... It's my pleasure to introduce Nuvation Bio. With us, we have CEO, Founder, and President David Hung, and CFO Philippe Sauvage. My name is Daniel Brander. I'm a biotechnology associate here at Cantor. And perhaps just for the audience who is maybe a little bit less familiar with Nuvation Bio's story, can you level set on the taletrectinib launch and what you're expecting over the next six to 12 months?
Yeah. So taletrectinib is our drug for ROS1-positive non-small cell lung cancer. We received FDA approval kind of mid-June, and at our first earnings call, we announced that just in the first seven weeks of launch, we had already enrolled seventy patients on taletrectinib, which we think is, you know, significantly better than we've seen with other ROS1 launchers. What's been interesting about that launch is that we're seeing very broad uptake across first, second, and third-line settings, so really all lines of therapy. We've seen uptake in both the academic and community settings, which is also great. And maybe most importantly, none of those patients came from clinical trials, so still continue. So these are all new patients. We had only six patients on from the early access program, but everybody else is just a new patient.
We're very excited about that launch. We think that this drug is extremely competitive. If you look at the other options currently for ROS1 therapy, crizotinib is a drug that doesn't cross the blood-brain barrier at all, which we think is an issue for a disease that 36% of the time when patients present with ROS1 lung cancer, they have a brain met already, and 50% of the time when they progress, brain is the first site of disease progression. We think it's important to have CNS coverage. crizotinib is not really an option there. If you're looking at entrectinib, another first-line TKI, the PFS of entrectinib is six months. If you look at repotrectinib, you look at just the quality of data and the discontinuation rate.
Repotrectinib is about 10% per month, so about 50% at five months, primarily due to issues with tolerability. If you look at taletrectinib, you know, in our JCO publication a year ago, we had a response rate of 89%, PFS of 46 months, which has not previously been seen with any drug in any cancer. With now five more months of follow-up, which went into our label, median DOR PFS have moved to no longer reached. We're very excited about that. If you look at the tolerability profile, we divide tolerability into clinical and non-clinical adverse events. If you look at clinical AEs, the most common AE is diarrhea, but 80% of that is grade one, and generally starts within two days but finishes within one day. It's really quite transient.
If you look at the most common non-clinical AE, just liver function test elevation. If you look at, this is primarily a paper issue because patients don't feel it when they have increased LFTs. Oncologists are very accustomed to dealing with LFT elevations. If you look at the three hundred and thirty-seven patients in the database, the number of patients who discontinued taletrectinib due to LFT elevation is one, so 0.1% discontinuation, right? So we think that overall, taletrectinib is highly effective, very tolerable, and we would expect this drug to become dominant in ROS1.
And you mentioned, you know, a pretty broad adoption across the disease spectrum. Do you think that that is truly representative, or do you still think that a fraction of the market might still be underpenetrated at this point?
I think that over time, given what we're seeing with this drug, over time, the second- and third-line rates for this, you know, they have the shortest duration of response, and this is really a first-line story. We're very excited that, you know, our last published median DORs, PFS are, you know, approaching four years, and now with the median so long to reach, you know, we don't know what the overall rate at, but it's long. We're excited about that. We think this will eventually become a first-line story, and that's what we're looking for. We think that there are other things that we have to address, and one is just a lot of testing.
While testing is about 100% in academic centers, I think depending on the community, there's room for improvement. In some community settings, the testing rate is as low as 50% or 60%. So we think that there's potentially significantly more upside there. But, you know, given the fact that precision oncology has really changed the world of lung cancer, where suddenly more particular mutations causing lung cancer of what used to be a death sentence, you know, only a couple of decades ago, now being one of the most treatable cancers on the planet, you have EGFR, ALK, and now ROS1, these have become eminently treatable cancers. That awareness has really increased NGS testing, which we think is now rising pie now with ROS1. So we anticipate testing rates will go up.
... Let's put a pin in the testing conversation. That'll come up next. In terms of the adoption and the ramp over the next couple of quarters, what are your expectations around that, and how do you expect the inclusion of taletrectinib in the NCCN guidelines to further drive the uptake?
Yeah, so we were pretty excited that IBTROZI got into the NCCN guidelines within a week of approval. That's pretty fast. I've not previously seen that, so I think that's a testament to how attractive IBTROZI's profile is and how important a treatment option it is for physicians and patients. So we were very excited about that. I think that, as you know, the NCCN guidelines just changed in January of this year, so it's a very new development. The old guidelines, up to the end of 2024, offered two options for the treatment of ROS1 patients. Because if many patients who had started IO chemo, the options were either finish the IO chemo or take a ROS1 agent.
The new guideline, which was issued on January seventh of this year, stated that if you were on IO chemo, IO is now contraindicated for ROS1 lung cancer, and that you need to switch to a ROS1 agent. So I think that is a very important development, but that even though physician adoption is probably never as fast as you want, I think that that's definitely a trend that is taking place. We're already seeing it in the internal guidelines of many of the large aggregators that we've been getting. So we think that's a very positive development, and it's the right thing to do for patients. Yeah, PFS of IO chemo, six to 12 months, and you can get a four-year drug. It's the right thing to do for patients. We think that's really, really important. So we're excited about that.
We think that while the NCCN currently doesn't specify which ROS1 agent, as I said, given the fact that Rozlytrek doesn't even get to the brain, you know, it's a very important site of disease progression, so we think you need to get a drug that gets to the brain. As I said, entrectinib sixteen months PFS now is pretty much outclassed by more modern agents, and we think that given repotrectinib's powerful efficacy profile, we think the clear choice will be repotrectinib. So yeah, very important that that will become the mainstay of treatment for the first time.
Okay, that makes a lot of sense. Maybe we can now return to the NGS testing. As you already alluded to, the rates are a little underwhelming, especially in the community setting. You had also talked about the differences between DNA-based and RNA-based testing, and that the latter is around 30% more sensitive to detect the ROS1 mutations. When you're talking about the adoption, are you talking about DNA or RNA sequencing, and how do you think you can help increase testing level?
Yeah, great question. So, you know, to date, most testing has been DNA-based. The RNA-based testing was approved in May last year, and it is now even in the NCCN guideline. So, so I think that over time, that will become standard, because particularly for ROS1 mutations, RNA is far more sensitive. So I think that will become standard. But as I said earlier, adoption of data is always somewhat challenging. So we think that over time, things will change testing, because it's about 30% more sensitive. That annual incidence number of 3,000 patients should increase to about 4,000 patients a year. It may take a year or so. You know, it's hard to know, but we are certainly speaking to advocacy groups.
We're speaking to diagnostics companies, as well as aggregators and, you know, both academic and community practices to just increase awareness of the importance of making sure that you do identify this mutation because it's so treatable and because, you know, early diagnosis makes a huge difference in the prognosis of the patient as a whole, and once you get a brain met, much, much more difficult situation, so given our PFS in the first line setting, you know, you really want to find this mutation quickly before you develop. It's just a matter of time if you don't treat it, so we think that it's very important to get tested early, as early as possible.
Do you expect a certain market to dominate taletrectinib uptake over the next few months? Are you focusing your attention on certain segments, I don't know, frontline starts-
Yeah
... switches from other drugs, or are you pursuing, like, an all-encompassing approach?
So I think, you know, we're going out there. So it. What we loved about the launch so far is that every sales meeting has had patient starts. So, as I said, this launch has been broad across every geographic, across both community and academic practices, across first, second, and third line treatment. So, you know, this is a rare enough genetic mutation that, you know, going after our, I think that our profile has shown outstanding efficacy in both front line and second line patients. And as you know, we have a biomarker-agnostic label, so it's really for everything. So we're, you know, we're not overlooking any segment of that.
Mm-hmm. Yeah, that makes a lot of sense. And then in terms of the potential switches, what has your feedback been from physicians? Have they primarily switched after progression on a different compound? Are they switching because of potential tolerability or because they want that better CNS coverage?
That's been a surprise to us. I will say that one of the greatest surprises for taletrectinib so far is that in general, in oncology, physicians switch from one drug to another drug only upon progression, unless there's just some significant tolerability. What's been very interesting about taletrectinib so far is that we've seen switches from crizotinib, retrospective, without necessarily having progression, and sometimes not even with tolerability. I think that that was a surprise to us, 'cause, in general, oncologists only switch upon progression.
We've seen switches for neither progression nor tolerability, which we think speaks just to the profile that we have, you know, 46-month PFS in the last patient, tolerability profile like that, you know, our discontinuation for LFT elevation is 0.3%. I think that that's attractive, and we're seeing it, which is good.
Yeah. Let's talk a little bit about the performance indicators. How should we interpret the early revenue contribution, given the free trial programs, stocking, and any potential lag between payers and...?
So far, we've only reported the revenues of Q2, so end of June. The reason why, you know, we, during our call in early August, we mentioned the patient number is that we really thought the revenues were not very significant to understand the real performance, right? It was just like the two weeks after approval, this revenue increase. So mostly driven by early revenues in each market, right? So the stock delivery channel and nothing else. And that's why we've insisted so much on the fact that we have, you know, 13 patients on drug at the end of the day. So that's what really matters. When we've looked about the way to incentivize yourself for sole launch, we've been very clear about patient numbers, putting patients on drugs.
Like David has said, you know, during the presentation earlier, patients are going to be on this drug for a very long time. So we are not shying away from samples, early free drug program, and everything that can help them get access to those advanced label. At the end of the day, we believe that every ROS1 patient, line agnostic, would benefit from getting access to the product. What we've always said as well during our call early August, was that these patients, one, we have put on free drugs, generally, we convert them to paying drugs in less than a month, vast majority of them.
So as we develop our launch and the proportion of, you know, new patients versus continuing patients will lower, the share of free drugs should go down as well because it's the patients start only. But, you know, the beginning, yes, it's going to be a little bit of free drugs. Again, 46-month PFS, it's not a problem to the patient on the drug fast. They're going to be on drug for the total.
And I know you have your, your clinical trial data from, parts one and two. Should we really think about the PFS and the median BOR of approaching four years as how long these patients will be staying on in the real world as well?
I do think so. Uh, and what's interesting about the TRUST-I and II data is that they're remarkably consistent with each other, so that gives us further confidence. And also, the data sets are large. You know, these are hundreds of patients that we follow over time. Our longest patients from our Phase I study are out, as I said, over nine years. So, um, you know, we think that we are expecting, uh, very long, but one of our Phase I patients has been out nine years, and his tumor is gone. So there's no evidence that he has anything to recur, so he's going to be on drug for probably a really long time.
So, you know, we are seeing-- the fact that we're seeing patients like that, gives us a lot of confidence that this is, this is a really well, the sound that it's going to be. That's the way it's going to be. As I said, you know, if you look at our clinical trial criteria, we included everybody. We don't really know it's moving. We're talking about a real-world population. We're going to see real-world population as well, because that's how they're doing.
Mm-hmm. Mm-hmm. And in terms of the pricing, the drug is priced at around $30,000 a month, slightly below Augtyro. Does that give you favorable formulary placement in any way? And what have the conversations with payers been like?
The conversation with payer has been very positive in general. Augtyro had a pretty good access, but there was still a little bit of step edits . We believe with the quality of the drugs, this is something that can be worked through, but that's a bit of red tape, and we wanted to avoid that.
The goal there, to price it like below Augtyro, is to make sure that the access will be even easier for prescribers, for patients, for everyone. Our conversation has been very, very positive. At the end of July, we already had 58% of live covers, a label, and we think this proportion will rise again. All patients, as I said, that we are starting to refer to commercial launch, I think. It's very, very different.
And the other thing we were to remember is that the average age of a ROS1 patient is much younger than the average patient. If we have plenty of patients in their thirties with ROS1 mutations. So I think that, you know, it's a different payer population, I think.
Okay. You mean because there is so much more life?
More commercial and less Medicare.
Yeah, exactly.
So getting access on commercial will be typically a little bit faster than Medicare. We will get access to Medicare through the right system, maybe a little bit faster than commercial. Will that help?
And it's just also harder to deny coverage to someone who's 38 years old-
Yeah, yeah.
and who has an offered drug that has a four-year free pass.
Yep. And in terms of gross to net, how should we be thinking about that? And if you, you know, talk a little bit more, I guess, with the age argument we just made about the payer mix as well.
So we've not said anything about gross net yet, but we'll have to make that assumption. As I said earlier, you will see a little bit more big drug at the beginning than over time. So this is something that needs to be taken into consideration. But at the end of the day, you're talking about a rare oncology drug, so gross net is not very high. You're not in a universe of diabetes, so
Okay. And in terms of the competitive dynamics, you know, the Augtyro launch has not been quite as strong. Where do you see you and IBTROZI handle better, and why do you think IBTROZI is going to perform better?
So there's the ROS1 is somewhat analogous to another drug, which is also really big business. If you look at the repotrectinib molecule, the binding affinity for ROS1 is very, very similar to the selectivity ratio is one. If you look at the affinity of IBTROZI for ROS1 compared to entrectinib, it's about ninefold on the IC50. What that means is that we can really, really inhibit ROS1 very, very thoroughly. We're talking about some nanomolar affinity for the target without causing prohibitive CNS toxicity through this entrectinib.
So that selectivity allows us to dose this drug at very high levels without getting prohibitive toxicity and really crushing the target, which is the most important thing, first of all, but also because the CNS penetration, the brain penetration is excellent, we still get coverage in the CNS. So we looked at our interpatient response of 66%, you know, right up there, up at any space, and we think that that's important. Another thing that's really interesting is that there's really some pretty compelling literature, entrectinib, which is an oncology, drives CNS metastasis. There's a very nice clinical study showing that in 55 patients where they were divided into patients who got brain mets and those who didn't get brain mets.
The ones who got brain mets had much higher entrectinib expression than those who didn't have brain mets, suggesting that entrectinib was involved in the CNS metastasis. Even more compelling, if you look at when the brain mets themselves were biopsied in those who developed brain mets, the level of entrectinib expression in the brain met was even higher than the already elevated tumor, suggesting that entrectinib is actually dispositive for development.
So, you know, some KOLs have called our drug the Goldilocks ROS drug, because it, you know, we certainly crushed ROS1, but not too much entrectinib, not too little entrectinib. I think that, that may be the reason that if you look at our, our intracranial response rate, it's 66%. Extremely high. So we think that, you know, in many ways, this is a very addressable one.
Yeah. Yeah, that certainly sounds like it could help the compound. In terms of the other potential entrant that might be following IBTROZI, having shown some pretty compelling data as well, help us how you think about that competitive potential headway.
So, you know, I'm not sure how you were quite compelling. If you look at all, we've seen second-line data. Look at the ROS published supporting only 55 patients. The response rate in just second line is 51%. Our response rate in second line is 56%. Importantly, if you look at the ROS-1 intracranial response rate, 48% versus 63. So no, we've looked at this, how it was having no entrectinib. I just told you, there's evidence that entrectinib drives capacities, therefore, we think it's something we do want to inhibit at least a little bit, not prohibitively, but we want to inhibit it enough to have an effect by seeing it passes. We think that that difference between 66% intracranial response rate for our drug, 48%, we think that's significant.
By the way, those numbers don't even include the fact that in the ROS-1 study, patients with a secondary oncogenic driver mutation were excluded. We had no exclusions in any of our data for any oncogenic driver. So our label was a real-world population of all comers... and those patients were exclusions, and there are almost no studies that we believe make for a more real-world population than we had. So in spite of that difference, we still have a response rate that's 14% much higher than what's been published in the second line setting for five point. So, you know, I think that we think the most compelling data set is ours. Yeah.
Yeah, that's--
Of course, very long already line agnostic.
Yeah. So that's the other thing. So we have a line agnostic label. You know, by next year, we think that the majority of the second and third line patients will be propped up by Josie, and not the first line setting those years ahead there. That's just the time it will take to get to even a four-year DOR. It's gonna be years, and we're already four years going, so we don't know where our DOR and PFS will ultimately equilibrate. As of, you know, as our last publication was already almost four years, and now it's not yet reached. So we just think that this profile is pretty extraordinary, and as I said, it's unprecedented for the, you know, oncology.
Mm-hmm. Let's spend the last five minutes or so on your pipeline and future outlook. You know, you have another asset coming up, safusidenib, a mutant IDH1 inhibitor. You've shared some very exciting data in low-grade, but also in high-grade IDH mutant glioma. Can you just briefly summarize these data?
Yeah. So, IDH1-driven, IDH-mutant gliomas are very difficult patient. There's only one drug approved, and it's only in low-grade IDH1 glioma, and that drug is vorasidenib. And if you look at vorasidenib, the labels, it only includes low-grade, and that was based on a clinical trial called INDIGO, where they had 11% response rate, but significantly improved progression-free survival to 11.7. So 61 proven to be a best, even though the response rate is quite long. Our, our safusidenib molecule came from Daiichi. In the first Daiichi study that was published, safusidenib response rate was 33%. So we think that compares quite favorably to the vorasidenib 11%. But more importantly, we're about to release a newest trial that Daiichi conducted.
Daiichi will be releasing this on a new trial that is just low grade, only at one dose, so it's quite clear, and you're gonna see not only another response rate reported, but for the first time, progression-free survival. We think that our data are really compelling, so much so that we're actually in discussions with FDA regarding a head-to-head trial against us. So that's in low grade. Interestingly, if you look at Royalty Pharma's royalty, Royalty Pharma paid Agios $905 million for a 15% US-only royalty on vorasidenib. If you look at the last two quarters of Servier, that suggests a run rate in the first six months already $750 million. The vorasidenib is going to be a big billion dollars.
The reason that, you know, these IDH1 mutant gliomas are such an attractive commercial target is because for low-grade diseases, their survival is 10-15 plus years. So we're talking about revenue stack, and you're talking about really a long, long time, even in the high-grade setting is 3-7. So again, we're talking about high-grade settings still being in excess of even one of the first line setting. If you look at vorasidenib response rate in high-grade glioma, 0%. If you look at safusidenib response rate in high-grade setting, in our published studies, we had a 17% response rate. But importantly, a third of those responses were complete response. Complete response in oncology mean the tumor disappeared. We've had one glioblastoma with the most difficult treat of all tumors.
We had one glioblastoma patient, whose tumor has been gone for three and a half years. We have a second high-grade glioma, oligodendroglioma, another very different tumor. The tumor has been gone almost two years. You know, we have seen that for any agent, and we are pretty excited about that. We've already kicked off a pivotal study for high-grade glioma. We've already started, and we are finishing our discussions with FDA on a potential head-to-head study against vorasidenib in the low-grade setting. But we think that, you know, the glioma market is a multi-billion dollar, because this, you know, this progression-free survival potentially is so long. And we think our data are by far the most compelling in this IDH1 malignancy. We're really excited about this.
Cool. That sounds like a great summary, and I know we're out of time. Maybe a quick summary of what we should watch out for the next.
We're excited about our next quarter earnings. We're gonna present earnings in November. You know, I think that'll give you your second data point on the trajectory of our launch, so we're excited about that. And we're really excited about finishing our potential FDA on the second pivotal study on the low-grade glioma.
And with that, we'll be kicking off two more pivotal studies that are both high- and low-grade glioma in a space that we consider to be a really big unmet need and a really large commercial opportunity. And then, given our cash balance, it's like $600 million today. You know, that's way more than we need to get to profitability, and with that excess cash, you know, we're looking at a lot of big opportunities we think are really. There are a lot out there, you know, recent difficult markets, so we're excited about that.
Great. Thank you so much for joining us.
Thank you.