Good afternoon, everyone. Andy Berens, Senior Biotech Analyst here at Leerink Partners on day one of our Global Healthcare Conference. We're very happy to have with us today Nuvalent. We have Jim and Alex. Thank you for joining us.
Thanks, Andy. Thanks to Leerink for the opportunity to participate in the conference.
Great. Well, it's a beautiful location. I'm sure you guys are very happy to be out of the Northeast for a little bit and get some of the sun.
It's warmer, and we just got a chance to check out the pool. It's pretty sweet.
Yeah. Yes, yes, it is. I'm surprised you made it back. Well, for those that don't know Nuvalent, maybe you could give a little overview about the programs and the company.
Sure. We are a company that's founded in deep expertise in chemistry, structure-based drug design. We focus on validated biology, kinase inhibitors is a nice place to start because they can sort of de-risk both the discovery and the development phase by focusing on small, specific patient populations where you believe your drugs might work. For us to make an impact in this space, we partner with physicians to understand from their perspective, what are the limitations of the therapies that they've previously developed and what are the needs of the patients they treat, and we try to use innovative chemistry to solve for that. We made a lot of progress building the company, and maybe Alex can share some of the key milestones ahead.
Sure. Yeah. We have a really exciting year ahead. We've made a lot of progress on our OnT arget 2026 operating plan with line of sight to first potential approval. Earlier this year, we laid out our milestones. For ROS1, the FDA accepted our NDA for TKI- pretreated ROS1, and we are working towards our PDUFA date of September 18th, and our commercial launch readiness efforts are well underway to support potential launch later this year. We also plan to submit TKI-naive data to the FDA to support potential line expansion into that setting in the second half of the year. For our ALK program, we completed our pre-NDA meeting with the FDA, and we're on track to submit the NDA for previously treated ALK for our neladalkib program.
We are also continuing to enroll the phase III ALKAZAR study in TKI-naive ALK, and then beyond the two lead programs, we're continuing to progress the HEROEX-1 phase I-A/I-B study for HER2-altered non-small cell lung cancer, and then we've also guided towards sharing a new development candidate by year-end. Importantly, we're well-capitalized to support all these milestones and in a strong position to execute on our launches and continue to build out the pipeline.
Great. Well, before we launch into each of the two individual programs, just maybe, there's similarity obviously into the company's approach to both indications. Maybe you could talk a little bit about that.
Yeah. It's really around listening to the physicians. I'll start maybe with the ALK program. There's six other approved therapies, and the first obvious question might be, why do you really need a seventh? If you talk to the physicians, they'll help you understand that there's really just two lines of treatment options. Most patients in front line receive alectinib. It works reasonably well, but patients will progress without mutations, and the only drug that works in that setting is a drug called lorlatinib. It works because it has some moderate coverage of ALK mutations. When they progress on lorlatinib, nothing works. We want to make a solution for that 3rd line patient population where nothing works. We also just wanted to make a drug for any ALK patient in any line of therapy.
If you learn from the physicians that most would tell you lorlatinib is a more active drug than alectinib, but it hits a specific off target that's dose-limiting, causes a broad spectrum of neurotoxicities. That was a learning for us. If we could do that same thing that lorlatinib does, meaning hit ALK mutations without hitting off targets, we would have a better second line drug. We can drive more durable responses in that setting, in turn, a better frontline drug than alectinib. That sort of opens up the approach for a solution for all patients with ALK-driven cancers. ROS1 is the same idea. It's listening for the physicians, understanding where those needs are and using innovative chemistry to solve for it.
Okay. Yeah. No, I think, definitely, both of these are indications. I mean, I hate to call any cancer chronic, but in lung cancer, they're both patients who are gonna be on the drug for a very, very long time if they can tolerate it, and I think both programs have that ability.
Yeah. That was the goal, Andy. Like, it's to, you know, try to turn these life-threatening diseases into more chronic type conditions. The keys we heard from the physicians was design solutions that can broadly cover the on-target acquired resistance mutations, whether ALK or ROS1, have excellent brain penetrance because patients with lung cancer will get disease that spreads to the brain. You need to get into the brain to treat patients with brain mets or to prevent the disease from spreading to the brain, and importantly, be selective for ALK and ROS1 as opposed to off targets that are dose limiting. If you can do those three things, we believe that is the best formula to drive deep and durable responses across any line of treatment.
That's what we've seen in our pivotal data readouts is both zidesamtinib and neladalkib can do that even in heavily pretreated patients, and it really portends well to what it can do when you start looking at less heavily pretreated patients, you know, hopefully driving more durable responses and ideally leading to more chronic-like conditions for these patients.
Maybe we could start talking a little bit about the ROS1 program and zidesamtinib. What have you guys shown, and how does it compare to the drugs that are on the market? There was a recently approved drug that's in the midst of a early launch. How does your data set and drug compare to what's already out there?
Yeah. When we started this program, there was only actually one drug approved, there was crizotinib. What we heard from the physicians is that although that drug works reasonably well for ROS1 patients, they will progress with either ROS1 mutations or CNS disease. Other drugs were in development at that time that could target either one or both of those key areas, ROS1 mutations or CNS disease. What they all shared in common is they hit off targets that were dose-limiting. The physicians said, "They're likely to get approved. We don't think they're gonna get a lot of uptake because of that off-target toxicity." What they would really wanted to see was a drug that has the profile of broadly covering ROS1 mutations, having excellent CNS penetrance, and importantly, being selective for ROS1 versus off targets that are dose limiting.
In that setting, you should work beyond crizotinib, and also you should work better than crizotinib. What we generated in our ARROS-1 study, first and foremost, this trial enrolled like crazy because this is the first and only drug that was designed specifically for ROS1 patients that has this profile. The physicians were excited for this differentiated profile, and the patient communities we collaborate where they're excited as well. What we showed is that in previously treated patients that have exhausted the available options, the drug works, it's active, and the responses are durable. We're seeing activity in patients with ROS1 mutations. We see activity in patients that have already taken brain-penetrant drugs like entrectinib or lorlatinib or repotrectinib or taletrectinib. No other ROS1 drug has shown that. We see high intracranial activity.
We're the only drug, the only ROS1 drug that shows high intracranial CR rates. We see intracranial activity even beyond the brain-penetrant drugs. We start thinking about durability. The durability has been incredibly encouraging. In second-line patients that have already taken the standard of care crizotinib in frontline patients has about a year and a half duration of response. Those patients that have already progressed on crizotinib, we see 93% of the patients still in response at that year and a half landmark. That doesn't happen in oncology. Typically, the duration of response will get worse and worse in subsequent lines of therapy. For zidesamtinib, it's going the opposite direction. It's getting better, the duration of response. That really speaks to the thesis of the program.
If you could broadly cover those key markers of disease progression, then it's the best opportunity to drive durable responses. That's the data we submitted for previously treated. We have a TKI-naive cohort ongoing as well. We shared an early look of how that's going, and very encouraging. 89% response rate, 96% of the patients still in response at that one-year landmark. High intracranial activity, including 67% intracranial CR rates. Again, no other ROS1 drug has that, and it really portends well for zidesamtinib driving years of durability in frontline patients and really, you know, being a game changer for the patient population, as well as representing a pretty compelling commercial opportunity.
Yeah. We used to cover, and obviously follow the ROS1 space for a while. I think, you know, what always was interesting to me was even with some of these next-generation compounds on the market, is how Xalkori, crizotinib had like three-quarters of the frontline usage, which was really interesting 'cause it's, you know, it doesn't have a very durable response. These other drugs are supposed to be improvements. They never actually conquered the frontline setting, you know, for the reasons you've just mentioned. There's a new, a new drug, a new ROS1 agent by Nuvation Bio. You know, what have you learned about that drug since it launched? I guess it's their third quarter now at this point.
Yeah. You know, what we heard from the physicians about all the other next-generation ROS1 drugs is that they all hit off targets that are dose limiting. The safety challenges this newer drug has are different, bringing more safety issues even beyond dual TRK/ROS1 inhibition, the CNS toxicities seen with drugs like entrectinib and repotrectinib. What we know is that the community oncologists, the feedback was once they tried those dual TRK/ROS1 drugs, they realized the toxicities were too challenging for those patients, that they did not have strong launches. You know, many of these patients that get diagnosed are typically younger. They're, they're in their 30s or 40s or 50s.
They have jobs, they have families, and if they have to deal with these off-target toxicities, really a challenge for that patient community and a challenge for the physicians that are trying to manage that. We had predicted that any drug that brings in additional toxicities is unlikely to perform well and displace crizotinib, and it looks like that's sort of what's going on here.
Okay. You guys, in terms of the enrollment, we'll talk about both the trials, what was your enrollment? 'Cause I think that is an important surrogate commercial eventual commercial demand.
Totally. We had originally planned to enroll about 250 patients. We used to get asked all the time, "How will you find those patients?" This is a competitive space. Large pharmaceutical companies are competitors. They have the other drugs we talked about in their portfolios. We always believed what the physicians told us, that with the first and only drug with this profile, physicians will be highly motivated to study this drug and to try it for their patients. We enrolled 540 patients in no time. It's one of the faster enrolling oncology trials out there.
Just sort of so proud of the team of keeping up with that pace to quickly generate this data. That put us in a position to submit an NDA late last year. We have a, as Alex mentioned, a PDUFA for September of this year.
Okay. Just to clarify, I think, yeah, I don't, I don't remember how long the other trials took to run, but the FDA views this as a very orphan indication, which is why they're allowing single arm data and, right?
That's right, Andy. There are four other drugs approved here. They were all received full approval off just after single arm phase II data. The reviews cited, you know, based on the relative rarity of the patient population, that's why they enabled that single arm approach, so we're taking a very similar strategy here.
Okay. Then you'll supplement it with the naive patients. How many patients do you think you'll need to expand the label?
As of June of last year, we showed data on the first 35, but we had already enrolled 104. That was more than we thought we needed. It's just that, you know, the precedent was to follow naive patients for 12 months post-response. We just didn't have 12 months post-response back last June. We'll be in a position the second half of this year to submit that data.
Okay. Great. Well, congrats on all the progress in the ROS1. More important to you guys, obviously, 'cause it's a much larger opportunity, is the ALK space. You know, there's also some unique features of this patient population that I think are worth paying attention to. It tends to be a younger population. They're very educated 'cause they're not generally smokers and the cancer diagnosis is a surprise to them. They're very healthy and they're very active in their treatment when they're diagnosed. A lot of them are younger and working age. In terms of, well, let's talk about the enrollment there. Like, how quick did the enrollment go in the ALK space?
Yeah. Just like ROS1, roughly targeting about 250 patients, we enrolled 780 patients, all within about a year. It's the fastest enrolling oncology trial small molecule in the history of our industry. It's a, you know, a once in a career type opportunity for the Nuvalent team to be part of a program like this. Honestly, it's a privilege to work on a program like this. I'd like to say it's because of the execution of the team. That's not the case. It's really about the patients. You know, the patients have been massive fans of Nuvalent because we've been collaborating with them for years. As you mentioned, Andy, they are motivated.
They understand the landscape, they understand the new treatment options, and they understand the, you know, the positive outcomes that their friends in the community were seeing on neladalkib, and it really drove a massive over-enrollment of the study and put us in a great position to quickly generate data to be in a position to submit an NDA in the first half of this year. That's a... Again, like I said, it's a privilege to work on a program like that. It speaks to the medical need, it speaks to the patient and investigator enthusiasm, and it starts to paint a compelling commercial opportunity, right? If there are that many patients that are excited about this differentiated profile, it's clearly would, you know, portend well to a commercial launch in that patient population.
Okay. In terms of the current market dynamics in the ALK space, you know, you have alectinib, which had been the drug of choice in the front line. There was data from lorlatinib, which you mentioned, in the introductory comments. What's happening in the commercial dynamic now? I know Pfizer presented the five-year CROWN data. We can talk a little bit about that, the strengths and weaknesses maybe.
Yeah. Yeah. Like I said up front, like most physicians would tell you lorlatinib is a more active drug than alectinib because it can cover some of the ALK mutations.
The challenge with lorlatinib was not the activity, it was the off-target toxicity. Some physicians make the choice to not go with the better activity because of the challenges of managing the toxicity. As you mentioned, a younger patient population, a population that has a job, that has kids, has family, has milestones, and the cognitive challenges associated with this off-target toxicity can really impact that the way you live your life. Alectinib still is today's global standard of care, even though it looks like to be less active than lorlatinib, but it really speaks to why there's an opportunity here with neladalkib, right? Imagine having that kind of durability where you can drive years of progression-free survival without that off-target toxicity, right? We are doing the randomized study to show our drug is a better drug than alectinib.
Half the patients on alectinib will progress without mutations. We cover those ALK mutations. We see alectinib-like durability beyond alectinib. That doesn't happen in oncology, but it's happening with neladalkib. We see double the durability of lorlatinib beyond lorlatinib. That doesn't happen in oncology, but it happens with neladalkib. This speaks to something special about this program, that ALK signaling is very much dependent on ALK signaling. If you can broadly cover ALK mutations and you can keep patients on therapy, that is the formula we believe to drive deep and durable responses across all lines of treatment, and clearly could be a game changer for patients and represents a compelling commercial opportunity.
That was another feature of the ALK opportunity that I think I neglected to mention, is that it unlike EGFR, which tends to be addicted to that pathway for 18 months or so and then become resistant, the ALK tumors tend to stay addicted to that pathway a lot longer. You don't see activation of MET.
That's right.
... as much, right? It's, it's several times. Even though it's a smaller opportunity in EGFR, the durability could be two, three times as long.
Yeah, we have reason to believe that you could significantly grow the market. That's interesting 'cause today's market for ALK is already interesting, right? Also just start where the patients are at. Like Alectinib is a good drug. It drives a couple years of progression-free survival for, you know, a patient being diagnosed with ALK lung cancer and hearing that there's a pill that could keep you alive for two years, you know, that's great, right? For a 30 or 40 or 50-year-old to hear two years, that's clearly not good enough, right? What if you can add years to that? That could be a game changer for that patient population, and it represents an ability to grow what is today a $2+ billion market into something larger, right?
We actually think the ALK market could grow to like where EGFR is today. You know, a 5, 6, $7 billion-dollar market. Having the best drug in this space is clearly an attractive commercial opportunity as well.
Can we talk about the CROWN data a little bit? I guess without neladalkib, what do you think would have happened in the Western markets? Do you think that lorlatinib would eventually become the dominant drug or do you think there would still be a usage of alectinib?
I mean, it was approved seven years ago, it still isn't the dominant drug. They've never done a trial showing superiority to alectinib, right? What's the reason, right? Because there's challenges associated with that particular drug. We are doing the trial to show our drug is the best drug. We're comparing it to today's standard of care. Some of the academics are gonna try to give the best drug up front, the lorlatinib drug, the most active drug. What they typically do, what we hear from them, is they start at lower doses, right? They'll start at, instead of the approved dose of 100, they'll start at 75 or 50, try to manage the toxicity. I would argue there's not really data to support that that can drive the same kinda durability.
I get their point about less toxicity is better for the patient, wouldn't it be better to have a, you know, a new solution that has that kind of durability without that toxicity? That's our strategy with neladalkib program.
For the CROWN trial, I don't remember the numbers other than the headline, you know, the patients at five years, that the median was a five-year duration, right?
No, it was. Yeah, it was instead of about two to little over two years with alectinib, it looks like lorlatinib, you know, the PFS is trending above five years. Obviously, that's interesting. If you look at the specifics, you know, there are many patients that are no longer on therapy at two years, right? For the patients that can tolerate lorlatinib, you could have a potentially long durable responses. There are a large percentage of patients that can't do that, and therefore, it's not the solution for all ALK patients. Better it, I mean, it clearly supports our strategy, try to make a more tolerated version that could broadly cover ALK mutations and drive that kind of durability.
In your trial, you've shown a fair number of patients that had resistance to lorlatinib but were still sensitive to neladalkib. What was the response rate in those patients?
Yeah. In the broadest patient population, you know, we see over 30% of the patients still respond. What really stands out is the durability. For patients that have ALK-driven disease, they're progressing on lorlatinib. They have single mutations or compound mutations. Lorlatinib is not good enough at hitting that. We see a 17.6-month duration of response beyond lorlatinib. In second-line, lorlatinib has a six to nine month. We are doubling the durability of lorlatinib beyond lorlatinib. That, again, that doesn't happen in oncology. It would typically get lower and lower in subsequent lines. We are doubling it. It tells us everything we need to know of why, you know, this is a better solution for patients that have ALK-driven disease.
Okay. You're about to submit your NDA with the data in the second-line plus setting. What are the gating factors at this point?
Yeah. We're on track to submit the NDA in the first half. We completed our pre-NDA meeting, late last year, and so at this point, it's really dotting I's and crossing T's.
Okay. The label that other ALK agents have gotten, not the final label, 'cause a lot of them have started in the relapsed refractory setting and then expanded into the front line. What did that label look like in terms of patients that actually hadn't formally progressed, you know, on other agents?
Yeah. When those other drugs like alectinib, brigatinib were first approved, it was off a single-arm, phase II data in patients that had progressed or were intolerant to crizotinib. I think that's what was reflected in the initial label, accelerated approval in patients that had progressed or were intolerant to crizotinib. They ran the randomized study in front line versus crizotinib, showed that, you know, they were superior and eventually got a full approval for ALK-positive non-small cell lung cancer. Lorlatinib did a study where, you know, most of the patients, actually all the patients had taken crizotinib or second-gen ALK TKI. On some instances, just a second-gen ALK TKI. In some instances, both crizotinib and a second-gen ALK TKI.
Original label was for patients that had taken either crizotinib plus a second-gen TKI or a second-gen TKI. What our strategy is here is that, as you mentioned before, there's nothing that works in that third-line setting, post-alectinib and lorlatinib sequential treatment. Our drug was designed to work in that patient population. We showed it was active. We showed it was driving durable responses. We have breakthrough designation in that setting. That's a pretty straightforward strategy. We also believed our drug would work better than lorlatinib in second-line patients because we can cover those ALK mutations better, both single mutations and compound mutations. We talked about before driving the more durable responses in that setting. Our strategy is to take that second-line data as well as that third-line data, package it together, you know, engage with regulators around a broader previously treated ALK indication.
That's what we're in the process of doing.
Did you also enroll patients that were intolerant to the other drugs?
Yeah. If a patient had tried the other therapy, whether they progressed or intolerant, they were eligible for those cohorts.
Okay. If, if you have a label that provides for treatment of patients that actually have formally progressed or are intolerant, would that suggest, I mean, I guess it depends on your definition of frontline, but to me, you know, frontline is could be somebody that just couldn't tolerate another drug still. You, you might have the ability to get some frontline usage-
Yeah.
with the label.
I think a good way to think about it is say a patient starts on a therapy. If they're having a good experience, both patient and physician, meaning that the patient's tolerating it well and the patient's responding, you can imagine the physician doesn't wanna do anything different. They keep going with that therapy 'cause the patient's having a good outcome. If the patient is struggling with either one of the two things, either activity or tolerability, the physician and patient might be looking for something different, right? If they're struggling with activity, they're gonna look for something different. If they really struggle to manage the safety, they might look for something different. That means that patient is gonna come off that therapy and potentially be eligible for the next one.
In the program where you enrolled a lot of patients, I mean, I guess you haven't given us the background characteristics yet. Do you think that you got a fair number of patients that were intolerant?
I'm sure. I'm sure. 781, we got a fair amount of everything. Yeah.
Yeah. Okay. It is possible, even without having the frontline trial readout, that you could penetrate some degree of patients that can't take lorlatinib for dizziness. What percentage of patients do you think that start lorlatinib have dizziness?
Well, just to be clear, the side effects with off-target TRK inhibition are not limited to dizziness. It's a range of issues. It could be cognitive impairment, mood effects, speech effects, sleep disorders. Some patients can have severe hallucinations or seizures, suicidal ideation. The challenging thing is it's tough to predict where you're gonna end up in that spectrum. Are you gonna be too dizzy to drive or work, or are you gonna have hallucinations? That's what's really scary for the patients, that not knowing what's gonna happen to you on this particular therapy in addition to managing your cancer. The best thing, solution, we believe, is to avoid those types of off targets by avoiding that, you know, these CNS toxicities, and that's what we're seeing with the neladalkib profile.
Yeah. Maybe one last question, and I'll open it up to see if there's any questions in the audience. The commercial footprint, you know, what's the company. I mean, this is obviously a drug that, you know, should be available, both drugs, globally. You know, what's your thought process about partnering it or doing it yourself?
Yeah. You know, for these opportunities, we feel like it is doable to, you know, not only pursue the U.S. commercial launch, but build ex-U.S. ourselves as well. Over the past 18 months, you know, we've been educating ourselves on what that entails and thinking through, you know, the specific strategy. It's, you know, a significant opportunity, and we're excited about it, but maybe you wanna share how we think about it more.
Yeah, I mean.
...broadly.
Sure. Sure. These are known markets. Like, we don't have to educate the world on the value of a ROS1 or ALK lung cancer drug. There's been approved therapies for, you know, greater than 10 years, that's globally. Our trials have enrolled incredibly well across all geographies. In fact, some of the best enrolling oncology trials in the history of our industry. Having the best drugs for known markets is incredibly attractive from a commercial standpoint, not just in the U.S., in broad geographies. We think this is a great opportunity for us to build the next great global biotech company, that's the strategy. Particularly in the macro conditions where pricing is a challenge, you know, having that optionality is a really attractive thing.
Now, if a partner comes along and they can create more value than we can create alone, you know, obviously we have a fiduciary responsibility to listen to that. Meanwhile, we're gonna try to build the next great global biotech company. It's an incredible opportunity for Nuvalent.
That just reminded me of one other attribute that I forgot to mention about the opportunity is, you know, ALK and EGFR are similar in that you're not checkpoint inhibitors are not used in those patients, unlike a lot of other target therapies, including ROS1.
That's right.
...you tend to find, you know, that EGFR and ALK were, those drugs were discovered before checkpoint inhibitors were discovered, and doctors look for and treat it, so you're not having to go or complement checkpoint inhibitors, which is a very unique attribute.
That's right. you know, we can learn from the last 20 + years of drug development, you know, led by the EGFR work in the early 2000s, where they showed that, you know, if a patient has lung cancer and has an oncogene driver, they're better off getting a targeted therapy than a checkpoint inhibitor or the chemo immunotherapy. We can build upon that. Most patients with lung cancer today, they get sequenced, and they get a targeted therapy.
All right. Let me see if there's any questions from the audience before we wrap it up. All right. Well, thank you, Jim, Alex. Big year. Congrats on all the progress.
Thanks, Andy.
The anticipation, I'm sure, of being a commercial company.
It's exciting. It's a thrill and a privilege to work on these types of