alectinib.
So that's the general strategy, and, you know, we're looking to push that forward with the data that we're generating.
Yep, and maybe you can talk about some of that data. I think, you know, was it a year ago, you presented some of that data, and maybe just start with the response rates, and you gave a lot of different sort of subgroups, so maybe just walk through maybe the key ones and, you know, how those compare.
Yeah. So, you know, it was a phase I study, and in phase I oncology studies, often physicians are gonna exhaust available options before they consider a-
Mm
Phase I trial, right? So patients have progressed through all the other therapies. It's a very difficult, advanced, heavily pretreated patient population, different than any other ALK study that we're aware of. And, you know, we designed our drug to be active in that patient population, and it was, right? Even in these very advanced patients, we saw the drug was active with patients that had taken the multiple lines of therapy, patients that had single resistance mutations, compound resistance mutations, patients that had disease in the brain. And importantly, the drug was well tolerated, and that was one of the things that we had heard was the limiting factor of lorlatinib advancement until those earlier lines is those CNS toxicities, and we weren't seeing that with NVL-655. So we think it sets us up for, you know, pushing our strategy forward.
You know, that was basically, like, the key findings.
Yep
For our phase I.
Yep. Makes sense. Maybe just talk about early signs of durability and what we, what you were seeing there.
Yeah, sure. So, in our last data presentation, you know, what we showed was that all patients who'd responded to NVL-655, they didn't progress, and so that was really encouraging, but it was also an early look, and so you know, a key focus area for the update that we'll share at ESMO coming up here is gonna be on additional follow-up and durability, and the learnings around those aspects from our phase I study.
Maybe you could expand a little bit on ESMO and just what are the key data points, you know, PFS and so forth? And maybe are there any specific subgroups we could look at? What's the bar? How to think about that? What's a good readout?
Yeah, so I think as Alex mentioned, like, the initial presentations, it really told you the punchline, but it was too early to really assess durability.
Yeah.
I think in single arm studies, often, you know, for certainly what regulators will look at is response rate, duration of response, and safety. So that, that's an opportunity for us to share what we're learning on each of those variables. What's the bar? Well, in third line, nothing works.
Yeah.
Right? There is no option for those patients. That's actually where we received breakthrough designation by the FDA, sort of highlighting that there's a medical need, and the early data is trending favorably in that setting. So any activity that's durable and well-tolerated, that's I think that's an advance for that particular patient population. In second line, lorlatinib is the standard of care, and it generates roughly a seven-month duration of response in that setting and, you know, we think there's limitations to lorlatinib in that setting. It's not, there's a narrow index for inhibiting ALK mutations versus that specific off target. It's called TRK. And because of that, it was dose limiting in their phase I study, and, you know, trying to give more drug to cover those mutations, was not possible, right?
So we had known that going into the design of 655 It's, let's design a compound that has a wide index for hitting those mutations versus TRK, and that includes both single mutations and compound mutations. And we saw that play out in our first phase I update, where we were seeing patients progress on lorlatinib with, you know, single mutations that was ineffective at covering or compound mutations that were developing on lorlatinib, and they were responding to 655 . And, as Alex mentioned, none of them had progressed by the time of the last data cutoff. So I think there's an opportunity to learn what happens with this updated data set. You know, we didn't have many lorlatinib-naive patients.
As I mentioned before, most physicians are gonna exhaust the available options before putting them on a phase I study. But, you know, the few-- the handful that we did have, the data there were, was trending favorably. So we'll share what we're learning in the second line setting, and we'll also share, like, you know, how that durability in the third line setting may translate to what you might see in those-
Mm-hmm
Earlier lines, and then ultimately, where we wanna go is front line, and for front line, it's very clear precedent you would need a randomized study and, you know, we've known what we wanted to do for a while there, and we're on track to disclose, you know, our strategy this year.
Can you maybe just talk about breakthrough therapy designation? You received that earlier this year, and just, you know, how that impacted your development.
Yeah, we received it actually for both programs, both our ROS1 and ALK programs. And I think it really speaks to, like, there's a medical need-
Yeah
That the regulatory agencies have identified, and typically, they grant a breakthrough designation if that medical need exists, and you've generated data showing that you're addressing that medical need. And then we received that for both our ROS1 and ALK programs. The advantages is it really provides an, you know, additional opportunities to have lines of dialogue with the regulators about getting these drugs to patients as fast as possible. That's our ultimate goal, is we want to bring these drugs to market to treat as many patients as possible. So having that open line of dialogue is a huge opportunity for Nuvalent.
Yeah
On both of our programs. As we mentioned, we're trying to develop them for all ALK and all ROS1 patients, and having more ways to communicate with the agency is an important opportunity for us.
Yeah. Maybe just talk about post the ESMO update, you know, sort of next steps for the program.
Sure. Yeah. So we're excited about the ESMO update. You know, in addition to the update, the phase I data, we'll also be sharing a status and enrollment update from the phase II portions for each of the programs as well. And as Jim mentioned, you know, we're on track to share more details around our phase III study design for the ALK program this year. And then, you know, beyond that, we've guided to having pivotal data from at least one of our programs next year, and our first approval for at least one of our programs in 2026.
Yeah. Just, yeah, the phase III strategy is frontline, correct? Have you mentioned anything about, you know, that design at all, or what are the sort of key factors you're still trying to-
Yeah. So we'll disclose the specifics this year, but we can share kind of how we think about the benchmarks.
Yeah. The, you know, the ALK space, we're really guided by. There's four randomized phase III that have already been-
Mm-hmm
Done in this setting. They've all been randomized one to one. They've all been progression-free survival as the primary endpoint. They've all been roughly three hundred patients. They've all taken about two and a half to three years from start of enrollment to the line extension approval. So that's, you know, good precedent to learn from. The standard of care has changed. It's no longer crizotinib, which each of those studies were run against. It's now alectinib. So we'll have a slightly longer study, a slightly larger study, 'cause the standard of care has changed. But, you know, it's a pretty, you know, great opportunity, you know, in the ALK non-small cell lung cancer is a disease, as I mentioned before, that has lots of treatment options.
Yep.
But often, these patients are diagnosed when they're younger, and though alectinib performs favorably, it's about a two-year progression-free survival. You know, if you're a younger patient in the prime of your life, two years isn't long enough.
Yep.
Right?
Yep.
So, it turns out that half the patients on alectinib will progress with ALK resistance mutations, so on-target ALK resistance mutations. And that really tells you that this, you know, ALK is a really interesting driver to target in cancer 'cause the tumors are so dependent on ALK signaling. So if you make a compound that has broad coverage of ALK resistance mutations, you can envision keeping the patients on therapy longer 'cause you're going to limit the number of escape pathways-
Mm-hmm.
for the disease and driving deeper, more durable responses. This is not something we made up, this is something that's tried and true in the oncology space.
Yep.
Like osimertinib is one of the most well-known examples in the EGFR space, EGFR lung cancer, where, you know, it about half the patients on earlier generation EGFR and ALK inhibitors would progress with, you know, on-target acquired resistance. And osimertinib addressed that mutation and eventually supplanted the standard of care. And the reason that's so interesting is, one, that creates much more durable options for patients, but also represents a very interesting commercial opportunity. So in the EGFR space, it took a $2 billion market at peak sales and made it a $5-plus billion market and growing.
So if we could take what is already an interesting market with alectinib, you know, roughly about $2 billion a year in sales, and we can drive significantly longer progression-free survival, you know, we think we could, you know, be a great option for patients and also represents a very attractive commercial opportunity.
Yep.
For Nuvalent.
Yep. Maybe just on the commercial opportunity, you know, is this something you plan to launch on your own, or are you considering partnering? You know, what would be the timeframe on that?
Yeah, I can share how we think about that. So, I mean, overall, we're in great shape. We have runway into 2027. We have, you know, the team that's experienced in executing these studies as well as the phase III study for ALK, and so that gives us a lot of flexibility. You know, there's potentially the opportunity to leverage a strategic partner as we think about global commercialization, you know, specifically outside of the US.
Mm-hmm. Gotcha. Okay. Maybe we can shift to the ROS1 program. You know, maybe talk about the unmet need there and kinda how your molecules profile is sort of stacking up.
Yeah, it's actually a very similar story to the ALK story, right? These are diseases that are related, and they're both driven by particular oncogenic fusions. And the needs that have arisen beyond the therapies are related. So we took a very similar strategy, discovery-wise, to solve each one of these programs. So in the ROS1 space, the current standard of care is a drug called crizotinib. Crizotinib is not highly brain penetrant, so patients will progress with CNS disease, and also they'll progress with ROS1 resistance mutations, and they turn out to be pretty much similar resistance mutations than what occur beyond alectinib and in the ALK non-small cell lung cancer space. So when those resistance mutations emerge, there's not a great option for those patients.
The other drugs that have been developed in this setting, you know, some of them, have CNS penetrance, some of them have some coverage of those resistance mutations, but they happen to be very potent TRK inhibitors, right? So same challenge that I mentioned before with lorlatinib in the ALK space is that they're actually dual TRK ROS1 inhibitors, hit TRK more potently than ROS1, and therefore, the patients experience these CNS toxicities. And we've not seen the broad uptake of those dual TRK ROS1 inhibitors in the ROS1 setting to displace crizotinib.
The physicians had outlined for us is what's truly needed here is a drug that can hit the original ROS1 fusion, can hit the ROS1 resistance mutations that are the disease-resistant pathways, have excellent CNS penetrance to can limit or treat the patients that have CNS disease, and importantly, be selective for ROS1 as opposed to the structurally related off-target TRK. And those are all chemistry problems, and
Yep.
We're a chemistry company, so we came up with a solution. Our solution is zidesamtinib, and it's a beautiful molecule. It can do all those things. It can hit the fusions, it can hit the mutations, it can get into the brain, it can avoid TRK, and, you know, we're excited about that program.
Yep. And maybe you can touch on some of the early clinical data you shared.
Yeah. Just like with the ALK program, you know, the phase I update is a very advanced patient population. These are patients that have exhausted available options. They've taken the other things, that nothing works in this patient population. But we designed zidesamtinib to work in this population, and it did. It did. It was active in all the patients. I'm sorry, in the broader patient population, if you look at the subsets where patients would have mutations, or patients would have CNS disease, or they've taken a number of therapies, or regardless of what prior therapy they took, approved or investigational, we still saw responses with those patients. And so we're quite encouraged by that.
It was active in the brain, and it was importantly, it had the safety profile that we were looking for, that was avoiding those CNS toxicities that the other drugs were showing. So, you know, we had transitioned this trial to phase II as of September of last year, and that study is ongoing, where we have registration-directed cohorts in both TKI-naïve and previously treated patients.
Yep. Sorry for that again, but maybe sticking with ROS and kinda the ESMO update and just, you know, what should we expect there? I mean, it's been a while since you've shared some of the data. You know, we'll include some of the phase II data as well as the phase I.
So similar story to ALK, how we're thinking about the updates for ROS1 at ESMO. It will be focused on data from the phase I study, which is fully enrolled. And, you know, as we talked about with our ALK program, we think we told you the punchline with the initial presentation, but that was an early look that we shared for ROS1. And so the focus here will be on additional follow-up and learnings around durability, and then we're also looking forward to providing an update on the status and enrollment from the phase II portion of the study.
And maybe a similar question just on the durability, and maybe PFS is the sort of key endpoint, but, you know, what's sort of the bar there?
Yeah. So in frontline, crizotinib is the standard of care. It drives about eighteen months duration of response, and, you know, as I mentioned, half the patients are progressing with ROS1 resistance mutations, and others are progressing with CNS disease, and we try to solve for that. You know, interestingly, crizotinib used to be the standard of care in ALK, non-small cell lung cancer, and four other drugs have shown they're significantly better than crizotinib in that space. But it still remains the standard of care in ROS1 because no one had ever developed a drug specifically for ROS1 patients. They've taken other drugs that they've repurposed for other targets and tried to develop them for ROS1 patients. Zidesamtinib has been designed specifically for ROS1 patients. It solves for all those other needs.
I'd point to, like, the data generated in ALK from a drug like lorlatinib, right? It has coverage of ALK mutations and CNS penetrance. The same reasons that patients are progressing on crizotinib and ALK are the same reasons they're progressing on ROS1. Lorlatinib has, like, a hazard ratio of point one nine in ALK non-small cell lung cancer versus crizotinib. What if you can do something like that in ROS1, right? You're talking about taking what is today, you know, an interesting market, maybe of crizotinib doing roughly $400 million in sales, and how much bigger can it get, right? Like, how much more durable responses can you drive by covering those resistance pathways or limiting the escape mechanism to the disease in the brain?
You know, we're really excited about zidesamtinib and, you know, what it might be able to do in that frontline setting. Now, our phase I data is not TKI-naïve patients, right? These are all patients that have exhausted available options. But, you know, our objective here is to tell what we're learning from a durability perspective, where these patients don't really have any options available to them. What kind of responses are we seeing? What? How durable are they? Are we seeing the safety profile, et cetera? And how does that guide how you think it might perform in those registration-directed cohorts-
Mm.
that are ongoing, both TKI pretreated as well as TKI-naïve patients.
Gotcha. Yeah, we have about six minutes left, so maybe we can shift gears to, you know, 330, and maybe just give us a little bit more background there. And I think you just started the phase I study, so maybe talk about the-
Yeah
-design.
Yeah. So the HER2 lung cancer. So HER2 is a target that, you know, most folks have heard of. It's a, it's a well-established, oncology target. There's been drug development against HER2 for the last two decades and many approved therapies. HER2 lung cancer is a little bit different than those other HER2, approved therapies 'cause it's, it's primarily driven by something called Exon 20 insertions. And, some of those other HER2 drugs have been tried to be repurposed for HER2 lung cancer. Well, it turns out they have a narrow index for inhibiting Exon 20 insertions compared to wild-type EGFR. And wild-type EGFR is the dose-limiting tox here. It, it's well known that if you inhibit wild-type EGFR, you'll get skin toxicities, GI toxicities.
The outcomes for those repurposed drugs have been pretty dismal: poor response rates, poor durability, 'cause it's not difficult for the patients to tolerate these drugs to drive deep and durable responses. That was the clear need we were trying to solve for, that we heard from the physicians, is design a drug that has that wide index for hitting HER2 Exon 20 versus wild-type EGFR. That's an interesting chemistry problem. That's in our wheelhouse. In addition, because it's lung cancer, unfortunately, lung cancer patients are the patients that are most predominantly going to get brain metastases. The disease will metastasize to the brain. You need to design a drug that can cross the blood-brain barrier, and NVL-330 does both of those things.
It's broadly active against HER2 mutations, particularly Exon 20 insertions, has the wide index for wild-type EGFR, and it's highly brain-penetrant in preclinical studies. So we're excited about it. We just started the clinical study earlier this year. It's called the HEROIC study. It's focused in lung cancer. I will tell you that that's where our near-term interests are. But NVL-330 also happens to be an excellent HER2 inhibitor broadly.
Mm.
HER2 is a driver in lots of different tumor types. You know, we can consider those opportunities down the road as well.
I guess, when's the next update for this program?
Yeah, so I mean, we were excited to announce that the first patient was dosed earlier this summer, back in July. And so, you know, we'll take the same approach as we have with our other programs, where, you know, we'll follow the progress and be data-driven and, you know, want to be able to tell a meaningful, clear story of what we're learning. So we'll provide more updates in the future.
Yep. Maybe just back to the first two programs, the ALK and ROS. And I think you mentioned providing some pivotal data next year. Is it for one program, for both programs? You know, how should we think about that?
Yeah, we haven't shared just yet which program. It could be, you know, either of the programs. We've shared that enrollment gone really well. We've been pleased how it's going across both of the studies. So we'll look forward to providing more updates in the future.
Okay. Okay, looks like we're just about out of time, so why don't we wrap it up there? Looking forward to ESMO coming up here, and thanks, Jim and Alex, for sharing your time with us today.
Thanks so much.
Thank you.