All right, thanks everyone for joining TD Cowen's Oncology Summit here ahead of ASCO and to some extent EHA as well. The next session up, we're really happy to have with us the team from Nuvalent, Jim Porter, CEO, as well as Alex Balcom, CFO. I have a whole set of questions that I've come up with before, and I'll go through with Jim and Alex, but we do want this to be as interactive as possible. For the investors on the line, any of you have questions that you'd like asked, you can either submit them through the portal or you can email me directly at mark.fram@tdsecurities.com, and then I will layer those questions into the discussion as well.
Maybe, Jim, just because it's most immediately topical, we'll start with ROS1 since you are about to, in the near future, release some data, but we, of course, will get to ALK as well. Maybe just with the ROS1 data update that's expected shortly, can you or Alex just kind of walk through what that disclosure plan looks like in terms of what data will be released, which Phase II cohorts, any data from that first line cohort, updates to the phase one cohort that we should also be expecting kind of alongside it?
Yeah, first of all, thanks so much, Marc, and the TD Cowen team for the opportunity to participate. I always appreciate the engagement. You know, we do have an exciting readout soon. Maybe, Alex, you can speak to the disclosure plans and I can talk about what will be included there.
Sure, yeah. So yeah, we're excited to share the top line pivotal data for TKI pretreated ROS1 patients in the first half of this year. Our preference has always been to share data at a medical meeting, but it can be difficult to time the top line data announcements with timelines for abstract submission deadlines. And so, you know, as such, we're planning to share our top line data in a standalone press release, and we'll seek to share the full data at a future medical meeting.
As far as what's included, you know, in this ROS1 space, Mark, something we've talked about in the past, there are other approved therapies. It starts with crizotinib as a standard of care. Its limitations are limited brain penetrance and the emergence of ROS1 mutations, and other drugs have been developed to try to address those needs, but they're helpful. In all cases, have been dual TRK ROS1 inhibitors. By inhibiting TRK in the brain, it brings in these cognitive or CNS adverse events that physicians have guided us to try to solve for.
If we can make a next generation ROS1 TKI that gets into the brain, be able to treat patients with ROS1 resistance mutations, but importantly, be selective for ROS1 versus TRK, then we can hit the target harder, drive deeper, more durable responses, and be an option for any ROS1 patient, regardless of line of treatment. That is the profile of Zidesamtinib. In the Phase II, we have registration directed cohorts for both TKI naive and previously treated ROS1 non-small cell lung cancer patients. Those cohorts have enrolled incredibly well. As of December of last year, we had reported that we enrolled 430 patients total, 330 in the Phase II. That is across TKI naive and previously treated patients.
We basically over-enrolled the study, and it's super rewarding for our team to recognize we're working on a program like this with such broad enthusiasm from the investigators and the patients that we're trying to serve here. With over-enrolling the study, we recognize, okay, we probably have enough to seek or to look at this data earlier. In the ROS1 space, it is the precedent that patients have been followed for about 12 months post response for the other ROS1 drugs that have been approved. Now, those in each case were from TKI naive patients. So we have the option to follow those TKI naive patients for about 12 months post response, or because there's a medical need in previously treated patients, cut that data first, right? Therefore, we understood that we did not need to follow those patients for as long as 12 months.
Cut that data first, clean that data, use that as our data that we can engage with regulators around seeking a previously treated ROS1 non-small cell lung cancer indication, and then follow it up soon thereafter with that TKI naive data. This first data set that's coming that Alex referred to would be for those previously treated ROS1 patients.
There is a couple of different kind of buckets of patients there in that previously treated moniker. Should we expect those to all be broken out separately or because this is top line and you are trying to preserve for a medical meeting that it will all kind of be lumped together? Just what is the structure going to look like?
Sure. Yeah, when the trial was incredibly inclusive, we had patients that as long as they had ROS1 lung cancer, they're eligible for the study. We want to make a drug that serves the needs of all ROS1 patients. We were very loose with the inclusion and exclusion criteria to basically include any ROS1 lung cancer patient. We're going to have patients with one prior, one prior with chemo, two prior, two plus prior. Similar to our phase one, we had a very expansive inclusion and exclusion criteria, and we still saw the drug was active in that difficult to treat advanced patient population. I would expect something similar for the Phase II.
We'll have data from all different ranges of patients that have received a number of approved or experimental therapies, potentially chemotherapy, patients that have very advanced disease, patients that have disease in the brain, patients that have ROS1 resistance mutations. We will be looking at all those variables. To your specific question, we recognize the interest in trying to tell this story at a medical meeting in the future, but we also understand the importance of sharing what we've learned from the phase two study. We will aim to tell a complete story around all the variables.
I think you can basically look at our Phase I data updates that we did at the triple meeting a couple of years ago or even ESMO last year of how we share the story of what we're learning from the Zidesamtinib clinical study. Is the drug active beyond all the other therapies? Is it active in the brain? Is it active against the ROS1 resistance mutations? How durable are those responses? Most importantly, what is that safety profile, right? That is going to be key for addressing the needs that the other drugs have yet to address. That is, being able to keep patients on therapy with a well-tolerated drug that can drive deep and durable responses.
Okay. I mean, you mentioned the prior approvals in the space have all been kind of broad, any line of treatment, but some of those did include at least some data in TKI experienced patients. Just what are the, in your mind, the key variables that investors should be considering when they try to make, with all the caveats that are necessary on it, trying to make cross-trial comparisons to those data sets when you have your patient population?
Sure. There are several key areas of the target product profile that we think are important: activity against mutations, activity in the brain, the safety profile, right? Those are the key things that we hear are limiting from either the approved or the other drugs in development from key investigators in this space. I think how we shared the data in our phase one helped tell the story that Zidesamtinib is the first and only drug that solves for each one of those needs, right? I think the feedback we received after our phase one data presentation is that this looks differentiated from the standpoint of being active beyond all the other therapies, being active in the brain, having activity against ROS1 resistance mutations, but importantly, having a well-tolerated safety profile so patients can stay on therapy.
Now, how our Phase II data will be judged, I would say it would be in the context of our Phase I, right? I think we set the benchmark for ourselves in phase one. That data were incredibly well received regarding Zidesamtinib in the phase one. Phase two, we're enrolling more of those patients. We're also going to use other more stringent variables that are more typical for Phase II studies, such as looking at blinded independent central review as opposed to investigator assess, which is more common for a Phase I study. I think that the phase one data really is the benchmark of how the phase two data will be viewed.
Okay. You mentioned one of the kind of key differences between the Phase I data updates previously and this is that it is moving to blinded central review. Just how should we think about how that impacts kind of a baseline expectation of response rate? Like should we expect pretty much the same, 5%, 10%? Just where do you?
It's difficult to tell. It's no doubt a more stringent criteria, but it's difficult to tell how that plays out. I don't want to diminish the expertise from our phase one investigators in any way as far as their ability to assess responses in the phase one. It's an experiment, and until you run the experiment, you don't know how it's going to turn out.
Okay. And then in terms of that subsequent medical conference, should we be thinking, obviously there are some prominent lung cancer or more general oncology conferences in the second half, is that a reasonable expectation for what you'd be targeting? Or is there just so much going on to get the filing in that the medical conference probably should wait a little bit longer?
We haven't provided guidance on which medical conference just yet, but yeah, as you mentioned, Marc, a handful of options in the second half of the year. We'll look to provide updates on that in the future.
In terms of the filing, obviously you need to produce this data cut that we're going to see a release shortly. What else needs to be done to finalize the submission?
This program has gone incredibly fast-paced. Actually, both of our lead programs, our ROS1 and AMPA, just to remind you, the company did not exist seven years ago. We have done everything from scratch where we built the company, did all the discovery work, identified the compounds, ran the clinical studies, and are on the doorstep of getting multiple drugs approved. It is an incredibly exciting time for the company. We planned for this. We planned that the trials would go really fast, and let us be ready to get the drugs to patients as fast as possible. All the work that goes into a new drug application, it is beyond just the clinical data, the non-clinical characterization, both pharmacology as well as safety, the manufacturing, and all the quality sections of the NDA.
We've had the opportunity to be working on those for a while to be prepared that once the clinical data comes, we could incorporate that into our NDA submission and proceed accordingly. I feel like we're in great shape for that next phase, which is to work with the regulators to get the drug approved as fast as possible, just getting that top line data first.
Okay. You mentioned the unmet need, particularly in this second line plus setting for ROS1. I mean, given that, should we expect the priority review is very likely, or how are you approaching that question?
I mean, our goal is to get the drugs approved as fast as possible, and we don't want to presume how the regulators will view it. I would say that Nuvalent is up to the task to use whatever regulatory levers potentially are able to, that are options for us to get the drugs approved as fast as possible. I don't want to speculate at this point what kind of review process it will be.
Okay. I think in terms of, you mentioned that difference in follow-up, targeted therapies often in these later line settings, we've kind of needed six plus, maybe a little bit more than six months of follow-up for responders. That front line historically has had more like 12. Given that kind of six month delta, it seems like you'll have first line, you should likely have first line data in hand, certainly within the review period, if not kind of as the filings actually being submitted. Is that the right way to think about it?
We haven't guided to when that data is coming. I can just tell you that that cohort is enrolled incredibly well, and we're going to do whatever we can to get the broader line ROS1 non-small cell lung cancer indication. I don't want to speculate of what the timing will that be, just because we haven't given clarity on that. We'll get through the top line for previously treated first and then look to update folks once we have more insights on the TKI naive.
Is there a mechanism by which a filing that starts as a second line plus? It starts out seeking a second line plus indication, can be modified with a mid-cycle update of data or something like that.
We're getting deep into the theoretics here. I'm sure there's lots of different options that one can consider. What you have our word for is that we'll exhaust any and all options to get the drug to patients as fast as possible.
Okay. I guess, again, on the first line strategy, right now, I think you have breakthrough designation in the later line. Is there value there in seeking first line breakthrough designation, or do you really have enough interactions already as it is that it really would not help very much?
Yeah. The breakthrough designation is often viewed, or not often, it is viewed as you're addressing a medical need that is not being met by other agents, and you have data in that setting. The breakthrough designation we have in later lines is reflective of the data we had in hand. Remember, in our Phase I, we only enrolled difficult to treat patient populations. These were very challenging patients where the other drugs were failing the patients, and our drug was active. That's why we received breakthrough. That breakthrough enables you to have more ongoing dialogue with regulators to get the drug approved as fast as possible. As the data from TKI naive patients emerges, we will use that to guide what strategies we should take with regulators to get the drug approved.
I do not want to guide one way or another, whether that's an option or a lever we're going to pull or not, really will be data-driven and based on the engagements we have with regulators. Already, I think we have good dialogue back and forth with regulators, and we will look to continue that across all of our programs.
Okay. Maybe from a commercial perspective, I mean, we often hear from investors that many are somewhat dismissive of the market opportunity in ROS1 lung cancer. Just what do you think they're missing? Maybe can you provide some ballpark of how big do you think this opportunity can be?
Yeah. We've had lots of these conversations over the years. And quite frankly, I feel like more and more are grasping the interesting opportunity ahead of us. We've never wavered at Nuvalent. We want to address patient needs. We know there are patient needs here, and we firmly believe that if you address patient needs, that you're creating an interesting commercial opportunity around it. So never wavered at all. This is how we view it. Crizotinib does roughly about $400 million in sales. We believe most of that is coming from the ROS1 space. But we also recognize Crizotinib is a limited drug in this patient population. It used to be the standard of care in ALK-positive non-small cell lung cancer. And clearly, other drugs have come along and shown they're much better than Crizotinib. Four different drugs have outperformed Crizotinib in randomized studies.
One of the more recent ones is Lorlatinib, which had a hazard ratio of 0.19. Five plus years progression-free survival compared to less than 12 months for Crizotinib. Now, the limitations Crizotinib has in ALK are the same limitations it has in ROS1, meaning the emergence of ROS1 resistance mutations and the emergence of CNS disease. Those are things that Zidesamtinib solves for in ROS1 lung cancer. We believe there's an opportunity here to really change the ROS1 treatment paradigm by driving deep and durable responses, more durable than what you can do with Crizotinib that has these limitations, especially with a drug that's designed to be well tolerated, to be selective for ROS1 so patients can stay on this therapy for extended periods of time. Zidesamtinib is the only ROS1 drug that has that profile.
I think what helps color sort of the, or sorry, I guess, obscure the challenges in the ROS1 space is that some of the other drugs in this space have been sort of someone at my door. I'm going to ignore. The other drugs in the ROS1 space have had somewhat challenging launches. Maybe that's due to what we heard from physicians, that these are not well tolerated. They are difficult to keep these drugs on for extended periods of time due to these off-target toxicities that are not associated with ROS1 inhibition.
Given that differentiation, and if you need to answer, Alex can answer at this point probably. Just should investors look at those most recent launches of Bitrepo and maybe shortly TeleTrectinib and the pricing that those companies have gone with as good proxies for how you would approach pricing? Or given that differentiation, should we think of Zidesamtinib as warranting a significant premium to some of those other options?
Yeah. I think it's a little too early to comment on pricing at this stage. Our focus is on generating the pivotal data. As you know, there are precedents out there, and that's certainly something that we'll take into consideration as we think about pricing for Zidesamtinib. More to come in the future.
Okay. Jim, you started to touch on the ALK space, which is probably a good segue to that as well. Maybe can you frame up the kind of the approach to the regulatory question there of what you need to show in the different lines, maybe using some of what we just talked about in ROS1, and how it differs for first line versus second line where Lorlatinib is an option for patients today, and then obviously to third line or greater where there really is nothing approved?
Sure, of course. Yeah, there's actually a lot of synergies and similarities between the ROS1 and ALK space, and we have a program for each. And so there's a lot of learnings we can bring from one to the other. In the ALK space, there's actually six approved therapies. So it immediately, first impression, it looks crowded, and how do you navigate that? But we learn from the physicians that they really think about it in two buckets. There is a front line therapy, which more often than not is Alectinib. That is the front line standard of care. And the only drug that works beyond Alectinib really is Lorlatinib. And the reason it works, it has some coverage of ALK mutations that patients develop on Alectinib, and it has excellent CNS activity. So it can treat patients that have progressed with CNS disease on Alectinib.
Now, when patients progress on Lorlatinib in that third line setting, none of the drugs work in that setting. Those patients often develop either ALK compound mutations or they have inefficient coverage of the ALK single mutations that Lorlatinib could not address. That was the immediate need we're trying to solve with Neladalkib is make a drug that can work in that third line setting that's active against these ALK mutations, both single and compound mutations, that's active in the CNS and can treat these patients that have exhausted the available options. Now, with each of the programs, we're looking not just to address that need, but how do we design a drug for any ALK non-small cell lung cancer patient? We look at those other therapies, and most physicians would tell you Lorlatinib's the more active drug than Alectinib.
It doesn't get a lot of front line uptake. The reason it does, even though it's more active, is because it's got these neurotoxicities that I mentioned on the ROS1 program. This drug, Lorlatinib, also inhibits TRK. It also drives these off-target adverse events that physicians have found to be dose limiting for their patients. With that understood, that became a key part of our target product profile. Could we do the things that Lorlatinib can do, meaning cover the mutations, have excellent brain penetrance, but do not inhibit TRK, have that large selectivity index? If we did that, we would have a better second line drug than Lorlatinib and potentially a better front line drug than Alectinib. That's been the goal. Neladalkib does have that profile, both preclinically and clinically.
In our Phase I, we saw patients that have exhausted available options, and they're still responding to Neladalkib. In many cases, we're driving deep, durable responses in those patients, which is really exciting because it tells you that these tumors are still highly ALK dependent. If you have a drug that broadly covers ALK and ALK resistance mutations, then you have the opportunity, no matter which line of therapy, to drive deep, durable responses in these patients with that compound. Neladalkib, that is the opportunity ahead of us. In our Phase II, we have a second line cohort. These are patients that most likely have taken Alectinib. We also have a third line cohort where they've taken multiple TKIs, but most likely Alectinib and Lorlatinib. In general, just like our Phase I, we would enroll any ALK lung cancer patient.
Regardless of how many lines of therapy they got, they would be eligible for our Phase II study. That is the strategy. In that third line setting, as I mentioned, nothing really works. There is no real benchmark. That is where we have breakthrough designation. We are able to show in our phase one that we were seeing roughly a little over a third of the patients were responding. Those responses were durable at the recommended Phase II dose. We only saw a single responder that had disease progression. It is really a really stunning result when you think about how advanced that patient population is. In that setting, we would say, okay, that Phase I is probably the bar of what we would expect to see, hope to see in our Phase II.
In the second line setting, where Lorlatinib is the standard of care, Lorlatinib delivers about a 31%-39% response rate in that setting. It has approximately a seven month duration of response in that setting. That is really what we're hoping to show is that we can drive much more durable responses than Lorlatinib can in that second line setting. That is what we saw in the phase one. We had a handful of patients that were Lorlatinib naive, and we saw good response rates and very durable responses. We also appreciate and acknowledge it was a small sample set. Within that phase one, we had many patients that have already progressed through Lorlatinib, and the durability looked very favorable in that setting. If that translates to phase two, I think that would be very encouraging for that second line cohort.
Ultimately, to get the front line, we view it as a randomized approach. That is going to be our Alcazar study comparing Neladalkib to the standard of care Alectinib, which we are on track to start soon.
Again, for that third line plus setting, like we talked about earlier for the late line ROS1, I think people's assumption is you need kind of six, maybe a little bit just over six months of follow-up to kind of show the responses are durable enough to get the FDA there. You mentioned that benchmark of kind of seven months DOR for Lorlatinib that you want to try to separate from in second line. Does that imply that we should also think about a filing strategy in ALK that is kind of staged by line like you're doing in ROS1, or is there something different about ALK?
That's not our base plan. Our base plan is that we would have both second and third line data later this year. I understand and appreciate the context of the question, but I think the seven-month duration of response is not a, it's not too high of a benchmark that it takes years and years to show differentiation. That makes sense.
Okay. And then maybe we do get a lot of questions about that first line because the efficacy data is so impressive for Lorlatinib, granted all the safety stuff you reviewed. The uptake certainly has not been robust, but we do hear over time a few more docs every so often saying they're starting to use it. Given that background, and then recently there was the Columbia adcom a week or so ago where the FDA did criticize Roche for having run a trial with a standard of care that had evolved to no longer be super relevant to the U.S. Just maybe can you kind of speak to how should we think about the ALK space evolving and why is there not a risk here that maybe Lorlatinib needs to be included as at least part of the comparator arm?
Alectinib has a two plus year progression-free survival. It is a phenomenal drug. It has been the standard of care for years and still is today. No doubt, Lorlatinib could be a better option for some patients and some physicians. They will turn to that, and they will try to manage through those safety challenges. That is clear that is not a good option for everyone. If you go just through the CROWN data, you can just see how many patients are no longer on therapy at two years. It is a significant number. If Lorlatinib had already run a randomized study and showed it was better than Alectinib, it is a different discussion. It is a different discussion because it would be pretty clear that Alectinib is no longer the standard of care and the drug has outperformed it in a randomized setting. That is not the case.
Today, most physicians, the majority, are prescribing Alectinib. Some have certainly switched to Lorlatinib, and we've done robust engagement with global investigators. We think we have the right study design. I think just the interest in Lorlatinib in the front line, it further helps support our strategy that we're on the right track here, that physicians would like to see a more active drug than Alectinib, especially if the drug is well tolerated, which we hope Neladalkib is that drug, the drug that can drive the deep and durable responses without seeing those corresponding safety challenges that come with off-target TKI inhibition.
Okay. Maybe in the last second here, there's also a third program in the clinic that we do not often talk about for HER2 exon 20. This is based while there are not approved drugs from a TKI perspective, there are TKIs that have some pretty interesting and compelling data ahead of you, including most recently BI showing some CNS activity as well. What is the unmet need that those molecules are still leaving on the table that you could address with NVL-330? Kind of what's the status of that program and when might investors start seeing data?
Yeah. Let me just explain the strategy, and then Alex can talk about the status. The HER2 lung cancer space is evolving. Everyone knows HER2 as a target. It's been a couple of decades' worth of research across tumor types. The driver in HER2 lung cancer is a little bit different. It's called HER2 exon 20. Some of those other HER2 drugs were repurposed for HER2 lung cancer with poor outcomes. The reason being, they do not have a wide index for inhibiting exon 20 compared to wild-type EGFR, which causes known toxicities, skin toxicities, GI toxicities. It's difficult for the patients to stay on therapy and drive deep, durable responses. That was the clear need: can you solve for that wide index? Because it's lung cancer, that's a disease that most commonly is going to metastasize to the brain.
We need to find a drug that is also highly brain penetrant. You can see the examples in EGFR, ALK, and ROS1, where that narrative has played out over the years. The first earlier generation drugs, less brain penetrant. You make better brain penetrant drugs. They outperform the earlier generation drugs. In this HER2 space, one of the drugs you highlighted, Zidesamtinib, has had some really exciting data. It's active in that space. Quite frankly, we had predicted it would be active. It has a wide index in all of our preclinical assays for inhibiting HER2 exon 20 versus wild-type. Therefore, you can drive those deep, durable responses because you're keeping patients on therapy at therapeutically relevant concentrations. In our preclinical assays, it is not highly brain penetrant.
When we compare that directly to NVL-330, which was excellent brain penetrant, and we know that could be a liability for patients with lung cancer. There have been some reports of some signals for CNS activity, but I think that you can also look to some reports from Crizotinib or lorlatinib, where those drugs also have some early signs of CNS activity, but you can clearly see what you can do better with a more highly brain penetrant drug when second- and third-generation drugs were made in that space. We feel like we're on the right track here. We're excited about HER2. Alex, do you want to share where we're at?
Yeah. In terms of the status, we're currently enrolling in the dose escalation. We haven't provided guidance on when we present data just yet, but as always, we'll follow the progress, make a data-driven decision on when to present data, and look forward to sharing updates in the future.
Also just add that this is a.
Unfortunately, that's all the time. Yep. Yep. Okay. No, no. Go Jim.
HER2 lung cancer is the first step for us. This is also a broadly interesting HER2 drug. You can imagine other development opportunities with 330 as well.
Okay. Unfortunately, we are out of time, actually over time. We are going to have to cut it off there. Thank you, Alex and Jim, for joining, as well as all the investigators on the line.
Thanks, Marc.
Thanks so much.