This is webcast, right? Hi, everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. I'd like to welcome Brian Sullivan, the CEO of, Celcuity. Thanks so much for joining us today, Brian. We're gonna do fireside chat format, so maybe to start off, if you want to give a one-minute intro to Celcuity. Sure. Celcuity is focused on developing treatments that address PI3K-involved cancers, and our lead compound is gedatolisib. Gedatolisib is a pan-PI3K/mTOR inhibitor. We have two active programs: a phase III program in HR-positive, HER2-negative breast cancer. We're currently enrolling that study. Expect to have data, first data, end of 2024, second half of 2024. The second program is one we announced in August that we'll be evaluating gedatolisib in patients with metastatic castration-resistant prostate cancer. Got it. Yeah, it's a great intro, and for gedatolisib in the breast cancer study, maybe talk about that phase III, the design, and, and how that study's enrolling. Sure. So it's an all-comer study. We're enrolling patients and evaluating patients who've progressed on their prior CDK4/6 therapy. That's the standard first-line therapy. Most patients will receive treatment with CDK4/6 therapy. You know, our goal is to evaluate how effective our regimen is in those patients. We're evaluating two regimens that have gedatolisib fulvestrant palbociclib and gedatolisib fulvestrant, comparing to a control fulvestrant with wild type. And then, we are doing separate analysis with patients who are mutated and comparing to alpelisib and fulvestrant. 700-patient total study, and, you know, we have two primary endpoints in the wild-type group, where we're comparing the triplet regimen against fulvestrant, and then, second primary endpoint, which we're assessing hierarchically, will be evaluated. We'll compare Arm B, which is the doublet regimen, versus fulvestrant. Got it. And on enrollment, how's that study enrolling? Any status update there? So far, so good. You know, it's a complex study, but it's actually fairly straightforward. One of the attractions of the study to our investigators is that, you know, essentially, 83% of patients will receive the equivalent of investigational therapy in most countries. One of our arms is evaluating alpelisib plus fulvestrant, and while alpelisib is approved in many countries, it's really only widely used in the US. Many of the payers in Europe, for instance, or Latin America, aren't approved to use alpelisib. So it's exciting for these investigators to, you know, be able to offer their patients, you know, novel therapy. And in addition, you know, the study, we think, is structured in a way to provide very clean data and answer a lot of scientific questions. For instance, we're enrolling patients who ideally are coming right off their prior CDK4/6, since that's the standard treatment paradigm for patients. We're going to give docs a very good perspective on that. We're also, you know, allowing evaluation of the individual effects of each of the drugs, fulvestrant, gedatolisib, palbociclib. And so I think we'll answer the questions of, you know, where the benefit is coming from. We're also separately powering the analysis in the wild-type group and the mutated subgroup. There have been a couple of studies recently in this space that powered a study to evaluate the mutated subgroup, whether it was ESR1 for a SERD or PI3K alterations for an AKT inhibitor. And then their second primary analysis was for the overall population. They didn't isolate separately the wild-type contribution, and that's a challenge for the FDA. We know just through our own interactions, that they are very interested in isolating the treatment effect with drugs that target or have a mutated patient population that could likely contribute or benefit. They want to confirm that the wild-type patient group also gets a benefit. So we ensure that it's possible with the overall study design. Makes sense. Yeah, I think the design allows you to isolate a lot of different, and answer a lot- Characteristics ... questions. Exactly. Right. And for your phase III, you mentioned that you're gonna have 200-plus sites across 20 countries for this study. In the last few months, I think you added Mexico, a few South American countries, and India to the study. Were these countries part of the original plan, and, and how do you expect the, the final patient composition to look? Sure. We originally had 23 countries. Some of the countries have very extended regulatory timelines, and in some cases, somewhat, you know, can have challenges in just getting approved. India would be an example of that. So it was in our original plan. We've received regulatory approval in India. U.K., since Brexit occurred, has experienced significant delays in reviewing regulatory submissions to conduct studies. We have received our regulatory approval, but it was at the tail end of our process. So we knew there was some chance that some of the countries would come in very late, and that's why we targeted the 23 countries, and we were successful in each one. We, we've targeted roughly 220 sites for the study. We achieved that, and you tend to want to overshoot a bit in your number of target sites 'cause you know circumstances come up. Some sites will lose their primary investigator, principal investigator, you know, and you just want to essentially anticipate that some sites might not perform or might need to be closed. Got it. And for patient composition coming from different regions, any- It's pretty much what we expected. I think, you know, the U.S. comprises, you know, in these studies, typically, it can vary quite a bit, but, you know, 15%-25%, and, you know, the rest is somewhat distributed according to population and where your sites are. ... Okay, makes sense. And since alpelisib, you, I think you mentioned earlier, South America doesn't offer it there, so you could-- that could help. No, South America, you know, I think is a very good opportunity to enroll patients. I think Europe as well, because while alpelisib is approved in Germany and the U.K., the payers haven't approved it, so- Right. -it's essentially not, widely used. Got it. Okay. And you had a Science Day recently, where you tested 8 factors to identify ones that could have impacted the overall response rate difference between Arm C and Arm D from your phase Ib study. You showed 3 factors that met significance there. Can you talk about the other 5 factors that did, likely didn't contribute significantly, and, how are you leveraging the significant factors in your phase III design? Sure. The five factors that didn't really show any correlation were related to tumor characteristics. You know, the presence of lymph nodes, presence of bone metastases, number of lesions, number of metastatic sites. So those, you know, in the correlation analysis we did, didn't prove to be significant. And you had a second component to that question. For the three that were significant, how are you leveraging all of this information? Sure. in your phase III? Well, the primary purpose of that analysis was to isolate the treatment effect of using a three-week-on versus one-week versus every-week schedule. And so we wanted to isolate potential contribution of different characteristics of these patients, and the ones that were most significant were the time on prior therapy, whether they had prior chemotherapy or not, and the duration of their prior treatment period. And in each of those, when we isolated the treatment schedule with those variables, we found that the treatment schedule was responsible for the difference in efficacy between a weekly schedule versus a three-week-on, one-week-off schedule. So on the basis of that analysis, A, we think the treatment schedule is very beneficial, and that provided the scientific rationale for the dose approach that we're using, the administration approach we're using in our phase III study, and we'll use, you know, in future oncology indications. Got it. Okay. And, you've also said that you expect the phase III patient baseline characteristics to be similar to your phase Ib Arm D experience. Is that what you've seen so far with the enrollment in your phase III? And, maybe give us some color on what baseline demographics will look like in the phase III- Sure Readout in a second. Well, as it turns out, we think there are several differences between the baseline characteristics we expect in the phase III versus Arm D, actually, to the good. In the Arm D population, we allowed patients who had prior treatment with a chemotherapy in the advanced setting. In the phase III study, VIKTORIA-1, we're not allowing patients to have had chemo in the advanced setting. And we did that so that we could get a clean read on the benefit we could potentially induce in patients who are coming off their frontline therapy. Since, for the most part, you'll see studies show that the treatment effect of a targeted therapy in patients who've had prior chemo, it will tend to be less than in patients who haven't received prior chemo. So we think that would be a to the good. The other to the good is that there were no Arm D patients that had bone-only metastases. Now, that comprises roughly 25% of the patient population. And if you look at results in these studies, in this population, you'll see that the bone-only patients tend to have a more favorable prognosis, and they tend to be more responsive. It depends on the drug, but you will tend to see a trend of favorability for patients who have bone-only metastases. So in the VIKTORIA-1 study, our phase III study, we are allowing patients who have bone-only metastases, as long as they have a measurable lytic lesion. And again, we think that would be a to the good. And we, you know, if you've assessed the net effect of that or try to get a sense of what that means, you know, in Arm D patients, the median duration of prior treatment was about 13 months, which, as it turns out, was almost exactly what we reported for median PFS. Patients who have received CDK4/6 inhibitors in the frontline setting have a median duration of treatment of roughly 20 months, you know, plus or minus. And so, you know, we would expect, although obviously there's, you know, we'll be... You can't predict everything, but we would think the median duration of prior treatment would be more consistent with what you see with patients who've had prior treatment on a CDK versus what we saw in Arm D. So net-net, we think we have a population that you know is biased to the good. I know in some cases in studies, changes in baseline characteristics can you know cause problems. In our case, we think these changes will, well, if nothing else, be a net neutral, but potentially you know could be favorable. Got it. Interesting. For the bone-only population, do you have an estimate of what proportion that's gonna be? Other studies report typically 20%-25% that enroll bone-only patients of the population. Got it. Okay. And let's see, maybe going back to your Science Day, you discussed gedatolisib development in breast cancer and prostate cancer and highlighted the drug's differentiating PK profile versus other PAM pathway inhibitors, and also the long half-life, which can maintain an effective concentration over the course of a week. Maybe talk a little bit more about those data and what% target inhibition was defined as effective, and is gedatolisib differentiated efficacy, is that mainly driven by the Cmax, AUC, or trough levels of the drug? Sure. We think there are two characteristics that are highly differentiated from geda versus other drugs that have been developed in this space that are responsible for its treatment effect. The first is its mechanism of action. Geda inhibits all four Class I isoforms, alpha, beta, delta, gamma, as well as mTORC1 and mTORC2. The treatment approach or the mechanism of action of the drugs that are either currently approved or probably going to get approved are what we would call single node inhibitors. They'll inhibit PI3K alpha, for instance, or mTORC1 or AKT. Because of the complex nature of the pathway, where each of these nodes, in effect, serves as resistance mechanisms or compensatory mechanisms that ensure redundancy, inhibiting only a single node can induce activation of other nodes within this pathway. With only a single node inhibition of approach, you're potentially taking a suboptimal approach. Geda provides comprehensive blockade of the pathway, and we think, as a result, you'll get more significant control over that activity. The other characteristic that's important is the potency of geda versus these other drugs. We did an analysis in live tumor cells using a growth rate proliferation assay. And the point was to assess potential cytotoxicity and potency of these different drugs, see what effect of a, you know, a comprehensive blockade has versus single node, a blockade of the various components. And we found that geda was 300-fold more potent than each of the other single node inhibitors and the only one that was cytotoxic. So clearly differentiated. So I think it's a combination of the mechanism of action, a more comprehensive blockade of the pathway, as well as a very, very high potency that allows geda to sustain its effective concentration. We would say the effective concentration is the IC80 value throughout the duration of its treatment window. Got it. Okay, that makes sense. For the potency, there could be trade-offs there, where that could lead to on-target toxicity, which seems difficult to avoid, given competitors' early safety data with a mutant selective inhibitor. How should we think about gedatolisib's better safety profile relative to prior developed PI3K inhibitors? And do you think safety advantages is mostly PK-driven? Sure. Well, there are really two characteristics that will drive with drugs that hit the PI3K pathway, drive potential tolerability or toxicity. The first is the route of administration. Geda is an IV-administered drug. Almost all of the other drugs developed in the space are oral inhibitors. And that's relevant because the two target organs that are responsible for most of the adverse reactions are the liver and the GI tract. Oral inhibitors obviously get processed and essentially build up concentrations in those organs. And that's relevant because just use one example, PI3K alpha regulates the glycolytic system. When that's inhibited, can disrupt the homeostasis and essentially, as a result, induce high levels of hyperglycemia. Gedatolisib, because it's IV administered, isn't initially processed through the gut, so it avoids that route. But that's only a necessary condition, not a sufficient condition. This is where the PK profile matters. The characteristic that's most important is the volume of distribution. You know, Gedatolisib essentially has a balanced distribution in plasma and tissue. And we think this is important and can be demonstrated when we review the safety data from another IV administered PI3K alpha inhibitor. This is a drug that's been discontinued, and it was primarily used for hematological indications. But this drug, very potent alpha inhibitor, IV-administered, similar amount of drugs, so you control, you know, all those factors. But it had very, very high volume of distribution, which essentially meant it was retained, you know, 50-fold greater concentration in tissue versus plasma. And that's not all to the good with an anti-tumor drug. But more importantly, in the context of PI3K alpha inhibition, it was retained significantly in the liver. And so even though it was an IV-administered drug, it had similar levels of Grade 3, Grade 4 hyperglycemia as alpelisib, an orally administered alpha inhibitor. And then I would say the final factor relates back to the potency. You don't need a lot of gedatolisib to induce and achieve the signaling inhibition of this pathway. And so, you know, the combination of very potent drug, it's IV-administered, that has a volume of distribution profile that avoids excessive concentration in target organs that are responsible for most of the adverse reactions. Got it. What's the drug that you're referring to? You mentioned or- Oh, copanlisib, which was a hematological drug, had a single indication under accelerated approval, and Bayer just announced it was discontinuing it. Got it. And is that data out there, the volume of distribution data? Is that- It is. No, yes, no, it's in, it's in our presentation. Okay. So you can see that we have a table that confuses everybody. Okay. And let's see, based on your conversations with FDA so far, do they want to see overall survival when you file the NDA? Also, maybe talk about expectations for control crossover to gedatolisib Arms A or B, and your strategy to isolate OS benefit in phase III. Sure. So OS is a key secondary endpoint for us. The FDA always wants to look at overall survival. The challenge when you're evaluating a study in the second line, in particular, is that you'll typically have very few events or relatively few events relative to what's needed to do a fully powered analysis. So you have immature data. What the FDA looks at, when we get to the point where we're submitting our NDA and the data's, you know, at that, with that data cut, is to make sure there's no negative trend. They want to ensure that there's no signal that suggests survival could be compromised, and that's part of the package. Everything we have, every analysis we do with the data at that time, will be provided to the FDA. I think with crossover, you expect a high, you know, reasonably high level of patients to crossover. It's hard to predict, but I think if you see other studies, you'll see, you know, 60%-80% crossover. And, you know, we've included in the protocol pre-specified analysis to tease out the crossover effect on overall survival. And that's, that's part of what we reviewed with the FDA when we were kind of meeting with them to, you know, align on the study design. Got it. Makes sense. We know gedatolisib works well in combo with palbociclib and fulvestrant. Considering there are a few emerging therapeutics targeting CDK4/6 and ER, how do you think the landscape is going to evolve over the next three years? Well, I think the most active area of development has been with oral SERDs, and there's been huge amount of activity. I think there've been, you know, five or six drugs that are probably currently being evaluated. You know, three of them, or maybe four, but three of them have reported Phase III results. Only one of them was able to demonstrate a meaningful treatment effect, but that was only in the ESR1 mutated subgroup. So I would say in general, the expectations that people had haven't quite been achieved, which doesn't mean they won't be achieved with some of the other drugs that are, you know, at earlier stages. But I think what the question ultimately in this space is whether the treatment effect by optimizing inhibition of ER, essentially, you've got the same targeted therapy, let's say, a CDK4/6 plus set of fulvestrant or letrozole and oral SERD. You know, what kind of treatment effect can that induce when you're essentially just optimizing one component of a treatment regimen? We think the biggest potential opportunity to improve the standard of care is by treating an untreated disease mechanism. We think it's fairly clear that PI3K/mTOR is involved in this disease. There are two approved PI3K/mTOR inhibitors in the space. They're not optimized, but they certainly show treatment effect. And so over time, we think a pan-PI3K/mTOR inhibitor like gedatolisib will be part of the standard of care. We've reported very favorable data when compared to published data for first-line drugs, that again helps really isolate or demonstrate the mechanism of the disease and the potential contribution gedatolisib could make to extending progression-free survival in this patient population. Got it. Interesting. And let's shift gear to your prostate cancer study. Sure. that you announced. So your phase I/II study is designed to assess gedatolisib in combination with darolutamide. Maybe talk about the design and rationale. Sure. So the goal was to evaluate men who've progressed on their prior androgen receptor inhibitor, the second-generation AR inhibitor. And, you know, there's a significant unmet need, similar to breast cancer in some ways, where, you know, novel drugs launched in the past 10 years significantly improved standard of care, but that in the second-line setting, the alternatives are only giving patients, you know, roughly 5-6 months of progression-free survival period. And so there's big unmet need. PI3K/mTOR has been, I think, well-described as involved as a driver of prostate cancer. The challenge is having the right PI3K/mTOR inhibitor to address the disease. We think gedatolisib, you know, kind of fits that criteria. And so the goal will be to, A, in phase Ib portion, confirm the dose that we should bring forward. And then secondly, with phase II, add an incremental number of patients so that we have 30 patients that we can evaluate with the recommended phase II dose, to assess the treatment benefit that you get when you re-treat patients with an androgen receptor inhibitor, but you are adding a pan-PI3K inhibitor on top of that. Got it. And, any thoughts on drug-drug interactions? There have been some reports of concomitant darolutamide use can reduce the Cmax and AUC for the drug it's being combined with. Maybe comment on that. So one of the favorable properties of gedatolisib is that it's very stable, it doesn't metabolize. And so in general, we have not found there to be significant drug-drug interaction. Darolutamide, actually, when we evaluate its profile, we don't expect to see any meaningful drug-drug interaction. But that has been one of the challenges with some of the other inhibitors in this space. And darolutamide, we selected that because it is very potent. You could argue it's more potent than the alternative androgen receptor inhibitors. But more importantly, it has a better safety profile. And so we think combining the two drugs will hopefully demonstrate superior efficacy and also greater tolerability than would be achieved with other androgen receptor inhibitors. Got it. We just came out of ESMO recently. There were a lot of prostate cancer updates there. Talk about where you see this combo positioning in the prostate cancer? Sure. Good for us has been the fact that there have been a number of PI3K drugs developed over the years, and so we've, you know, kind of scoured the literature and evaluated the results from the various clinical trials done breast-- prostate cancer. There was an interesting study done with a now-discontinued pan-PI3K inhibitor that was combined with enzalutamide and reported, you know, over 10-11 months median PFS more than double what was reported in the control arm, which was enzalutamide. And so, you know, that was, in a lot of ways, an inferior drug to gedatolisib, both mechanistically and its overall stability. Its drug concentration was significantly reduced when combined with gedatolisib. As it was a less potent drug, you know, not cytotoxic, but-... Regardless, it demonstrated a meaningful treatment effect. So, you know, that to us provided a proof of concept of the potential benefit. And if we're able to, you know, achieve that level of progression-free survival, we would hope better, but we'll see. We think that we would be very, very competitive with, you know, compared to, you know, what's been reported recently, as a good second-line alternative for these patients. Got it. Okay. Your primary endpoint for the studies are PFS at six months. What data do you think you'll report in first half 2025, and you could potentially get a read of PSA response and other measures faster than rPFS? Would you report these data before you have the final? So we want to report meaningful data, and really in this setting, we think rPFS is the most important endpoint to assess. And so when we have enough patients to do, you know, kind of a reasonable preliminary analysis with rPFS at six months as the dataset, then that's when we'll report that data. Got it. And, you recently announced a $50 million private placement. Can you share more about the background of the deal and how the proceeds change your operating plans? Sure. Well, this was an unsolicited proposal. We weren't out raising money. We felt we had enough cash to take us through data readouts. You know, this investor had great interest in what we're up to, and, you know, essentially offered to invest at current market. And, in this capital market, I think it's wise, prudent to consider taking money when it's available, even if you, on paper, don't think you need it. You know, you really can't anticipate the future. So at the one, you know, conclusion we made was that it was just prudent to strengthen our balance sheet. The net effect is that we think it will provide sufficient runway to take us to middle of 2026, which we think is well, well beyond when we expect to have our data. You know, if you can enhance your balance sheet, provide greater runway, it's, you know, a very positive development for us, we think. Makes sense. Well, this has been a great conversation. Maybe to close out, if you just wanna highlight key catalysts investors should be focused on. Sure. So with our VIKTORIA-1 study, the phase III study in breast cancer, we expect to report in the second half of 2024 the primary analysis of that'll in that wild-type subgroup. And then in the first half of 2025, we expect to report out the results in the mutated patient subgroup, and then again, in that first half 2025 timeline, report out the first and preliminary results in the prostate cancer study. Got it. Thanks for joining us today, Brian. You're welcome. No, it's my pleasure.