All right, I think we're ready to get started. Welcome, everyone. I'm Josh Schimmer from the Cantor Biotech Equity Research Team. Very pleased to introduce from Nuvalent, we have Jim Porter, Chief Executive Officer, and Alex Balcom, Chief Financial Officer. Why don't we start with a quick snapshot of the company, and then dive into some interesting aspects to view the unmet need you're looking to address?
Sure. Great. First of all, Josh, sincere thanks for the opportunity to participate, and thanks to the Cantor team, for the invitation to be here. A little bit about our company. We're about seven years old. We are a precision oncology company. The foundation of the company is a expertise in chemistry, structure-based drug design. I myself am a trained chemist. Our founder is a Harvard chemistry professor. We try to apply innovative chemistry to make better solutions for patients with cancer. We focus on validated biology, so clinically proven kinase targets. There's over ninety approved, so it makes a lot of sense to de-risk the biology in that, in that way.
And then, to make sure we make an impact, we go talk to physicians who developed the earlier generation inhibitors, understand from their perspective, what are the needs of the patients? What are we solving for? And then, we apply innovative chemistry to that. Made a lot of progress building the team. Maybe Alex can share some of the highlights.
Sure, yeah. So high level, pushing forward with two drugs towards potential approval. And in terms of where we're at, zidesamtinib, we presented our top-line data back in June. We're looking forward to presenting the full dataset upcoming at World Lung. And we've initiated the NDA submission for pretreated ROS1 patients, and we're working towards completion of that this quarter. For NVL-655, we're on track to present pivotal data by year-end. We've also initiated the phase III ALKAZAR study back in July, and then continuing to progress our HER2 program, the phase Ia/Ib HEROIC study as well.
We chatted briefly last week. You mentioned something that I found quite interesting, that you'd been at a patient advocacy group meeting, and that there's actually patient advocacy groups for both ALK and ROS1. First of all, tell us about these organizations and your connectivity with them, and a little bit maybe about their significance.
Yeah. It honestly, it's such a privilege for Nuvalent to collaborate with these outstanding organizations. We were keyed into them by the physicians. Back when we were in stealth mode, no one had heard of Nuvalent, but the physicians knew us, and they said, "There are actually ALK-positive and ROS1 groups that are dedicated to this. You should talk to them." And since then, we've been, you know, really benefited from outstanding collaborations. Typically, these are diseases that patients get diagnosed when they're relatively younger, thirties, forties, and fifties. So I found that they, they're. Because of that, they're online. They're talking to each other. They form this community. They understand the landscape, they understand the options that are evolving, and they advocate for better options for patients.
Our goals are directly aligned with their goals, so they've been cheering us on. They've been helping us. They've been... Our trials enroll like crazy, mainly because the outstanding collaboration we have with these groups that are pointing patients to the Nuvalent studies.
In terms of the deficiencies you're looking to address relative to other ALK and ROS inhibitors, it sounds a lot of it may be CNS based, but maybe kind of frame where you see the unmet medical need in those tumor settings.
Yeah. So we learn from the physicians. So in the ALK space, there's six approved therapies. So the obvious question is, like: Do you really need a seventh? Like, how does a seventh fit into this space? But the physicians helped us understand it's actually just really two sequential options. Most patients front line get alectinib. When they progress on alectinib, the only drug that works is lorlatinib. When they progress on lorlatinib, nothing works, so we need to solve that third line. Most physicians would tell you the second-line drug is actually more active than the front-line drug, but they don't use it because the second-line drug has neurotoxicity signals, right? So if we could learn from that, we can make a drug like.
Broadly cover mutations, be active in the CNS, but importantly, this is where the chemistry comes into play, be selective for ALK versus those off targets. We would have a better second-line drug than lorlatinib and a better front-line drug than alectinib, and that's the goal of the company, is make a solution for all the patients, no matter what line of therapy they're in.
So when you look at the package inserts of those products, CNS side effects don't jump off the page at all. They're not really listed as a prominent side effect. They're not listed as a common reason for discontinuation. So, like, why do you think it's not being picked up in those trials, but you're hearing it? I'm guessing not just from physicians, but now patients from the community, too?
Yeah, so the CNS side effects show up as a variety of different things. It's not a single event. So some patients can have hallucinations. Some patients could have the severe suicidal ideation or mood disorders or sleep disorders or speech disorders. Some patients are too dizzy to walk across the room or operate in their job. So what the FDA did is actually, in the summary basis for approval for drugs like lorlatinib, entrectinib, repotrectinib, they went through, and they collated all those terms, and they said, "You lump all those terms together..." Oh, for lorlatinib and entrectinib, it's over half the patients have these CNS effects. For repotrectinib, it's nearly 80% of the patients have these effects, and you know, what one physician might call dizziness, another physician's calling something different because there's some subjectivity to it.
But when you talk to the patients, it's very clear it changes their life in a way. Remember, younger patient population in the prime of their life. Otherwise, if their therapy is impacting their ability to live day to day, that matters. It matters in a tangible way, and that's why physicians have largely stuck with alectinib in the community setting, 'cause alectinib doesn't have these CNS toxicities, and therefore patients can continue on their day-to-day routine before going to a drug like lorlatinib that's gonna impact that quality of life.
But your sense of kind of the real-world tolerability and persistence on therapy, because, again, in the package inserts, there. It's not, like, a high rate of discontinuation from the CNS side effects, but is it different in the real world?
Yeah, so once you're on lorlatinib on a clinical trial, if you're gonna come off of it, there are no other options for you. So those physicians in clinical studies are gonna do everything they can to keep the patients on study. But if you talk to physicians, even the ones that are comfortable using lorlatinib, many of them will tell you they don't use the approved dose. They'll actually scale down the dose to 75 or 50 because it's better tolerated. Now, I'll tell you, Josh, that matters from a resistance coverage perspective. If you give less drug, you're gonna get less activity against their ALK mutations that drive resistance, and that's why we see many patients that come on our trial that have progressed on lorlatinib with ALK single mutations or compound mutations. We don't have that same challenge.
We broadly cover those mutations with a wide index for the off targets that are dose-limiting, so we can really hammer them and drive deep and durable responses where those other drugs have come up short.
Right. I mean, we first learned maybe in the HIV world how important tolerability is for persistence and prevention of emergence of resistance. I don't really feel like we've seen it as much in oncology, but maybe we are starting to see it here.
Yeah. You know, the idea here is, you know, ALK and ROS1 are very interesting oncology targets. The tumors are highly dependent. It might be 'cause they're fusion proteins, but the tumors are highly dependent on ALK and ROS1 signaling. If you can broadly cover the ALK mutations, if you're active in the CNS, then you're taking away those easy progression pathways for the tumors, right? And the tumors, you know, it's gonna take longer to find bypass mechanisms, which equates to more durable responses. So keeping patients on therapy is a good way to drive more durable responses. We're seeing that with both our ALK and ROS1 programs. Like, as an example, in our ALK phase I, we only saw a single patient in this advanced patient population at the phase II dose that had disease progression that responded.
In our second-line ROS1 pivotal data, second-line to patients, they've already progressed to one line of therapy. At a year and a half, 93% are still in response. That's, that's pretty stunning durability data, right? So we're really encouraged by that, and it speaks to why ALK and ROS1 are interesting targets to go after.
Why don't we drill into ROS1 as zidesamtinib, and maybe frame it relative to the current standard of care, which I guess remains crizotinib, even though there have been a couple of other ROS1 inhibitors approved, as you noted.
Yeah, yeah. So crizotinib, you know, it's a good drug for ROS1 patients. It's a repurposed drug, right? Remember, it's a former MET inhibitor, but then ALK is a target, so it gets approved for ALK, then for ROS1. Its limitations are it's not highly brain-penetrant, and it's not really good at covering ROS1 mutations. So those are the same, the two main reasons patients progress on crizotinib, either with CNS disease or ROS1 mutations. Now, there are other drugs that have been developed that solve for one or more of those things, but what they all share in common is they hit off targets that are dose-limiting. In fact, the same off targets that we mentioned before, the neurotoxic off targets. And physicians told us, although those drugs...
It's good to have those new drugs approved, they're likely to get approved, but they won't get a lot of use in the community setting based on managing these neurotoxicity signals, right? So if they really want to make a drug for ROS1 patients, what you need to do is you need to hit the mutations, get into the brain, but be selective for ROS1, and that's what zidesamtinib profile is, and that's what we're seeing both preclinically and with our clinical data.
So what's interesting, given your framing of the very high persistence on therapy, every data update becomes important, right? 'Cause it's giving us more and more clues around persistence on therapy. So I think your next update's gonna be at World Lung. Maybe give us a sense of what we should be looking for, and how do you expect that persistence to evolve? Do you have a target scenario in mind for, like, how many years on therapy patients are likely to remain?
Yeah. So, looking forward to presenting on the podium at World Lung, and for this data update, we're planning to leverage the same patients and the same data cut as we did from our June top-line announcement. And so, you know, with that data, we showed meaningful responses, regardless of prior line of therapy, you know, CNS disease or mutational status. So can expect that, you know, in this update, we'll further illustrate those points with some additional details.
And I guess you'll proceed with the filing for the TKI pre-treated patients, but clearly, there's also a very straight path to first-line. How far behind would first-line be?
So, the precedent in the ROS1 space is each of the drugs have been approved off a single-arm phase II, following the patients for twelve months, right? Twelve months post-response, that gives you a sense of the safety and the durability of those responses. Now, we recognize there was an opportunity to cut the data earlier for previously treated patients 'cause there was a medical need. We had breakthrough designation in that setting. We had aligned with the FDA to cut that data for six months post-response. So that was the first data we presented earlier this year. Just need a little bit more follow-up for naive patients. But that trial is, that cohort has enrolled incredibly well. As of a few months ago, we had north of a hundred. We had significantly over-enrolled the study.
You know, we'll continue to work with the regulators around how much data we need to show to support a line-agnostic registration strategy.
And so, the timing for the next TKI-naive update is to be determined, or have you kinda laid out a more?
Yeah, we haven't.
Okay
Given the details yet of when that comes.
Do you think you need the label to get adoption in the first line? Might you get NCCN guidelines approvals? And just given the significant differentiation, it would seem to be very quickly perhaps a treatment of choice.
Yeah, you know, eventually, we hope that this is the option for any ROS1 patient, regardless of line. You know, we hope that all the approvals come, right? Front line, previously treated. So we're gonna do whatever we can to make that happen as fast as possible. I don't wanna guide to exactly, you know, when that the front-line approval happens or when the listing in NCCN. We recognize the importance of that. We're building relationships where groups are making sure all physicians are aware of our data, both previously treated and the naive data, and we'll make sure the NCCN committees are also aware of that. But when that happens is really gonna be under their control, their determination.
I guess the approved ROS1s kind of frame the commercial market, at least as a starting point. Maybe talk about the current sales profile, and then we can think about ways you might be able to scale up from there with an improved product.
Yeah, the best way to think about this is, crizotinib has about $400 million in sales, global sales. And crizotinib is a decent drug, but it's, you know, we believe there's an opportunity for improvement. As an example, crizotinib used to be the standard of care in ALK, right? And there are much better drugs in the ALK space, and it has significantly grown that market. Lorlatinib has a 5x improvement over durability compared to crizotinib in ALK. 5x . Five plus years versus less than a year, right? And the reason lorlatinib is more active than crizotinib are the same reasons zidesamtinib is more active than crizotinib in ROS1. We solve for the same things: mutations, CNS disease.
So if something similar plays out in the ROS1 space, you're not talking about a marginal improvement in the durability. You're talking about a multiple-year improvement, and what that commercial opportunity becomes is to be determined, but we just, what we know is it's interesting. It's interesting. We don't wanna put a ceiling on where it is, but it could be a game changer for patients, and it could be a compelling commercial opportunity.
Is there a kind of benchmark analogue that you look at to maybe guide where you think the durability might wind up?
Look, like, and you know, we saw this play out in eGFR, right? eGFR was a $2 billion market. Osimertinib solved for the same things we're solving for, right? It was mutational coverage, CNS penetrance, and better tolerability, right? It did all three of those things. It doubled the PFS, right? And it tripled the market. It went from $2 billion peak sales to $6 billion and growing, right? That's with doubling the PFS. We're looking to do multiples here-
Right
In the ROS1 space, so I don't know what the ceiling is.
So that, that's the, by far, probably the biggest market expander force, but there are potentially some others that are meaningful, maybe not in the same ballpark, but still meaningful. Higher overall response rate, potentially premium pricing relative to crizotinib. I guess that one might be a little bit harder to address, but conceptually, maybe you can give us some a framework.
Yeah, sure. So on the pricing, you know, we haven't provided any specific guidance at this stage, but obviously can look to the precedents for the drugs that have been approved in the space. So, you know, you mentioned, some have priced at a premium, so, you know, we'll consider those precedents, as well as the profile of zidesamtinib, and, you know, other factors.
Are there patients with ROS1 mutations, either lung or even beyond, that are not on a ROS1 inhibitor currently that could also come onto therapy?
Yeah, yeah, you know, this is a space that because these targets, ROS1 and ALK, have been around for a while, lung cancer patients, we believe 80%-90% are getting sequenced, whether in the academia, academic setting or in the community. And if they find a ROS1 or ALK driver, they put them on a ROS1 or ALK TKI. That's, in general, already happening. Now, will that be slightly improved over time? Yes. I think the field overall is getting slightly better, but we don't expect it to get significantly better. It's, it's already pretty good. I think where the real drivers here are, you mentioned one of them, there's premium pricing is a, is a potential driver. I think the real driver here is the durability, right?
That the tolerability extending durability, like that is something that could really be a game changer for one, for patients, but also from a commercial standpoint.
Maybe we can toggle over to ALK now. I guess as that data is evolving, help us kind of establish the compare and contrast relative to-- specifically to lorlatinib, which you flagged for NVL-655.
Yeah
If I'm probably not pronouncing that perfectly right.
NVL-655, yeah.
Neladalkib.
So the space is, again, alectinib frontline. When they progress on alectinib, lorlatinib's the go-to. When they progress on lorlatinib, nothing works. So we have that third line patient population in our phase one, where we saw deep, durable responses. These are patients that have taken lorlatinib, but nothing else works. We've received breakthrough designation there. We had a handful of second-line patients. Now, we have reason to believe that our drug will work better than lorlatinib in second line, and the reason is, lorlatinib, it's difficult to cover the ALK mutations with lorlatinib because you bump up into the TRK activity. So when they went higher in their phase one to try to hit the mutations harder, they saw the CNS toxicity. They had to back the dose down, where they get limited coverage of ALK mutations.
We see patients come on our trial that have progressed with either inefficient coverage of ALK single mutations, or what happens is a second mutation starts to grow in. That's called a compound mutation. That second mutation grows in, lorlatinib can't cover it. Our drug was designed to, it was optimized for these mutations, so we can hammer them, and we can drive durable responses, even if patients have already taken lorlatinib.
So if you play that out, you would presume they are less likely to progress on NVL-655 in second line with those mutations, 'cause we're covering them. So what our phase two pivotal study has been designed is a third line patient population where nothing works. That's a pretty straightforward experiment. A second line experiment where, can we show better durability than lorlatinib? Lorlatinib has a seven-month duration and response. We're showing more than double that beyond lorlatinib in our phase one. So if we see anything in that ballpark, it's a compelling case, we believe, to make to regulators around a broader previously treated ALK label, and then for our frontline strategy, we have the randomized study versus alectinib.
Okay, got it. I guess as we look in the lorlatinib-naive TKI experience, you have generated. It's a little bit maybe more of an apples to apples comparison to lorlatinib, and it looks like you're kind of nudging them out on overall response rate, 60% versus 50%. But I guess, kind of as you infer, your real point of differentiation is not in response rate. It's gonna be in durability.
Yeah, well, the responses are gonna be largely dictated, do you have ALK-driven disease or not, right? If you have a bypass mechanism in play, none of the ALK drugs are gonna work very well as a monotherapy, right? So it really and it's very much influenced by how many patients that have ALK-driven disease coming onto your study. If they have ALK-driven disease, we have reason to believe our drug will drive more durable responses in those patients than a drug like lorlatinib.
There are some data updates coming later this year. What should we be looking for, both in non-small cell lung cancer or potentially other solid tumors, ALK-positive solid tumors?
Yeah, so, maybe I'll start on, like, the data, and then Alex will explain how we're gonna present it. So we have a cohort, as I just mentioned, of second-line patients and third-line patients for ALK non-small cell lung cancer. They were both designed to support registration. That, we're gonna present later this year. We also have an exploratory cohort, which we're intrigued by. This is, you know, ALK's the driver and beyond just lung cancer, right? So there's a dozen different tumor types, and what the challenge there is that physicians don't have a lot of data to point to, to go for a reason to go sequence those patients for ALK, right?
But if we can show that there's an interesting signal with an ALK TKI in this patient population that has, say, pancreatic or colorectal or some other tumor type, then you can maybe drive more sequencing, more testing, and more use of TKIs in the future. So, we had an exploratory cohort to look at that, and we're gonna present that as well.
You wanna talk about where, how we're gonna do this?
Yeah, in terms of the disclosure plan, so our plan is to take a similar approach as we did for the top-line announcement for ROS1, for the pivotal data for NVL-655. So, you know, preference is a medical meeting, but with pivotal data, it can be difficult to time that with the abstract submission deadlines. So it will be top-line press release, and then we'll follow that with the full data at a future medical meeting. And then the ALK, you know, solid tumor data that Jim mentioned will be presented at ESMO.
In terms of the ALK-positive other solid tumors beyond non-small cell lung cancer, any preliminary estimate as to the unmet need and the number of patients you could address, perhaps proportionate to that lung cancer setting?
Yeah, it's what's a challenge here, Josh, is there's not a lot of literature because, you know, the physicians are less likely to do large studies in those patient populations to sequence for ALK. There's certainly some reports out there that are based on small n, right? So it can be quite variable what those incidence numbers-
So you're gonna answer the question for us.
Yeah. I mean, we're gonna try to show data that hopefully drives more physician interest, right?
Now, what I can point to is that other strategies that caught our attention. You know, the Loxo Lilly drug, selpercatinib, the RET inhibitor, they did an interesting experiment. They got approved for RET lung cancer. They got approved for RET thyroid cancer. But they also had a tumor-agnostic cohort, where they had about 40 patients, and the FDA gave them a tumor-agnostic label for the RET-driven cancers.
How are you even finding patients for this study? Do you have to go out and screen for ALK, and in doing so, answer the question, or are they already identified somehow otherwise?
You know, it's building relationships with physicians, it's building relationships with the ALK-positive advocacy committees. We did publish some data that showed that the drug is broadly active against ALK mutations, and we'll continue to keep on doing that. And this experiment we're presenting at ESMO maybe helps even drive more physician interest to enroll that study.
Now, given how robust Alecensa is in the first-line ALK setting, as you go into the ALKAZAR trial, maybe frame that program and when you might start to be able to see separation of that.
Yeah. You know, most phase III studies are some sort of leap of faith, right? And for drug developers, it's good to build up conviction in those studies before you embark on such a long, expensive study. In this case, we have a lot of precedents and a lot of things we can learn from the literature. Four other randomized studies have been run in the ALK front-line space, right? And they each chose crizotinib as a standard of care. So you can actually compare the alectinib data and the lorlatinib data and pretty easily convince yourself that lorlatinib would beat alectinib in a randomized phase III. So we don't have to take that big a leap of faith. We can just say lorlatinib would beat alectinib. We think our drug is at least as active, if not more active, than lorlatinib.
We have a lot of conviction that this experiment should work. It's a pretty cookie-cutter experiment. It's four hundred and fifty patients, not small, four hundred and fifty patients, randomized one to one, PFS as an endpoint. Here's the standard of care. We think our drug is better. Let's go, go show that, right? The reason our drug should be better: we can cover the mutations, alectinib cannot. Alectinib's still a good drug, couple of years of PFS, but what if you can do much better by not letting those patients progress with ALK mutations? That could be a game changer for those patients and quite a compelling commercial opportunity.
When might you expect a first interim look at data to occur?
So there's three things that influence data availability: the enrollment rate, the event rate, and the actual stats plan. The enrollment, we expect it will go well. You know, the phase II was one of the fastest-enrolling oncology trials we're aware of. So there's a lot of interest in our program. But I don't think that's gonna be gating. It's really, like, the event, how fast the events happen, right? And alectinib - well, we hope on the alectinib arm, right?
Yeah.
And if that's a two-year PFS, you know, it only can go so fast. So we put out a, on clinicaltrials.gov, a primary completion date of late 2029. That's an estimate. We haven't talked about the stats plan, we haven't talked about whether the trial includes an interim analysis or not. I will tell you that, in this space, some of the other drugs did include an interim analysis, so we can learn from that. Like, what was received well and not by the FDA, and we designed our study accordingly.
There is kind of this shift occurring with maybe alectinib now moving into the adjuvant setting, lorlatinib not approved in that setting. As we're trying to frame the market here, then combined now, they're like close to $1 billion in the U.S.
Yeah.
B ut hard to kind of figure out how much is adjuvant first line. So as you kind of enter the market, initially in the second line and beyond, and then move into the first line, like, how are you thinking about the dynamics there?
Yeah. So it's our perception that the overwhelming majority of alectinib sales come from the advanced metastatic setting, not from the adjuvant setting. Now, I'll tell you why. I mentioned before that most of these patients are younger when they're diagnosed. They don't expect to have lung cancer. It comes out of nowhere, right? And often the physicians don't catch it until it's stage IV. Like, there's no reason to go check a thirty-year-old patient that they might have an aggressive lung cancer diagnosis. Like, why? Why, right? So, unfortunately, in many cases, it's so progressed, it's already spread, and alectinib already is the standard of care for that patient population. So there are, you know, a small percentage of lung cancer patients out there, let's call it maybe 20% or less, that they do fortunately catch it earlier.
In that setting, surgery is the option, and up until recently, it was surgery and watch and wait, or surgery, and now alectinib is an option. Those patients, they might get alectinib, but that represents a new patient population. I don't necessarily think that impacts the overall market that alectinib has today.
Maybe in the last minute, not enough time to cover everything, but I do wanna talk about NVL-330 and what the strategy is there. What's the liability you see in other HER2 TKIs that maybe, you may be able to address?
Sure. Real quickly, HER2 space is one that is well-trodden. You know, multiple decades of small molecules, ADCs, antibodies. You know, within HER2 lung cancer, the driver is a little bit different than the drugs for, you know, HER2 breast cancer or HER2 colorectal cancer. It's Exon 20 insertions, and those other drugs don't work particularly well there because you need a wide index for hitting exon 20 compared to wild-type eGFR. We solved that with NVL-330. In addition, you need excellent brain penetrance, and NVL-330 solves for that as well. So we're excited about that trial. We could also expand beyond lung cancer and go into other tumor types. So we're really excited about where this program can go.
All right. Well, we just scratched the surface, and but I think did a great job kind of framing the unmet need and how Nuvalent is really bringing value to a lot of patients. So, Jim and Alex, thanks so much for joining. Thanks, everyone.
Thanks, Josh.
Thank you.