Hi, everyone. I'm David Dai, one of the biotech analysts here at UBS. Thank you. Thanks for joining our inaugural virtual oncology day today. We continue our session with Nuvalent. It's our great pleasure to welcome Jim Porter, Chief Executive Officer, and Alex Balcom, Chief Financial Officer. Alex and Jim, thank you for joining us.
Thanks, David. It's a real pleasure to be with you, and sincere thanks for the opportunity to participate in the conference.
Excellent. Great. Jim, maybe you can just help us understand Nuvalent at a high level. For anyone who is new to the story, can you give us just a quick introduction of what Nuvalent is and some of the key programs in development?
Sure. Nuvalent Inc is about seven years old. We're founded with a deep expertise in chemistry and structure-based drug design, and we like to apply that chemistry to discover, develop, and deliver a portfolio of precisely targeted therapies for patients with cancer. At the foundation of the company is that core chemistry expertise. We focus on validated biology, and the rationale there is clear, that we can accelerate the discovery phase and the development phase by focusing on validated targets, running small focus studies to understand whether your drugs work or not. To make an impact here, we partnered with physicians that had developed earlier generation kinase inhibitors. We want to learn from them. They are the experts in the space. What are the needs of the patients they treat? What are the limitations of those therapies? Let's use innovative chemistry to try to solve for that.
In about seven years, we've quickly advanced the portfolio of compounds. The first program, we just completed our first NDA submission for. The second program has pivotal data reading out soon. They both have breakthrough designation. They both address medical needs, and we think they both have an opportunity to make a significant impact for patients. Beyond that, a broad portfolio of compounds in our discovery portfolio, that same idea, listen to physicians and see where we can apply innovative chemistry to it. Happy to go deeper into any of those areas, David.
That's a great overview. Yeah, you guys are definitely one of the leaders in innovative chemistry here, and you have two very exciting programs, actually three very exciting programs in development. Maybe let's focus on sort of the near-term, you know, a program that has some near-term kind of updates. Zetacentenib, right? It's for ROS1-positive non-small cell lung cancer. By the way, just completed an NDA submission two weeks ago. Congrats on that. A big milestone here. On that front, how has your experience with the FDA engagement been so far? Has there been any kind of changes in the FDA interactions, given all the things that are happening at the FDA?
Thanks, David. Yeah, the completion of our first NDA submission is a massive milestone for the Nuvalent team. As I mentioned, the company is only seven years old, and from scratch, we invented a new compound, developed it, and now have completed our first NDA submission. Clearly a sign of outstanding execution by my colleagues at Nuvalent. To answer your question directly, no, we haven't seen any impact, really. In my 20+ 25 years in the industry, mostly in the oncology space, I found the interactions with the FDA, you have to bring your A-game. They're very good at what they do. They're thorough. They're diligent. They know the landscape. They know the needs. They're very good at looking at, they're diligent about looking through the data, understanding.
You better make sure that when you interact with them, that you are up to speed on all aspects, because they're going to bring their A-game. You need to bring yours as well. We've seen no drop-off or changes in any way that impact that perception, and we look forward to continuing to collaborate with them to get these drugs to patients as fast as possible.
Got it. Just on the interaction with the FDA, you know, of course, the OR and DOR has been the primary endpoint you're using for approval. Any signals that you got from the FDA in terms of using survival endpoints for approval? You know, anything you can share on that front?
Yeah. In the ROS1 space and in the ALK space, actually, we're greatly aided by the fact that other drugs have been developed in the space. We can learn and understand from those other approaches how those development strategies were tackled and how they were viewed by the regulators. In the ROS1 space, there's actually four approved therapies. Each of those four approvals came off of single-arm studies that utilize ORR and DOR and safety as the primary measures to understand the benefits and risks of the drug. With each of those approvals, they received full approval off of those single-arm phase II studies. We took a similar approach, understanding that precedent and also aligning with the FDA. We have a previously treated cohort that we followed for six months. We aligned with the FDA on that approach.
We cut that data, and we submitted that data in our recent NDA submission. For TKI naive patients, the precedent has been to follow those patients for 12 months. We're still letting that data mature, and we're going to work with the regulators to get that data submitted as possible as that data continues to mature.
Got it. Since you already have breakthrough designation for Zetacentenib, curious, you know, what's the chance of receiving a priority review for Zetacentenib in ROS1, you know, TKI pretreated non-small cell lung cancer patients?
Yeah, we do believe there's a medical need. We do think that Zetacentenib has a chance to address that medical need. As you mentioned, we do have breakthrough designation, which is often, you know, regulators are going to look at what are the needs and how in the data available to address that need. As far as the type of review, that's out of our hands, right? That's something that the regulators will decide. We will work with them to make sure that we can do whatever is necessary on our end to get the drugs reviewed and approved as fast as possible. As we learn more about how the FDA is viewing our submission and the review timelines, then we'll provide more clarity on that.
Got it. OK. Talk a little bit more about the data here. Maybe, Jim, can you just maybe help us understand the data you recently presented? You actually saw it in the data presented at WCLC recently, too. Maybe just help us understand some clinical data there. Give us some perspective around what we're seeing in TKI in pretreated cohorts, and what's sort of like the benchmark that people are looking for in this particular population.
Yeah. You know, the target product profile that we've been working towards really came from the physicians in the space. They had said, you know, based on what was the standard of care at the time, crizotinib, that drug worked reasonably well, but it had some limitations. The drug was not highly brain penetrant, so patients would progress with CNS disease, or patients would progress with ROS1 resistance mutations. We needed to solve for those two things. Other drugs have tried to solve for one or more of those things, but with each of those other drugs, they bring in other off-targets that they also inhibit in addition to ROS1. Inhibition of those other off-targets has held back the development of those other drugs, because it leads to these off-target toxicities, these dose-limiting toxicities.
It's been difficult for physicians to manage the patients on those therapies, and they've largely stuck with crizotinib as the standard of care. The goal for Zetacentenib was to develop a drug that can hit the mutations, can get into the brain, but importantly, was selective for ROS1, so that we did not bring in those off-target dose-limiting toxicities. Zetacentenib is the first and only drug that has that profile. What we showed in our top-line data was, even beyond all the other therapies, our drug was active. It was active beyond those other therapies in patients with ROS1 resistance mutations. It was active in the brain. Even when patients are progressing on CNS-active drugs, like entrectinib or repatrectinib or talotrectinib, our drug is still active in the brain, which really is a high bar that no other drug has shown.
Most importantly, it has that ROS1 selective tract-sparing safety profile that's been lacking from the other drugs in this space. We're quite encouraged by that. What it's resulted in is we're seeing activity that's driving these responses that look to be durable, right? As an example, in patients that have progressed on one prior TKI, what we're seeing is at the year-and-a-half landmark or 18 months, 93% of those patients are still in response. That's quite encouraging, because these patients have already progressed on another line of therapy. It bodes well to, as you push the drug up earlier in the treatment paradigm, their responses might become even more durable than that. I think it's definitely trending in the right direction, and we're excited about the path forward for Zetacentenib.
That's really, really interesting and helpful here. One thing that we noticed at WCLC was that we had a conversation with some physicians. Of course, they were impressed with the overall efficacy and durability data, but they were also surprised to see some of the onset of the peripheral edema, which, you know, to them indicates some tract inhibition. They worry about the long-term toxicity associated with tract inhibition here. Jim, can you just help understand, you know, what are your thoughts around the peripheral edema here, and what are some of the long-term safety kind of issues you're thinking about?
You know, thanks, David. Yeah, we actually see the Zetacentenib safety profile as very favorable and differentiated compared to any other ROS1 TKIs out there. I think most physicians agree with us. I think that's why you see the massive enrollment momentum we've had in this study. We used to get asked, like, how are you going to find these patients? We just enrolled 540 patients in really, you know, very limited time. That speaks to the enthusiasm that investigators have for this differentiated profile, as well as the patient advocates, which are very active in this space and have pushed a lot of patients towards our study. The peripheral edema signal, that's something that's due to excessive fluid accumulation in the extremities, and it's not associated with tract inhibition.
The exact etiology of edema is not fully understood, but I will tell you that many TKIs in oncology drug development have this associated edema signal. These include drugs like lorlatinib, crizotinib, alectinib, brigatinib, lezertinib, repotrectinib, entrectinib, the MET inhibitors, tepotinib, capmatinib. These are pretty common signals for kinase inhibitors. Many of those drugs I just mentioned are perceived to be well tolerated, and they're also not tract inhibitors. This is not a tract-related signal. We are not seeing those safety signals that are commonly associated with the tract inhibitors like repotrectinib, entrectinib, talotrectinib, lorlatinib, et cetera.
Got it. OK, great. Thanks for providing that perspective here, Jim. Moving on to the TKI naive cohorts, we have seen 35 patient data that shows some impressive OR and DOR. Of course, we are eagerly waiting to see the updated pivotal data. Maybe just help us understand, Jim, when should we expect to see the frontline data in TKI naive cohorts, and help us understand what kind of expectations should we be looking for in terms of the OR and DOR?
Yeah. We had a cohort directed towards registration in TKI naive patients. As of the data cut back in June, we basically announced that we had enrolled 104 patients already in that cohort, more than we actually needed. As I mentioned before, David, the precedent has been to follow naive patients for 12 months, whereas we cut the data for previously treated patients at six months. We need a little bit more follow-up on those patients. We showed how the first 35 were trending, and it clearly was favorable, 89% response rate. The 12-month landmark of duration response was 96%. We're seeing deep responses in the brain, right? That's by design. We had designed a highly brain penetrant drug, and five of the six patients with CNS disease responded. Four of them had an intracranial complete response. That's different than any other drug in this space.
Those drugs have not demonstrated intracranial complete responses. Importantly, it has that differentiated safety profile. We're going to continue to follow that cohort and work with the regulators to consider a line agnostic extension as that data continues to mature.
Is there a bar or benchmark we should be looking for here for the OR and DOR side of things?
You know, most of the patients, most of the drugs in the ROS1 space in the frontline are going to have high response rates, right? If you have ROS1-driven disease, it's likely the patient's going to respond if there is a, you know, you're using a ROS1 inhibitor. What's key here is how durable those responses can be, right? I mentioned before, crizotinib was a standard of care. 40% of those patients are progressing with known ROS1 resistance mutations. If you cover those ROS1 mutations, you're going to take away that pathway as a potential disease progression pathway. In addition, if you're highly brain penetrant, you're going to take away that pathway as a potential source of disease progression. Zetacentenib does that. What Zetacentenib also does is it's, you know, well tolerated, so patients can stay on therapy.
We only saw in our full data set only 2% of the patients discontinued due to any adverse event. Keep in mind, this is a very advanced patient population, and only 2% of the patients are discontinuing due to any adverse event, whether it's related or not. That is what we think is the recipe for keeping patients on therapy and driving more durable response. What we're going to want to understand is how durable are these responses, and how does that compare to a drug like crizotinib that has those liabilities? I think that's the real variable here.
Understood. Let's assume that the TKI naive data is going to be positive next year. How soon should we expect, you know, NDA filing, given that you already, you know, did the NDA filing for Zetacentenib in TKI pretreated patients? What should, how should we think about potential approval timeline here?
I can take that one. We haven't provided the guidance on timing just yet. Jim mentioned the precedent of following patients for 12 months post-response. We'll continue to follow the data from the TKI naive cohort and then engage with the FDA on a potential line agnostic expansion and look to provide updates in the future on timing.
Do we expect the review to be shorter? Because this is going to be a, you know, it's an sNDA instead of, you know, actually a full NDA.
Do you want to take that one?
Yeah. It's really something that we haven't commented on at this point, David, of exactly what the submission strategy will be for the naive patients, other than that we're going to do whatever we can to collaborate with the FDA on getting that data reviewed and getting the drug approved for all ROS1 patients, including frontline patients. Once we have the data and we've aligned on that submission strategy, it's probably a more appropriate time to talk about what review timelines might look like.
Yeah, understood. Your competitor, Nuvation Bio's talatretinib, the launch was pretty impressive, right? Does that strengthen your confidence in Zetacentenib's market potential in ROS1, either naive or pretreated non-small cell lung cancer populations?
Yeah. I mean, we believe there's clearly a need for ROS1 patients. As I mentioned before, crizotinib is a standard of care, and a number of other drugs in the space were designed to address some of the limitations, whether it be CNS disease or the emergence of ROS1 resistance mutations. All of them brought in additional challenges in that they hit off targets, including, you know, the most recently approved drugs. We've seen with the enrollment on our study that clearly these patients exist, and clearly there's enthusiasm for new options that address those needs of ROS1 patients. We remain, you know, enthusiastic about, you know, our path forward with Zetacentenib, and we're looking forward to delivering this for patients.
Got it. Great. Let's move on to nanodelcub, the ALK inhibitor in ALK-positive non-small cell lung cancer here. It looks like you will be presenting a poster at ESMO for nanodelcub in pretreated ALK-positive non-small cell lung cancer from the ALKOV1 study. Just curious, is this the pivotal data we should be expecting here? Maybe you can also provide some detail around data expectation for this ESMO update.
Yeah. There are actually two data readouts we have for our ALK program in the second half here, and maybe we'll walk through each one of them. Alex, do you want to start first on our top line?
Sure. Yeah. For our top line data, we're on track to deliver that by year-end, and we're planning to take a similar approach as we did for our pivotal data that we reported for Zetacentenib. Our preference has been shared data at a medical meeting, but it can be difficult to time the top line data with the abstract submission deadlines. We're planning to share our top line data as a standalone press release, and then we'll look to share the full data set at a future medical meeting.
The other update is we do have a poster that's been accepted for presentation at ESMO. This is around tumors outside of non-small cell lung cancer. ALK is a driver in a number of different tumor types, probably like a dozen or so. The challenge there is to get physicians to sequence those patients for drivers like ALK, right? Then to try TKIs as compared to whatever the standard of care is in that particular indication. We had an exploratory cohort in our phase II to enroll patients with those other tumor types. With a compound like nanodelcub, which broadly covers ALK mutations, which has excellent CNS penetration, and we believe is designed to have a good safety profile, this could be an attractive option for patients in these other tumor types. We are going to share what we've learned so far at ESMO in that exploratory cohort.
That's interesting. These are ALK-positive solid tumors. Maybe, Jim, can you just level set some of the market opportunity for the ALK-positive solid tumors? What % of the solid tumors will actually have ALK-positive mutations?
It really ranges, David. It also is limited by the lack of good options for those patients. I think if you go back 20-something years ago, this is how the development in lung cancer started, right? All patients just used to get the standard of care, like chemotherapy. Scientists and drug developers established that there are actual drivers to target, like EGFR. EGFR therapies were developed and shown that they actually work much better than the standard of care. Today, the standard of care is to give a targeted therapy, like an EGFR therapy for patients that have EGFR-driven lung cancer, right? Not chemotherapy or chemoimmunotherapy. That is what we're looking to do across other tumor types.
If you can show that you have an oncogene-driven cancer in, let's say, pancreatic cancer or colorectal cancer or something else that typically you give a tumor-directed therapy, then potentially you can start shifting the way physicians think about treating that disease. We are happy to participate in trying to push the field there if we have a drug that could potentially address that, such as nanodelcub or Zetacentenib in the ROS1 space, where the same theory is true.
Got it. Yeah, that's just really helpful. In terms of the data update, the pivotal top line data update, we should be expecting this in the second half of this year or by year-end. Could you maybe just set some expectations for the potential benchmark we should be looking for in terms of OR and DOR?
Right. The standard of care is alectinib. When patients progress on alectinib, they get lorlatinib. When they progress on lorlatinib, nothing works, right? We wanted to design a drug for any line of therapy, right? We'll start in that third line. Nothing works. That was the majority of our phase I patient population. We had enrolled patients that had progressed on all the available therapies, including lorlatinib. Nothing else works there. Our drug was active. It drove durable responses. It was active against mutations, both single and compound, active in the brain, and it had that well-tolerated safety profile. We received breakthrough designation in that population, demonstrating that there's a clear medical need. I imagine the way our phase II is going to be viewed is, how does it translate from phase I to phase II?
There are no other relevant data benchmarks to point to, because, as I said, nothing else works in this patient population. In the second line, we also have a cohort directed for this patient population. This is where lorlatinib is the standard of care. Lorlatinib can drive responses in this patient population because it has some coverage of ALK mutations, and it has good CNS penetration, right? However, we believe lorlatinib is limited in this patient population in that it hits off-target tract very close to where it hits these ALK mutations, right? It's difficult to hit these ALK mutations hard. We see patients come on our phase I that have progressed on lorlatinib due to inefficient coverage of ALK single mutations, or they actually develop a second mutation called compound mutation, and lorlatinib is not active against those either.
Our drug was designed to, it was optimized to cover these mutations broadly. We think there's an opportunity to clearly differentiate from lorlatinib on durability in the second-line patient population. The response rates are in that 30%- 39% range, but the durability is only seven months in this setting. In our phase I, we saw more than double that in a patient population that had already progressed on lorlatinib, right? That's meaningfully different than what lorlatinib can do. If we see anything in that same ballpark, we think there's an opportunity to use that second-line data in conjunction with our third-line data to have discussions with regulators around a broader previously treated ALK indication. In addition to that, we have a front-line study compared to alectinib, randomized phase III ongoing. That's our approach to front-line ALK non-small cell lung cancer development. Hopefully, that makes sense.
Yeah, that makes a lot of sense, Jim. We have about three minutes left. I just want to spend the next couple of minutes talking about your HER2-altered non-small cell lung cancer program. Maybe just give a quick update on the NVL-330 trial for HER2-altered non-small cell lung cancer and any kind of timeline toward data expectation here.
Yeah, that's a tricky name. Heroics. Heroics is how we pronounce it. Although, I don't know if that's proper English, but that's how we pronounce it. Yeah. Let me tell you about our NVL-330 HER2 program. HER2 is obviously a well-known cancer target, a couple decades' worth of drug development in the space, small molecules, antibodies, ADCs, you name it. There's been lots of drug development across tumor types for patients with HER2-driven cancers. HER2 lung cancer is a little bit different in that the main driver is something called exon 20 insertions, HER2 exon 20 insertions. They are not the driver in those other tumor types, right? Some of those other HER2 drugs were repurposed for HER2 lung cancer, and the outcomes were not very favorable, right? Poor response rates, poor durability.
There's a reason for that, a scientific reason, in that those drugs do not have a wide index for inhibiting HER2 exon 20 compared to wild-type EGFR. It's well known that wild-type EGFR inhibition causes skin toxicities, GI toxicities. It's difficult to keep the patients on therapy. You get a lot of interruptions, poor response rates, poor durability. That's a chemistry problem, one that we wanted to tackle, and we did with NVL-330. In addition, because this is lung cancer, patients will get brain mets. It's very important to have a compound that has excellent brain penetration. NVL-330 does have that. We think that positions it quite uniquely in this setting as a TKI that can broadly cover HER2 exon 20 with that wide index versus wild type and have that good brain penetration. That's a pretty attractive profile for HER2 lung cancer patients.
That's where our phase I focus is. The compound is broadly active against HER2 cancers, HER2 immunes. You can imagine all the other places where HER2 drug development has happened, including where HER2 ADCs have been developed. You know, having a HER2 brain penetrant TKI is a very attractive option to consider in the treatment arsenal for those other cancers as well. That's a future development opportunity we can consider with this program as well.
Got it. This is really, really helpful discussion here, Jim. I don't have any more questions. I think we're almost on the top of our hour here. Maybe just one quick sentence to highlight some of the key catalysts we should be watching for over the next 6- 12 months.
Want to take that, Alex?
Sure. Yeah. We're looking forward to sharing the pivotal data from the ALKOV1 study by year-end, and then continuing to follow progress for our HER2 program as well. We haven't shared timing just yet, but we'll look forward to providing updates in the future as we watch the data there. We talked about the solid tumor data for the ALK program as well that we'll have at ESMO coming up.
Excellent. Great. Thank you so much for taking this time to speak with us. You know, we're definitely looking forward to more exciting news over the next 6- 12 months from Nuvalent. Thank you again for attending the virtual oncology day.
Thanks for inviting us, David. Really appreciate it.
Thank you.