Thank you, and welcome to our HCW Bio C onnect Conference. I'm Robert Burns, Managing Director and Senior Biotech Analyst at H.C. Wainwright. I'm joined by David Hung, the CEO of Nuvation Bio, and Philippe Sauvage, the CFO of Nuvation.
Thank you for having us.
For those who may be unfamiliar with Nuvation, could you provide a brief overview of the company, its pipeline, as well as that innovative DDC platform?
Nuvation Bio is a company I started in 2018. We took it public in 2021. We have four clinical assets. The most advanced asset is taletrectinib, a ROS1 inhibitor that we're expecting FDA approval on at the latest on June 23. Our predicted date is June 23 this year. Our second program is safusidenib. It's a mutant IDH1 inhibitor being developed for glioma. We find that program particularly interesting because we've had responses in high-grade gliomas like GBM that we haven't seen before. We have one patient who's had a complete response so far for 3.4 years, a second high-grade glioma who's been in a complete response for 95 weeks. We just have not seen durability like that with any agent in gliomas of any sort. We find that very exciting. We have a third program, which we call the DDC program.
You all know what ADC is. This is like an ADC without the A. Instead of using an antibody to target a small molecule warhead, we found a way to do that with a small molecule target or a couple to a small molecule warhead. This makes it an order of magnitude smaller than an ADC. One of the limitations of ADCs is that they do not actually cross cell membranes that well and often have to release their payload because they do not cross well to get the payload into the cell. That can cause off-target toxicity. Our DDCs, although it is very, very difficult chemistry, you figure out how to fuse two active small molecules together into a single small molecule that is basically bispecific in its activity. We are now in the clinic in five different indications, including patients who failed ADCs.
Our fourth program is the most selective. It's the most BD2-selective BET inhibitor in development. It's called NUV-868, and it's similar to pelabresib. We finished phase I, and now we're considering a number of strategic alternatives.
While we focus on the lead asset first, taletrectinib, obviously, as you said before, the PDUFA date is June 23. You know, from everything I've seen with the pooled TRUST, TRUST files, you know, that data is quite encouraging. It's extremely encouraging. I mean, let's put it bluntly, at least from my perspective. For those who may be unfamiliar with that dataset, maybe give us an overview of why it's so differentiated relative to all the prior ROS1 inhibitors that have come before.
Right. Taletrectinib has been studied in two pivotal studies: one called TRUST-I, one called TRUST-II. The TRUST-I study was a 100% Chinese study. The TRUST-II was a 90% non-Chinese study, a global Western study. Together, TRUST-I and TRUST-II comprise one of the largest datasets ever assembled in ROS1. There are over 400 patients in our safety database. What we showed in the pooled analysis of that data is an overall response rate of 89% and median progression-free survival of 46 months. To put that in some context, there are actually no drugs in any solid tumor indication in the history of oncology that have been able to match an 89% overall response rate and 46-month median PFS.
Even if you look at the drug I developed at Medivation, XTANDI today, the biggest drug in the world for prostate cancer, that's a 59% response rate. They need 20-month PFS. If you look at Tagrisso, the biggest drug ever in the history of lung cancer, $7 billion a year sales, we're talking about a 77% response rate and 19-month PFS. Our 89% response rate and 46-month PFS is really at the top of an already elite group of cancer agents. We're excited about that. On top of that, the tolerability profile of taletrectinib is very attractive. Our discontinuation rate of 6.5% is very, very favorable. We've been able to address some of the CNS liabilities that can be seen with ROS1 agents because of the homology between ROS1 and a related protein called NTRK B.
Given our therapeutic index of somewhere between 11-20-fold for ROS1 over entrectinib, we've been able to make a drug that is highly tolerable. We think that, you know, with this drug, with this kind of activity, we think it's a very attractive alternative for patients, given that the standard of care used to be IO chemo and the median progression-free survival of IO chemo was 6-12 months. Now we have a median progression-free survival so far of 46 months. I have to remind everyone that these trials are still maturing. That 46-month median PFS was as of our data cutoff a year ago in June of last year. With our more recent data cuts, that data is going to continue to mature.
Just as an example of what new data we're getting, just a month ago, I received some of our long-term follow-up on our very first patients in one of our phase I trials. Of the first 15 patients in one of our phase I trials, one patient out of the 15 is out seven years, one's out eight years, two are out nine years. One of those nine-year patients is a complete response, so he has no tumor, and he's still going. Again, these medians will continue to mature over time. We didn't expect that when we started this program, and it's an example of how powerful the drug is because we're still seeing, as we mature, medians getting, you know, we're seeing treatment durations getting into the nearly decade range.
For a disease that's super aggressive, you know, ROS1 lung cancer is particularly aggressive because about 36% of these patients present with a metastasis in the brain, and 50% present with brain as the first site of disease progression. Super aggressive disease. As I said, standard of care IL chemo used to be a PFS of 6-12 months. To see them now with a median of almost four years and some patients reaching almost a decade to us is really exciting.
Yeah, I certainly agree with you. It's almost unheard of to see these types of responses and PFS rates for any type of compound. Now, when we think about the competitive landscape, obviously a lot of people point to [audio distortion] . So I want to get your thoughts on the data that that asset has generated, especially from a safety profile perspective.
First of all, I'll just start by saying that taletrectinib is the only ROS1 inhibitor in development that has been granted breakthrough designation in both the first and second line. No one else has gotten that. On top of that, we were assigned the priority review by FDA. Just giving you an idea, FDA's seen everyone's data, and we are the only one to get BTD in first and second line. That's the first thing I'll say. The second thing is our safety database has over 400 patients. You know, our competitors, I think we're talking about a dataset so far out to public of about 20 patients. It's a very, very small dataset. You know, they're several years behind us. I think that, you know, it remains to be seen how good the data will be.
I think that the right thing to do is to, when the data come out, to compare apples to apples to see whether that's necessary. We feel we think it's going to be pretty hard to beat 89% response rate and 46-month median PFS that's still growing as we get longer follow-ups. I think we feel pretty confident that our dataset is the bar to beat. We think that the value proposition that taletrectinib offers for ROS1 patients is pretty extraordinary.
Yeah. No, I'm definitely in that camp along with you, David. And you know, one of the things that, you know, a lot of people thought had trouble wrapping their head around in the past was, you know, when we saw the continual improvement of, you know, from crizotinib to lorlatinib to entrectinib to repotrectinib, you know, why is it that the sales of these agents sort of plateaued and they really haven't hit that billion-dollar mark yet? And then earlier this year, the NCCN guidelines changed. Yeah. Talk to me a little bit about that. And you know, how are you thinking about how are you thinking about the commercial opportunity for this agent, how investors should be factoring this in, as well as factoring in the non-dilutive financing with Sagard ?
The ROS1 landscape has changed dramatically over the last few years. As I started off by saying, the standard of care for ROS1 lung cancer used to be IO chemo. Yeah. If you look at the logistics of how ROS1 gets diagnosed and then managed, you can understand why IO chemo is used the way it is. Imagine, you know, the average ROS1 patient is about 20 years younger on average than the average lung cancer patient. Fifty years old versus seventy. Imagine you have a lung mass, you get biopsied on a Monday. The pathology comes back really fast. By Tuesday, you find out you have cancer. Your NGS testing may not come back for two to three weeks. You have a 50-year-old person who's a highly varied career, still working, generally raising family, super nervous, anxious.
They want to be on something. They start IL chemo because they won't know for two to three weeks what their mutation is. In two to three weeks, the mutation comes back and it shows ROS1. You'd think that they all switch. The reason they don't switch is because the old NCCN guidelines said if you had a ROS1 upfront and you knew it, of course, the recommendation is to take a ROS1 agent. The NCCN guidelines also said if you didn't know your mutation status, but had a biopsy that showed cancer and you take IL chemo, if you subsequently find out you have ROS1, you have two options. Recommendation number one is finish the IL chemo, including maintenance. Recommendation two is to switch to a ROS1 agent. As you know, there's a lot of momentum in this powerful thing, right?
You've already started on IO chemo, and you find out you have a ROS1 mutation two or three weeks later, a lot of patients don't ever switch to ROS1 because the NCCN actually recommended IO chemo continuation as one of their two recommendations. That all changed on January 7 of this year. Now, given the fact that we know the PFS of IO chemo is 6-12 months, we know that repotrectinib's PFS is 36 months. When the repotrectinib data came out, that was so different from IO chemo that the NCCN redid their guidelines. On January 7, they published new guidelines that say that now if you are started on another first-line therapy and are subsequently found to have ROS1, you need to stop that ROS1 therapy.
I'm sorry, if you have lung cancer and start IO chemo, if you're subsequently found to have a ROS1 mutation, you need to stop the IO chemo and need to switch to a ROS1 agent. On top of that, the NCCN went further to say that if you are subsequently found to have a ROS1 mutation, IO is now contraindicated. That is the first time ever that treatment guidelines have been not only shifted to recommending ROS1 agents for ROS1 mutations, but to saying that IO chemo is actually specifically contraindicated for patients with a ROS1 mutation. I think that is going to significantly influence practice. I've now traveled to quite a few new centers over the last few months, and many of them are already switching their internal guidelines to be compliant with NCCN new recommendations.
You know, when we think about, you know, the commercial opportunity then, you know, I guess this is more a question for you, Philippe. You know, how are you thinking about potential revenues for taletrectinib as well as factoring in that non-dilutive financing that you orchestrated earlier this year?
Yeah, I think to David's point, the reality is that there are many patients today that should be treated with ROS1 TTR and are now treated with ROS1 TTR even before us. Yeah, they should not be treated the way they are today. What has been very interesting, I mean, David has made lots of KOL and seen those recommendations change, but we've also seen early days with a little bit of an uptick in scripts, like about 20% uptick already in script of ROS1. The marketplace is changing. People realize that they have to go through the ROS1 TTR, which is the right way to go. If you think about the market opportunity, you have about 3,000 patients a year, we were saying earlier.
If you stay close to four years on therapy, which we would expect, you're talking about a prevalence of 12,000 patients, and you apply the price of repo or whatever price you see fit, and you can see immediately you have a multi-billion dollars of profit. I think this aspect that you can start with a market, which is today relatively small, but can become much bigger, is not new to ROS1. We've seen that in ALK, we've seen that in EGFR for exactly the same reason, stacking up of patients, more patients getting on therapy, because those targeted therapies are much better than what's out there. The value of the product was recognized by our great friends at Sagard, with whom we did these deals that you're mentioning.
When you think about it, we got $150 million royalty financing for 5.5%, even less than that because there are like layers, but 5.5% of U.S. sales. You can do an easy math. You have $150 million, 5.5% of U.S. sales. What does that mean for the value of the product? Immediately, you can see it's a multi-billion dollar opportunity. For us, it's both this validation from external partners, as you see, this great opportunity, but it was also the way to signal to the street and all investors, we already thought we had enough money never to raise any cash for this company anymore, but now we're really, really sure we have enough money never to raise any cash.
Yeah. You know, that's really encouraging because obviously, when we think about the current environment that we're in in biotech, obviously, you know, there is a cash crunch for a lot of companies, right? The ability to finance or to raise more cash is restricted for a lot of these companies, right? Because they don't have the pipeline and the repertoire that you guys have internally. That is a de-risking investment factor, at least from my perspective. You know, now shifting to the actual PDUFA date, June 23rd, obviously, you know, we know about the recent cuts at the FDA. We've now seen two PDUFAs be delayed, most likely because of the cuts at the FDA. What sort of confidence do you have that this PDUFA is going to come on time?
We've had extensive interactions with the agency ever since we submitted our NDA. First of all, we received the priority review. Secondly, I mentioned, you know, there are really no oncology agents that have shown a profile like taletrectinib. As you can imagine, it is being treated with a higher priority. We've had extensive discussions, and we feel, based on the rapidity of FDA responses, which, by the way, we really commend them on, they've been incredibly efficient and responsive to everything during this whole process. We feel very confident that we will be approved no later than June 23 and possibly earlier. We, you know, we think that we have not seen any evidence of any slowdown of any sort, at least with our application.
Okay. You know, while we shift gears now to your IDH1 and then we're self-assisted, you know, one of the things that I find extremely encouraging is the CRs that you're seeing for this agent, right? It also seems that there are some immune-modulating aspects to this compound, which you wouldn't expect from a small molecule, but it seems like the AE profile, you're seeing these IRAEs. Talk to me a little bit about the comparison to vorasidenib and why this potential immune-modulating component is extremely important.
What's really interesting about our safusidenib data, if you look at vorasidenib's response rate in low-grade glioma in the Indigo study, it was 11%. In our first study, our response rate in low-grade glioma was about three times that, 33%. If you look at vorasidenib's response rate in high-grade glioma, it was zero. No CRs, no PRs, no minor responses. If you look at safusidenib's response in high-grade glioma, it was 17%, but a third of those were complete responses. If you said correctly, one of those complete responses was a glioblastoma. You know, as you know, this is one of the most aggressive of all cancers and certainly of all brain cancers. That patient's tumor has been gone for 3.4 years, which we just find striking. The second patient's high-grade glioma has been gone for almost two years.
What's really interesting about our responses is that we don't see them before six months. They kick in really slowly, somewhere between 6 and 12 months, which is exactly what you see with IL agents. The fact that we're seeing these really durable tails is also very reminiscent of an IL agent. You also mentioned correctly that our adverse events are unusual. If you look at the top eight adverse events of safusidenib, five of those adverse events are immune. We see skin hyperpigmentation like vitiligo. We see a rash like you might see in lupus. We see arthralgia like you might see in rheumatoid arthritis. We see alopecia like you might see in alopecia areata, another autoimmune disease. Vorasidenib has none of those immune-type AEs. We have clearly immune-type AEs.
If you look at a preclinical study we did where we took xenografts in immune-compromised mice versus immune-competent mice, safusidenib had effects in immune-compromised mice, but they were modest. If you look at mice who had an immune system to activate, safusidenib made a dramatic improvement in mortality in the mice, whereas vorasidenib, even at five times the clinical dose, had no effect at all. There is something fundamentally different between safusidenib and vorasidenib. We think this is something that really needs to be developed. We just finished a meeting with the FDA, and we will shortly be posting our pivotal trial designs to get safusidenib registered. We are super excited about that program. We think that this is one of the biggest unmet needs in all of cancer. As you know, high-grade gliomas especially, there is nothing good right now for that.
Even for low-grade gliomas, we think that, you know, 11% response rate is still relatively modest. Even though vorasidenib was approved on a progression-free survival benefit, which was substantial, you're going to see data later this year where we're going to present for the first time progression-free survival of safusidenib in low-grade glioma. We think, again, it's very, very consistent with how different these two drugs are. We're very excited about that program.
Obviously, I'm not going to ask you that, and can you apply this to the potential trial design? Because you haven't disclosed it yet. A different type of question is, you know, given the trial design that you already have envisioned in your mindset, how long do you think it will take until we see initial data from that pivotal trial?
I can't really, you know, speak to that because that does speak a little bit probably to the trial design that we're going to disclose shortly. You know, we think this is a very doable program. You know, we clearly our priority as a company is to get this drug to patients as quickly as possible because it's such an unmet need. We think this drug is so unique. We are trying to, you know, conduct the trial as rapidly as we can.
Okay. Completely fair. While we shift to your other asset, which is part of the DDC, came out of the DDC platform, NUV-1511. You know, this is currently in phase I trials. You're going to explore, I believe there's five different tumor types, if I recall correctly. You know, when do you think we might see initial data for that asset? And when are we actually going to figure out what the target is and what is the warhead that you've attached to? Obviously, I believe it's cytotoxic, right?
We have not said a lot about the left and right ends of the molecule. What we have said is that one end is a really well-known chemo agent that everyone knows about. This agent is effective, but highly toxic. The left end of the molecule, or whatever, the other end, we have not disclosed what that is, except to say that it is an FDA-approved drug. It actually is not even used in cancer. It binds to a target that we think is relevant. We fuse these two things together. We have been in patients now for quite a while. We were testing five cohorts. The first cohort is patients who failed ADCs, so women who failed in HER2 or treated LV with breast cancer. Nothing works there. We were testing women with HER2 negative metastatic breast. Again, nothing works there.
We're testing men who failed XTANDI for prostate cancer.
One-year-old drug?
Yeah, my old drug. And, you know, in our preclinical models, 1511 has activity there even when XTANDI has failed. So we're testing men with that. We're testing women with platinum-resistant ovarian. No good options there. And then one of the worst of all tumors, advanced pancreatic, where there's really just nothing but chemotherapy and really a very poor prognosis with that. So those are the five cohorts we're testing. And we should be announcing data towards the second half of the year.
Is this going to be a medical meeting type of presentation, or is this going to be more a press release sort of corporate event?
I think we always probably prefer to present it at a medical meeting. It depends on the timing a little bit because, you know, we're still conducting the study. You know, I don't know exactly when we'll have enough data to generate the signal that we think we need to present it publicly. It should be some words toward the second half.
Okay. We've pretty much run up on our time, but David, Philippe, I really appreciate you joining us. I can't wait to see all the data. You know, I'm pretty sure you guys are going to be approved for taletrectinib. I look forward to it.
Thank you so much.