Good morning, everybody. My name is Cory Kasimov, one of the senior biotech analysts here at Evercore ISI, and it's my pleasure to host our next discussion with Nuvation Bio. Excited to have the company's CEO, David Hung, as well as CFO, Philippe Sauvage, with us today. So thank you guys very much. And maybe the best place to start is to hand it over to you, David, for a brief update on the Nuvation story, a little bit of the history of the company for those less familiar.
Sure. Thanks for having us, Cory. So Nuvation Bio has started around a drug-drug conjugate program. That's how the company was founded. And over the course of the last few years, we were looking at a number of BD opportunities. We looked at over 200 different assets and finally found an asset that we really liked, taletrectinib and safusidenib, which were owned by AnHeart, a private company in China. So we bought the company this year, about six months ago. And based on that, now we have a pipeline of four different assets: two late-stage from the AnHeart acquisition and two early-stage from the founding of the company around the DDC program and then another program with the BD2 selective BET inhibitor. So with our two late-stage assets, taletrectinib's NDA was filed in October. We anticipate NDA acceptance later this year and a commercial launch mid-next year.
Safusidenib is a mutant IDH1 inhibitor for the treatment of gliomas, and we anticipate getting into a pivotal study on that sometime next year. The drug-drug conjugate program is in the clinic. We're in dose escalation around our first drug-drug conjugate candidate called 1511. And then our fourth asset, NUV-868, which is a BD2-selective BET inhibitor, has completed phase one.
Okay. Sure. So let's go into this AnHeart acquisition a little bit more. It really changed the company on its dime. Can you discuss a little bit more in terms of the background of this deal, how it came to be? I think the rationale is pretty obvious, but you can go into that too.
When we saw that we were looking for over two years at BD opportunities, and when we found the AnHeart target, we were particularly intrigued because in many ways, we thought of it as a perfect storm. It was a private company in China in the middle of COVID lockdown. It was really not widely appreciated by many outside of China. It had two assets that we thought had very compelling data. Taletrectinib had been tested in two large studies: one pivotal study called TRUST-I, which was an all-Chinese study, a second global study called TRUST-II. And we had reviewed all the FDA correspondence, and it was clear to us that the drug had a potentially best-in-class profile and that we believed that the drug would be imminently ready for NDA submission. So we decided to buy the company.
Actually, our first two offers for AnHeart were all cash offers. But the chairman of AnHeart, Min Cui, also really liked our drug-drug conjugate program, so they declined to accept our cash offers, and they insisted they wanted an all-stock deal. So, of course, the fact that they wanted an all-stock deal gave us even further confidence in the asset. We had already done extensive diligence on the asset and liked a lot, but we ultimately did the deal with a $280 million stock in this all-stock deal for the asset. We also were really, really intrigued by the safusidenib data, which we believe is a potentially best-in-class asset as well in the mutant IDH1 glioma space.
And so, given those two assets, we thought this was a really great opportunity for us to jumpstart our company into a late-stage company and, in fact, within the next six months or so, into a commercial-stage company.
Okay. Yeah. If these assets pan out, this deal is going to be looked back upon pretty remarkably. So you mentioned TRUST-I and TRUST-II. Can you provide kind of the key highlights of the taletrectinib data?
Yeah. So the taletrectinib data in TRUST-I and TRUST-II comprise one of the largest data sets ever assembled in the ROS1 space. It's a total of 337 available patients. And if you look at the profile of taletrectinib compared to the other ROS1 inhibitors, so there are two first-generation ROS1 inhibitors, one crizotinib, the other entrectinib. And if you look at the overall response rate of those drugs, which, by the way, they still sell about $500 million a year, entrectinib and crizotinib have a response rate of about 70%, 68% and 72% for those two drugs respectively. If you look at repotrectinib, the first, second-generation ROS1 TKI, the response rate is 79%, and taletrectinib's response rate is 89%. And that 89% is actually comfortably above the upper bound of the 95% confidence interval for repotrectinib, 79%. So we believe that that is clearly a best-in-class response rate.
If you look at the progression-free survival in the first-line setting for first-generation TKIs, it's about a year and a half. Repotrectinib's PFS is 36 months, and we just announced a couple of months ago that taletrectinib's response rate in the first-line setting is 46 months. So just to put that in some context for you, our response rate of nearly 90% and our progression-free survival of 46 months has only been seen in a handful of drugs in the history of oncology, in any indication. So if you even look at drugs like XTANDI from Medivation, the PFS in the PREVAIL study was only 20 months, and that's a $6 billion a year drug. If you look at TAGRISSO in eGFR, that's another $6 billion a year drug. In the FLAURA study, the PFS of that drug was 19 months.
So 46 months really puts this in a really elite group of drugs. And so we feel that this is a really, we believe it's a best-in-class asset, and we're really excited about launching it next year.
How aware is the physician community of the product, this data, and how differentiated do they see this? These aren't head-to-head studies, so.
So we just got these data, the pooled TRUST-I and TRUST-II data in October. We just presented them at ESMO. So these are relatively new data, and we are in the process of educating physicians around the country on this asset. The feedback we've gotten so far has been extremely enthusiastic. So I would say, I mean, we've had several, many KOLs now tell us that this is a best-in-class profile. So we feel very comfortable. And there's a lot of experience in ROS1, and so it's not, it's clear that these numbers are comfortably above the rest of the pack. So we feel very, very enthusiastic about this.
Okay. Great. And how about the safety profile of taletrectinib?
That's another thing that we are very enthusiastic about. If you look at our main competitor, which is repotrectinib, the major liability of repotrectinib is that although it hits ROS1 very avidly, the affinity of repotrectinib for a homologous protein, NTRK, especially TRK B, is very similar to its ROS1 affinity. So the therapeutic index is really one. It hits ROS1 and NTRK B equally well. So it's a one-to-one ratio. As a result, NTRK B is associated with CNS toxicity. And if you look at the dizziness rate as an example in repotrectinib, it's 65%. Taletrectinib, on the other hand, hits ROS1 between 11x-20 x harder than it hits NTRK B. So it has a significantly larger, order of magnitude different, better therapeutic index than repotrectinib.
As a result, our dizziness rate is less than a third of Repotrectinib, and as a result, most of those are grade one. So if you look at the discontinuation rate of taletrectinib, it's really at the bottom of all the other ROS1 TKIs. I mean, crizotinib's discontinuation rate is almost double our discontinuation rate. Entrectinib is significantly higher. So we believe that our tolerability is excellent. The major liability for taletrectinib is elevation of liver function tests. But as you know, many TKIs cause that, and oncologists are very accustomed to dealing with elevation of liver function tests. This is more of a paper issue, not a laboratory. It's a laboratory abnormality, a paper issue, not a clinical issue.
So physicians are very accustomed to dealing with that, and we feel very, very comfortable that if you look at discontinuation rate, which is the bottom line of tolerability, taletrectinib is at the bottom of the pack in discontinuation. So we believe that's a good reflection of how tolerable the drug is.
Do physicians typically take just dose-reduce?
Yeah. So the way that you generally deal with LFT abnormalities is either a dose interruption or a dose reduction. And as I said, the bottom line is discontinuation. And if our discontinuation rates are really, they're 7%. So at the bottom of the pack. So we feel that this is a drug that is really a best-in-class drug from both an efficacy standpoint as well as a tolerability standpoint.
From a design standpoint, was the molecule designed to avoid the dizziness? Was that something?
Right. So the molecule was designed with about an 11- to 20-fold increased affinity for the ROS1 target over NTRKB. So that was because looking at repotrectinib with a one-to-one ratio for ROS1 over NTRKB, that was associated with a profile that made tolerability very challenging. So with taletrectinib, Daiichi, which were the people from which this molecule originated, designed this molecule to have a much higher therapeutic index against NTRK. So as a result, our tolerability profile is significantly better on the CNS front.
Okay. And then how do you think about the commercial opportunity with ROS1 non-small cell lung cancer?
So if you look at the incidence of ROS1, it's about 3,000 patients in the U.S. per year. But that is not a small market given the PFS that we have. So the way to look at it is that every year, if you take 3,000 patients times the average repotrectinib selling price, which is $350 a year, that's a billion dollars every year. So in year one, you get a billion. Year two, you get a billion. Year three, you get a billion. Year four, you get a billion. But because the PFS is almost four years, everyone from year one should make it to year two and year three and year four. Everyone from year two should make it to year three and year four. So you get stacking of revenue.
So year one, if year one revenue is a billion, year two revenue is $2 billion, year three revenue is about $3 billion, and year four, you get 46 months, means you get 10 out of the 12 months in the fourth year, should be about $3.8 billion as a total market opportunity when this drug equilibrates in its fourth year. So we think that that's a pretty large market. And if you look at the eGFR space, where TAGRISSO is by far the dominant drug, they have 95% market share. If you look at the ALK space, that's another example where the leader of the pack dominates that market. We believe that our efficacy and safety profile will allow taletrectinib to dominate that market. So we anticipate a majority of market share for taletrectinib in the ROS1 space.
So of that $3.8 billion a year opportunity, we believe that we should capture most of that.
Okay. And then can you talk about launch plans in the U.S., how you're building the sales force, and also how you're thinking about tackling the rest of the world, partnering, going to the market?
Sure. So we've hired Colleen Sjogren, who was one of my superstars in the XTANDI commercial launch at Medivation. So she's our Chief Commercial Officer. We've already hired the senior leadership team for the commercial team in market access and sales ops and medical affairs. And we are going to wait until probably six to eight weeks before launch to hire the sales reps. But we're anticipating an acceptance later this year and a priority review and full approval, which should happen around mid next year. So we would anticipate a commercial launch sometime around June next year.
Okay, and outside of the U.S.?
Outside of the U.S., we're going to partner it. So we're already in discussions with potential European partners. And in Japan and China, we are partnered with Innovent in China and Nippon Kayaku in Japan.
Okay. And I mean, I was going to ask about the balance sheet later, but just talking about more non-dilutive funding, but you have a pretty strong balance sheet as it is.
Right now, we already have $550 million in cash. So we can bolster that further with a partnership.
Okay. All right. Perfect. So we don't have a ton of time left, but I want to make sure we get and cover some of these other programs. So safusidenib, maybe starting with the commercial opportunity there and what that is with IDH1 glioma?
IDH1 mutant gliomas are a significantly larger commercial opportunity than even ROS1. And as you know, there's only one drug that's approved for the treatment of mutant IDH1 glioma, which is recently approved, vorasidenib. And vorasidenib just announced in a phase III trial called the INDIGO trial a significant improvement in PFS from 11 to 27 months with vorasidenib. But if you look at the INDIGO trial, the actual response rate in that trial was only 10.7%. So a good PFS, but not a particularly robust response rate. In safusidenib's phase II study, the first phase II study from Japan, we reported a response rate that was 3x the INDIGO response rate, 33% versus INDIGO's 10.7%. So we think that's a pretty interesting number.
We're going to be presenting new data on yet another Japanese study next year from Daiichi, where we again show a very robust improvement over vorasidenib in the safusidenib dataset. We're particularly excited about that. If you look at vorasidenib's response in high-grade gliomas, it was zero. If you look at the response rates in target lesions in high-grade gliomas, grade three and grade four, there was a 7% response, sorry, 17% response rate in safusidenib, of which complete responses were seen at 6%. We actually had a GBM, which had a complete response, so the tumor disappeared, and at 174 weeks, was still gone. We had a second high-grade glioma whose tumor and target lesion disappeared, and at 95 weeks, was still gone.
Compared to vorasidenib, 0% high-grade response rate, we think again, safusidenib is a very, very interesting molecule, and we're very enthusiastic about taking that into a pivotal study.
Okay, and so what would that pivotal study look like?
We're in discussions with the agency right now, and we're going to try to figure out what we'll need to do. We have quite a few options we could pursue. By the way, I should mention that the vorasidenib asset, just Royalty Pharma paid $905 million to Agios for a 15% royalty on vorasidenib in just the US, so valuing vorasidenib in the US at around $5.5 billion. So given the fact that we have a significantly higher response rate in low-grade glioma and clearly a much higher response rate in high-grade glioma compared to the 0% response rate of vorasidenib, we think this asset has real value. And we're in the process of now trying to decide what pivotal studies we're going to do, whether we're going to do low-grade and high-grade or both.
We'll get some agency feedback on that, but we're pretty excited about that asset.
Okay, and I wanted to also work in a question on the DDC platform you mentioned upfront and kind of where you are with that and what we can be looking forward to.
Yeah. So DDCs were kind of our take on a way to improve ADCs. Everyone's very familiar with ADCs, where you couple a warhead to an antibody, which targets the warhead. We decided to try to do that with two small molecules. So using a small molecule target and a small molecule warhead, which gives you far more flexibility in ways you can target both intracellular or extracellular targets or both. It was difficult chemistry, but we finally succeeded in getting a lead molecule called NUV-1511, and that went to the clinic earlier this year, and we're now in dose escalation. And we hope to announce some data on that program sometime next year.
Okay. And so I guess that's a good segue into the last question we have in the last minute. You obviously have a lot of regulatory news coming next year, and big event coming in the middle of the year. As we start thinking about 2025, what are some of the other value drivers for Nuvation?
You know, I think clearly the most important value driver would be the approval of taletrectinib, and we anticipate that to happen mid next year and then the commercial launch. We would also anticipate taking safusidenib into at least one pivotal study or more. And we think that will be a significant value driver. Announcing data from DDCs, if we see positive signals, that could also be very, very compelling because the DDC platform is truly a platform. We have potentially dozens of molecules behind that 1511 molecule because we can mix and match multiple warheads with multiple targeters. And so if we show a proof of concept with our first molecule, we think that sets the stage for potentially multiple generations of products from that platform.
And then we still have 868, which we're waiting to see what happens with FDA and pelabresib, which announced a positive trial in myelofibrosis. And if that drug gets approved, then I think 868 could be interesting as well. But we're waiting to see what happens with FDA and that molecule.
Terrific. Well, it sounds like a very exciting year ahead. So good luck and look forward to following the progress.
Thanks so much, Cory.