Welcome back to the 45th Annual TD Cowen Healthcare Conference. I'm Mark Frahm from the TD Cowen Biotech team. Next session, we're really happy to have with us the team from Nuvalent. We've got Jim Porter, the CEO, as well as Alex Balcom, the CFO, from the team. And I have a whole list of questions I'll go through, but also anybody in the audience, feel free to raise your hand, and we'll try to get your questions answered as well, if you have any. But maybe to start off with, Jim, you want to kind of just high-level takeaways that you did have in earnings release the other day? Just the kind of status update on the company, and then we'll dive into some specific questions.
Sure, sure. First of all, thanks, Mark, for the opportunity, and thanks to TD Cowen for the invitation to participate in the conference. It's a thrill to be here in our hometown talking to folks about bringing new medicines forward. So yeah, we're making a lot of progress in the company. This year, we have a number of forthcoming catalysts, including for both of our parallel lead programs, ROS1. We are expecting pivotal data from our previously treated ROS1 cohorts. We're expecting that in the first half of this year, our first NDA submission by the middle of this year, and we're expecting pivotal data readouts for our ALK program later on this year, and that's for previously treated ALK patients. We're also about to initiate our frontline ALKAZAR study. It's a randomized study versus alectinib for TKI-naïve ALK non-small cell lung cancer patients.
We have a third program in development, our HER2 program, and we keep advancing that through phase 1 development as well. A lot of exciting momentum at the company, all positioning us to have our first approved product by next year.
Okay, with that, maybe we'll start with ALK. So you have phase 2 expansion cohorts. Just let us know your thoughts on which ones, which of those various cohorts are going to kind of support that and potentially support the initial label.
Sure. Yeah, let me just orient to the landscape. So the standard of care today for ALK non-small cell lung cancer patients, most patients receive alectinib as a frontline therapy. When they progress on alectinib, the only thing that works for those patients is a drug called lorlatinib. And when they progress on lorlatinib, nothing works. So our drug was designed to work for any ALK non-small cell lung cancer patient. So starting in third line, where they progressed on sequential alectinib, lorlatinib treatment, our drug was designed to work in that patient population because it covers a broad range of ALK mutations. It's highly brain penetrant, and we have breakthrough therapy designation in that patient population.
In second line, where lorlatinib is the standard of care, we designed a drug we think can drive deeper and more durable responses than lorlatinib because it has better coverage of ALK mutations, and it's importantly selective for ALK versus TRK, which is dose limiting for lorlatinib. Therefore, we can keep patients on therapy and drive more durable responses. So we're expecting data from both of those cohorts, both second line and third line ALK non-small cell lung cancer later on this year.
And then you'd anticipate that you'd be seeking approval for, I guess, alectinib-experienced ALK-positive lung cancer.
Our strategy is to bring both those second and third line cohorts to discuss with regulators around a broader previously treated ALK non-small cell lung cancer indication.
Okay, and then do you need all that data? Like, how mature of data do you think you need to have that discussion? Because there's always an evolving with phase one, right? More patients coming in, more follow-up, more duration. What type of data set do you think you need?
Yeah, so we've been very fortunate to have excellent collaboration from the physicians that work with us on the ALKOVE-1 program. You might have seen that earlier this year, we announced by December, we had actually enrolled around 600 patients in the trial altogether, 460 patients in the phase 2 alone, and that was in the first 10 months of the study. It's a really remarkable execution by the team. I think it speaks to the momentum that we have on the program. It speaks to the excitement the physicians have for this differentiated target product profile. Also, it starts to paint a pretty compelling commercial opportunity if you think about where that need exists and how NVL-655 can address that. So how this often works is you want to follow a certain amount of patients for a defined period, meaning are you driving responses in these patients?
Are you shrinking tumors and for how long is what regulators often want to look at, so we will at some point cut the data, meaning we'll have enough patients that we've followed for X amount of months and showed how durable those responses are, and then bring that package forward to the regulators to discuss with them as a registration-enabling data set.
When you've given the guidance of having data from these cohorts by the end of the year, will you have, at the time that you release some of that data, will you have already had that conversation with the FDA, or that's a '26 event after you've shown us the data?
You can imagine that with all of our programs, you're always having an ongoing dialogue with the FDA. And so once we start clinical development on our programs, either ROS1 or ALK, we have an ongoing dialogue with the regulators. And we also are greatly aided in the fact that both of our lead programs have breakthrough designation with the FDA. That affords even more opportunities to engage with regulators to have a back-and-forth dialogue. The best way to think about it, there is no defined formula for how to do this, right? So it's always going to be based on what the medical needs are, how the regulators view those needs, the data you've generated for your programs, then how it addresses that need. That's going to inform that back-and-forth dialogue, and that will guide a Nuvalent approach as well.
Maybe you want to talk through how you view the market size in this TKI experienced ALK space, and how does that differ if you get the label that you're seeking versus if, unfortunately, the FDA says, well, lorlatinib does work in these patients? It's a fully approved drug. We only want you going in third line.
Yeah, so the ALK market is quite interesting to us. First and foremost, we want to drive more durable responses for patients. We want to make an impact for patients, but we also are building a business, and having a commercial opportunity that exists in the ALK space is quite intriguing for us. Today, ALK is a $2.5 billion market. It's dominated by alectinib, which is the frontline standard of care. In the previously treated setting, we believe lorlatinib in 2023 had about $500 million in sales, and most of that was coming for previously treated ALK non-small cell lung cancer. We also recognize that lorlatinib is a limited drug in that patient population. We know it has roughly a 31%-39% response rate and a seven-month duration response. We don't believe that's good enough.
We think there's an opportunity to drive deeper, more durable responses with NVL-655 because we have broader coverage of ALK mutations. We can keep patients on therapy longer, and hopefully, driving more durable responses, we can not only start to capture that previously treated ALK market, we can grow that market because the drugs are limited in that patient population. So it's difficult to put a number on how big it can be, but our goal is to increase that market by driving more durable responses.
Okay, and I know you said there's no set formula, but back to the seven months that you just mentioned for lorlatinib and second line, when you look across lung cancer or maybe broader in oncology, where are some precedents of how far you need to be from that to justify that broad label as an initial approval where you won't have a comparative study?
Yeah, well, just to put it in perspective, our own data, look at ALKOVE-1, the phase one data we presented back at ESMO. We had a very advanced, difficult-to-treat patient population, and the median duration response was more than double that seven months. It was 14.4 months. And if you looked at patients at the recommended phase two dose, in fact, only a single patient had progressed. So that kind of durability is different. It's really interesting. And we would hope to do something like that as we keep pushing forward in our phase two. If we can show deep, durable responses in patients that have progressed on lorlatinib or are lorlatinib-naïve, we think we could use that to guide our discussions with the regulators.
Okay, and previously you mentioned over, I think, 600 patients have enrolled across cohorts. Obviously, we did have that updated ESMO, which had a variety of different types of patients. Should we think of, I know you haven't disclosed exactly how many in each cohort, but should we think of that 600 patient population as kind of roughly a similar type of mix as what we saw at ESMO, or is it skewing because of the definitions of some of these cohorts?
So our phase two actually has a number of interesting things that we're looking at. It has the second and third line cohorts that I had mentioned earlier. So the post-alectinib or the post-lorlatinib patients. It also has a solid tumor cohort. So ALK is a driver in other indications beyond lung cancer. So we have an exploratory cohort there. We also have a TKI-naïve cohort. So the rationale there was to be able to generate some data to understand how the drug is performing in that patient population while our frontline study that is randomized is ongoing. So the 600 patients was from all of those cohorts combined, and they've all enrolled quite well.
Okay. You started to touch on that first line, the ALKAZAR trial. You walked through the design there, and I guess is it just activating? Are there still contracts to be signed, or what's rate limiting to actually dosing that first patient right now at this point?
Yeah, so sites are open. So we're open for enrollment, and we expect to start the trial imminently. So the study, the ALKAZAR study, is a randomized study comparing our drug, NVL-655, to the standard of care alectinib. It's randomized one-to-one, 450 patients. The primary endpoint is progression-free survival by blinded independent central review, standard secondary endpoints. This is not a reinvention of the wheel. This is a tried-and-true space in ALK non-small cell lung cancer. There are actually four frontline ALK, TKI- naive non-small cell lung cancer studies that have already been executed in this space. So we're learning from those drugs. It gives us a lot of confidence that we have the right strategy in place, and we've learned from those trials and designed our study accordingly. Ours is going against a different standard of care, alectinib, than the previous ones, which was crizotinib.
But based on the data that's available from those other drugs, it gives us a lot of confidence in our trial design as well as our probability of success.
How should we think about enrollment timelines? I know you don't have enough data internally yet on exactly how enrollment's going, but when you look at, say, those other four trials, just how long should we think about this trial needing to actually complete enrollment?
Yep, so those other trials were about 300 patients. They all took about two and a half years from start of enrollment to the line extension approval. So our trial is larger, slightly larger, and slightly longer because we're going against a different standard of care. The things that will influence data availability, which I imagine is what you're getting at, is when will we see data from ALKAZAR? There's threefold. One is enrollment rate. Second is event rate that hopefully in the amount of the events that are occurring on the alectinib arm. And then third is the statistical analysis plan from the study. We think enrollment will go well, as evidenced by what we've seen on the other trials, our ARROS-1 and ALKOVE-1, broad participation from the patient advocacy groups and the physicians that we collaborate with.
The thing that's likely to be gating though is event rate, not enrollment rate. And we can learn from the data that's available from alectinib as a median progression-free survival of 25.7 months, and that is used to help guide where we predict events might happen on the ALKAZAR study. And the third thing around the stats plan, we don't get into the details there. We kept those discussions between us and the regulators of how we design the study. We often get asked, will the study include an interim analysis? Without getting into the details, the way we generally think about it is we learn from the other drugs that have been studied in this space, and some of the other precedent studies do in fact include interim analysis. So we can learn from that and design our study accordingly.
On clinicaltrials.gov, you'll notice that we have an estimated primary completion date of October 2029. That's just a line in the sand. It's just an estimate. But those three things, enrollment rate, event rate, and stats plan, help us come up with that estimate, and we'll obviously push forward to try to get that data.
Okay. I think what we hear from some investors on the enrollment piece is a sense that many of us have that there is maybe not complete broad adoption of lorlatinib in the first line, but there is some level of growing enthusiasm to use it in the frontline setting among clinicians and a fear that that might then impact your ability to enroll this trial since lorlatinib is not the comparator arm. Just your thoughts on that?
Yeah, no doubt that physicians have interesting options to choose from for ALK non-small cell lung cancer patients, and we've talked to them. We've talked to global physicians. This is a trial that we've been planning for years, and we definitely believe we have the right design. It's based on feedback from physicians across the globe that treat ALK non-small cell lung cancer patients. Although some will point to lorlatinib as the more active drug, those same physicians will point out that lorlatinib is challenged by the neurotoxicity signals that are observed with that particular therapy, and therefore some will actually not use it for frontline patients, and today, the majority of global physicians will go to alectinib as the standard of care, so that helped influence our decision considerably. That is the preferred standard of care globally.
Will some of the folks, particularly at the major academic centers, increasingly go to lorlatinib? Of course, yeah. They want to give the most active drug. They have experience managing some of those safety signals, so they're willing to try that for their patients and see if they can manage through that. But they also give us that feedback that they recognize that the majority of physicians will not go to lorlatinib. They have less experience managing the neurotoxicity signals, and they guide us that the trial design we have is indeed the right one. So we think it'll enroll well, as evidenced by the enrollment we've seen in our other studies, and we think we have the right plan in place to do so.
And then obviously the primary endpoint of ALKAZAR is PFS. But when we think about the potential value of the interim, obviously it can get you a label earlier, but it also may impact the ability to actually look at OS. Do you think there's significant value in letting this trial run to potentially be the first ALK agent to show a survival benefit?
Yeah, and it's interesting that none of the approved ALK therapies have actually shown an OS benefit in their ALK non-small cell lung cancer studies. So in each incidence, sorry, each study, the data were premature at the time of the data readout to understand if there was a safety advantage. So the FDA cited that in each of those approvals. Listen, our goal is to get the drug to as many patients as fast as possible. So if there is a way to generate a data cut on the ALKAZAR study to get the drug approved faster, that's what we're going to be interested in because we think it's a way to get the drug to more patients. We'll certainly have the opportunity to continue to follow patients and understand what the performance of the drugs are over time, even after that data readout.
Okay. And we've mostly been talking about kind of approval strategy all in relation to the FDA. What's the latest on outside of the U.S.? What are your thoughts? Can these expansion cohorts support that? Do you need to wait all the way to ALKAZAR data?
Yeah, so all of our studies are global studies, both ALKOVE-1 and ARROS-1, and similarly, ALKAZAR is a global study as well, and so we have a strategy there, and we'll engage with regulators as the studies progress.
And then the other topic that comes up with investors on ALK is just the idea, and this is broadly about targeted therapies as adjuvant. How much interest do you have in that, and when's the appropriate time, to the extent you want to pursue it, when's the appropriate time to kind of start those trials?
Yeah, so.
Or maybe just less advanced settings and broadly, not just adjuvant.
Sure, sure. Yeah, NVL-655, we believe, is a best-in-class ALK non-small cell lung cancer TKI. We want to take it to as many ALK patients as possible. That includes in the adjuvant setting. Just to orient folks, what Mark's referring to here is that so the majority of ALK non-small cell lung cancer patients, somewhere in the neighborhood of 75, 70% of patients are diagnosed in the stage IV and the advanced metastatic setting, right? So, for a small percentage of patients, they're diagnosed in the stage 1B to stage 3A setting, and the typical course of treatment for those patients is often surgery or resection, and then either watch and wait with those patients or treat with chemotherapy.
And the last year or so, alectinib-generated data and got an approval showing that they outperformed chemotherapy in that setting, and that's great for patients in that setting and have a new option. Is NVL-655 an option for that? We think it could be. It's not a current strategy for NVL-655. Right now, our focus is on the previously treated advanced metastatic setting as well as the TKI-naïve advanced metastatic setting. But as we generate more data, including the TKI-naïve cohort we have in our phase 2, perhaps we can use that to guide future decision-making about where to take this further for ALK non-small cell lung cancer patients.
Okay. Maybe we'll turn to ROS1 now. Maybe just at a high level, market sizing. I think we often hear from investors skepticism of the market size in ROS1, particularly because of some of the launches that have happened more recently. Just your latest thought on market opportunity, and what do you think investors are missing when they make that analysis?
Yeah, so we hear some of that skepticism from time to time as well, but I think more and more are appreciating the opportunity that Nuvalent sees in the ROS1 market. So just to orient folks, the standard of care is crizotinib. Other drugs have been approved in this space to address the limitations of crizotinib. Crizotinib, patients can progress with ROS1 mutations, and it's not highly brain penetrant, so they can progress with CNS disease. So other drugs try to solve for one or more of those things, but they've often hit off-targets, and those off-targets lead to dose-limiting toxicities, and that has been a challenge for physicians to adopt those other therapies because it's difficult to keep those patients on the therapy to manage those toxicities. So, the guidance to us was to try to design a drug for ROS1 patients. That's never been done.
No drug has ever been designed specifically for ROS1 patients until zidesamtinib. So, to hit the fusions, to hit the ROS1 resistance mutations, to be active in the brain to treat patients with brain mets, and to avoid those off-targets that are dose-limiting. And zidesamtinib does indeed have that profile, both preclinically and with our clinical data. So, the market today, crizotinib is about $400 million in sales. We think that that is mostly coming from ROS1 non-small cell lung cancer, as there are much better drugs in the ALK space where crizotinib was originally approved. Crizotinib, we think we can improve upon that by driving more durable responses.
And just to put it in perspective, crizotinib used to be the standard of care in ALK non-small cell lung cancer, and other drugs have shown they're much better at driving more durable responses in ALK non-small cell lung cancer, like lorlatinib. And the reason lorlatinib is much better than crizotinib in ALK are the same reasons zidesamtinib is much better than crizotinib in ROS1, because coverage of mutations and CNS disease. And so, if we can drive much more durable responses in that ROS1 space, we're not talking about capturing a $400 million market. We're talking about potentially growing that market. We often hear, well, the other drugs that have been approved in the space have had poor launches. So, doesn't that deter you? Absolutely not.
The physicians told us all along that these drugs, although they're likely to get approved, they don't solve for those needs, and they're unlikely to use them once they get approved. And so, drugs like entrectinib and repotrectinib, which have not had stellar launches, the physicians have sort of guided that that's likely to be the case. But you can see with the enrollment momentum we have in ARROS-1, we enrolled 430 ROS1 patients. I think that shocked a lot of people that, one, there were that many patients out there and that they all went on the trial. And so, I think it speaks to the interest that the physicians have in this differentiated profile. And if that carries through once zidesamtinib is approved, you can imagine bringing more patients into the pool and driving deep durable responses, growing that market.
So some of those newer agents that haven't launched, the greatest, but their initial and only approvals are broad across lines, kind of irrespective of TKI experience. And that's not the filing strategy that you guys disclosed earlier this year. Can you explain that difference? Why is your initial application going to be for TKI experience rather than all-comers ALK?
Yeah.
Or sorry, ROS1.
Yeah, sure, sure. So, we're on track, we believe, to have our first approved product by early next year, and the ALK program is right behind it too. If we get these two drugs approved, it'll be some of the fastest that's ever been done in biotech, period, from starting a company from scratch to getting two new drugs approved. So, we're pretty excited about that. We saw in the ROS1 space a lot of momentum on that program. We had started the program, the phase two, in September of 2023, and we are expecting pivotal data readouts imminently for that program. Often the way regulators will look at this is, and particularly in the ROS1 space, those other drugs, they followed the patients for 12 months, right? Those TKI naive patients.
Did they shrink the tumors and then follow them for 12 months to understand the durability of response? We're employing a similar strategy for our TKI naive patients, and we hope to have that data soon for those TKI naive patients. But already we had the data for previously treated patients. You don't need to follow those patients for as long as 12 months. With the enrollment momentum we had in the program, we were enrolling 30-something patients a month, and it's actually expensive to keep doing that. So, we said, okay, here's an opportunity. We can actually cut the data on the previously treated patients, engage with the regulators now, because we believe zidesamtinib is addressing a medical need there. We have breakthrough designation there.
We could potentially get the approval first in previously treated patients while that TKI-naïve data continues to mature and then bring that data to the regulators to talk about a line extension strategy. So, we did not want to wait for the TKI-naïve data. I've always been taught in my career as a drug developer, get the drug approved as fast as possible. That's the basic principles of drug development, and this is the path to do so.
I think when you look broadly across targeted therapies, generally in those refractory settings, they need about six months of follow-up versus that 12 plus that you were just referring to first line. One, is that a fair assessment of the landscape? And then that would imply that you would actually have the 12 plus month follow-up on the first line patients' kind of maybe shortly after you've actually filed and during the review cycle. Is there an opportunity to kind of adjust the indication statement you're seeking during the review, or do you need to wait then for the NDA to hopefully get approved and then file an SNDA?
Yeah, sure. So, I totally appreciate the question. Just a matter of general practices at Nuvalent, we don't comment on the regulatory interactions we've had and the dialogue, but your assessment of the precedent is correct that previously treated patients often followed for about six months and TKI-naïve for about 12. So that is a precise assessment of how we view the landscape as well. But I think the best way to think about it is previously treated data is going to be available soon, TKI-naïve data soon thereafter.
Okay, and the disclosure strategy around those kind of two different cuts as we get them?
Yeah, so our preference in the past has been presenting at medical meetings, but for top-line data, it can be difficult to time that with abstract submission deadlines, and so we are planning for a press release for our top-line data, and then we'll follow up with the full data set at a future medical meeting.
And all of that is within this half and then for ROS1 and within 25 for ALK, or is it just the press releases that your're kind of referring to with that guidance?
Sure, yeah, so we've guided top-line data for ROS1 previously treated patients first half of this year and ALK by the End of the year.
Okay. But so medical meetings are maybe within that, but may also be beyond the.
Yeah, we'll provide more specifics there in the future.
Okay. In the last few minutes, maybe turn to the HER2 program. There is an agent ahead of you that has breakthrough designation, seems headed towards approval in the not-too-distant future. What is the unmet need beyond that agent, and how does 330 fits into that?
Sure, sure. I think most are quite familiar with HER2 as a target. A lot of drug development in HER2 cancers over the last two decades. HER2 lung cancer is a little bit different than a lot of those other HER2 cancers. The major driver is something called exon 20 insertions, and other HER2 drugs have been repurposed for HER2 lung cancer with poor outcomes. So poor response rates, poor durability. And the reason is they don't have a wide index for inhibiting exon 20 versus off-target called wild-type EGFR, which leads to skin toxicities, GI toxicities. And if you have a wider index, you can hit the target harder, you can drive more durable responses, and the drug you're referring to is from Boehringer, zongertinib. It can do that.
It actually has that wide index, and you've seen good response rates and good durability from the early data from zongertinib. And that wasn't a surprise to us. So, we pride ourselves on doing chemistry at Nuvalent, and we make all the molecules. We have a really good understanding of which ones look good preclinically, and which ones do not, and how they might perform in future clinical experiments. And we had predicted zongertinib would look good because it had that wide index. However, in our preclinical experiments, we also understood that drug not to have good brain penetrance in preclinical assays. And that is a limitation in lung cancer development. I think you can look through the history of oncogene lung cancer drug development, EGFR, ROS1, ALK.
Earlier generations that don't have good brain penetrance, they often get supplanted by drugs that do, because unfortunately, lung cancer patients are prone to get CNS disease. So NVL-330 solves for not only the wide index for HER2 exon 20 versus wild-type, but also good brain penetrance. So, it clearly represents a differentiated profile, and we'll continue to learn from the drugs ahead of us, but we like the position that we're moving forward with.
Given the design of the trial, how quickly do you think you'll be able to show that those preclinical differences are playing out in differentiated clinical outcomes?
It's an experiment, so I don't want to predict. We were able to show that relatively quickly with both ROS1 and ALK, which were similar experiments that we were running, but every experiment is unique, and we'll see. Don't know.
Okay. Unfortunately, that's all the time we have, so we're going to have to cut it off there. But thanks a lot, Jim and Alex, for joining, as well as everyone in the room and on the webcast.
Thanks, Mark.