All right. Big crowd. All right. Welcome, everybody. To our chat this afternoon, Brian, Celcuity, thank you so much for joining us. Oh, you're welcome. Let's start with a bit of a ten-thousand-foot overview before we get into some of the nitty-gritty. Sure. How do you feel going into 2024? What should we be focused on? What's coming next for you? Sure. So, you know, our lead drug is gedatolisib, a pan-PI3K/mTOR inhibitor. We have two active clinical programs. One's a phase 3 study in HR-positive, HER2-negative breast cancer, and the second is in metastatic castration-resistant prostate cancer. We expect to get data from one subgroup of our patients in the breast cancer study, second half of 2024. Then we'll get additional data in the first half of 2025 for that study, and then we'll get early data in the prostate cancer study, first part of 2025 as well. So we're busy with our global phase 3 study, and more to come. So obviously, we've seen a ton of different drugs in the PI3K pathway, let's say- Sure ... broadly speaking. Can you talk a little bit about the differentiation from gedatolisib- Sure - and the others? greater- So what's interesting is that this pathway is one of the most important pathways in cancer, right? But it's also one of the hardest to drug. 6 nodes are involved, you know, 4 class I isoforms, mTOR 1 and 2. Couple ways to evolve around. Well, exactly, and each of these nodes serve as compensatory resistance mechanisms. So gedatolisib at low nanomolar or sub-nanomolar concentrations inhibits all PI3K class I nodes, as well as mTOR 1 and 2. There are 3 approved PI3K inhibitors, PI3K pathway inhibitors, but they're each single-node inhibitors, so essentially, they'll inhibit alpha, or AKT, or mTOR 1. The challenge is that by only inhibiting a portion of this pathway, you're really getting second-best or third-best levels of efficacy. It's not the optimal approach. And so the rationale for what's been done to date, or where the reason why these companies have gone to single-node inhibitors, is because of the challenges for toxicity. Yes. The pathway, when it was first discovered, led almost every major pharmaceutical company to develop pan PI3K/mTOR inhibitors, 'cause that was the biological imperative. If you want to control this pathway, that's how you should approach blockade. But they were too toxic, so none of them made it out of phase I. So then you just had the development approach basically say, "Let's chop off mTOR. Most of the drugs in development now are really single isoforms. Getting narrower and more specific. Yeah. But it's interesting. One of the, I think, the head fakes that has occurred, because the only approach to date that's worked has been single-node inhibition, is the assumption that potentially the pathway is only relevant if a mutation is present. But we think the data we've presented, and also the nature of the pathway's involvement as a cancer driver, suggests that it's intrinsically involved, independent of the presence of an activating mutation. And so our early phase data essentially reported comparable results on ORR and median PFS, independent of PIK3CA status. Well, why don't we start with that breast cancer- Sure ... that I think you're referring to there? Yeah. Can you walk us through what you were seeing and what the- Sure ... the landscape looks like? Sure. With these PI3K. And also that, exactly what the background treatment is, 'cause sometimes it's easy to confuse dataset with the one out there. Well, so we're focusing on our phase 3 study is focusing on patients who are second-line, who've received prior CDK 4/6. So the standard of care in this setting, 85%+ probably of women will receive CDK 4/6 inhibitor plus letrozole, an AI inhibitor. And so in our study, early phase study, we evaluated treatment-naive patients, so women who hadn't received treatment in the advanced setting. With that patient group, we reported 48 months median PFS, 79% ORR. Okay, that compares to a standard of care in that first-line setting. Again, ours is a single-arm study, so these other results are randomized, but roughly 25 months is the benchmark, 55% ORR. So would suggest to us we have very strong rationale to move this drug to first line. But the study we're doing now is in second line, you know, women who've progressed on their prior CDK. CDK. The data for that group of patients was, with the dosing regimen we're taking to phase 3, was 12.9 months, and that, for all comers, 63% objective response rate. Now, our phase 3 study is evaluating, essentially, independently, we're evaluating patients who are wild-type and or mutated. So we're isolating those two populations for statistical assessment purposes, so powering those two subgroups. And so the control that we're comparing against in the wild-type population is fulvestrant. Mm-hmm. If you look at the results that have been reported in two randomized studies that use fulvestrant as a control, essentially, median PFS was only a couple of months. So a very low bar to beat, essentially. You know, we reported 13 months, roughly, in our early phase study. So we think a significant margin for error, if you want to think of it that way, or high probability, or what we would characterize as a high probability of success. And then in the mutated population, our control is alpelisib fulvestrant, which there have been two studies done in the post-CDK space, and essentially, if you average those results, about 6.5 months is the bar we have to beat. And so again, we feel like we have substantial margin for error, in- How do you feel about the impact of novel SERDs or estrogen modulators? So, you know, two years ago, everybody thought this is gonna transform care for breast cancer. The first two results that came out didn't get out of the gate. Mm-hmm. One has been approved, elacestrant, but only in patients with the ESR1 mutations. And so there have been some others that have come out with some promising results. You really have to tease out what their prior treatments were or the- Mm-hmm ... stage of these patients, because a lot of that data is confounded by that. But regardless, I think the takeaway that for most of the KOLs we talk with is that clearly there's gonna be an opportunity for oral SERDs. The challenge will be, and this would be our perspective as well, that if you're essentially optimizing treatment of a target that these patients are already receiving treatment for, the increment or incremental benefit needed, for instance, to get a first-line approval is gonna be significant. I mean, eight months incremental PFS with just an optimized targeting of that mutation. Okay, our perspective would be the biggest opportunity to improve standard of care, typically, is if you're treating an untreated disease mechanism. Right. That's our approach. Essentially, we're saying: Look, PI3K pathway is intrinsically involved in breast cancer. It's not being treated. If you were to stack up the data we reported in that first-line setting, the results we have weren't a function of adaptive resistance. These patients were treatment-naïve. So if you were to look at the incremental treatment benefit patients get from hormonal therapy, you double it when you add CDK4/6. If you were to look at our data, you'd say, "Wow, big step function increase in median PFS." We think that's a reflection of the overall disease mechanism in breast cancer, where you've got three pathways that are driving it, and the optimized benefit- You hit all of them. Treat them all three. Treat all three. Brian, can we spend a couple of minutes on the phase 3 design a little more specifically? Sure. The way I read it is that the VIKTORIA trial, it's two different phase 3s embedded within one. Yep. If we think about the wild type, for example- Mm-hmm. ... three arms, it's the triplet of your drug plus CDK4/6 plus fulvestrant. My sense is the primary analysis would get all 0.05 p-value alpha going to the triplet versus just fulvestrant. Is that accurate? No, it's actually a hierarchical design. So we're essentially testing arm A versus C, which is triplet versus fulvestrant. Right. If that passes, then we test the double- The residual alpha goes to the next, meaning you get all- Yes, exactly. We're not sparing almost all the alpha. There's not, there's kind of nothing. Got it. What do you-- I guess, what's your expectation on the triplet? Basically, CDK4/6 add-on versus not in that arm A versus B analysis. And is the dose identical, by the way? Yes. Okay. So essentially, our schedule is a 3-week on, 1-week off schedule. Right ... administered IV. We would expect, you know, it's that there to be a significant increment with the benefit of just gedatolisib added to fulvestrant, and then potentially a corresponding and a similar benefit- I see. By adding palbociclib. The rationale for that is that CDK4/6 involved. These patients become potentially resistant to this, probably because, I mean, you know, the hypothesis is that they're becoming primarily reliant on PI3K/mTOR, but they don't adaptively, the tumor doesn't adaptively mutate, and they're still sensitive to CDK4/6s. And so there's a lot of data that's been generated that says, "When you inhibit PI3K, AKT, mTOR, you're going to reactivate CDK4/6 pathway, which essentially means you'll resensitize these patients to a CDK4/6 inhibitor. Got it. I know, it's amazing. Okay. Can I ask about your choice of palbo? Mm-hmm. Now that we've got OS data for ribo- Right ... and we're starting to see that. So our early phase data was with palbo. And I would say, actually, I can't take credit for it, but with the move towards palbo, or rather ribo, in the first-line setting, you know, this study is done in a second-line setting. So these patients will potentially get the benefit because there's some data that suggests switching- Mm-hmm ... can induce some incremental benefit, in patients who've already progressed on their prior CDK4/6. So essentially, if this market over time evolves to one where it's primarily ribo, it had been up until two years ago, 80% palbo. Certainly. And so over time, probably you know, who knows what the share will ultimately be, but it'll be more than 50% ribo. That most of these patients then will potentially, certainly won't be disadvantaged. Maybe there's even an extra- I think so from a clinical standpoint. I think clinicians are saying, "Well, that would be great, actually," because you're giving patients, you know, new hormonal therapy, fulvestrant versus letrozole, potentially just a switch in the CDK4/6, and you're adding inhibition, PI3K. Those pathways are still involved. Those other two pathways are still involved, so you need to essentially clamp it completely. And that's why we think there's an opportunity to move upline. Brian, do you ever get questions on sort of Piqray orals versus the IV setting? Maybe more so before some of your efficacy data emerged, but considering fulvestrant's also not an oral anyways, do you think that matters commercially? I don't think it does. And there's 2 reasons for that. I mean, ultimately, efficacy does matter, right? I mean, the first best, you know, benefit, the most important benefit, first order benefit, is efficacy. All things being equal, if you have 2 routes of administration, one's more convenient, sure, the more convenient one may win. But ultimately, these patients are seeking, and the clinicians are seeking the drugs that are most efficacious, right? Secondly, in this setting, you know, having patients come by every week hasn't been considered burdensome, and that these are motivated patients. And with a two-week period from, you know, their day 15 dose to their dose in the next cycle, it was manageable. I guess the best test of that, I mean, it's a relatively small sample, was that we had women on, you know, treatment naive on the drug for a median of 48 months. Right. If that's burdensome, if it was not tolerable, they wouldn't stick around. They'd get off treatment. So we think that that will resolve itself. But, yeah, if you think about the served market, it's a $5 billion served market potential in the second line setting. So big. You can use whatever haircut you want, you're still ending up with a big number. Right. We would say that there won't be much delta associated with IV versus oral. And particularly with oral drugs, you won't have a drug that's well-tolerated, or at least as well-tolerated as we think gedatolisib will be, that's orally administered, because the activity that's affecting takes place in the liver and oral drugs are processed through the liver. Can we back up to something I think that we maybe skipped over a little bit- Sure ... which is the safety profile? Sure. You know, we started off this conversation- Right ... by talking about the liabilities- Sure ... of a pan- PI3K. So, right. The biggest obstacle to essentially properly or most effectively addressing the pathway is the safety challenge. And so PI3K alpha essentially is responsible for regulation of the glycolytic system or glycolysis... that activity primarily takes place in the liver. So oral drugs are processed through the liver. The last place you want alpha inhibition to take place is there. And the other toxicity associated with this class of drugs has been in GI, again, aggravated by oral administration. So because geda is IV administered, you avoid that first pass through your gut or GI, and because of the volume of distribution, essentially balanced concentration in liver, or rather in tissue versus plasma, so we don't get overly concentrated. And you'd see our grade one or grade three, grade four hyperglycemia monotherapy was 1%; palbociclib, 26%. So, very significant. But geda is more potent, and we've done some work that shows, you know, geda is 300-fold more potent in live cells than either of these single- But we're all talking about on-target toxicities, and this is where- This is where I think there's a big misnomer. Mm. There's two components to toxicity. One is, okay, the target you're affecting. Two is the target organ. You know, where does the activity take place? We avoid that. And the third is the amount of drug. And so what's interesting about these oral drugs is that they're not very potent. They need 20 times more drug than is required for geda. And just, you know, more drug you have to dose the patient, especially if it's- More accumulation- more in the organs ... in the organs that you don't want to hit. Exactly. So, potency actually can work in your favor, especially if you're oral, and I think, you know, there's some people trying to figure that out. Or you can try to spare, you know, wild type in this setting, but, they're second-best solutions really to addressing the, In our last minute or two, I'd love to talk a little bit about prostate, if that- Yeah, maybe just before that, though, the if there's one thing, Brian, at a more surface level, across all these data sets on efficacy and safety that we just discussed, I mean, you know, the blood sugar issues on Piqray, some of those issues are well understood. The thing that I've sort of struggled with a little bit is, as I look at a lot of your data sets, they look fairly straightforward on the- Mm ... PFS comparisons, and yet I find the interest on, the next-gen SERDs or degraders to be a lot more than what I'm seeing here, in spite of some of the data- Mm ... that you've been able to put up. And there's a lot more anticipation that data sets will become something, but they're not- Right. But they're... Yeah. I- Why, why do you see that in? I think sometimes, you know, hypotheses create their own momentum, and, you know, you have six companies out there promoting this idea. Okay. And so you've got a lot of brains- Have you seen a very clear data set? No ... that would suggest anyone can actually track at the type of PFS you've been able to put? No. Let's just talk about the 12-month PFS- No ... in second, third-line setting. I think that would be very, very unlikely. I really don't see any data that suggests- Because there's orders of multiple difference in valuations between you versus if you added- No, I look, I mean, that's why you guys are here. Sounds like I know. No, I do know. I think it's Or is it just because people think of it as an IV Piqray, so they don't wanna spend time on it, and they don't really- I think the pathway itself got put in the penalty box- Okay ... and so, you know, that, that's a starting gate. And I think that oral SERDs have been out there for five years promoting this idea that you can potentially improve benefit. We've got an opportunity to maybe be in the adjuvant setting to replace tamoxifen, you know, five-year treatment period, you know. And so I think there's the notion that there could be some, you know, big pot of gold at the end of that rainbow, but I think it's a much higher risk of those drugs- Got it ... achieving some of those, Got it ... outcomes. I know we're well past time. I got stuck on that elevator 'cause it's- Yeah ... so efficient- Right ... to the eighteenth floor. But we should hit up prostate for one quick second just before we wrap up- Sure ... if that's okay? So the hypothesis, we're combining gedatolisib with an androgen receptor inhibitor in men who progressed on their prior androgen receptor inhibitor in metastatic castration-resistant cancer. Hypothesis is that it's a hormonally driven cancer, similar to breast cancer in a lot of ways. These two pathways are involved. That's been well-characterized. And so essentially, by retreating patients with an androgen receptor inhibitor, but in combination with our drug, you'll resensitize these patients to the androgen receptor inhibitor and essentially provide a meaningful incremental benefit. There was an analog study done with not a very good drug about five years ago. It was a pan-PI3K inhibitor, not very potent, some drug-drug issues, tolerability issues, but it reported a doubling of median PFS in this setting when it was combined with enzalutamide. So that essentially provides, we think, a proof of concept for what we're doing. Our hypothesis would be, if that drug with its limitations could generate those kind of results, and that was a randomized study, you know, we would at least hypothesize that we should at least be able to do as well. Mm-hmm. Mm. And so that you know, provided the rationale- Mm ... for us to proceed in that setting. So that study's just getting going now. Well, I think- There you have it. ... we, we didn't get an opportunity to talk about a lot of stuff- No ... that would be very interesting. No, that's fine. But, thanks so much for joining us. You're welcome. Brian- Brian- It was great talking. ... timing of that readout for the, first- Early, early readout will be first part of 2025. Wow, so this is not so far. Okay. Yeah. Excellent. Yep. Good luck. Thank you. Good luck. Thanks so much. We'll see a lot more data from the other side, too, by then, so- Yep. No, we will. Excellent. Yep. Thank you very much.