Welcome to day two of the Citizens Life Sciences Conference. My name is Silvan Türkcan and I cover precision medicines at Citizens, and it's a pleasure to have everybody here. Now I'll be hosting Nuvation Bio, David Hung, co-founder and president. Thank you so much for joining us, and Philippe Sauvage, CFO. Thank you.
Thank you.
Maybe to kick it off, you recently had earnings. If you could just talk to us about the IBTROZI launch, how that's going, and some of the dynamics that you discussed.
Yeah. I think the IBTROZI launch has gone very well. We have two full quarters so far. In the first two quarters, we had 432 patients, a little over 200 a quarter, which is about six times what we saw in the first two quarters of the AUGTYRO launch. By the way, our two quarters with all other ROS1 TKIs combined, we have exceeded that by a significant margin, so we're, you know, pretty pleased with that. We have, I've seen all lines of therapy prescribed, even though the majority of our prescriptions still are in later lines because this is typical of oncology launches. We have seen first- line use and we've seen that growing, so we are excited about that.
I think that, you know, we've had sales in every sales territory. Our 47 sales reps in the field have all had success in all of the geographies. We think the launch is going pretty much as we had hoped.
Maybe talk about these lines of therapy, and I think it's, you know, obviously there was some volatility around the earnings call and I think there's a lot of eyes on it, but in my mind it's because of the duration of therapy is so long in the front line . Obviously, and then decays. So that kind of maybe threw people a curve ball. If you could just discuss like what the dynamics there are and how you penetrate into early lines. Maybe if you can point to some examples from other launches where, you know, is this very typical to start on the line?
Right. If you look at the duration of therapy, by different lines of therapy, it's, you know, it exponentially decreases with later lines. If you look at our progression-free survival, in the first- line setting, you know, we're talking about 46 months or longer. If you look at the second- line setting, that drops by, you know, a quarter.
Down to one quarter of that. If you look at, you know, probably third- line plus, you're talking now probably a quarter of that. I think that what you generally see in oncology launches is later line patients, because number one, they're already identified because they've all been on previous TKIs and already have a ROS1 diagnosis, whereas incidence patients have to be diagnosed new. It's a slower process. The prevalence pool is the easiest pool to address, but they tend to be experienced and have shorter durations of therapy.
If you look at, you know, the kind of patients we're getting, we don't have complete visibility into that yet because unless the patients seek reimbursement assistance, and unless they come through our portal called Nuvation Connect for that, we don't really know anything about their profile. You know, we've had actually relatively few reimbursement challenges, so not that many patients have come through our portal for reimbursement assistance. Out of the 432 patients that we have treated so far, the number of patients who have come through our portal looking for assistance is only in the double digits.
The only glimpse into lines of therapy that we see are from those double digit numbers of patients, and that's such a small fraction of our 430+ patients that it's hard for us to make a guess at this point that we're confident in as to what the lines of therapy will be. We've said that the majority of them are still third- line plus, you know, second, third- line plus, but we do have first- line patients and we do expect that to change, you know, virtually monthly. We are already seeing some decrease in third- line plus. We're seeing some increase in first- line. We have said that 75+% of our discontinuations are third- line plus patients.
As you would expect, because I said the duration of therapy drops off exponentially with later lines.
To your point, Silvan, when you were out asking about benchmarks. This is really typical. Like you start with patients in late line in oncology and you gradually get to first- line, and what's really encouraging is every data, like David said, points in the same direction. We're getting more on this first- line patient. We don't see any emerging adverse event which is outside of what we saw in clinical trial. We see the kind of duration on therapy for all those lines that was to be expected.
Exactly as expected.
Yeah. I guess with your long duration of therapy, it makes a real big difference, like KRAS inhibitors. It you know.
If you go from four months - six months, it's not that big of a deal. Just to clarify, and we got this question from a few investors, is about your discontinuation. The discontinuation is due to progression, right, in the late-line patients?
Very much, yeah.
The discontinuation rate due to side effects, is that in line with what you've seen in the trial?
We haven't seen any discontinuations due to something that was unexpected. We think that, I mean, again, we're looking at a relatively small pool of patients, but from what we've seen, everything seems to be in line with our clinical trials. We, you know, we actually view the fact that 75% of our discontinuations being in third- line plus to be very positive thing, 'cause it confirms that our earlier line patients are actually lasting a long time on drug. I think that, as Philippe said, no surprises, which is always a good thing, 'cause you always wanna make sure that your real world data are similar to your clinical trial data, and we have every reason to believe that it is.
As of when I put these questions together, I think the consensus was just shy of $150 million. How do you view that? Estimate for this year for your first full year of sales?
Yeah, I think we're comfortable with that. We have said that it won't be a linear road to that $150, but I think that we are seeing the kind of growth that we expect, and we do see an increase in first- line. Revenue stacking will become more important in the second half of the year, and we think that we feel pretty comfortable with that consensus number.
Yeah. A way to think about it, Silvan, for your model is that those first-line patients, these numbers is growing. Quarter-over-quarter. Of course, at the beginning, we had those late-line patients which are going down, so the total seems flat. Actually, the dynamic of the first-line patients is really going up. Of course, the accumulation of a line is a curve, right? It's gonna be more at the later part of the year that we'll have those sales as we have more and more first-line patients to take on for a long time.
Right. Often, as happens with launches, can you just talk a little bit about the gross to net dynamics? Are they? Were you giving away a lot of free drug in the beginning or not? How can we think about it?
Of course, like all pharma company, we are trying to be responsible citizens. There are multiple ways to get access to IBTROZI. The start program which refer to free drug has been very limited, which is, I think, a testament to how good we have been in terms of reimbursement. Typically, at most, a couple of weeks. I don't think we have any patients that has been on the samples for more than a month. Really good there. We do have a PAP program for patients that are functionally uninsured or don't have any reimbursements. It's also very typical. Beyond that, it's just typical negotiation. It's a space with multiple drugs, so we had to negotiate with some payers.
Very important for us to have access, and that's why our gross to net has been increasing a little bit. We said that in the first quarter we were a little bit above 25%, and we still expect it to increase a little bit and then stabilize.
Great. Maybe about the one number that stuck out is that you mentioned on the earnings report that your growth was six times, or your on-ramp six times the patient numbers than the other. I don't know if it was all ROS1 combined or one of them, but can you just talk about that on-ramp in terms of patient? Like, does that point to an expansion of the ROS1 opportunity, or is it just, you know, very fast penetration into the existing share?
I mean, I think that we were talking about the actual number of new patient starts. If you look at AUGTYRO's first two quarters, they were doing 30-something patients per quarter. We, you know, we did about 200. You know, we do think that we had a pretty rapid adoption of our drug. We do think that good drugs expand markets.
If you look at what happened with osimertinib, you look at what happened with alectinib in lung cancer, we know that drugs that actually work do expand markets. We would anticipate the same thing in ROS1. But also, there's a lot of upside in terms of ROS1 testing. It's still not where it needs to be. Academic testing is probably close to 100%, but community testing is definitely south of that. Because of the precedent set by EGFR and ALK, RET and now ROS1, I think that testing will increase. I think the market will increase. The other change in the dynamics of the market was that current DNA testing would predict 3,000 patients a year, but RNA testing is now becoming standard of care in certainly many academic centers and hopefully in the community soon.
RNA testing is about 30% more sensitive than DNA testing, so the market will grow about 30% if we just move from DNA to RNA testing.
The NCCN guidelines, obviously, they changed early in the year with respect to ROS1, what you do once you find out. You're supposed to switch a patient off the IO and replace treatment with ROS1. Do you experience that already this early in the launch? Any more tangible data that you're collecting on this?
Yeah. The NCCN guidelines changed on January 7th of last year, so it's about a year ago. Now IO is contraindicated, and because of that contraindication and now the recommendation to use a ROS1 agent, that alone should grow the ROS1 market as well. Because a lot of those other patients used to just take IO, if they ever got to a ROS1 agent, they were much farther advanced and probably did not do as well. I think that that's going to increase ROS1 TKI use and, you know, physician behavior is never immediate to change, but I do think that we're already seeing some changes in practice based on those NCCN guidelines. We would expect that to accelerate, especially when a drug like IBTROZI has the kind of efficacy profile and tolerability profile that we have.
We think that there's a really good reason now to use a drug not only because NCCN contraindicates IO and recommends ROS1 TKIs, but because now we have a ROS1 TKI with a literally unprecedented duration and response and a tolerability profile that makes it really easy to use.
Right. Can you talk a little bit about your maybe commercial capabilities at this point? Is it the sales force right-sized at this point? What are kind of the next focus points for the sales force in terms of, you know, getting in new hospitals or convincing some doctors that are not prescribing yet or just staying on top of the ones that are already prescribing?
Sure. We look at where the ROS1 patients are. We believe that about, you know, 25%-30% will be in academic centers and about, you know, 65%-70% will be in the community. Right now, where we're finding our patients is the reverse of that.
We're finding most of our patients right now in academic centers because they tend to be early adopters, and community takes a little longer. What our sales force has been focused on is now trying to reverse that, and we're already seeing movement now toward increasing community use where the majority of patients are. It just takes a little bit longer in the community. We think the sales force is the right size. We have 47 reps, but because of the way that community oncology is structured out, the vast majority of community practices, you don't really see mom-and-pop practices anymore like, you know, decades ago, but they're now aggregated into large community systems, like OneOncology or Florida Cancer Specialists , US Oncology.
Because of that, it's a lot more efficient to reach those patients 'cause now we go to these centers and you know, familiarize them with IBTROZI and we can reach a lot more physicians with more efficiency than previously. I think we aim to see the patients come from academic and community sources in accordance with their epidemiological split.
Great. Maybe for those not as familiar with your asset, could you just like review, let's say, the label and the benefits it brings to the ROS1 indication with respect to the other TKIs that are out there?
Yeah. If you look at first generation TKIs in ROS1, you know, the PFS for entrectinib is 16 months. For crizotinib, it's 19 months. The response rate for both those drugs is between 68%-72%, so average of 70%. If you look at repotrectinib or AUGTYRO, the response rate is up to 79% and the PFS in the first- line is 36 months. If you now look at IBTROZI, our overall response rate is now 89% with a PFS in the JCO publication of a year ago, which is still maturing at 46 months. You know, pretty clear that the benefits that we're seeing are substantial. In fact, there are actually no oncology drugs in any cancer that have shown a combined response rate and PFS as long as IBTROZI.
We think that's a pretty unique profile, and we're gonna keep updating that label. We recently updated it last year at the end of the year, showing now that duration of response has now moved up to 50 months, which now puts it among the very, very elite. You know, only LORBRENA or lorlatinib with a PFS of 60 months exceeds that. You know, our data is still maturing, so we expect that. That could even change further. We are already in a very rarefied atmosphere in terms of our responses and durability of responses. We think that's pretty competitive.
Also very importantly, if you look at our intracranial response rates, they're also very high, and that's important because ROS1 lung cancer is a disease that's gonna get into your brain at least 86% of the time. 36% of the time it starts in your brain at diagnosis, and then another 50%, it'll progress in the brain as the first site of disease progression. You need to have good central nervous system coverage. Even in the second- line setting, if you look at our intracranial response rate of 66%, that's so far the highest seen of any ROS1 TKI. We feel that the profile is pretty robust.
Yeah. What's kind of the impact or what could be the dynamics with the generic crizotinib and entrectinib? Like how would that-
crizotinib doesn't get into the brain at all. It's even though it used to be used in ROS1, it's actually not medically appropriate today. I guess if 86% of the time you're gonna get a brain met, to use a drug doesn't even get in the brain, it's just, it's not good medical practice. We think crizotinib is a drug that should no longer be used in ROS1 disease, 'cause if you give it, you're just taking a gamble with whether or not you're gonna get CNS coverage, and 86% of the time you're gonna lose because it's gonna get to the brain.
I think that if you look at you know ROS1 treatments for ROS1 lung cancer, I think you need to pick drugs that have really durable responses because that means by definition you are working well against resistance mutations and you need to use drugs that get into the brain and have high brain activity, 'cause that means that you're actually addressing the single biggest determinant of long-term survival, which is development of brain metastases.
I know you had some liver monitoring in the very beginning. Does that come up as any issue stopping uptake or-
Not at all. LFT elevation is a paper issue. Most patients don't even know they have it 'cause they're not symptomatic. If you look at our six most common adverse events, LFT elevation were number one and number two.
In spite of that, in spite of being the two most common of our six most common adverse events, out of 337 patients in our database, the number of patients who discontinued IBTROZI due to either elevation of AST or ALT was one patient. one out of 337 is 0.3%. That was our discontinuation rate for liver function test elevation, which we think is really, you know, the best among the TKIs that we've seen.
Obviously there's some eyeballs on Nuvalent who may launch a competitor later in the year in a later line, and then maybe next year in the earlier line. Can you just talk about, you know, how you view the competitiveness here versus, you know-
Sure.
Their potential profile?
Nuvalent is applying for a second-line plus label, so their launch will be in second-line plus. If you look at the data they presented so far in the second-line setting, their response rate is 51%. That 51% response rate is caveated by the fact that the ARROS-1 study excluded any secondary oncogenic driver mutation that wasn't ROS1. Our response rate in the second- line is 56%, so about 10% higher than Nuvalent. That 56% includes every oncogenic driver. We made no exclusions. We would argue that 56% with no exclusions beats 51% with exclusions. If you look at Nuvalent's confirmed response rate and the intracranial response rate in second-line setting, it's 45%, again, excluding any secondary oncogenic drivers.
Our intracranial response rate in second- line, including all drivers, was 21 percentage points higher than that, at 66%. We think that's pretty significant. If you look at the post-entrectinib response rate of Nuvalent's drug after you fail entrectinib, their response rate's 33%. Ours is 80%.
We do think that there's a significant difference between the two drugs. We have not seen any metric so far where Nuvalent's drug has been able to match, much less exceed any metric of performance that we've seen. You know, we think that IBTROZI is a really efficacious drug. As I said, there are no cancer drugs in any indication that have matched our efficacy in the first-line setting. By the way, you know, we think the prevalence pool of second-line plus patients is probably in the range of 1,000. Well, we're getting 200+ patients per quarter. By the time Nuvalent launches in the third quarter, we will have probably treated a majority of those patients and then moved upstream to first- line.
We think that we're really well-positioned with the way this drug is working.
Great.
To your point, Silvan, just reminding everyone one more time, so we'll be launching in first- line two years after us. That's a lot of time in our industry.
Yeah. Yeah, you need to bring something better to the table. Otherwise.
Exactly.
Hard to penetrate. Maybe can you talk to us about your adjuvant plans? You know, that's a very big population.
We are the only ROS1 TKI that's doing adjuvant. You know, that says several things. Number one, to go to the adjuvant setting where patients are generally asymptomatic, you have to have a drug that's really tolerable.
The fact that we've been encouraged by KOL to do that, and we have now done it, again, speaks to the tolerability profile of our drug. As I said, if you look at our top six adverse events, our discontinuation rate for any of those is 0.3%, so pretty tolerable. The reason the adjuvant space is important is because now you're talking about the farthest upstream you can go. When osimertinib did their adjuvant study, you know, that led to their getting 100% market share.
We think that, what, you know, we're the only ROS1 TKI that's doing an adjuvant study, so we're. You know, even if anyone decide to try to get to the adjuvant space, they'll be significantly behind us. So you know, we think that we're going to own that space and subsequently will be the first drug used in ROS1 lung cancer, period.
Right. Maybe switching gears, you know, I have many more questions on this, but you know, it's a very interesting asset, and that's why we picked up coverage in the first place. You also have safusidenib. If you could just talk about your progress here and with your IDH1 inhibitor.
safusidenib is a mutant IDH1 inhibitor. There's only one mutant IDH1 inhibitor approved in glioma. It's called vorasidenib or VORANIGO, made by Servier. What's been striking about that compound is that, in just their last quarter, they generated $258 million in sales in their fourth full quarter, which is remarkable. That means that they're already on a billion-dollar run rate, for a drug that's only approved in one of the four parts of the glioma pie. If you divide the glioma pie into high grade and low grade, it's about 50/50, but each of those segments can be divided further into high risk, low risk. There's four pieces of that pie. vorasidenib is only approved in one of those pieces, low risk, low grade.
If you look at vorasidenib's response rate in low risk, low grade, their response rate was 11%, and at one year, 23% of their patients had progressed. At two years, 41% of their patients had progressed. If you look at safusidenib's response rate and PFS in the same population, the low risk, low grade, instead of 11% response, we had a 44% response rate. Instead of 23% progression at one year, we had 4% progression at one year. Instead of 41% progression at two years, we had 12% progression at two years. When we look at the low risk, low grade part of that pie, we think that Safi's data is more robust
Importantly, vorasidenib is not approved in the other three pieces of the pie, so high risk, low grade, low risk, high grade, high risk, high grade. We're doing a study called SIGMA that addresses all the other three pieces of that pie. If that gets approved, we'll be the only drug approved in three of the four pieces of the pie. We're also doing a second study targeting grade 3 oligodendrogliomas because in that population, they all have measurable disease, but they can't. Because they live so long, 12-14 years on average, they can't take radiation and chemo for those 12-14 years, so they need an oral therapy like safusidenib. Because they have measurable disease, that trial is a response rate trial.
We think that potentially if the response rate is very robust, a drug could be approved based on response rate alone in that population. We cite as precedent, OJEMDA's approval in pediatric glioma from Day One based on a response rate trial in 77 patients. We have kicked off a 40-patient trial in the grade 3 oligodendroglioma patients. We will have a readout on that data set next year, but we'll start to see some data this year.
If we start to see any response rates that are significantly higher than chemo, which is about 5% response rate, we think that warrants a discussion with the FDA to ask them what number of patients they would want to see to make this an approvable trial. As I said, OJEMDA was approved on 77 patients. If we had to make a wild guess, we'd think maybe 80 or so. We'll see what FDA says. It depends on how robust the responses are. But we think there probably is a pathway to approval with a response rate if the response rate is robust data. We're gonna start to, you know, think about that toward the end of the year when we start to get our first patient data back.
Yeah, great. Well, thank you, David. Thank you, Philippe.
You're welcome. Thank you so much.
Thanks for joining us today.
Good to see you.