Nuvalent for the next fireside. We've got Jim Porter, CEO, and Alex Balcom, CFO. Jim, thanks so much for joining us. Maybe just introduce Nuvalent and the ongoing regulatory process for both the ROS1 and ALK inhibitors.
Sure. First of all, thanks, Brad. Thanks to Guggenheim for the opportunity to participate in the healthcare conference. You know, it's a really exciting time for us building the company. At a very high level, let me make a few comments about who we are. At the core of our company, we have a deep expertise in chemistry, structure-based drug design. We focus on clinically validated targets, so validated biology kinase inhibitors. There's over 100 approved kinase inhibitors today, so you can accelerate both the discovery and development phase. And we partner with physicians to learn from their perspective, what are the limitations of those therapies? What are the needs of the patients they treat? And we try to solve for that with innovative chemistry.
So we've made a lot of progress building the company, and advancing our portfolio. Alex, do you wanna share what our guidances are?
Sure, yeah. So for ROS1, the FDA accepted our NDA for zidesamtinib in TKI-pretreated ROS1-positive non-small cell lung cancer. We have a PDUFA date of September 18, and the commercial readiness efforts are well underway to support potential US launch later this year. And then, we're planning to submit data to the FDA to support potential indication expansion for TKI-naive ROS1 in the second half of the year. For our ALK program, we completed a pre-NDA meeting with the FDA to discuss NVL-655 in TKI-pretreated ALK-positive non-small cell lung cancer, and we're on track to submit that NDA in the first half of the year.
And then, we're continuing to progress the phase 3 ALCAZAR study in TKI-naive ALK, and then beyond, you know, the regulatory progress on the lead programs, we're continuing to advance our HER2 exon 20 phase 1b/2 study in HER2-altered non-small cell lung cancer. And then, we've also guided to disclosure of a new development candidate by year-end.
Okay. Now, the PDUFA for ROS1 is in TKI-pretreated. I guess, can you help us understand the process of then getting a ROS1 line-agnostic filing and approval?
Yeah, sure. The precedent in the ROS1 space was to follow patients for 12 months post-response. We saw an opportunity in previously treated to cut that data earlier. We eventually aligned with the FDA on 6 months post-response. That was what the submission for late last year was. The frontline patients, the naive patients, as of June of last year, we had enrolled 104. That's well more than we needed. We just kept enrollment open to, based on the need. There's a lot of enthusiasm for the cohort, but we wanted to follow those patients for longer. So what we've guided to is that we will submit that data to the FDA in the second half of this year for the, you know, consideration of a line-agnostic extension.
Okay. Now, taletrectinib is starting to gain some momentum in the U.S., and I'd just like you to talk about the confidence in your ability with zidesamtinib to carve out market share and switches for that drug after physicians just went through the process of switching some patients to the taletrectinib molecule.
Yeah. So what we— you know, our approach in this program has always been guided to what physicians have been looking for. They're looking for a drug that could hit the original fusion, hit ROS1 mutations, get into the brain to treat patients with CNS disease, and importantly, be selective for ROS1, 'cause if so, it's a better chance to have a well-tolerated profile. Our drug, zidesamtinib, is the first and only drug that has this profile. No other drugs in this space do. And so we've enjoyed a lot of momentum on the program. Quite frankly, the trial enrolled like crazy, because the physicians were, and the patients we collaborated with, were very excited for this differentiated profile. I think it sets us up well, as we approach commercial stages with this particular program.
Our drug is driving durable responses across every line of treatment. It has excellent activity against patients with ROS1 mutations. It has deep, durable responses in patients with CNS disease. It has CNS activity beyond all the other agents, including other drugs that are CNS penetrant. No other drug has that. It has high CR rates in the CNS. No other ROS1 drug has that. So the differentiation that we've enjoyed through preclinical development as well as clinical development, we think there's an opportunity that carries in the commercial setting, and we're excited to, you know, get that to patients.
Okay. And then for ALK, you've generated single-arm data to negotiate with the FDA about a broad TKI-pretreated label, not just third line. So what pitch will you make to the FDA with that data to help secure that?
Yeah, so in the third-line setting, nothing else works. We have breakthrough designation. We are seeing durable responses. I think it's a pretty straightforward story. Your question, Brad, is around the second line, you know, where lorlatinib is the standard of care. Lorlatinib has a 7-9-month duration response in that setting. We are seeing double the durability of lorlatinib beyond lorlatinib. In patients that have yet to receive lorlatinib, we see, you know, 60+% of the patients still in response at 1.5 years. We are seeing alectinib-like durability in second-line patients. That doesn't happen in oncology. In oncology, durable responses, the durability of response gets worse and worse in subsequent lines of treatment. We're seeing it look better in subsequent lines of treatment compared to the previous agent, and that really speaks to the attributes of NVL-655.
The reason it does that, it has excellent activity against ALK mutations... has excellent CNS activity, and importantly, it's well-tolerated. The patients can stay on the therapy. The other drugs, particularly lorlatinib, they cannot do that, right? So I think there's a clear argument to be made of like, here's our second-line data, where lorlatinib is the standard of care. We're driving more durable responses. The drug is also active beyond lorlatinib, doubling the durability of lorlatinib beyond it. I think there's a pretty compelling argument to be made for a broader previously treated ALK indication, and that's what we're putting into our, our submission.
When will investors have a sense for how the FDA views this second-line situation? Is there an ability to know if they agree during the filing acceptance process, or is this something of a discussion that continues until an ultimate approval or label?
In FDA, decisions are always made, from our understanding, at the time of approval, right? So what is the landscape at the time of approval, and what data do you have to support that? Now, we may have some insights along the way of how that's progressing, what we will communicate along the way, to be determined, you know, but we, we understand the FDA precedent has typically been at the time of approval, make the decision. I think we have a great argument to be made, and, I think we're in great position to, you know, put that forward.
Okay. In frontline patients, where durability is maximally important, you've demonstrated the capability of the molecule on that end. You did show in the update last year, there was some LFT elevations. What was that rate in the treatment-naive patient group relative to what we see with alectinib or some of the other ALK TKIs? 'Cause we know it's on target, but what was the rate differential?
Mm-hmm. So the transaminase elevations are things that are signals that are very commonly observed in kinase inhibitors in general. It's observed in all the approved ALK TKIs. The signals are often transient, they're reversible, they happen early in treatment, they're typically low grade, they're asymptomatic, so the patient doesn't understand that they have this signal. It's more of a that there's a blood draw, and the physicians will understand that there's, you know, might be a spike in transaminases. Because they're transient, because they're reversible, because they're asymptomatic, they're generally managed through either a dose interruption or a reduction. That's how the physicians on our trial have been managing them, just like they do with other ALK inhibitors. We did not break down the data between naive patients and all patients. We just treated across all the patients.
This was our, our safety events, including transaminase signals. What I can tell you is that relatively small percentage of patients will ultimately discontinue due to a transaminase elevation. It was less than, a small single-digit, percentage-wise. Speaks to that the, the physicians are managing through it, and we can see with the enrollment and the durability we're getting, it's really not having an impact on, on our program.
In the announcement, you made a change to the Phase 3 protocol to control for some of this. What specifically was that? Just to make sure it doesn't impact the dose intensity and durability.
A couple more blood draws in the first couple of months. So, typically, there's the standard amount of blood draws that a physician will do when they're treating lung cancer patients. We ask them to do a couple more just to make sure that, you know, if they do see it, there's an opportunity to manage through it. The worst thing that could happen here is a physician might prematurely take a patient off due to a spike in liver enzymes, right? We hope that a patient on NVL-655 might take NVL-655 for many years and have excellent durability. It would be a real shame if in the first month or so, they prematurely take the patient off. So we said, "Okay, do a couple more draws.
If you see it, just hold the dose, and then you can restart it, and typically, the signal is not gonna recur.
Got it. So patients are able to stay at the maximum dose versus dose reduced longer term.
That's right.
Got it. Okay. Now, my next question is gonna imply something about your prior strategy, so let me know if the implication is wrong, but why have you recently narrowed your strategy to go it alone with ex-US commercial instead of considering a strategic partnership?
Yeah. So, you know, it's an audacious plan, let's put it that way. A couple years ago, I would tell you it probably wasn't our strategy. It was to find an ex-U.S. partner to commercialize in the U.S. ourselves. So we built up that U.S. infrastructure. We're in great position today to launch our two drugs, which are coming imminently, and I'm really excited about that opportunity. But what we recognize, first of all, there's macro issues around pricing, and that's evolving seemingly weekly, monthly. So, you know, having complete ownership of our products, it gives us more optionality and flexibility to navigate wherever that may go. In addition, these are known markets. These are established markets. We believe we have the best drugs for these markets.
We believe that the enrollment has been massive in our studies, and the durability has been really interesting across all lines of therapy. That's the perfect setup for trying to try to deliver these drugs to patients outside the U.S. as well. The trials have enrolled really well outside the U.S. So we spent the last couple of years, you know, trying to educate ourselves more on, like, okay, is this possible that a small company could actually build these capabilities? And the answer we learned is, yes, there are other companies that have done this, and they have done it well. What can we learn from them? What went well? What didn't go well? Let's build those capabilities. Now, I recognize that's challenging, but why not? If you have this opportunity, so few companies ever do. I think we have the portfolio to pull it off.
I think we have the drugs to pull it off, and I think we have the team to pull it off, so we're gonna do it. I also recognize that, you know, if a partner comes along and suggests that they can create more value than we can by ourselves, we have, you know, a responsibility. We have a fiduciary responsibility to listen to that. We will, obviously. Until then, we're trying to build the next great global biotech company.
Okay. So we talked about the timelines in the U.S. regulatory-wise. What is the process and timelines for getting both of the drugs approved ex-U.S.?
Yeah, so on the timelines, at this stage, we haven't yet disclosed anything about what those are, but would, would note that, ARROS-1, ALKOVE-1, ALCAZAR study, these are all global studies. Enrollment's gone well across geographies, and we have global registration strategies in place for both of the programs. So, you know, look forward in the future to providing, you know, more granularity around timelines there. Do you wanna add anything on the process, Jim?
Yeah. So yeah, on the process, you know, we're trying to build those capabilities. Like, the last year and a half, we've been working with consultants to educate us on what does the build look like, right? And we started pushing forward on some of those work streams. It's not gonna be as fast ex-US as it is in the US. US, it's we're hopefully gonna launch this year, right? But build those capabilities outside the US, and also, we're currently recruiting for a head of international
So thanks for this, this platform to put the plug out there if anyone's listening in. You know, it's if you're interested in, you know, creating lots of value for patients for many years to come with a, a really interesting portfolio and building a global biotech company, we're hiring, so, look us up.
Well then, how much will it cost to stand up and maintain ex-US commercial for products like these? And as you think about your balance sheet, is that fully funded to incorporate that? I mean, I know we will hopefully have some US revenue coming in tail end of this year and into 2026, so there is some offsetting, but you'll be building ex-US commercial before that's, you know, frontline ALK-
... and that's really taking off, et cetera.
Yeah.
Yeah-
Can we start on the process?
Go ahead
... and you talk about the financial, the budget part.
What we've learned by talking to others in this space is it's important to be strategic, right? It's... First of all, there's an evolution, there's macro issues that are going on. It's not necessarily press the gas in all geographies at the same speed, right? Be strategic about, you know, how the regulatory processes are going, how the pricing and reimbursement, the market access issues are going, and make your resourcing decisions accordingly, right? So there might be some geography that it's going quite well, okay, that's where you're gonna, you know, double down and put those resources in to maximize that opportunity for patients. In other geographies, it might not be going as well, and so therefore, you don't wanna maximize. So that dictates the process.
Maybe you would just talk about how the budget part.
Yeah. So I can add, you know, from the cash perspective. So we ended this past year with about $1.4 billion in cash, and so we're in a really strong position that provides us with operating runway into 2029. And so, you know, I, I won't commit that the entire ex-US build is, you know, funded within our, our current cash balance. But as you noted, the current guidance doesn't include revenues from sales, and so I think, you know, we're in a really strong position to continue to build the company globally.
Okay. Well, in terms of the opportunity of that build-out, you have some wonderful new slides in your deck about the-
... commercial opportunity and TAM for these markets. So maybe walk through, kind of the outline of those and, and what you think you can really achieve with these two products sales-wise nowadays?
Yeah, it, it was mostly just illustrative. We always get asked of, like, you know, "Can you paint the picture for us?" So we tried to paint a picture. I recognize you and your team and this audience are very good at making models and can do it in a more, detailed way. Our way was just pretty simple. Just take the peak sales of the, the, the standard of care and look at today's prices for the, the approved therapies. Just show that with more time on therapy, which we're seeing in our trials, we're seeing patients have more durable responses, how could that market grow? And just- and we think the ROS1 market could clearly could grow. It could look like something like today's ALK market. You know, $2+ billion.
We think the ALK market, which already is $2+ billion, could grow to something like today's EGFR market, which is, you know, 2-3 times that. So that's... You know, we're trying to make an impact for patients. That's the goal, but we're also building a business, and those are pretty attractive markets to build a business around, particularly a global business. So that's... We just tried to provide that illustration for, you know, for stakeholders to take a look at.
Okay. And now, you mentioned the difference in pricing power across the globe and how that's ever-changing. Do you still expect this class of drugs to have about 60%-70% of sales generated ex-US, like we saw for alectinib, or should we have some different expectations for that?
You're right, there are, these are medical needs across all geographies. I will tell you, our trials enrolled well across all geographies. I also tell you our expanded access, there's been tremendous demand across all geographies for NVL-655 and zidesamtinib. So there's clearly a market there. In the ALK and ROS1 space, yeah, 65%-70% of the market was coming outside the U.S. That's not the same for most oncology drugs, right? So those markets are pretty well established. We do need to get the drug to those patients, and we do need to build those markets to realize the full potential of this drug, so that's the goal. What the exact number is of what we would predict, we're—I think we're not there yet to really give that guidance.
Okay. Then, kind of bringing this all together, do you look at the ALK and ROS1 inhibitors as sufficient alone in terms of a commercial opportunity to try to build out that global infrastructure? Or are you thinking about this longer term, as you can wrap in other products? You've got the HER2 name in the pipeline. You've suggested you'll announce some new ones in the coming future. Is it the current plus later, or the current sufficient enough?
Yeah. We're trying to build a global, sustainable biotech company. Sustainable companies, in my opinion, need to do three things well: they need to be able to discover drugs, develop them, and ultimately deliver them. There are plenty of examples of companies that did one or two of those things well. They weren't sustainable. You need to do all three. I think we've proven we can do the R and D. Our company's only seven and a half years old. From scratch, we've discovered and developed two new drugs, we've submitted an NDA for one, we're about to submit an NDA for them. That's pretty much record time in biotech. We have a third program, it's really exciting. We have a fourth program that's coming. Is ROS1 and ALK sufficient enough to support a global biotech company?
In the near term, yeah, I absolutely think it is. But I also think these, this is the tip of the spear for Nuvalent. There's lots of exciting things we're working on. We have the tremendous opportunity in front of us to build the next great global biotech company, and we, we're executing on that vision.
Okay. On the HER2, it's been in the clinic for over a year. I guess, why have you kept the data in your back pocket, so to speak?
Kept it? No, no. No, we, we're excited about it. You know... Maybe we'll talk about our guidance, Alex, a little bit.
Sure, yeah. So, we're excited about the progress that we're making with the study, as well as, you know, the broader potential for the program. We're taking the same approach as we have with our other programs, follow the data, wanna ensure we have the ability to tell a clear story. So, we haven't guided just yet, but we'll look forward to, you know, providing updates in the future as we get closer and have more line of sight into, you know, specific venue for the data.
Okay. I guess, what do you hope that first data to showcase about the molecule, and is that- is it gonna be a different story than maybe the ROS1 and ALKs were unfolded?
Yeah, so the needs here are, you want to be able to hit exon 20 with a wide index compared to wild-type EGFR. So you want to avoid the skin toxicities and the GI toxicities that have plagued sort of these dual EGFR HER2 inhibitors. Therefore, you can hit the target harder. So you're looking at safety, right? You're also looking at, do you have activity, and can you drive durable responses in these patients that have HER2-driven lung cancer? In addition, because it's lung cancer, you need good brain penetration, 'cause patients unfortunately will get CNS disease, so it's a drug active in the brain. Now, preclinically, our drug has that profile. In fact, it's the only drug, we believe, that has that profile. There's another exciting drug called zidesamtinib, it was recently approved.
It can do some of those things, it has excellent selectivity for HER2, HER2 exon 20 inhibition compared to wild-type EGFR, good tolerability. We do not believe it has good brain penetration, and that's something that, in the lung cancer space, you know, EGFR, ALK, ROS1, first-generation drugs get replaced by next-generation drugs that have better brain penetration. So I think, you know, the, what, what's been done with zidesamtinib helps de-risk our lung cancer strategy. So what we want to show in phase one is: Do we have those things? Do we have the activity? Do we have the, the safety profile? Do we have activity in the CNS, right? Those are important components of our target product profile.
But I would not posit that the most interesting thing we could share about the HER2 program is not necessarily the phase 1 data, but where are we going, right? It's a given we're going forward in lung cancer. That is our priority. But HER2 drug development, there's a wealth of opportunities. There's lots of HER2 drug development across solid tumors, for small molecules, antibodies, ADCs. And the longer those patients stay alive, the more likely they're gonna get CNS disease. Well, what would be nice to combine it with is a small molecule that's brain penetrant, that has excellent CNS activity, that's well-tolerated, and that broadly covers HER2 mutations. That's NVL-330. So there's a lot of opportunities we can take this program beyond just lung cancer.
So that's where we're positioning, like, how do we tell that story of, "Here's the safety and the dose from phase one. We're going forward in lung cancer. Where else are we gonna go, and why?
Mm-hmm. Okay. And then, just quickly for the fourth program, I know it's unnamed, but can you sketch the parameters of the areas you've been focusing on?
It's listen to the physicians, where are the medical needs, what can we apply innovative chemistry to, and being disciplined that this is the best possible solution for patients. So we work on a whole range of things in discovery, a wealth of programs. We only put things forward that we think have met that bar the physicians have outlined for us. This program has. It's coming this year. The reason I can guarantee it's coming this year, 'cause we've already discovered it. We have it.
Great. Well, any other positions you'd like to plug for hiring? I know you guys are rapidly expanding. No. Okay, well, thank you so much, Jim. Thank you, Alex, and thank you, everyone, for listening in.
Thanks, Brad.
Thanks.