All right. Good afternoon, everyone. I'm Andy Berens, Senior Biotech Analyst at Leerink Partners. Thank you for joining us at our second conference in Miami. We're joined today by Nuvalent, CEO James (Jim) Porter, and Alexandra, CFO. Thank you for spending time with us. For the next 30 minutes, we're going to focus on Nuvalent and what's going on in this room and try to ignore everything outside of this room and talk about your company. Anyway, for those that are not familiar with Nuvalent, can you just give a brief overview of what you guys are doing?
Sure. First of all, Andy, thanks to you and the Leerink team for the opportunity to participate in the conference. It's great to be here in Miami talking with the greater community. We're really excited about what we're building at Nuvalent. Our focus is to create precisely targeted therapies for patients with cancer. At the foundation of the company is a deep expertise in chemistry and structure-based drug design. We focus on clinically proven kinase targets. There are over 90 approved kinase inhibitors, 70 of them for patients with cancer. It's a well-validated biology. You can accelerate the discovery phase and the development phase by running small focus studies to understand if your drugs work as intended.
We partnered since the beginning of the company with physicians that have developed the earlier generation kinase inhibitors, learned from them, learned from the experts that understand the space, they understand the needs of patients and what we're solving for through innovative chemistry. They often pointed us to certain resistance mutations beyond the original therapies where the needs exist for patients. They will often point to off-targets of concern. If we can make more selective inhibitors, we can keep the patients on therapy longer, drive deeper, more durable responses. That is how you get the best-in-class therapies that can move up the treatment paradigm. We made some progress building the company. Maybe Alex can share the highlights there.
Yeah. At the beginning of last year, we had announced our On- Target 2026 plan, which guides our path to first potential approval in 2026. Earlier this year, we laid out milestones. We are planning for pivotal data from previously treated ROS1 patients from the ARROS-1 study in the first half of this year. We are planning to submit an NDA for previously treated ROS1 patients mid-year. We are also planning to present pivotal data from our ALK program from the ALKOVE-1 study for previously treated patients by year-end. We are on track to initiate the phase three ALKAZAR study in the first half of this year and continuing to progress our phase one HEROEX-1 study for HER2 as well. We were able to bring in funding last year. We are well capitalized to continue to drive these programs forward.
Great. Thanks for that overview. Just remind everyone, this is an open forum. If you have questions, just let me know. I have some questions of my own, and we'll jump into those. Let me know if anyone has any questions. Obviously, we're fans of what you guys are doing. I think you're going after established markets, but there are established markets that have incumbents that have Achilles tendons that you guys have addressed and can exploit. Why don't we talk a little bit about, let's start with the ALK market, what drugs are important there, and where do you see the holes in the existing therapies that you guys have been able to leverage to introduce your drugs?
Sure. You're absolutely right. There's greater than 15 years of clinical research in the ALK space. There's actually six approved therapies. The immediate question might be, do you really need a seventh? Our answer was guided by the physicians, like, absolutely. They would like to see new options for patients. They helped us understand how to think about it. Of those approved therapies, the patients in front line often get the standard of care Alectinib. When they progressed on Alectinib, there's only one of those drugs that will work in those patients, and that is Lorlatinib. When patients progress on Lorlatinib, none of the approved therapies work in that setting. Those patients often have what's called ALK compound mutations. That means two mutations in the kinase domain of the ALK oncogene.
We designed our drug to work in any line of therapy, starting with that third line setting where nothing else works. We've shown deep and durable responses in that setting. Physicians will often point to Lorlatinib being the more active drug compared to Alectinib. However, it has stayed as the second line therapy, and Alectinib is the front line. The reason being, Lorlatinib hits a specific off-target called TRK. The inhibition of TRK in the brain leads to neurotoxicity signals. They had guided like, if you could solve for that, if we could do what Lorlatinib can do, meaning cover ALK resistance mutations, have good brain penetrance, but avoid that off-target of concern, then we in essence would have a better second line drug than Lorlatinib and in turn a better front line drug than Alectinib. That was the strategy.
NVL-655 both preclinically and clinically has that profile. We are showing activity beyond all the other therapies, even beyond Lorlatinib where nothing else works. We have a median duration response of 14.4 months across all dose levels. In fact, at recommended phase two dose levels, we see very little progression, only a single patient that progressed in our phase one. It is quite encouraging. We also have some encouraging data in second line treatment. As Alex mentioned, we are about to kick off our front line ALK trial to compare to Alectinib.
Okay. Lorlatinib had some important data for the ALK space, five-year data from the CROWN trial. Maybe we could talk a little bit about the pluses and minuses. What did they show there? Has there been any benefit, or have they started to gain market share in the front line setting since they have presented those data?
Yeah. We have worked very closely with the physicians that executed the CROWN trial. We're the leading investigators on the Lorlatinib program. What they would often share with us is, like I said before, this is the more active drug compared to Alectinib. The challenge with Lorlatinib is that off-target toxicity. Those same physicians, they have more experience investigating Lorlatinib in clinical studies, and they would be prone to using it or try to manage through those toxicities for those patients. They'd also be the first to tell you that they appreciate that the broader community is unlikely to do so, that the neurotoxicity signals are challenging to manage. They would say that they're likely to see Alectinib remain the standard of care. That has largely been the case.
There's been some slight shift in the uptake of Lorlatinib in front line, but Alectinib today still remains the standard of care. We saw that as an opportunity. If we could solve for that, meaning we have the profile that has broad coverage of ALK mutations, both single mutations and compound mutations, we have comparable brain penetrance to Lorlatinib, and we are not seeing those off-target TRK CNS signals. We have a potential to drive just as durable responses as Lorlatinib, maybe even better, without those corresponding safety issues. It sets us up really well to push this program forward to both second line and front line patients.
What did they show in terms of durability? Did they have a lot of, I know they had a fair amount of patients dropped out in the first two years that were censored out of the data analysis. Did they have dose reductions and discontinuations that could impact the efficacy that they saw?
Yeah, you're right, Andy. The five-year PFS number was about 60%. Greater than five years median PFS, which is remarkable. That's a remarkable outcome. As you point out, I think it was around 38% of the patients are no longer on therapy at the two-year mark. It's clearly not a great drug for all ALK patients. That's an opportunity. If we have a drug that's better tolerated and can keep patients on therapy, this is an opportunity to potentially drive those deep durable responses like Lorlatinib can do without those safety issues for a broader amount of patients. The data we've generated thus far were showing that durability even beyond Lorlatinib. It really speaks to why ALK, and this is the same for our ROS1 program as well, they're very interesting oncology targets. The tumors are incredibly dependent on ALK and ROS1 signaling.
Even a drug like Alectinib, which works very well in the front line setting, a two-year median PFS, you're still seeing about half the patients progress on Alectinib with ALK mutations. That tells you the tumor is incredibly dependent on that original fusion driver. If you have broad coverage of ALK mutations, which Nuvalent does, this is an opportunity to drive deep and durable responses for those patients.
Right. Just to clarify, that's in contrast to like in the EGFR where you might activate an alternate pathway for resistance. This is actually an aberration in the ALK pathway. If you can still drug that pathway, the tumor should respond.
That's absolutely correct. Osimertinib is a phenomenal front line drug for EGFR non-small cell lung cancer patients. The PFS is about a year and a half for front line osimertinib. You do not see a lot of on-target acquired resistance to osimertinib in front line. Usually, it is these bypass pathways that are popping up. That tells you, at least we infer from that, the tumors are less dependent on EGFR signaling as compared to an ALK or ROS1 tumor. It is an attractive target, EGFR, but maybe not as attractive as ALK or ROS1.
Right. One other thing that struck me when I started to look at this space in detail was the ALK patients are very unique, even relative to EGFR patients. And even in the EGFR setting, one of the benefits for Tagrisso has been the high quality of life. Patients are pretty motivated. They like an oral agent. It's kind of been the reason, I think, that Amivantamab hasn't done so well, even with data that suggests that there could be some benefit, at least on PFS in the front line setting. But ALK patients are even younger and more motivated, and they're going to have their disease a lot longer. I think it would suggest to me that the quality of life is really important to those patients. They're all probably working and very active.
Absolutely. I've had the real good fortune over our time at Nuvalent to build relationships with the patient advocacy groups in both the ALK and ROS1 setting. What strikes me is, as you said, these are folks that are often in the prime of their life, diagnosed when they're relatively younger, late 30s, 40s, 50 years old. They have a lot of life ahead of them. The ALK and ROS1 drugs have done great things for them. Alectinib has a two-year median PFS. That's remarkable for a lung cancer diagnosis to have at least median patients going out two years. If you think about what I just said, if you're in your 40s, two years is not enough. It's clearly not enough. This is why this is such an attractive opportunity for Nuvalent.
With broad coverage of ALK mutations with NVL-655 , we could potentially give extra years of progression-free survival for these patients. That would be a game changer for them and something we're really excited about doing. That also represents an interesting opportunity for building a business around because it represents a commercial opportunity where you're going to build up the prevalent patient population by treating patients for years and driving deep and durable responses. We're really excited about that program, first and foremost, to make an impact for those patients, and secondly, for building a business around it.
What type of mutations would you expect to see to 655 eventually? Have you guys gotten some insights into where is it going to be activation of alternate bypass mechanisms, or is it going to be point mutations? What do you think you'll see to 655?
This is the bread and butter of the company. We love digging through the available literature for lots of different targets, not just ALK and ROS1, and talking to the physicians and understanding where the puck is going. Where are the mutations likely to happen so we can start designing research programs for that? That is how we came up with both our ALK and ROS1 program. We would like to do that for our current ALK and ROS1 program, but quite frankly, we have not seen a lot of disease progression. That is a great thing. Our discovery scientists are at the ready if we understand where the emergent needs are beyond ALK and ROS1, we will try to solve for them. With so few patients progressing, there are actually no real trends we can draw.
We really don't know what the liabilities are today, which is pretty cool.
Yeah. One thing that also struck me, and to your question about do we need a seventh ALK inhibitor, is the enrollment rates of the trial have been superlative. What do you think has driven that? Do you think it's a fair proxy of what the commercial need is in the indication?
Yeah. I've been doing oncology drug development for 24 years, and I've never been a part of programs like this. It's super rewarding and humbling for the team to work on programs where you believe you're on the right track. We've enrolled 600 patients in our ALK trial. 460 were in the 10 months since we opened the phase two. I'm actually not aware of any oncology drug that's enrolled that fast in any oncology single arm phase two trial. To be involved in something like that, it makes the team feel like we're on the right track. We're doing something important that we're making impact. Obviously, it speaks to the investigator enthusiasm for the differentiated profile. It speaks for the broad collaboration we have with patient advocacy groups, which funnel patients to our studies. It starts to paint a compelling commercial opportunity.
If we're going to enroll that fast in a clinical trial, what will it look like on the market where this drug is available for all patients? That has been our emphasis over the last year, getting ready for the next phase of bringing these drugs to market. We've had similar types of momentum on the ROS1 space as far as enrollment. It's really, really exciting time for the company to be involved in things like that.
Okay. Why don't we talk about the update that we're going to see for the ALK program? You're going to have two big data releases. This is a pivotal program. In terms of what that's going to tell us, I mean, obviously, the trial is going to open the door potentially to second line plus setting. Even beyond that, what do you think we'll learn that can be extrapolated to the front line opportunity?
Yeah. In the phase one data we presented at ESMA last year, we are showing deep and durable responses even in that third line plus setting. That is where we have breakthrough designation. That is where there is a clear medical need. We are showing beyond Lorlatinib where nothing else works, duration of response that was not met. In fact, only a single patient had progressed, roughly about 40% response rate. Very encouraging data in that setting. We had some second line patients in the phase two. Not a lot. That was not the focus. We expected to enroll very advanced patients, and for the most part, we did. In those second line patients, mid-50s as far as response rate, and we actually only saw none of those patients progress at the recommended phase two dose. That is quite encouraging.
We know in the second line, Lorlatinib, although it works very well in front line, it is a more limited drug in the second line as a 31%-39% response rate and a seven-month duration response. We are seeing more than double than that beyond Lorlatinib. It sets us well off. We have always believed we can drive much more durable responses in that second line setting. In our ALKOVE-1 study, our phase two, we have both second line and third line registration cohorts. That would be Lorlatinib experienced patients in third line or Lorlatinib naive patients in second line. Those data will be available later on this year.
Okay. There'll be, I guess, a mutational profile done on that data set eventually. I don't know if it'll be in the initial data release, but you'll be able to tell which patients respond and which ones, I guess, don't respond in that trial.
Yeah. What we've tried to do in the phase one is tell a clear story of all the variables, whether it be the broader patient population, what were their prior therapies, did they have ALK resistance mutations, either single mutations or compound mutations, do they have disease in the brain, how does the drug compare against that whole target product profile. To your question, that we believe is important to paint the picture of why it would work even better in front line patients. If we can do all those things, it should work really well in front line patients and drive deep and durable responses because their patients are unlikely to progress with those on-target acquired resistance mutations or with disease in the brain if you can treat them in the later lines in that setting.
Right. Okay. What do we know about the, not to pick at the bucket that's half empty, but the ones that did not respond, do you have any insights into what caused those patients to be non-responders in your phase one, two?
There's a possibility in these late line patients that other mechanisms did come into play, that you do see some other mechanisms that have started to emerge beyond three, four, five, six lines of therapy. I would suspect that could be the potential reason. If the patient's disease is still driven by ALK, ALK fusions or ALK mutations, there's a good chance that our drug is designed to address that. If I were to guess, the other patients could have more complex disease going on in those later lines.
Could there be a combination approach eventually to address those patients?
Yeah. Having a well-tolerated drug is critical for the combination type strategy. We are not there yet. We are pushing forward on the monotherapy approach, but the safety profile is indeed indicative of a good combination partner should we want to explore other strategies for those types of late line patients.
Okay. One of the pushbacks I'm sure you've heard, I've heard is it's going to take forever to run a trial in the front line against Alectinib. The other pushback is, why aren't they going after Lorlatinib? I mean, I personally don't think Lorlatinib is the standard of care, and it probably won't be in the next five to ten years. What do you say to those views that this is going to take forever to even with the rapid enrollment? What do you say to that?
Sure. The Alcazar trial is something that we've known we wanted to do for years. We've been talking with investigators that have developed the other drugs and some that are even fans of Lorlatinib as a front line therapy. As I mentioned before, they would try to manage through the toxicities for their front line patients, but they also recognize the global community as a whole is probably not going to do that. That's why Alectinib today is still the standard of care. We've done our diligence and talked to global physicians. They're excited about the Alcazar trial. It's a potentially treatment paradigm changing study comparing Nuvalent to Alectinib, the standard of care, 450 patient study, randomized one-to-one, PFS as the endpoint. We expect the trial to enroll really well. Will some physicians prefer Lorlatinib in front line? Yeah, they will.
It's a more active drug. I think for this particular clinical study, this is the way to go.
You may want to talk about our plans of getting this ready.
Yeah. The team is working on getting sites activated at the moment, and we're on track to dose the first patient in the first half of this year.
Okay. I guess you haven't given official guidance, but do you think it's like a six or seven year program like some people worry about? This might be the next decade before you see the data.
We are greatly aided by the fact that because I mentioned there's 15 years' worth of researchers, there's actually four randomized phase threes that have all been done in the front line ALK non-small cell lung cancer space. We are not really charting new territory here. We are learning from the other drugs that have come before us. That's an advantage in drug development. We could basically, as an example, go look at the available Lorlatinib data, go look at the available Alectinib data, and pretty reasonably convince ourselves that Lorlatinib versus Alectinib, if we want to design that study, we know what it would look like. It would probably look a lot like our Alcazar study, 450 patients comparing this drug to that drug, and we would think Lorlatinib would pretty easily win.
If we have a drug that's as active or more active than Lorlatinib without the safety issues, it's a great advantage for us to have that precedent to guide our clinical development strategy. It's somewhat of a de-risking literature available in this space that allowed us to come up with this design. There are three things that influence the trial execution and data availability. That would be enrollment rate, event rate in the stats plan. We expect enrollment to go well. Either way, we don't expect that to really be gating it. It's the event rate. By event rate, I mean how fast the progression events happen in either arm. We would hope the Alectinib arm, how fast those events happen, that's likely to be the gating item. In the stats plan, we don't necessarily share that externally.
We obviously align with the regulators on the stats plan. We often get asked the question, will an interim analysis be included? Based on we have to put a line to say on clintrals.gov, you can go look at our listing. We have a primary completion date estimated to be October of 2029. That does not mention the stats plan. That does not get into whether or not we have an interim analysis. I'll tell you in this space, other drugs often do include interim analysis. We clearly are learning from those who've come before us, and we designed our study accordingly. I think the trial's going to go well. While that trial's executing, we have some exciting milestones ahead of us, the approval potentially of ROS1, the approval in the previously treated ALK setting.
We're going to start having those milestones upon us pretty soon and potentially start building those markets for both ROS1 and ALK patients while that front line trial is ongoing.
Okay. I think that we'll switch for the last five minutes to ROS1. One of the key differences between ALK and EGFR and all the other actionable mutations, I think, has been the presence of checkpoint therapy is a lot of times introduced by the physician before the actionable mutation is discovered or acted upon. Now, at least with ROS1, there's a recommendation to stop the checkpoint inhibition. Just wondering, do you think that's a big milestone difference that's going to change kind of how these patients are treated and eventually the commercial opportunity? Because it's been tough for the ROS1 agents have been pretty limited commercially.
Yeah. So actually, I actually don't. I think this today, it's more reflective of where the field is. We believe that across the academic and community centers, that based on the last two decades of development in the oncogene-driven lung cancer field, it's pretty standard if a patient has lung cancer to get sequenced. And if they have a driver like EGFR, ALK, ROS1, MET, they're going to go on a TKI, not checkpoint, not platinum-based chemo. The TKI is the way to go, even in the community setting. We don't think that was necessarily going to that changed the update of the NCCN was going to necessarily change treatment decisions. It's just more reflecting of where the field is. Now, with respect to the poor or maybe the less than stellar launches of the other drugs in this space, that's not a surprise to us.
In fact, we were told when we started this program that crizotinib is the standard of care. There's another group of drugs, the trectinibs, the entrectinib, the repotrectinib, the taletrectinib. They all hit TRK and ROS1. They all experience these CNS toxicities that we talked about before, Lorlatinib. One or more of them are designed to solve some of those issues with ROS1 patients, meaning brain penetrance or ROS1 mutations, but they all bring in the safety challenges. The physicians that we worked with told us entrectinib likely to get approved, but won't have a good launch. Same thing with repotrectinib, likely to get approved, won't have a good launch. We are not surprised at all that those drugs haven't had a good launch because the physicians don't like managing those toxicities. They have largely stuck with crizotinib as the standard of care.
Until now, there's this now we actually have the first and only ROS1 selective inhibitor that can do all those things because it can get into the brain to treat patients with brain mets, and crizotinib is not good at that. It has broad coverage of ROS1 mutations. That's what many patients are progressing on crizotinib with ROS1 mutations. And it's very selective for ROS1. It's not hitting those off targets. I would say the safety profile we've generated with zidesamtinib is one of, if not the best, I've seen for an oncology drug. It is an extremely well-tolerated drug. We can have the potential to keep patients on therapy, drive deep and durable responses. I would point to the enrollment we've seen in our ROS1 study.
We used to get asked, if Roche and BMS have trouble launching these drugs, are you going to really be able to find ROS1 patients? We always believed we would. We've enrolled 430 ROS1 patients, 330 in our phase two since opening it just a year and a half ago. It's gone really well. That puts us in a position to have data imminently for that program. I think that speaks to the differentiated profile. It speaks to the investigator enthusiasm. It paints the picture of the commercial opportunity. We believe the opportunity is there, and we're about to deliver that data.
The addressable market, you said it's predominantly Xalkori. Xalkori is also proven other indications like ALK, although it's not really that dominant there. The other two you mentioned too, if you had the right drug to treat these patients, how big a market do you think this actually is?
Yeah. I would point to the crizotinib sales of a little under $400 million as mostly being ROS1 because I mentioned before, there's five better ALK drugs than crizotinib. It doesn't really get used in that setting. It's $400 million, but it's limited in that setting. I mentioned before, in ALK, Lorlatinib has a five-plus year PFS compared to crizotinib's 12 months. The reason Lorlatinib's way that much better is the coverage of mutations and activity in the brain. Those same limitations exist for crizotinib at ROS1, and we solve for that. If we could do something similar there, you're talking about giving extra years of progression-free survival. How big does that get? It's bigger than $400 million. It's about how many extra years you get would dictate how much the market could grow.
Do you know the real-world experience on Crizotinib? How long are the ROS1 patients on Crizotinib in general?
I don't happen to have that number on my fingertips. I think the median duration response is about a year and a half for crizotinib. What the real-world treatment duration is, I don't have it in my fingertips.
Okay. Let me see if there's any questions from the audience before we wrap it up. All right. Thanks everyone for joining us. Thanks, Jim.
Thanks.
Appreciate it.
Thanks, Jim.
Continue doing what you guys are doing.
Thanks for the opportunity.