We are very happy to have the CEO of Nuvation Bio, David Hung, up here with us. Nuvation, which I might say has one of the largest balance sheets in all of small-cap biotech, just embarked on a pending transaction as well, which we're gonna talk about. But, David, it's great to have you here with us at the conference to review Nuvation and the pipeline, and all the things coming up. So without further ado, David Hung.
Thanks so much, Mike. Thank you all for coming. So we have a fair number of new developments at Nuvation Bio, which I'll talk about today. I think our recent acquisition of AnHeart now makes us a late clinical stage and global oncology company. We acquired with AnHeart two assets. One is taletrectinib, which is a ROS1 inhibitor that we believe has the potential to be best-in-class, and we are in the process of completing two pivotal studies for that drug, which we believe will support an NDA filing and a commercial launch next year. With AnHeart also comes safusidenib, which we believe is another potentially best-in-class drug. It's a brain-penetrant mutant IDH1 inhibitor, which is currently in phase II for the treatment of IDH1 mutant glioma.
We also have in our pipeline a drug called NUV-868, which is a BD2 selective BET inhibitor, that we are in the process of completing a number of phase I combination dose escalation studies. And finally, we just got into the clinic a molecule called NUV-1511, which is the first of our drug-drug conjugates, which we're particularly excited about. Now, we have a robust cash balance of almost $600 million on our balance sheet, and given our acquisition of AnHeart, we are now positioned to be a commercial organization by 2025. As I just outlined, we have our number of programs in our pipeline. Our first asset, finishing 2 pivotal studies, our second asset in phase II, and then a number of other assets being developed in earlier stage programs.
So let's start with taletrectinib. We think this is a really interesting molecule. We received breakthrough designation for taletrectinib in the U.S. and China in both the first and second-line settings. We filed the Chinese NDAs in both first and second line, and they've been accepted, and we've been granted a priority review. And we think that this is gonna be a really interesting launch next year, because we believe this is an underappreciated opportunity, and only with this molecule, has the potential to address this important unmet need with a molecule that's really tolerable and highly efficacious. Taletrectinib has an outstanding overall response rate and safety profile, and is also highly brain-penetrant, which is important because many of these patients go on to develop CNS mets.
Also importantly, this drug is highly active against certain mutations that develop over time. So in the second-line setting and later, we believe that we have robust efficacy. This drug was in-licensed by AnHeart from Daiichi Sankyo, and we maintain global rights except the major Asian markets, which have been out-licensed. Non-small cell lung cancer accounts for about 80%-85% of all lung cancer, and ROS1-positive non-small cell lung cancer is about 1%-3% of that population. Right now, there are three currently approved therapies for treatment of ROS1-positive non-small cell lung cancer, and that's crizotinib and entrectinib, which are first-generation inhibitors, and more recently, repotrectinib, the Bristol Myers drug acquired from Turning Point, as a second-generation inhibitor, and you can see the estimated sizes of the patient populations on the right of the slide.
So taletrectinib is now completing two pivotal registration studies. These studies are large. The combined number of patients in these two studies is about 327 patients, and we believe that they'll support breakthrough designations in the U.S. and China. The outline is outlined here. The TRUST-I is a pivotal Chinese study, studying 60 milligrams of taletrectinib in both TKI-naïve as well as TKI-pretreated patients. TRUST-II is another pivotal study, but that includes Western patients, majority of which are European and American patients, and again, studying a number of cohorts. We just presented data on TRUST-I at ASCO this past week, and we'll be presenting updated data on TRUST-II at a major medical conference later this year.
As I mentioned at ASCO, we presented our most recent TRUST-I data, which simultaneously were published in the Journal of Clinical Oncology. This included efficacy data and long-term follow-up from 173 patients. Importantly, if you look at these patients, they differ from other previous studies in having a significantly larger percentage of patients with prior chemotherapy experience, so a more difficult to treat population. If you look at the overall results, the efficacy results were robust. Taletrectinib had an overall response rate of 91% in ROS1-positive patients who were TKI-naïve. If you look at the second-line setting, in patients who were TKI-experienced, taletrectinib still had an overall response rate of 52%.
If you look at the median duration of response and PFS in the TKI-naïve setting, the median DOR has not yet been reached. The lower bound of the 95% confidence interval for DOR is over 30 months, so we think this is a very competitive number. If you look at the TKI pre-treated population, the DOR was a median of 10.6 months, but I think it's important to point out here that in this number, these are very immature data, where the median follow-up was only 9.7 months. So I think that with longer follow-up, that number should increase. If you look at the efficacy of taletrectinib in the CNS, this is a highly brain-penetrant molecule.
In the TKI-naïve setting, 88% of patients had objective responses with taletrectinib in their brain tumors, and in the TKI pre-treated group, the overall response rate was still 73%, so a very striking efficacy in an important compartment, which clearly contributes to the heavy mortality and morbidity of these patients. From a safety side, the safety profile of taletrectinib shows that the drug is extremely well-tolerated. I think maybe the best way to look at that overall is to look at the treatment discontinuation rate, and only 5% of patients on taletrectinib had a TEAE that led to treatment discontinuation, so a very competitive number, which I'll go through comparisons with other TKIs in a little bit. So how does this drug stack up against other ROS1 TKIs?
Well, in the first-line setting, you can see here, taletrectinib compared to first-generation inhibitors, crizotinib and entrectinib, and the only second-generation TKI approved for ROS1, which is repotrectinib. You can see here that the overall response rates for crizotinib and entrectinib are in the range of 70%. The overall response rate for repotrectinib is 79%, and here, taletrectinib's response rate is 91%. I'll point out that the upper bound of the 95% confidence interval for repotrectinib's response rate is 88%. So our 91% compares very favorably with even the upper bound of the 95% confidence interval for repotrectinib. Whereas entrectinib and crizotinib have roughly 20-24 months median DOR, repotrectinib has 34 months.
The median DOR was not yet reached for taletrectinib, and certainly with maturing data, we hope to have a number sometime in the future, but currently, that number has not been reached, and it's in a very competitive range. If you look at intracranial overall response rates, 88% for taletrectinib compares very favorably with other TKIs, and this is not surprising, given its high brain penetrance. In the second-line setting, you can see that the repotrectinib overall response rate is 38%, and taletrectinib is 52%. Now, a lot's been talked about with the Nuvalent drug, NVL-520. Their overall response rate in the second-line setting, which is the only data we have to compare with ours, is 48%.
So again, our 52% response rate appears to be, competitive with other TKIs in the second-line setting. If you look at repotrectinib's median DOR, it's 14.8 months, and we reported at ASCO that our median DOR was 10.6 months. But I wanna point out that these data are very immature, and that 10.6-month DOR for taletrectinib was based on a median 9.7 months of follow-up. So with longer follow-up, we would expect that number to increase, so I think that's important to keep in mind. There's a mutation called G2032R, which is one of the more common resistance mutations, with, with ROS1 treatment, and you can see that the overall response rate, for repotrectinib is 59%.
Taletrectinib's response rate for this mutation is 67%, which is basically 8 out of 12 patients showing a response. The Nuvalent drug showed a 78% response rate. That was 7 out of 9 patients, but you can see that it's basically one patient difference separating those two numbers. If you look at intracranial response rates, our response rate of 73% compares very favorably with repotrectinib's 38%. Now, Nuvalent does report a 100% response rate, but that but that was based on 3 out of 3 patients. So again, I think that, you know, not, not a lot separating those two drugs from a numbers standpoint. That comes down to basically a single patient.
If you look at the safety profile, I think one of the more important ways to measure the tolerability of the drug is to see how often it's either reduced, interrupted, or stopped. And as I mentioned, if you look at the third set of bars from the left, the discontinuation rate for crizotinib is 12%, for entrectinib, it's 9%, for repotrectinib, it's 8%, and taletrectinib is about 5%, so roughly half the average rate of discontinuation for the other TKIs. And then, if you look at dose interruption or dose reduction, you can see that taletrectinib, again, compares very favorably to the other TKIs.
The most common and probably worrisome side effect of repotrectinib, the only other second-generation inhibitor, is neurological toxicity with repotrectinib has a 63% dizziness rate compared to 23% for taletrectinib, which the majority of which are grade one. So I would say that in this regard, we think that again, taletrectinib compares quite favorably with other TKIs. We anticipate launching taletrectinib next year, and as I mentioned earlier, we've been granted a priority review for 2 NDAs for taletrectinib in China and breakthrough therapy status in both the U.S. and China, and we, well, we're excited to have the opportunity to launch this drug. Our license agreements provide for royalties from our Chinese partner, which is Innovent, and then from Nippon Kayaku, which is our Japanese partner in Japan.
We also acquired, with the AnHeart acquisition, a second drug called safusidenib. It's a mutant IDH1 inhibitor, and we think this is a another potentially very important drug because patients with glioma really have very few options. Currently, the only drug approved for the treatment of the diffuse IDH1 mutant glioma is vorasidenib, which was the the Servier drug. So, if you look at the size of the IDH1 mutant glioma market, it's somewhere between 13,000 and 18,000 patients. About two-thirds are grade 2 or lower grade glioma, and about a little over a third are higher grade, grade 3 glioma. And right now, the safusidenib data set approaches 100 patients, with our sponsor, Daiichi, in Japan, and then us conducting a phase II study, globally.
So if you look at the recent Agios deal with Royalty Pharma, Royalty Pharma paid Agios $905 million for a 15% royalty on vorasidenib, the Servier drug. We think that that's a pretty interesting transaction because it attributes a significant value to this asset in IDH1 mutant glioma. We think that that sets us up favorably because we believe that safusidenib offers potential benefits over vorasidenib. If you look here at a phase I study where these two drugs were compared, the vorasidenib response in non-enhancing glioma, which is the lower grade glioma, is 18%, whereas safusidenib's response rate in the same population was almost double that, 33%.
Maybe even more importantly, if you look at higher-grade glioma, grade three, which are defined as enhancing gliomas, the vorasidenib response rate is 0%, and the safusidenib response rate is 17%. I think that, given the value that you can attribute from the Agios deal to the license of the rights for the royalties for vorasidenib, I think that this potential difference and benefit over vorasidenib, if we can confirm this in a pivotal study, could lead to significant value creation for Nuvation Bio. We're in the process now of trying to figure out what our pivotal study design will be and how to move this forward. As I mentioned, also, we have another program that's in clinical development. It's our BD2 selective BET inhibitor.
If you look at the history of BET inhibitors, I would say that their history has been checkered, plagued mainly by a lot of toxicity and not necessarily very impressive efficacy. But there are two subdomains of BRD4, one called BD2 and one called BD1, and there's some data that suggests that a inhibitor of BET that is more BD2 selective could offer significant benefits in tolerability as well as efficacy over non-selective, BD2, BD1 inhibitors. This was largely based on a science paper that was published a number of years ago, showing, again, potential benefits of primarily inhibiting BD2 and showing how this could potentially increase the therapeutic window.
Importantly, I think that the most recent data by MorphoSys with pelabresib, pelabresib being a selective BD2 inhibitor, shows that that molecule was well-tolerated and had pretty significant efficacy in myelofibrosis, which led to the acquisition of MorphoSys by Novartis recently. If you look at NUV-868's efficacy profile here, this is in combination with enzalutamide. If you look at these xenografts, with vehicle treatment on the far left, you can see that they grow rapidly. With enzalutamide alone, they also grow rapidly.
If we use a very low dose of 868 in the light blue, you can see there's not much difference from enzalutamide, but if you increase that dose and now add enzalutamide, if you add enzalutamide, you can see there's significant difference between 868 in combination with enzalutamide versus enzalutamide alone. And if you look now at the far right, two sets of bars, in the light purple, this is 868 by itself at a higher dose, but more importantly, in the far right, in combination with enzalutamide, you can now see that the majority of those xenografts are showing significant tumor regression in combination with enzalutamide.
We've also shown in preclinical studies that not only does NUV-868 potentiate the effects of enzalutamide, but it also appears to potentiate the efficacy of PARP inhibitor. So again, we believe that we believe NUV-868 is a combination drug that has the potential to synergize with other drugs, in this case, enzalutamide or PARP inhibition, to create better tumor responses. We are in the middle of a phase I dose-escalation study, and we still have yet to declare an MTD for our combination trials in combination with olaparib, the PARP inhibitor, and enzalutamide, the novel AR antagonist. So we're waiting to reach an MTD in this program, and hopefully we'll announce those results when they're mature.
And also then finally, our DDC program with a molecule called NUV-1511 is something that we're particularly excited about, program upon which this company was founded. I think all of you are familiar with ADCs. ADCs are antibody-drug conjugates, where an antibody targets a small molecule warhead to a target on a cell. But these are large molecules, and as a result, are delivered IV only, are limited to cell surface targets, although the warhead can be released in inner cells, and because they're large macromolecules, are complex and expensive to make. When we started Nuvation Bio, we filed patents around a new concept of developing drug-drug conjugates, so basically the ADC without the A, using a small molecule instead to target another small molecule warhead.
We're talking about molecules now that are orders of magnitude smaller than ADCs, and as a result, they can be given orally or intravenously. They can work on the inside or the outside of the cell. They're highly permeable across multiple membranes and also are simpler and cheaper to make. The concept was, they're taking a drug X against target X and drug Y against target Y, and finding a way to fuse their binding domains together so that you can make a bispecific small molecule. And we've shown by doing that, we can create molecules that have really strikingly different efficacy and safety profiles from the molecules that they were derivatized. This is just one example. This is NUV-1511, the DDC that has currently entered the clinic.
We haven't said a lot about what the components of this molecule are, except to say that one part of it is a well-known, widely used chemotherapy agent. You can see here, looking at these two xenografts, in the black line, you can see vehicle treatment, in the gray line, you can see the targeting ligand alone, so which doesn't do much. If you look at the dark blue line, we're looking at the chemo warhead by itself, so having some efficacy, but when you fuse the light gray component to the dark blue component, you get the light blue line showing striking improvement in efficacy, and you don't see it here, as well as tolerability due to the selectivity of the combination molecule.
We've also been able to show that the mechanism of this drug is interesting because even intermittent treatment with this molecule for even a couple of days leads to sustained tumor regression and inhibition over many weeks. In here, we treated these xenografts for 2 days, and yet 28 days later, with no further treatment, we're still showing complete inhibition of tumor growth. So we're excited about this molecule. As I said, it just started in the clinic in March, and we hope to be approaching therapeutic levels of this drug in patients towards the end of the year, and we'll report accordingly. So we are in a dose-escalation study right now, a standard 3 + 3 design, and once we hit an MTD, we'll be expanding those dose levels and with backfills up to 50 patients.
We're studying 5 different tumor types. These are all indications for which there are very limited alternative therapies. So the first indication is post-Anheart or post-Trodelvy breast cancer. So the patients who failed Anheart or Trodelvy right now have very, very limited treatment options. The second indication is pancreatic cancer, as you know, a notoriously difficult to treat cancer. Third is platinum-resistant ovarian cancer, the fourth is castrate-resistant prostate cancer, and the fifth indication is HER2-negative breast cancer. So those are the 5 indications we're targeting with NUV-1511, and we're looking, hopefully to get to a therapeutic level sometime, towards the end of the year. So with that, that's our company in a nutshell. We have a pretty exciting portfolio, both late- and early-stage assets.
We have a very strong cash position, and as I said, we're gonna be a commercial organization by next year. So we're really excited about our prospects and look forward to telling you more about our progress in the coming months.
Thank you, David. May I ask?
Of course.
One or two questions?
Sure.
Thank you. Thank you for that update. Maybe, just focusing on the ROS1 asset, obviously, there were some data at ASCO, from the China study. What, what should we expect in terms of the second global study that's coming up? Does that support a regulatory FDA filing? And, talk about that data coming up. What should we expect?
Yeah, so the
Thank you.
The Chinese study, TRUST-I, was 173 patients, so pretty large study. The TRUST-II, which we'll report data on later this year, is 154 patients, so again, a pretty large data set, the total number of patients treated with taletrectinib is among the one of the largest datasets for ROS1 positive lung cancer. The difference between TRUST-I and TRUST-II is that TRUST-I is a Chinese study, and TRUST-II is, the majority of patients are actually Western patients, Europe and U.S. So, but we anticipate both populations going into our NDA filing. So far the data we reported for both studies show remarkably consistent data from both datasets.
Importantly, our last TRUST-II report, which was at ESMO last year, had a data cutoff that I believe was over the summer last year.
Mm.
So our TRUST-II dataset we'll report later this year will be almost a year longer follow-up than that. So we think that's gonna be important, especially for things like duration of response data. And as I said, you know, we think that the datasets so far have been remarkably consistent, and we believe that both together will form a robust NDA package.
Let me ask a different question, as well, and I think it's important to set the stage. So this data looks very strong and very impressive. It looks better than the Turning Point data. So the question then comes up, David, how did you get this asset from China?
Yeah.
Because I'm sure every cancer company would be looking for that if Bristol paid $4 billion for that one.
So.
How did you get that?
So I think there's a little bit of luck involved and a few other things. So I think in many ways it was a perfect storm, because I think COVID and the Chinese lockdown.
Mm
Actually, restricted travel to China, and this is a Chinese asset, and I think that you know, because of obvious reasons, it just didn't have high visibility being locked down in China. You know, we were able to find it. We looked at over 200 opportunities before we found this one, and when we saw the data, and when we. You know, clearly it wasn't lost to us that Turning Point, you know, BMS paid $4 billion for that asset, and we were able to pay around $280 million in stock for this asset. So for us, that was a pretty good arbitrage. Working to our advantage was the fact that the primary investor in AnHeart, who was well aware of Medivation, also was impressed with our programs internally at Nuvation Bio, particularly like the DDC program.
Mm.
In fact, our first two offers to Anheart were both all-cash offers.
Mm.
They rejected both of them.
Yeah.
We were told, ultimately, that they did not want a dollar.
Mm.
They wanted only Nuvation Bio stock.
Right.
Clearly, that positioned us.
Yeah
Favorably because the strategic partners that they were also talking to couldn't do that.
Yeah, they will. They are now invested here in.
They are
And that they believed in the opportunity long term, and not just.
They did, so.
Cash and run, you know.
So they didn't want a single dollar in cash. They only wanted stock, which again, you know, positioned us favorably to get the asset. But I think a combination between that and the fact that this was a Chinese asset during a China lockdown was, you know, very helpful to us.
Very good. Well, thank you very much for that update. Appreciate a lot going on, and I know you have a full schedule, so thank you very much. We look forward to more data this year.
Thanks.