We are thrilled to have Nuvation Bio. We have David Hung, Founder, President, and CEO with us. Philippe Sauvage, CFO. Thanks, guys, for joining us.
Thanks for having us.
Yeah. I do not know, David, do you want to kick it off just with any sort of high-level stuff before we get into any details?
Yeah, I think it has been a really great year for us. As you know, IBTROZI got FDA approval a little over a year ago. We have had a little over a year of launch, and IBTROZI has been a very strong launch. We are already the number one ROS1 TKI today on the market. I think that the uptick of IBTROZI is consistent with what we believe is a best-in-class profile, an unmatched duration and response of over four years, a very tolerable safety profile with an extremely low discontinuation rate. I think that a very strong CNS control for a disease that gets to the brain a lot.
I think that the launch of IBTROZI has gone really well, and I think that it will continue to go well, considering the fact that now we don't see any real competitors on our horizon, given the most recent label for t aletrectinib, which I think is challenging. Again, with CNS warnings and precautions, which we don't have, adverse events that, again, we don't have, and frankly, efficacy that doesn't match our metrics. I think that we are in a good position there. Safusidenib, you saw the three-year data. I would say that data's pretty unprecedented. 52% response rate at three years, 79% non-progression at three years. That's just not been seen in glioma, high or low-grade glioma, by the way. We feel very comfortable there.
We're in a number of pivotal studies for safusidenib and are just in the process of getting those trials enrolled and hopefully completed soon. I think we're in a comfortable position there. Our cash with the shoe now is about $700 million, so we're comfortable on cash. We have plenty to get us through to profitability, as we've said. We have internal programs with our DDC platform that we're going to be updating the street on later this year. But I would say all in all, it's been a pretty strong year for us, and we're in a pretty comfortable position.
Awesome. Okay. Well, Dave, let's start with IBTROZI . The part of the long term is to get more patients taking IBTROZI in first line, and those patients would have a super long duration of therapy when that happens. Maybe give us where you are now, where you think you could be, not guidance, but call it a year or two from now.
Yeah. About 85% of our patients right now are first-line patients, which is pretty good. As I said, we are the leading ROS1 TKI among our competitors. But our biggest challenge isn't really so much our competitors as just the practice, especially in the community. Right now, even with ROS1 disease, there's still a lot of IO chemo being given, more than it should be. There's a huge difference in outcome with IO chemo versus a precision oncology agent like a ROS1 TKI. And there are multiple publications showing that even if you were to switch patients to a ROS1 agent after just 35 days on IO chemo, your survival never catches up. In spite of that, we still see significant amount of IO chemo use. So that we're trying to change, and we're all over NCCN trying to make sure that those guidelines are really adopted.
The NCCN actually contraindicates IO for a ROS1 disease, yet it is still done. We are trying to really make sure we educate physicians on that point.
What do you think the tipping point is for that? NCCN is obviously a good program.
Yeah. The NCCN guidelines changed about a year and a half ago. Nothing happens quickly in clinical practice, but I think that we are at that point where I do think that ROS1 TKIs are being appreciated more on IO chemo, at least. We have had a very concerted effort at multiple community centers, some of the larger aggregators to review their IO chemo use compared to their ROS1 use. When we educated them, we were actually able, in one center, to double their ROS1 TKI use, and another center, to triple their use. Education does work, but it is a little bit of a center-by-center education program. Some of these centers are very large, so that if you hit one center, you can capture many patients in many states. It is worth doing, and we are doing that.
One big competitor for us is IO chemo. I think that is where we have a lot of improvement to have. The second thing that we need to improve is just testing in general. Even if you look at other precision oncology cancers like ALK or EGFR, even 10 years out, even those cancers are not being tested for 100%. We have seen that in academic centers, ROS1 testing is close to 100%, but in community centers, some of the lower centers can have testing rates as low as 30% or 40%. That is another major educational effort. I think that now there are so many precision oncology agents that gradually will increase. That is a rising tide that should float all boats.
I think that the recent selpercatinib data in RET, showing the incredibly robust hazard ratio, 0.17 in the adjuvant setting compels even earlier testing for RET, and as a result, it should compel testing for all lung cancer mutations. You can't just look for one mutation. You're going to look for all of them. I think there are a number of tailwinds that should help us, but right now, I would say those are our biggest challenges.
Is there some level of evidence from testing that you feel like would be a real momentum driver? It seems you're totally right. There's tons of testing across the oncology landscape for biomarkers, et cetera. But can you build awareness through that? Is there more work to do, I guess, is the question.
I think there's always more work to do. Testing in 2026 should be 100%. There's such a huge difference in outcome for patients if they get a precision agent versus IO chemo. So it's a no-brainer clinically, and yet it just isn't done. I think that we are seeing increasing in testing, which if you look at selpercatinib sales, they're increasing. If you look at ALK and EGFR, they've all increased over the years, too. I think that it will get there. And I suspect that ROS1 is just really in the same position as those other agents. So I feel confident that we'll get there. I do also think that testing itself is getting better automated. It's a lot less cumbersome now to get an NGS test result back because, in many centers, they're actually automatically flagged. They're actually pooled.
They're actually consolidated and highlighted and put to the front of your chart. So there are a number of things that make using NGS a little bit easier, and I think that those things will improve the uptake of precision oncology agents in general.
And maybe just at a high level, where are we OUS with regard to these drivers versus the U.S.?
We're partnered with Eisai.
Yeah.
Eisai is going to be covering Europe. I think there are a lot of the same issues in Europe, I think.
Okay.
But those agents, the other precision oncology agents, sell well in Europe. So I think that we probably face less of the issues of IO chemo in Europe than we've seen in the United States. But I think that testing in general can still improve everywhere. But I would say that in Europe, we feel pretty confident that we're in good hands with Eisai on that.
Yeah. Okay.
Oh, by the way, to mention, if you look at Japan and China, by the way, testing rates are really high. There is very little IO chemo use. Perhaps that is related to financial incentives for IO chemo that do not exist in China and maybe less so in Japan. We do see extremely high testing rates and the use of the appropriate agents there. There are differences around the world. I think the U.S. is one of the more challenging areas, but we feel that we have easily the best agent out there. Our growth has been good, and our adoption seems to be on track. We still do feel confident about it.
Okay. I guess one of the final questions on IBTROZI, just the TAM. Talk a little bit about the peak opportunity as you see it, maybe U.S., then through Eisai, the rest of the world.
The epidemiology, and we have actually confirmed the epidemiology internally by reviewing electronic medical records across multiple large aggregators. In one such study, we took over 39,000 medical records of patients who had non-small cell lung cancer and looked at the number of ROS1 diagnoses that they had among those 39,000 patients, and we found exactly 2.1%. The literature says 2%, we found 2.1%. The market is there.
If you look at the number of non-small cell lung cancer patients and take 2%, that is about 3,000 patients per year. If you multiply that times the drug price, which is about $350,000 a year, that is about $1 billion for every year of new patients. But because of our four-year plus stacking, that $1 billion in the first year should go to $2 billion the second year, $3 billion and $4 billion in the fourth year.
A little over $4 billion in the fourth year. That's with DNA testing. If RNA can detect about 30% more than that, which it should, that could be conceivably $5+ billion if you can get all 3,000. That's a theoretical maximum. You're not going to ever get 100% of that. But we do think that the market is large. It should be well over $1 billion if we just look at the current epidemiology and multiply that times current drug price and our duration of response.
Perfect. Any other IBTROZI questions? Anybody? I guess the last one is the duration of therapy, are there lessons to be learned maybe in the real world today versus the clinical practice? Maybe if you see people discontinue, what is the reason in the real world and maybe your long-term view on matching the PFS information.
Yeah. The reason that we're so bullish on the future of IBTROZI is that so far in our over a year since launch, we have not seen any surprises to us. The patients on IBTROZI seem to be staying on us exactly as long as we would expect from our clinical trial so far. So, no surprises. I think that one of the reasons that our drug is taken for as long as it is not only is it highly efficacious, but if you look at our six most common adverse events out of our 337 patients, only one patient discontinued drug for any of the top six AEs. Even though LFT elevations are our most common AE, LFT elevations are clinically invisible. People don't know they have it.
For the most part, I would say that we've been very encouraged by how long patients are taking the drug. As they get more and more used to it and managing some of the more common adverse events, that should continue. So we do feel that what we're seeing in the real world is good, and we're pleased with it. Now compared to our competitors who have far more challenging tolerability issues that are much more clinically apparent than things like LFT elevations, we feel that our advantage will just be consolidated going forward. We think it's going to be pretty hard to beat a 15-month DOR, and this.
Right.
We're already years ahead of many of our competitors, and it's just going to be really hard to beat that. How do you beat a 90% response rate?
Right.
No drugs in history have had a 15-month DOR and a 90% response rate. We feel comfortable on the efficacy front, we're probably never going to get beat. On the safety side, patients are taking it because the discontinuation rate is pretty low. We feel pretty good about this launch.
In your discussions with investors, IBTROZI to safusidenib to the rest of the platform technology, what would you say is the distribution? Are most people focused more on safusidenib?
I think, yeah, people are mainly focused on IBTROZI. Safusidenib is-
Okay.
something that I don't think people have really spent a lot of time.
Okay.
Because of our, when we announced that our first pivotal readout would be 2029, I think that was just too far out for anyone to give it any attention.
2039 to most people.
It might as well be. Since we announced our first pivotal study, we actually have announced several other studies that are now enrolling patients and looking at response rate, not PFS as endpoints. The advantage of response rates is that they can happen much sooner. We know that, at least for a couple of other glioma drugs, you look at Chimerix or Day One, both of those companies have glioma drugs that have been approved only on response rate. We know that's an approval endpoint. If you look at the Chimerix approval for their glioma drug, it was based on 50 patients and a 22% response rate. That was 11 responses out of 50 patients. That's not a lot.
We are enrolling multiple studies now covering all four types of glioma from low risk, low grade to high risk, high grade, and we think that, at least in the studies that have response rates as endpoints, the readouts are going to be considerably earlier than 2029. As a result of that, we are getting a little bit more attention.
I guess let's talk a little bit more about safusidenib in detail.
Yeah.
Could you walk us through maybe for those who are still ramping on the story, the development programs that you are evaluating the product in?
If you look at the only competitor we have in IDH1 glioma, it is vorasidenib. If you look at their INDIGO study, which was the study upon which they received approval, in their phase III study, vorasidenib had 11% response rate in low-grade glioma and a 0% response rate in high-grade glioma. When we announced our Daiichi data, we showed that, if you look at in low-grade glioma, safusidenib's response rate was 44%, and in high grade it was 17%. But a third of that, 6%, were complete responses, which means the tumor disappears. We had a GBM patient whose tumor disappeared for three and a half years, another high-grade oligo that has been gone for about two years. So very robust responses. If you look at progression rates in the vorasidenib trial, in INDIGO, at one year, there was a 23% progression. We had 4%.
In the INDIGO study at two years, they had 41% progression, and we had 12%. Again, pretty big. Now, vorasidenib and safusidenib both announced recently three-year follow-up. At three years, if you look at the non-progression rate for the safusidenib arm now, it's 79% at three years out. It does, really, that's just not really been seen before. That's a very durable response for a brain tumor that has had no therapy really until vorasidenib. If you look at our adverse event profile, only 7% drug discontinuation due to drug-related adverse events, which is pretty well tolerated. I would say that efficacy and that tolerability we feel it's going to be a winner for us.
This is a huge market because even though the actual number of patients with glioma is about the same as ROS1, low-grade glioma patients can live for 20+ years without drug, and even high-grade patients can live four to seven years. We're talking about the worst glioma patients still having a potential DOR longer than IBTROZI first line, and the low-grade gliomas having a potential DOR 5x of IBTROZI. If that materializes, that would be one of the largest commercial opportunities ever seen in oncology. I said that IBTROZI, if you look at the TAM there, with RNA testing, it could be $5 billion a year maximum TAM. In low-grade glioma, it could be 5x that because it's just 5x longer DOR, right? If you look at vorasidenib pricing, they're priced at $40,000 a month, so 30% higher than IBTROZI.
Just looking at that makes the TAM of this opportunity dwarf ROS1, and we think ROS1's already big.
Are there lessons learned from the Servier launch? I know we don't have a lot of visibility on that. From a commercial setting, can you look at that to have a proxy for awareness? Can you look at-
Yeah.
their clinical plan, maybe to try to pull the trigger a little earlier? I know you mentioned response rates being.
Right. We can only glean Servier sales from Royalty Pharma's royalties.
Yeah.
But when we look at the Royalty Pharma royalties in the last quarter, vorasidenib is on about a $2 billion a year run rate after only 18 months on the market. So it's done great. It's the only glioma drug approved. So it's done great, and the market is there, and there are no conflicting practices, like IO chemo or something, because no one does that for brain tumors. So I think the vorasidenib launch has taught us that the market is exactly what we think it is. It's there for the taking. We think that, I mentioned that at one year, vorasidenib's progression rate is 23%, which means that in the 18 months since launch, as of last quarter, they had treated over 5,500 patients, which means a quarter of those have already progressed or are progressing.
That's well over 1,000 patients, 1,250 patients that are already progressing and in need of another agent. So that market is there. So, we think that safusidenib will fulfill that need.
I guess what sort of KOL feedback are you receiving regarding safusidenib and the opportunity there?
We've received shockingly positive KOL feedback. Most of these KOLs are reluctant to call a drug better than another without a head-to-head trial. Almost every KOL we've spoken to said, "Yeah, your drug is better than vorasidenib." That's something we don't see very often. We just had a major KOL at one of the large institutions here make that comment to us. I think the data are hard to compare because as I said, when you have almost 80% of your patients still on drug at three years, there isn't anything close to that. Yeah, I would say that our KOLs love this drug, and our trials are enrolling exactly on track because people like the drug.
Great. Yeah. You mentioned data 2029. Could you maybe walk through the trial design and maybe what we could see?
Yeah. This is a maintenance study for, it's called the SIGMA trial, and it's to take patients who fail standard care therapies, and it's against a standard of care, and it's a progression-free survival endpoint. It's just slow when you want to wait for events to look for progression. You have to wait for progression, and if you have a drug that has a really long time to progression, it's going to take a while. We think that that study will read out in 2029. Shouldn't be longer than that. It's been on track for enrollment. But I think that what's maybe more exciting to investors, and also in some ways to us, because we want to get this drug out as quickly as we can. We're looking at a number of studies, populations that are amenable to an endpoint that's a little sooner to read out.
One example of that would be grade 3 oligodendroglioma. Almost all these patients have measurable disease. Unlike the SIGMA patients who do not always have measurable disease, all the grade 3 oligodendroglioma have measurable disease, which means that they have a tumor that can be assessed for size and response when you treat it. That should be a response rate that we can see. We have another study, which is maybe even more exciting, which is the post vorasidenib trial. These patients, as I said, a quarter of them will fail vorasidenib in the first year. But once they fail, they do not really have a lot of options. If we can show responses after a vorasidenib failure, and we know these tumors are there because they are growing, because they are failing. They are actually growing.
If safusidenib can shrink those tumors, I think that will have a huge halo effect on people's perception of the drug. To work where something has failed, I think always makes a drug look superior. I think that if we can show changes in response, compared to vorasidenib , I think that is going to be a very positive trial for us. The second thing that I mentioned on a last quarter earnings call is that we are also looking at something called tumor growth rate. Because when tumors are growing, their slope is positive. A positive slope to a negative slope without changing your slope. That has to reflect the change in tumor growth rate. We have actually now looked at our data and have shown that in every one of our cases where patients respond to therapies, there is a change in tumor growth rate.
The growth rate slows and then it goes from positive to negative. And we think that is clinically meaningful. The FDA does not currently accept that as approvable endpoint, but as we accumulate more and more data, we intend to continue to pursue that conversation with them, because I do not think anyone is going to argue that a growing tumor is less good for a patient than a shrinking tumor, and that is reflected by the TGR, the tumor growth rate. Response rate is still a gold standard endpoint, but we think tumor growth rate can and should be another endpoint to consider, and that would be even sooner to read out than response rate.
Quick question on the development plan. Is there a switch study maybe to do over the long term? I know obviously you are going after patients that are refractory, and that is a tangible population. But do you think, eventually you could do something to that degree, or maybe an earlier line? What are the challenges, I guess, of having vorasidenib as the standard of care today?
Yeah, I do think that. It's interesting that even today we're getting a lot of calls from low-grade patients who are contemplating vorasidenib, but would rather be on safusidenib. They're asking if they're eligible for our trials because they've seen the data and they think the data are better. We do think that if we show responses in any of these populations, SIGMA, the grade 3 oligodendroglioma, the post-vorasidenib study, we think that would be compelling for patients to receive it earlier and earlier. Because as good as vorasidenib is, their data doesn't really compare to safusidenib's, and I think that our hope would be that patients don't even switch, they just start safusidenib no matter what they have, because I think it's probably the better drug if they have low-grade or high-grade disease.
Yeah. Jeff, I think what's important to keep in mind is that of course, we are talking about several trials, but the hope at the end accumulates to build a whole glioma population, right? You have the low-grade glioma. We are doing that ex-U.S. in places where you have no access to vorasidenib. That puts us into approval there and to be used exactly in the same place than vorasidenib can be. Then with the post-vorasidenib, evidence of further efficacy with a grade 3 oligodendroglioma, evidence of further efficacy, and with a high-grade glioma, evidence that we work even when vorasidenib doesn't. I think when you sum all of that together, it becomes pretty clear if we are successful for all those trials, we are going to grab the whole market.
Because why would you pick something which is less efficacious, especially for something like a brain tumor?
Yeah.
Great. Yeah. I guess, could we talk a little bit more about the global opportunity? I guess how is awareness ex-U.S. and just how are you looking to expand?
I think this is a disease which is obviously everywhere in the world, and everybody will treat it. I think from the point we were making earlier with taletrectinib, it is a very different proposal because, to some extent, ROS1 can be missed. This will not be missed, and this will be only in centers that are very strong doing brain cancers. You do not do that everywhere, right? I think in terms of promotion, the number of places we need to go, and where it works, it is a very easier, to some extent, population to reach, if that is your question. Vorasidenib today is in the U.S. I think they just got a pricing in Japan, which was relatively high, which is good news for the value that they put in that market. They are in negotiation in Europe.
We will develop something for the whole world, just like they did.
Yeah. As Philippe said, it is really hard to miss a brain tumor because the brain is confined by the rigid skull, and you cannot grow without causing so much pressure that you get clinical symptoms. No one misses a brain tumor. Its diagnosis is pretty quickly. I think that the market is there. We have already seen the vorasidenib uptake. They are selling a ton of drug. They have extremely high uptake, and in fact, they are even getting uptake in patients who are not even on their label. A testament to how desperate these patients are and how much they need some therapy. If we can show what we hope to show in these populations, we think that safusidenib could and should take the entire glioma market.
Great. I guess any other safusidenib, or we can move over to DDC?
Yeah.
Great. Yeah. Let's talk a little bit about the DDC platform. Maybe could you walk us through the technology here and how it could be differentiated?
The idea behind the DDC is, we certainly all know about ADCs, but the problem with ADCs is the A part is really big, so it doesn't allow that molecule to cross cell membranes very well. Many of those ADCs have to be cleaved to release their warhead. When they release the warhead, that warhead is no longer actually targeted. It can diffuse elsewhere. You get interstitial pneumonitis. You can get lots of systemic side effects. The idea behind a DDC is making the targeter and the warhead, both small molecules, or combining two warheads. You can mix and match your payloads in multiple ways, but because they're all small molecules, they're in order of magnitude smaller than ADCs, and now readily can access intracellular compartments and go into the cell and get into the tumor. We think there are real advantages there.
When we started our program a year ago, we had a candidate that we took into the clinic, and when we got into humans, we learned a lot of things about how these. This is a first-in-man study, so when we learned a lot of things about how NUV-1511 worked when we were in patients. And while we actually did see responses, it wasn't perfect. We learned things that we thought we could improve, and our idea is that if we take a program into the clinic, our hope is to take it into pivotal studies. But if we're going to commit $100+ million to a pivotal study, we want to make sure that molecule is as fine-tuned as we can make it. We decided to do that.
We decided to redesign some of our molecules with some of the considerations that we learned from our first study, and we've been doing that. Hopefully later this year, we'll be announcing an update to that program.
Just to be very clear, this is really hard to do, right? Don't take it the wrong way. Because it's very easy to combine two molecules to make something that doesn't do anything at all. That's relatively easy. But to combine two molecules to make sure that it retains both properties that made those molecules very successful one way or another in oncology, that's a hard part, and that's why we've been really building a lot of understanding of the way that works. That gives us a potential of having really this strong platform where we can come up with more and more molecules in that space. If you can combine them, on top of that, make them synergetic, then it's really the Holy Grail.
Because what we see in ROS1 or IDH1 are diseases that are driven by a single mutation to some extent, very strongly by a single mutation, so that's easy, but that's unusual in cancer. In most cases, you have several processes going on at the same time. But you can combine your agents, make them synergetic so that you're blocking several parts of the several processes going on, then you can hope to have the same kind of super long efficacy we've seen in ROS1 and IDH1, and that's a promise of our DDC platform.
Yeah. Philippe is right. It took us five years to figure out the chemistry. It's really, really tough. But when we do see activity, when we manage to make a molecule active on both ends, we see activities, and we see profiles that we don't see with any other agent. So it is exciting, but it's been challenging.
I guess final question, when you think about Nuvation looking to next year, maybe talk about what you think the most compelling part of the story would be. Is it the commercial adoption? Is it potential data?
I think through next year, I think there are a couple of things we'd like to see. Number one is if IBTROZI really starts to take off with first-line and revenue stacking. We think that we are clearly going to be the leader in that area, so we're excited to see that finally take hold and testing increase and IO chemo use go down. We think safusidenib should have some. We're going to start to see some data from our trials next year. It's hard to know when. Our shortest time to response in a safusidenib patient is a response in two weeks, but our longest time is over a year. That's why we can't really tell you when we think that we're going to see those responses.
We know we do see responses, and when we start to get those, I think that's going to be super exciting. Because as soon as we see any significant responses, we're going to be going to FDA and asking them,
Yeah.
What do you need to approve this drug?" As I said, Chimerix had 11 responders to get approved, so it's not a lot of patients. Hopefully we'll have DDCs chugging along, and we'll still have a ton of cash, and we're also looking out always for exciting business development opportunities, and so that's something else that we also keep focusing on.
Okay. Thanks, guys.
Thanks so much, Jeff.
Later on .