Hello everyone. Welcome to day two of the Cantor Global Healthcare Conference. My name is Li Watsek, a biotech analyst here at Cantor. It is my great pleasure to welcome our next company, Nuvation Bio, for a fireside chat. With me today is David, CEO, and Philippe, CFO. Thank you for joining me. Maybe David, I will turn it over to you to give us a 10,000-foot view of the story before we get into the pipeline.
Great. Thanks, Li. Thanks for having us. Nuvation Bio, I think we are on really solid footing. We launched IBTROZI, our ROS1 inhibitor, a little over a year ago. I think with now all competitors' data out in the open, I think it is pretty clear that IBTROZI is the best drug in class. If you look at our efficacy, 90% response rate, 15-month duration of response on the first-line setting. That is actually never been matched by any drug in any indication in oncology.
So I think we are clearly the best ROS1 drug. Our tolerability, again, with an overall discontinuation rate of 6.5%. Discontinuations for any of our top six adverse events at one in 337 patients. Again, extremely tolerable drug. The reason that this opportunity is so unique and underappreciated is that very few drugs in oncology have durations of response that are even close to 50 months.
Because of the 50-month duration of response, that leads to revenue stacking that you generally just do not see. Even though the epidemiology tells you that there are 3,000 ROS1 patients newly diagnosed in the first-line setting every year, if we were just to multiply that times the current drug price, that would be $1 billion a year. For every year thereafter, up till 4+ years, you would expect an additional $1 billion. So $2 billion in the second year, $3 billion in the third year.
$4 billion in the fourth year. So that is where you can see the revenue stacking leads to a significant number. That is with the epidemiology based on DNA testing, which is 30% less sensitive than RNA testing. When RNA testing becomes standard of care, we could even see that potential $4 billion market exceed $5 billion. Where are we with relation to that? As I said, 3,000 new patients a year by DNA testing, that is 250 patients per month. If you look at the number of first-line patients, in our first quarter of launch it was 70, second quarter was 80, third quarter was 100, fourth quarter was 140. If you just look at where we are right now, at 140, that is almost 50 patients a month. The market is 250 patients per month by the epidemiology.
After a year, we are already a fifth of the way to capturing the entire pie. We think that with other new changes, like the NCCN guidelines changing to now contraindicate IO, that will further increase the adoption of ROS1 agents. Then with a general increase in testing, that will further increase the uptake of drugs like IBTROZI. I think we are doing extremely well on that launch, and we look forward to updating you with every quarter that we announce our sales for the quarter. Safusidenib is our IDH1 drug for gliomas. I would say that that program is really exciting because we just recently announced three-year follow-up data with that program.
If you look at our only competitor in the space, which is vorasidenib, if you look at safusidenib's non-progression rate of 79% at three years, so only 21% progression at three years, we would say that that has just not been observed before in gliomas. Our response rate at three years has increased from 44% to 52%. Again, not observed before. I would say that program looks extremely promising. We are going after all four pieces of the glioma pie.
So low risk, low grade, high risk, low grade, low risk, high grade, and high risk, high grade. You have four clinical trials that are targeting all four pieces of that pie. The SIGMA trial is a PFS study that will not read out until 2029. We have a study against placebo that will also be a PFS trial that will read out in 2029. But we have two other trials that have response rate endpoints that could read out significantly sooner. One is a grade 3 oligodendroglioma trial. Because these patients all have measurable disease, we will be using response rate as the primary endpoint. If we look at Chimerix, which got their drug approved in DIPG on the basis of 11 responses out of 50 patients, we think something around a 20% response rate is potentially approvable. Then we are doing another study, which is in post-vora failures.
These are patients who failed vorasidenib, and if we show responses with safu in those patients, we think that is really exciting, because now these patients have no other treatment options today, and we believe that would allow us to capture the entire vorasidenib market. Again, VORANIGO has treated more than 6,000 patients since launch. We know that the progression rate for vorasidenib at one year is about 23%, so about a quarter of those should have failed by now. We think we need to get something like 50 patients and show roughly 10 responses to potentially have an approvable package.
We are pretty excited about that. Our drug conjugate platform is our two-small-molecule conjugate platform, which is kind of like an ADC without the A. We are using two small molecule drugs. We are going to announce an update on that in the second half of the year. From a cash standpoint, we have $700 million on the balance sheet, so we are very comfortable, far more than we need to get to profitability. With that, I think we are feeling very comfortable where we are.
Yeah. That is a great overview, David. Let us start with the IBTROZI launch. As you mentioned in your Q2, you had a very nice frontline patient mix in terms of percentage. It is about 85% in new patient starts. How should we think about the long-term growth trajectory from here as you guys shift more—
Yeah.
—towards the frontline?
Yeah, so that is a great question. As I mentioned, we started with 30% of our patients in frontline to 40%. Now it is 85% in the frontline setting. With that, we have still only captured, right now, 20% of the theoretical 3,000 patients per year in the frontline setting. So where else are we going to get it from?
First of all, we are already the market leader among our competitors but there's still more to be had. There's still some repotrectinib sales. There's still some crizotinib sales. We hope to eventually cannibalize all of that. Number two, in spite of NCCN guidelines, we know that especially in some community centers, IO chemo is still being used. In some centers, as much as 40%. We think that as NCCN guidelines kick in and people start to really realize there's a many-year difference in survival between IO chemo and a ROS1 agent, we think that we will start to convert that IO chemo use to ROS1 use.
And that's going to also potentially even double our sales. Then on top of that, we know testing rates, while they're high in the academic centers, in some community centers can be as low as 30%- 40%. So we have potentially even double sales based on just improvement of testing rates in the community. We're at 50 patients now. If we were to double from IO chemo, that would take us to 100, and if we were to double that from testing, that could take us to 200. And that'd be closer to the 250 theoretical patients that are maximally available in the frontline setting.
We are going to continue to just educate physicians on the vast difference in outcome between IO chemo and a ROS1 agent. We'll continue to take market share, we believe, from other current ROS1 agents. And testing in general has increased because many precision oncology tests now have turned lung cancer into one of the most treatable cancers on the planet if you know you have one of these mutations.
Another point I want to raise is that if you look at the selpercatinib RET study with LIBRETTO-001, the LIBRETTO-432 study, that hazard ratio of 0.17 was one of the most robust hazard ratios ever seen in this adjuvant study. Which means that you're going to need to look for RET mutated lung cancer earlier, because you can reduce your risk of death 83%.
That's going to be a rising tide that floats all boats. You don't look just for RET, you look for everything. Things like that will also move the testing far more forward and increase overall testing. We think that those things will continue to accelerate our discovery of first-line patients and treatment of those patients.
On the point of physician guidance, I know it takes some time to change physician behavior and still some physicians are using IO chemos. But beyond just education, what other things can you guys do to facilitate that transition into using a ROS1 agent? Is it more of a problem in the community or the academic centers?
It's definitely more of an issue in the community. I think most academic centers are pretty comfortable using precision oncology agents for precision mutations. I think that in many community centers, many of them still give a lot of IO chemo, and that's kind of their default thinking. I do think that we're not leaving it entirely to the hands of the physicians. We're educating them, but we also have very close connections with patient advocacy groups.
We're making sure that our digital marketing campaign also reaches patients broadly because this is a rare disease and digital marketing is extremely efficient in reaching a broad swath of patients. We're not just targeting physicians, we're targeting physicians, we're targeting advocacy groups, we're targeting patients, and I think all of that together has already resulted in us capturing already 20% of the maximum ROS1 market in just a year, and we think that will continue to grow.
And we're also targeting organizations themselves. We have partnership with multiple organizations around the U.S. to just look at what they do, what is their practice how does that evolve, how many ROS1 patients are they treating with a TKI? And we just show to them the gap between where they are and where they should be from a patient pool perspective. And this is extremely powerful because nobody can challenge the fact it's better to give a targeted agent than IO chemo. So those organizations, especially in the community, have been consolidating, aggregating
And there are organizations that are really trying to push best practices into practices everywhere, and those partnerships have been extremely useful to change behavior. In some cases, we've doubled the number of patients, in some cases, we've tripled the number of patients. So this is really also another way to say, "Hey, look at what's going on in your organization compared to what is best for patients, and how can we help you to reach that kind of level?
Okay. Then, we know GSK is going to perhaps get their front-line label for their ROS1 agent. It is already approved in second-line plus. How do you think this market share dynamic will play out next year once it gets a front-line label?
So I think that we saw the JUDGE-RETRO label last month.
I think that it is pretty clear that it was not what was anticipated.
Yeah.
Nuvalent had always touted JUDGE-RETRO as a CNS-sparing ROS1 agent. Not only was it not CNS-sparing, but they actually received a CNS warnings and precautions, which makes now IBTROZI the only ROS1 agent without a CNS warnings and precautions.
If you look at the incidence of JUDGE-RETRO's CNS toxicity, it was 25% already, even though their follow-up period is a quarter of ours. We know that with longer follow-up, you get more adverse events. At already 25% with just a quarter of our follow-up, we would expect that to increase significantly, potentially even up to repotrectinib or beyond repotrectinib. We don't think that's going to make it easy to use. On top of that, other adverse events that weren't even anticipated. 22%-25% incidence of pancreatitis, 38% peripheral edema. These are things that make a drug very cumbersome. Our most common adverse event is liver function test abnormalities, but that's invisible to patients. They don't even know they have it.
When you have CNS tox, and swelling, and pancreatitis, you know you have something wrong. We think that's going to make it difficult, especially in the front-line setting, to be on drug for a long time.
Given the fact that we are now the only ROS1 agent without a CNS warnings and precautions, we think that gives us now a huge advantage on the safety side and with our unprecedented efficacy, I would say that we don't think we actually have a close competitor. If you look at just the efficacy in the second-line setting with, JUDGE-RETRO, 48% intracranial response rate versus our 66% response rate, again, not close. I think that we're feeling extremely comfortable with where we are. We expect to take market share continually away from our competitors.
Our biggest competitor is actually IO chemo.
And testing. That is where we are really focused. But I think compared to other competitors, I think we are extremely strongly positioned.
Yeah. We also have not seen any long-term data from.
That is correct. There is no—
Yeah.
—significant front-line data presented for that agent. I don't know how you beat 90% response rate in 50—
Yeah.
—months DOR. It's going to be very challenging to even match that, much less beat it. I think we're very comfortable with where IBTROZI's profile sits, and we think that right now the way we're going to get to the 100% is to change prescription behavior with IO chemo and increase testing, but that's where we need to be. But we're already a fifth of the way there after just a year.
Mm-hmm. I mean, right now you have a pretty nice two-year head start. What else can you do to accelerate the entrenchment in the front-line setting?
I think the biggest thing we can do to enhance entrenchment is just to give physicians experience with the drug. If there was one criticism with ENHERTU, it's that they didn't have a lot of U.S. experience.
Now we've had a year of U.S. experience, and physicians who use IBTROZI love IBTROZI. I would say the thing that's entrenched IBTROZI use more than anything else is physician experience with it.
We've now seen many physicians re-prescribe IBTROZI because of their good experience with the drug. I think that will only continue to accelerate given the fact that if you look at other alternative options, there isn't anything close.
Mm-hmm. Maybe switching to safusidenib, your IDH1 inhibitor for glioma. I think this is a very compelling opportunity. What are investors missing about safu?
I don't think they're really missing anything necessarily, except that when you look at two of our trials reading out in 2029. I t's just hard to get a lot of investors excited about such a far—
Yeah.
—term readout.
Yeah.
I think, I'm not sure they're missing it, I think it doesn't attract their attention because those are farther away. What they might not appreciate is how quickly the other two trials could potentially read out. Those are response rate trials. We've already said that we're going to have 40 patients enrolled in the grade 3 oligo study by next year. What we don't know is how long it will take to see responses. Our shortest responses have been as soon as two weeks. Our later response could take a year or longer. We don't know of those 40 patients how many response we'll see by next year, but it's conceivable that we'll see enough to be of interest to FDA to start our discussions.
The other thing that we've already discussed with FDA and will continue to pursue is when you have a tumor that's growing, its slope is positive.
When you look at a response, by definition, its slope is negative because the tumor is shrinking. There is a lot of difference between a positive slope and a formal renal response. We would argue that any time a tumor flattens out its growth curve or goes down, even if it hasn't had a formal 50% reduction in volume, that's of benefit to a patient. To my knowledge as an oncologist, no one ever died of a tumor that hasn't grown. We would argue that there is real clinical benefit to slowing down the growth rate even before a patient hits a formal response, which is a relatively arbitrary criteria. If they're not growing their tumor or even shrinking it slightly, it's hard to argue that's not of benefit to a patient. In fact, what's interesting, if you look at our three-year data, 79% of our patients have not progressed.
Many of those patients at three years weren't responders.
They just didn't progress. They're still alive and still on drug. That really supports my point that you don't necessarily have to have a response to have clinical benefit. One thing we're going to talk to FDA about is once we get some response rate data, we're going to present our tumor growth rate data and show how tumor growth rate changes can precede response by a long time, months or even years. We believe that there's still real clinical utility of that. What's also interesting is that vorasidenib has also presented tumor growth rate data as well, showing that change in tumor growth rate and that by definition precede the response.
You can't go from a positive slope to a response without change in your tumor growth rate. By definition, it has to change. The two drugs that are being developed in IDH1 glioma both have shown TGR changes. We think that that's a very interesting endpoint, and we would love to see if FDA would consider adopting that endpoint as an approval endpoint. We'll have that discussion and see what happens.
Okay. How do you explain that safu shows better results in the higher-grade glioma than VORANIGO? Do you think it's just—
Well, first of all—
Yeah.
—I would say safu shows better results in high and low grade.
In the initial INDIGO set, the response rate for vorasidenib was 11%.
In our initial data set with Daiichi, it was 44%, so it was a pretty big difference. In the INDIGO study, VORANIGO's response rate in high grade was 0%. Ours in our first study was 17%, so I would say we were better in both high grade and low grade.
These two drugs are not equivalent. While they both are IDH1 inhibitors, if we look at our adverse events compared to VORANIGO's, five of our top seven adverse events are immune adverse events like vitiligo, rash, arthralgia. Vorasidenib has none of those effects. Their primary AE is liver function test abnormalities.
We believe that safusidenib does have an immune component independent of its IDH1 activity, and we've actually started to characterize that in our preclinical work. We don't think the drugs are equivalent. When we look at the time to onset of responses with safu, it sometimes takes months or even a year.
When we get responses, they can last for multiple years. We have one GBM that has disappeared for three and a half years. It looks like an IO agent. We think that safusidenib, in addition to being an IDH1 inhibitor, is also potentially a novel IO agent, and we don't think these drugs are in any way equivalent, and we believe the clinical data support that.
I think that is such an interesting finding that safu will have this immune-like effect. Do you think it is on target or off target? Do you guys have any assessment to do?
We do have some data on that. We are not talking about that because clearly we are using that data to analog our next molecule.
But I think, Li, to your previous questions about what our investors are missing, it is really important to understand that with our development plan, we are not only going after the VORANIGO market, but we are going after the whole glioma market. It is really a development plan with high grade, low grade, high risk, low risk. Everything is in there with steps, obviously, with first results in maybe by 2027 and then 2029, like David said. But it is really capturing the whole opportunity.
I think it's something investors have a hard time to reconcile because VORANIGO has been doing so well already.
I guess just on that point, obviously, you're running four different trials, looking at four buckets of patients. How would you rank the probability of success? Which one's more de-risked?
Well, I actually believe that all have a great chance of success just based on our data.
If we look at the SIGMA study, as I mentioned, in the study we just published at three years, we had a 52% response rate, and 79% of patients had not progressed at three years.
There is no drug today that can show those kind of data. I would say that looks pretty good to me. If you look at our INDIGO-type study with safu against placebo in places where VORANIGO is not approved, VORANIGO got approved, our response rate is higher, our PFS is longer. I think that looks pretty good. If you look at the post-VORANIGO failure study
Given the difference in activity, especially in some of our. If you look at higher risk grade 2s and lower risk grade 3s. It is a spectrum. It is a lot of overlap.
Yeah.
The fact that we have seen such dramatic effects in that grade 2, grade 3 interface, we think that the chance that we will show activity after VORANIGO is very high.
Then in the grade 3 oligo, and we had 17% response rate in recurrent high grade. Grade 3 is easier than that l ower risk.
We are close to 20% on the high-grade recurrent disease. We would expect to meet that bar in a lower risk, lower grade disease.
I think that we feel that we have a really good chance at all of them.
I guess for the post-VORANIGO study, do you have any direct clinical evidence showing that you have activity after VORANIGO? Have you treated any patients in the sort of post—
We don't have that direct comparison. What I will say is that if you look at VORANIGO's, the INDIGO study, which are mainly low-risk, low-grade patients.
We certainly have higher risk, low-grade patients and low risk, high-grade patients which we've seen responses in.
The fact that VORANIGO did not have those responses that we have them strongly suggests to us that there's going to be a spectrum of patients where there's that overlap. They didn't have those responses that we had those responses.
I'm going to guess this drug will work there because we're seeing responses in an overlap population that they did not have a response in.
Mm. When do you think you will be able to finish enrollment for this cohort? You only need 40, 50 patients?
We've said that we're going to have 40 patients in the grade 3 oligo study done by 2027.
Clearly, we think that the number of patients the FDA will need for approval is 50. We really start to see responses, we're going to increase that to 50.
Then we haven't given a number for the timing or the timing of the post-VORANIGO study.
I would say that all four studies, at least the studies that have started, are all on track. There's a lot of enthusiasm for the molecule. The patients are out there. If we look at the post-VORANIGO study, vorasidenib has treated over 6,000 patients since launch.
Yeah.
We know from the INDIGO study, 23% progressed at one year.
About a quarter of those 6,000 patients probably either have progressed already or close to progressing. Out of the 1,500 patients, we need 50.
We need to show responses in 10.
Yeah.
We don't think it's going to be really hard to find those patients.
Yeah, it seems like you should have plenty of patients—
I think so.
—out there. For the ex-U.S. phase III study in grade 2 disease, has the FDA confirmed with you that the ex-U.S. data can support U.S. approval?
We haven't discussed our FDA correspondence publicly, but everyone realizes that you can't do that study where there's VORANIGO.
It's just prohibitive.
We will have plenty of other data sets in addition to that study. We're going to have the SIGMA study. We're going to have the grade 3 oligo study. We're going to have the post-VORANIGO study, and we're going to have safety database on many, many, many patients. We believe that that trial is well-positioned.
Some of those studies will be heavily skewed towards the U.S. If you think about the post-VORANIGO study, that will be a lot of U.S. patients because that's where there are the most VORANIGO patients—
Right.
—obviously. I think the other thing to keep in mind that we are pointing out to investors is that because of the difficulty to do any head-to-head trial in that space, it is going to be extremely difficult for anybody else to come after us, too. Which means that by doing this, we are probably the last company, if you want, that can do ex-U.S. versus placebo low-grade glioma study. After us, it is going to be practically impossible, which means that it really kind of makes a market for us, too, for a long time.
Even in the U.S., I think that safu could be the last IDH1 molecule approved because how do you go head-to-head against that?
Yeah.
It is just virtually impossible.
Mm-hmm. Lastly, maybe just touch on business development. What would be the sweet spot for you guys in terms of bringing new assets?
We want later stage. We would love to have something that fills the gap between now and—
Yeah.
—the 2029 safu approval. But we want something that is great ROI, compelling data, an important unmet need. Something like the AnHeart deal. That was a great deal for us.
That was a great deal, yeah.
We'll be very disciplined. We do have a fair amount of cash, but we want to make sure that we spend it wisely, so we're going to be very disciplined. There's a lot of stuff out there right now, and I think that there's going to be a lot of opportunities.
Okay.
We didn't have time to spend a lot of time on this, but obviously, with the DDC platform.
Yeah.
We also have an early-stage pipeline. So it's not like we're in a company that has nothing after, if you want. At some point, we do have something after. We have an early-stage pipeline. We have safusidenib, which is more advanced. We have IBTROZI, which is already on the market.
If we can find something compelling, to David's point, we will do it, of course, but it's not something we absolutely have to do, right?
Okay. Great. It looks like we're out of time. David and Philippe, thank you very much for the time today.
Thanks so much, Li.
Thank you, Li.