Okay, let's go ahead and get started. My name is Chris Raymond. I'm one of the biotech analysts here at Piper Sandler. It's my pleasure to introduce our next presenting company, which is Nuvalent. Today we have the CEO, Jim Porter, sitting next to me, and then to Jim's right is the CFO, Alex Balcom. So just a reminder for everyone, this is a fireside chat format. It's meant to be very informal. So if you have any questions in the audience, please just raise your hand. I'll make sure your question gets asked and answered. I have a ton of questions for you guys. Before we delve into that, maybe, Jim, if you wouldn't mind, just level set the conversation. For those who may not know Nuvalent, just give us sort of an intro on the story, the setup, and then we'll dive into questions.
Sure. First of all, Chris, thanks so much for having us at the Piper Conference. Thanks to the Piper team for the opportunity to be here. So Nuvalent is a company we started in 2018, based in Cambridge, Massachusetts. The foundation of the company is a deep expertise in chemistry, structure-based drug design. I, myself, am a chemist. The founder is a Harvard chemistry professor, Matthew Shair. We focus on clinically proven kinase targets. The rationale there is kinase inhibitors are well validated, 80+ kinase inhibitors approved. And we partner with physicians from the outside of the company to learn from their perspective what are the limitations of the therapies that they help develop for their patients, what are the needs for their patients. And then we use innovative chemistry to solve for them s o we launched the company around those principles in 2018.
In a fast forward, 6+ years, we have two programs that are in phase II pivotal studies. Both are expecting pivotal data readouts next year. Both have demonstrated clinical proof of concept. Both have FDA Breakthrough Therapy Designation. We have a third program in phase I and a robust discovery pipeline behind it.
Great. So really a little editorial from me. One of really the sector's great success stories over the last couple of years. I guess I didn't know you guys were only around since 2018. You've done quite a lot to have two basically pivotal readouts coming next year. And also two arguably best-in-class agents that we're going to get into here. So maybe let's do that. So I want to dive straight into zidesamtinib for ROS1-positive non-small cell lung cancer. So maybe just first talk about ROS1 as a target, how often it's mutated, what the pathogenesis looks like, et cetera. And then we'll dive into some other questions.
Yeah, it's a target that's very interesting in that it's about 1% to 2% of non-small cell lung cancer. The original kinase is involved in early development. In a very small percentage of folks out there, unfortunately, undergo a gene rearrangement that causes it to fuse with another protein and drives uncontrolled growth. There's multiple drugs approved for ROS1 non-small cell lung cancer. The standard of care today is crizotinib. It has limitations, though. We hear from physicians that not highly brain penetrant and also the emergence of ROS1 resistance mutations can lead to patients' disease progressing. Other drugs have tried to solve for either one of those two things. What they have in common, though, is they often hit a specific off-target called TRK. Inhibition of TRK in the brain leads to neurotoxicity signals that physicians have been reluctant to supplant crizotinib with these other agents.
The guidance to us was try to solve for that, have a molecule that can get into the brain, treat patients with brain mets, or to prevent brain mets from occurring, to have coverage of ROS1 resistance mutations, and to importantly target ROS1 and avoid this off-target TRK, the drug would be well tolerated. That's the strategy for zidesamtinib.
Yeah. And so ROS1 hits hard, spares TRK one. That's sort of the premise. And we've seen relatively differentiated data. Let's just talk about maybe the design of your ongoing ARROS-1 phase I/II trial for zidesamtinib. Phase I is a portion of dose escalation. But talk about the doses you've tested so far and why those were selected going forward.
Yep. So in the phase I, obviously, the objective was to identify the recommended phase II dose and understand the safety. We did a dose escalation from 25 to 150, ended up selecting 100 milligrams once a day as the recommended phase II dose. That dose had excellent coverage of ROS1 and ROS1 mutations, both in the periphery and in the brain. And it was well tolerated. And it was active beyond all the other therapies. That's guided our dose selection. The phase II is where we've evaluated that dose at the recommended phase II dose.
Just so, the updated data from the phase I portion at ESMO this year, we were looking. I don't want to lead the witness here, but I'll just say, so we were looking at the subgroup results in the second and third line cohorts, which we think showed a very favorable comparison to repotrectinib, for example. What was your bar for efficacy? And just maybe for folks who haven't maybe paid too much attention, the results you had.
Sure. Sure. So the takeaways from the ROS1 update were maybe first and foremost is we showed that the phase II is going quite well. We showed the enrollment cadence. We enrolled 230 patients over the course of a year, which we used to hear feedback of, "This is a rare tumor type. And are you really going to be able to find these patients?" And the answer was clear yes, right, because we have buy-in from physicians and investigators that are interested in this differentiated profile. The phase I data, the key updates were that the drug was active beyond all the other therapies. So this is a unique patient population. They've exhausted the available options. And the drug is still active. It's active in patients with ROS1 resistance mutations. It's active in the brain a nd importantly, it's well tolerated.
We had already shown that in the previous update for the ROS1 program. What was really different here, though, was the durability, and it really speaks to why ROS1 is an interesting driver. Even in these late-line patients that have exhausted available options, we're driving deep and durable responses in these patients, and that portends well to what you might see if you push the drug into the earlier line setting. You can broadly cover ROS1 and ROS1 mutations. The drug's well tolerated. You might be able to drive even more durable responses, so that durability is what really stood out, and that's across all the patients in that phase I study.
Obviously, the other part of the story is the safety profile, right? No TRK-related toxicities. Another piece is it is getting into the brain, but you have a decent amount of measured CNS activity. Maybe talk a little bit about that and the importance.
Yeah. Yeah, so lung cancer, unfortunately, is the cancer type that's most commonly going to metastasize to the brain, so if you're going to develop a drug in lung cancer, you need to design a drug that has excellent brain penetration to either treat those patients that have brain mets or to prevent the disease metastasizing to the brain. That's a chemistry challenge. That's in our wheelhouse. That's what we like to take on is these types of problems, and importantly, we had patients that had exhausted drugs like lorlatinib or repotrectinib. These are highly brain penetrant drugs. Patients had progressed on those therapies in the brain, and we saw evidence of clinical activity, clinical responses in those patients in our phase I data.
So it was really proof of principle to us that this drug was not only active beyond the other therapies, it was active in the brain beyond highly brain-penetrant drugs, which means that we're on the right track here.
Great. And so you selected the 150 mg QD dose as the go-forward dose, which is the third highest. I know I asked a question on dose, but just walk through the decision process. I think there was some Project Optimist considerations from the get-go on this. But just walk us through, Jim, why that was the dose.
Yeah. The dose selection was guided on the lowest dose level was active and the highest dose level was safe, so we really could have chosen any dose, and that's very rare in precision oncology that you have that type of opportunity. Usually, you're trying to trade off how much safety you take on versus maximizing the efficacy signal. We saw comparable exposure-response relationships for both safety and activity across the entire dosing interval, so we actually used pharmacokinetics to guide our dose selection, where we showed that at both 75 mg and 100 mg, we had excellent coverage for all the patients throughout the entire dosing interval for that target efficacy threshold. We went with the higher dose, 100 mg, that allows us to have even a dose reduction and still be above that threshold.
So it's a unique example here as far as we're aware in precision oncology, where we had that kind of luxury. And it was, as you pointed out, very important for us to align with the regulators on that dose selection. And we did indeed get that buy-in.
So you have a readout, as you mentioned, pivotal readout next year. And you're enrolling both ROS1 inhibitor-experienced patients and TKI-naïve patients. And I think you also have a cohort of ROS1-positive any tumor. So what do you hope to see, I guess, in the TKI-naïve cohort?
Do you want to speak for the timing?
Sure. Yeah, so as Jim mentioned, we've been excited about the enrollment in the study and have guided to sharing pivotal data next year for the program.
As far as what we hope to show per cohort, for TKI- naïve , the standard of care is crizotinib. It has about an 18-month duration response. We think you could do better. The reason we think we could do better is that crizotinib has roughly half the patients progress with ROS1 mutations. The same drug used to be the standard of care in ALK non-small cell lung cancer. Drugs like second and third generation drugs came along that solve for the liabilities of crizotinib and showed they can drive much more durable responses than crizotinib. If you can drive much more durable responses than ALK, the same should be true for ROS1. It has the same liabilities there zidesamtinib solves for.
So if we can significantly improve upon that in that TKI- naïve cohort, not only is that a game changer for patients, that's a potentially very interesting commercial opportunity. For previously treated patients, there really is no good option today for those patients. And zidesamtinib was designed to solve for that. And that's currently where we have breakthrough therapy for third line ROS1 TKI. I think also the breakthrough designation helps speak to the FDA sees there's a need there. And the evolving data we're generating and supporting that is addressing that need.
Okay. Excellent. Why don't we pivot maybe now to 655? That's your second program, but obviously a pretty visible and important value driver for you guys for ALK-positive non-small cell lung cancer. ALK, as folks may know, is much more prevalent than ROS1 mutated patients. Maybe just compare and contrast ALK-positive with ROS1. And maybe a second part of that question, Jim, is when it comes to designing an ALK inhibitor, what were the major differences, I guess, when you set out versus the ROS1?
Yeah. There are a lot of synergies between the two programs. Some of the same needs in ROS1 are directly relevant to ALK, so ALK, there's actually five approved therapies. Front line patients receive alectinib as a standard of care. When they progress on alectinib, the only drug that works is lorlatinib. And when they progress on lorlatinib, nothing works, so we're looking to solve for all those lines of therapy, starting in third line where patients have something called ALK compound mutations, so that means multiple mutations that have occurred in the kinase domain, so 655 was designed and optimized for that setting. But we recognize that's a niche. And we want to develop it for all ALK patients. We can actually learn from the other therapies. Most physicians would tell you lorlatinib is the more active drug, even though it's primarily used in the second line.
The reason it's used in second line and not front line is it hits that same off-target that we mentioned in ROS1. It's called TRK, so an inhibition of TRK in the brain leads to neurotoxicity signals. That's been dose limiting for lorlatinib and been a patient management challenge. Most physicians have stuck with alectinib as a standard of care and use lorlatinib in that second line salvage setting, so that was a learning for us. If we could design a drug that can do what lorlatinib could do, meaning cover the ALK mutations, have excellent brain penetrance, but could avoid that off-target inhibition, then we would have necessarily a better second line option than lorlatinib and a better front line option than alectinib, and our data thus far suggests that 655 does indeed have that profile.
Great. And so you're running right now the phase I/II ALKOVE-1 trial, similar design to ARROS-1, I would argue, with phase I dose escalation. And you've got a dose expansion part of the study. Anything you specifically want to highlight here with ALKOVE-1? It seems like you've had a majority of patients who are heavily pretreated with at least two other ALKs, I think specifically lorlatinib experienced. Maybe talk about what that sort of means for the trial.
Yeah. Yeah. So the update at ESMO was really well received. And I'd say the key takeaways, one, just like with ROS1, was the enrollment momentum we have in the phase II. So we enrolled 230 patients in the first six months of the study. And honestly, I've never been part of a program that has that kind of momentum. And I think it speaks to the interest that the physicians have. It speaks to the medical need. It speaks to the eventual commercial opportunity. It speaks to the momentum the program has. So our team is really excited about that. Second was showing that the drug was active where all the other therapies have failed, right? So they progressed through alectinib or lorlatinib and in many cases, other TKIs as well. And in many cases, chemotherapy. And our drug was designed to be active there. And it was.
It was active in that patient population. It was also active in the brain, which is important for the reasons we discussed before, and the safety profile is critical here, that that's the reason that lorlatinib really hasn't seen the front line uptake, and we are seeing the safety profile that's indicative of an ALK selective TRK-sparing design, and that gives us the confidence to push it to the earlier lines of treatment, so the phase II has registration-directed cohorts for both second line patients and third line patients, so we think that that collated data could help us support a previously treated indication, and then we also announced recently our phase III trial, which is a randomized study one-to-one compared to alectinib in TKI- naïve patients.
Yeah. And so a similar sort of safety TPP, which you hit, obviously, with the TRK-sparing aspect. One sort of aspect of the safety data that did generate a decent amount of questions was there were some grade 3, 4, AST, ALT increases. This is precision oncology, TKIs. I mean, we should expect this, right? But just maybe sort of comment on that from what your KOLs are saying, etc.
Sure. Sure. Most kinase inhibitors have transaminase signals. There are laboratory abnormalities that they're well understood and well handled. As an example, alectinib is the standard of care in ALK non-small cell lung cancer, generally perceived as a well-tolerated drug, and approximately half the patients have transaminase signals, so this is something that we'll continue to monitor, but in general, we've seen the profile in our physicians that are developing 655 in collaboration with us see it as a well-tolerated drug with, importantly, avoiding those neurotoxic signals.
You also measured CNS activity and intracranial tumor response to remind folks what that was.
That's right. So lorlatinib is, from our perspective, one of the gold standards in oncology drug development for getting into the brain and treating patients with brain mets. So we use that as the barometer for all of our preclinical experiments, making sure our drugs are just as brain penetrant as lorlatinib. And importantly, we are seeing patients on our study that progressed on lorlatinib with CNS disease and respond to 655. So that was really proof of principle to us that if we can show our drug is active in the brain even beyond a highly brain penetrating drug like lorlatinib, then we're clearly on the right track there.
So you're now in the midst of enrolling the phase II portion of ALKOVE-1. This is a bigger variety, I guess, of subgroups. You get two to three prior ALK inhibitors of any generation, one prior second gen inhibitor, prior lorlatinib, and then also TKI- naïve . Just walk through the decision to go with all these subgroups .
Yeah. So we designed a drug, we believe, for all ALK patients. And so the two most critical cohorts there are the second line and third line cohorts where we designed those to support registration. The other cohorts are more to just continue to generate data to guide future development strategies. The TKI- naïve cohort was really just a data generation. We aren't necessarily waiting for that cohort to initiate the front line study, which we're going to start in the first half of next year.
Yeah. And then so a big update, I guess, at ESMO is you said you'd have top line data next year. I know you hadn't formally guided, but that was on which one would have which pivotal data. But we're assuming this program would be a 2026 event. So a surprise to us, if anything else. But so it clearly would indicate maybe enrollment's going better than expected. Is this just another setup like the ROS1 where word of mouth gets around? Physicians enroll more patients when they have a better buzz around a drug?
Yeah. I mean, I think we have been really pleased with the enrollment. And part of it is we partner with the patient advocacy groups. And they're really strong advocates. And they're well aware of Nuvalent. And they funnel patients to our studies. And so we've been very pleased with that.
Excellent. Okay. And so you touched on, Jim, the front line plan at the trial. I think you've dubbed it the ALKOZAR study in TKI- naïve patients. There's been if I get questions from investors, it's, "Okay. This is a long study." Just walk through the dynamic there in terms of when we'll see the readout, etc. Maybe just walk through the design, if you would, when you expect to start. And moreover, the motivation to run this if you're going to have a subset of TKI- naïve patients from the ALKOVE work.
Yeah. Well, first of all, they're right. It is a long study. But it's for a good reason, right? So ALK non-small cell lung cancer, the patients that get diagnosed with this, they often get diagnosed earlier in their lives, so in their 40s or 50s. And someone in that age bracket, I find, to be relatively young in the prime of their life. And it's awful that they get this diagnosis. It comes out of nowhere. And alectinib has done great things for this patient population, no doubt. It made a huge impact. It delivers about two years of progression-free survival, which is great. Many cancers don't have that kind of treatment option. But two years when you're in your 40s or 50s is not good enough. I think we all probably could agree with that, right? So what if you can do much better?
Half these patients are progressing with ALK mutation. Progressing with ALK mutations means that you could probably do better. 655 was designed to address these ALK mutations. When the similar strategy was done in the EGFR space, osimertinib, half the patients were progressing with EGFR mutations on gefitinib/erlotinib. Osimertinib doubled the progression-free survival. What if we could do that here in the ALK space? It would be a game changer for these patients. It would give them extra years of progression-free survival. On top of that, that makes for a very compelling commercial opportunity for a drug that gives years of progression-free survival. We made the drug to do it. Of course, we're going to go do it.
Awesome. Okay. We got about a minute and a half and we've only talked about your first two programs. There's other stuff, obviously, part of the story. Maybe let's just jump into NVL-330. That's your next up, the third program in your repertoire, HER2 targeting. Kind of intriguing. I think most people think about HER2 as a biomarker for breast cancer, but you're looking at this in non-small cell lung cancer. Just maybe talk about the role in non-small cell lung cancer and just the premise behind this program.
Sure. I can give the quick pitch. So most have heard of HER2 as a target for other tumor types, as you pointed out, breast, colorectal, others. In HER2 lung cancer, the specific driver is something called Exon 20 insertions. And a lot of those other HER2 drugs have been repurposed to study HER2 lung cancer with poor outcomes, poor response rates, poor durability. It's because they have a narrow index for inhibiting HER2 exon 20 compared to wild-type EGFR. And if you hit wild-type EGFR, you get skin toxicities, GI toxicities. 330 was designed to solve for that. In addition, because it's lung cancer, you need excellent brain penetration. 330 also solves for that. So the HER2 studies started in July this year. And we're excited about it.
Excellent. Well, lots of big news coming up next year and lots of progress behind you guys. So anyway, thank you very much for the time.
Thanks, Chris.
Thanks.