Conference Transcript - NVCT 2026-05-19

Ron Bentsur, CEO

of systemic side effects that they encountered namely immunosuppression and cardiovascular risk and things like that and the reason for that was because they weren't very specific in fact they were the polar opposite of that there were very dirty compounds they hit many different targets and when you have too much of a good thing you can start running into these types of issues and that's in fact what happened to them so the first thing was to try to come up with a drug that was very specific. So from day one, at the University of Edinburgh in Scotland, which is where this compound was inlicensed from by us, this drug was rationally designed to be a much more specific, a much cleaner, selective SARK inhibitor. That's the first thing. The second thing is the mechanism of action by way this compound shuts down the SARK kinase. So the SARK kinase, just like most kinases, not all, but most of them, has two active domains, what's called the catalytic domain, that's where the signal transduction process takes place, the passing of the phosphate molecule. But there's also the scaffolding domain, basically the communication hub of the kinase. Ideally, you wanna shut down both of these. And what we saw with the prior attempts to come up with these SARC inhibitors is that they're only able to shut down the catalytic domain and not the scaffolding domain, whereas NXP900 is able to shut down both of them for a much more potent, we believe, even much more effective shutting down of the SIR kinase. So as I mentioned before, the phase 1A and the drug-drug interaction studies have been completed. We'll talk about those briefly. In the phase 1B, which is kind of where the tire meets the road, started six or seven months ago, something like that, and it is very much ongoing, with preliminary data expected in the summer, probably the late July, early August time frame. So this is the selectivity that I talked about. So this is a kinome heat map comparing NXP900 to Dasatinib, which is one of the three prior SARC inhibitors that were developed. And you can see that Dasatinib is very dirty, lights up like a Christmas tree, so it shouldn't come as a big surprise as to why when you start treating patients with Dasatinib, you can start running into issues because there's just too much crosstalk when you start hitting a whole bunch of targets. Whereas NXP900, as you can see, is very, very clean, and that was by design from day one to try to come up with a very selective SARC inhibitor. The second thing, and don't worry about the busyness of the slide, is this mechanism of action aspect that I talked about. So you wanna be able to shut down both the catalytic domain, which is down there, and the scaffolding domain. And the easiest way to see the difference is when you look at the three-dimensional crystallography pictures of the binding of NXP900 to the Sarkinase versus the satinib, the sutinib, Sarkatinib to the Sarkinase. So when you look at those three-dimensional crystallography pictures, what you basically see is that the kinase remains in what's called an open conformation. It remains basically upright, it's still partially active. So those drugs are unable to shut down the sar kinase completely. Whereas in contrast, when you look at the binding or the three-dimensional crystallography picture of the binding of NXP 900 to the sar kinase, you see that the sar kinase is in what's called a closed conformation. It's basically shut down, completely incapacitated, and that's really what you want to achieve. We feel that's a better outcome. In terms of the phase 1A, so that was the dose escalation, basically the safety study, so it was in all comers, and we tested obviously a wide variety of doses, started off very low. At 20, we did 20, 40, 80, 150, 200, 250, and 300 mg per day. This is a once a day oral. And in terms of safety, you'll see on the next slide, generally unremarkable, so that's good. We certainly didn't see any of the major safety signals that were seen in the past with the other SORC inhibitors, the immunosuppression and the cardiovascular issues and things like that. We certainly didn't see any of that, and we haven't seen any of that in the ongoing phase 1B, so so far, so good. What was particularly interesting about this phase 1A is that we actually looked at a pharmacodynamic parameter which was the level of SARC inhibition. So you can take blood from the patients and measure the before and after levels of SARC. And what we saw was that at doses of 150 and higher, so 150, 200, 250, and so on, you get to about 90 to 95% SARC inhibition. That's very profound. We believe that's very potent. And when you compare that to the pharmacodynamic data that was generated back in the day for these other three SARC inhibitors, they kind of max out at around 45 to 50 percent, whereas we're at 90 to 95 percent steady state. So that's a pretty dramatic difference we feel, and hopefully that'll play out in our favor in the clinical trials. This is the safety chart from the phase 1A. Generally unremarkable, there's obviously a little bit of GI, there's always some diarrhea and a little bit of nausea and things like that when you give an oral to oncology that's kind of par for the course. We did have some cases of pneumonia. You can see it down below. I can assure you these things were scrutinized and adjudicated with a fine tooth comb by a very wide and respected panel of medical monitors. And none of these were adjudicated to be drug related or possibly drug related. So these really had nothing to do with the drug. And this is this pharmacodynamic data that I talked about. I wanna draw your attention to the right side, the right table over there. So this is basically steady state. What do we mean by steady state? Basically, patients have taken the drug for 28 days, every day for 28 days, then they come in, that's a cycle, that's basically the first cycle. And then they come in on day 29, which is basically day one of cycle two. And before, before they take that 29th dose, the measurements are taken. And what you can see down there in turquoise is the level versus baseline. And you can see that it basically comes down by a good 90%. So that's what we mean by 90% SARC inhibition at steady state. And that is a very encouraging result from our perspective. In terms of the drug-drug interaction study, so the combinations that we wanna run in the phase 1B, one has already started with the drugs of, two drugs in non-small cell lung cancer, the first one's called Tigriso, the second one is called Gorlatinib. Those drugs have basically in their package insert contraindications with drugs that basically stimulate things like CYP3A, CYP450, and things like that. So we needed to rule that out in order to be able to combine with those drugs. And in fact, what we ended up seeing is that NXP900 is in fact a weak inhibitor of CYP3A and those families of enzymes, so that's actually a good thing, and obviously that facilitated the ability to conduct these combination arms. I'm not gonna go into too much detail here, but what's important to understand, and I'd be happy to talk offline with any of you about this slide, this basically is the rationale for the different biomarkers and genetic signatures that we look for in the patients that are coming into the phase 1Bs, or we are enriching the patient population for different mutations and alterations of things like the S1 overexpression. That makes sense, right? The S1 being the main culprit within the Sark family. If that's overactivated, yeah, that's a patient we want because we feel that we can shut down the S1 pretty effectively. So obviously that, we believe, increases the probability of success. And there's some other proteins and mutations that we're looking at that we're including in the phase 1b, things like FAT1, YAP1, and some others. But they all basically make a lot of sense when you do a deep dive into the mechanism of action and the cascade and where the Sark kinase sits. This is actually a very interesting case study, we feel. So one of the three drugs that were tested back in the day was a drug called Sarkatinib. This was AstraZeneca's attempt to come up with a Sark inhibitor, and one of the studies that they conducted was this study here. So they enrolled about 25 non-small cell lung cancer patients. These were all refractory non-small cell lung cancer patients. And what they saw was the following. They actually had two PRs in one stable disease that almost added up to a PR, 29% tumor shrinkage, where the cutoff is 30%. So roughly a 10, maybe 12% response rate, something like that. So obviously that's not enough to move forward, or it's certainly not for a big pharmaceutical company like AstraZeneca, but a couple of key takeaway points that are important for us. So first of all, number one, there was a signal of activity. You don't get PRs by chance. So we know that this SARC inhibitor did something to these patients, that's one. Two, AstraZeneca did not enrich the patient population that came into the study. They did not look at any of these biomarkers that we're looking for to enrich the patient population. This was an all comers, refractory non-small cell lung cancer patient population that came in. The third thing is, when you look at Sarkatinib objectively, we feel versus NXP900, it's not nearly as good as NXP900 in terms of its ability to inhibit Sark. Again, maximizes it around 45 to 50% in terms of its ability to shut down Sark in the pharmacodynamic models that they did back then. And so when you add all this up, we really like our chances. We're enriching for the patient population. We've got a much more potent SARC inhibitor. And we're on our way in the phase 1B. And you know, fingers crossed, we'll see positive data. So the phase 1B program has several cohorts in it, basically several shots on goal, if you will. So there are actually five monotherapy cohorts where the drug is acting on its own. So you've got two distinct subpopulations within non-small cell lung cancer, adenocarcinoma patients, and squamous lung carcinoma patients. Then you've got renal mesothelioma and a basket group that looks at patients that have these different mutations, which are mostly, it ends up being that these are mostly head and neck, esophageal type of patients, so that's basically what we're seeing in this basket group number five over there. And then we've got two combination arms. The first combination that has already started is with osamertinib, which is Tigriso. Tigriso is an EGFR inhibitor, major, major blockbuster, it's an AstraZeneca drug, it's gonna do about $7 billion this year, or something like that, the mainstay of EGFR inhibition. But unfortunately, patients can benefit for extended periods of time with osamertinib, sometimes even for two, three, four years. But inevitably, patients will stop responding and they'll become resistant to Tigriso treatment, and that's when you want to try to catch them and try to reverse that resistance. So that's one of the combination cohorts. The second one, which is gonna start in a few weeks, is with an ALK inhibitor, also in non-small cell lung cancer, called lorlatinib. That's a Pfizer drug. Second line ALK gives a very prolonged benefit. The median PFS is approaching five years with lorlatinib, so obviously it's a very effective drug, but again, same story. Eventually, patients will stop responding, and that's when you want to try to catch them. So that's basically the rationale for doing these combinations. And this is kind of what prompted this whole idea of doing these combinations. So just to draw your attention to the right side over there. This was the highlight of a publication that came out about three and a half years ago, Nature Communication, a very prestigious medical journal. This was actually done by the AstraZeneca R&D group. This wasn't us, this was independently done. And what they did here was, they took Tigriso-resistant cell lines, and they tried to resensitize these cell lines to Tigriso treatment by taking Tigriso in combination with a bunch of other drugs to see which combination could reverse the resistance. And lo and behold, the combination with NXP-900 won this dog and pony show. And by the way, they refer to the drug here as ECF-506. That's a name that the University of Edinburgh, which is where we licensed the compound from. That's a name that the university had for the drug, but it's NXP 900. So obviously that was kind of the first time where we actually saw third party independent data supporting the thesis for possibly combining with Tegrisso to try to reverse the course for Tegrisso resistance. And then we ourselves replicated this experiment here, and we did some in vivo studies as well. Everything came back very consistent, very strong. And now, this is a cohort that's very much off and running. We started enrolling patients into this group, into this specific cohort a few months ago. On the left side, same type of a rationale with Lorlatinib. Also, this was an inbound that came to us from the University of Vanderbilt. They had conducted some work with Sark inhibition as it relates to Lorlatinib resistance. They saw very good results, and obviously we amplified that from there. And that's basically the basis and the foundation for the cohort, the combination cohort with Lorlatinib, which is going to start in a few weeks. Another combination that we're looking at potentially is with RAS. Again, there's been some data that's been generated. This is actually data that was published last month at the ACR conference. And I can tell you that there are two independent, very well known universities that have approached us wanting to conduct some experiments of their own. because preliminarily they've shown some very interesting activity in their own labs looking at SARC inhibition as it relates to basically amplifying the RAS signal. So hopefully we'll be able to do something along those lines as well. In terms of the market opportunity, this is where we feel this pipeline in the pill opportunity really, I think, comes to light. When you look at the potential addressable patient populations here, they're very substantial. They're in the tens of thousands. Just to give you an example, back in our prior lives at Urogen and at Stemnon, the two companies that I mentioned before, the first approval for Urogen, for Jalmito, was in a disease called upper trachearothelial carcinoma. That's about 2,500 patients. And for Elzonris, it was an indication called BPD-CN, a hematological tumor, about 800, 900 patients on a good day in the US. So this is really orders and orders of magnitude bigger than anything that we've dealt with in the past. And this is just for the monotherapy potential, looking at these different alterations, so yes one amplification, fat one mutation, and so on. And when you look at the combination approach, so at any given point in time, in any given year, there are about 20,000 patients, roughly, maybe even 25,000 patients, that basically fail to GRISO. Now, don't worry about, you know, AstraZeneca, unfortunately for humanity, you know, they can replenish this patient population very easily with newly diagnosed patients, but the fact of the matter is that roughly 25,000 patients drop off that merry-go-round every year. Those are the patients that we want to try to treat to try to reverse the Tegryso resistance. ALK about half of that, and then there's some other possibilities for combinations, but I think the take home message here is that the addressable patient populations that we're talking about here are very substantial. A little bit of housekeeping. So we finished the first quarter with about $25 million of cash. Our burn rate is very controlled. It's about $4.5 million per quarter, which is, I think, pretty rare in our industry to come across a company that I think is very financially disciplined. So we have about 16, maybe 17 months of cash of runway from where we sit. But keep in mind that we expect to have a preliminary data readout this summer, so in late July or early August. And of course, some subsequent data readouts after that, every three months or so. So hopefully, that'll give us more than ample opportunity to refill the tank at hopefully much higher prices and everyone will be happy. I don't think anyone will complain. In terms of the analyst coverage, obviously Joe is one of the covering analysts. He's very, very well versed on the story. So, you know, if you do have questions, you know, obviously I think Joe is a very, very good address to be able to answer those questions. And again, in summary, we're talking about a drug that has tremendous potential, a very unique SARC inhibitor, trying to learn from the shortcomings of the prior attempts, and really trying to, you know, rationally design a drug that can really, after, you know, having seen the experience with the other SARC inhibitors, to be able to come up with something that is much more potent, much more selective, and so far, at least in terms of safety, we certainly haven't seen any of these, you know, really horrible and prohibitive things that those other SARC inhibitors encountered that really prevented them from getting these all-important solid tumor approvals that everyone wants to get. So that ends the formal part of the presentation. Thank you all so much, really appreciate your time.

Speaker 1

Thanks a lot, Ron. John, I actually just have one question here for time's sake. When you consider the commercial profile for NXP 900, what role, you touched upon this earlier a little bit, but what role do you think a diagnostic will play in? Is this a commonly available diagnostic and will you use it to identify patients?

Ron Bentsur, CEO

Thank you, John, I'm glad I'm on the platform. So for five minutes in my life, it can be taller than you. But the, so it's a very important question. So all these biomarkers and all these mutations, Fortunately for us, we don't need to come up with a companion diagnostic, that would be pretty horrific. These are all things that are available with the standard next generation sequencing panels that are out there in probably 95% of the oncology centers in the country, so Foundation, Illumina, these are all standard panels, so that's very fortunate for us. Thank you very much.