All right, let's kick off our next session. Good morning, everyone. I am very excited to host Celcuity, and with me is Brian Sullivan, CEO and Co-founder of the company. We have a lot to go through, a lot happening in the company. Yeah. Before we get there, I'm going to turn it to you for opening remarks. Sure. I guess the most important thing to understand about Celcuity is that we're focused on treating diseases that involve the PI3K/AKT/mTOR pathway, which we refer to as the PAM pathway. Our lead candidate is a multi-target inhibitor of that pathway, and it's able to comprehensively shut it down. The pathway itself represents probably one of the most important oncogenic pathways overall, but also one of the most challenging to drug. The real advance that gedatolisib has demonstrated so far, and I'm sure we'll get into that, is the superior efficacy and better tolerability you can achieve with the approach Geta takes relative to the approved drugs in this class that have essentially narrowly targeted the inhibitor, or rather this pathway, in a less efficacious way. Fantastic. The FDA granted priority review, and you guys have a PDUFA date coming up very soon, in July. Yes in that wild-type population. Yes. How's the commercial prep going for that, and what does it take? Sure. You're referring to our phase III study in second-line breast cancer, where essentially we evaluated patients who, HR plus or HER2 negative advanced breast cancer, lacked the HER2 mutations. Showed fantastic results, really unprecedented results. We've anticipated success. In this business, you have to plan for success, so we began building our commercial organization over two years ago. We've since completed the build-out of that organization as well as the other infrastructure that's required. Sales force has been hired, trained, and ready to go. All right, fantastic. You guys have the mutant that you guys presented, the data. What is the NDA submission timeline for that? Sure. This will be an NDA, we have a small molecule, and our plan is to submit what will be a supplemental NDA sometime in the third quarter. Okay, great. In addition to breast cancer, I know Geta is also being evaluated for prostate cancer. Can you talk about the rationale for prostate and what is that opportunity? Your phase I-B/II trial design and the status for that, and also when can we see data? Sure. Prostate cancer has a similar underlying biology as breast cancer. They're both hormonally driven diseases. A lot of non-clinical work, as well as some clinical studies, have shown and demonstrated that this pathway, the PAM pathway, is involved. Optimizing treatment of this pathway is critical to really inducing what we think is a necessary and clinically meaningful benefit. We have a phase I-B/II study that's ongoing. It's essentially dose finding. We've reported out results, preliminary results, for the first two doses that we evaluated. Very encouraging results. We hope to provide updated data with results from additional doses later this year at a medical conference. Overall, we're optimistic. The population that we're treating are men who have metastatic castration-resistant prostate cancer. They've progressed on a prior androgen receptor inhibitor. Represents a population that's similar in size as the women that we're targeting, hoping to treat in breast cancer. A very sizable population. If you think about breast cancer and prostate cancer, they're two of the three largest populations that are available to treat, and we think gedatolisib has an opportunity to essentially improve the standard of care in both. Got it. You guys got a runway into 2027. What does that include and not include? Well, we actually just raised some additional money. We raised about $575 million recently. Combined with the current cash, we think that takes us through 2029, at least through 2029. We think we have a long runway. That funds, obviously, our commercial launch, also funds two additional phase III studies that we have, and we can talk about those, in the advanced breast cancer space. Right, also the commercialization. The commercialization, exactly. Okay, fantastic. Let's dive deeper into geta in that second line setting. In that VIKTORIA-1 study, in that study one for the wild type patients, you guys perform, I think, subgroup analysis for that geta triplet and also the doublet. When you look at the mPFS across the different subgroups, like geographic areas and then time for the disease progression. Right Various other metrics, there seem to be some mixed data. Sure In terms of the consistency across different attributes. How should we interpret the mixed results for this group, and how would it affect you commercially when you? Sure Go and try to. Sure sell the drug across different regions and things like that? It was interesting. We saw in patients who were enrolled in the U.S., Canada, Western Europe, Asia-Pac, that median PFS was about 17 months, almost 17 months. Whereas in countries, Latin America, Eastern Europe, patients enrolled there, the results weren't as favorable. We think, just based on analysis of dose reduction, interruptions that were triggered for palbociclib, the CDK4/6 inhibitor, that it probably related to those countries, less frequent or less use of CDK4/6 inhibitors. We think CDK4/6 pathway is important to inhibit, particularly in the wild type setting. As far as the countries that have a lot of experience using CDK4/6 inhibitors, we saw 16 months in the second-line setting is unbelievable. That's great. I think in those other countries, which again represent, if we just look at it from a commercial standpoint, relatively probably less than 5% of the potential. We don't think that will have a big impact. We would want to commercialize there, make the drug available. Certainly, we would focus on helping them understand better how to manage palbociclib, not dose reduce. How to essentially manage patients according to the label. I think if that happens, you'd see more similar results across these different regions. I see. Okay. Got it. At ASCO, very exciting, you guys presented that phase III VIKTORIA-1 in the study 2 population- the PIK3CA, the mutant population. Can you summarize the results there- Sure The key learnings? It seems like the market did not seem a little disappointing. The hope to see a higher benefit. Is that a fair expectation? Two things. One, the data was the first head-to-head trial of a drug comparing two PAM inhibitors. Ours is a multi-target inhibitor. We compare it to a PI3K-alpha inhibitor called alpelisib that Novartis has. We showed the highest mPFS ever reported in the second-line setting for therapies that include an endocrine backbone. That's obviously fantastic. We also showed the highest objective response rate in breast cancer in the second-line setting for regimens including an endocrine therapy. The results were, to be frank, great. We doubled mPFS benefit for these patients. I think what the market got wrong, and I think over time we'll pay more attention to, is that actually we exceeded the implied expectations people had. As you know, people can zero in on a single number and when they need to dial into two. There were some assumptions made about what the study arm could do 12, 13 months. Again, they also were assuming about seven and a half months for the control. Implied hazard ratio, if you do that analysis, is again in the 0.6 range. We reported a hazard ratio of 0.5, actually significantly better. The reason why they, I think, have not quite understood how good that is because alpelisib only did five and a half months, 5.6 months. We reported 11.1 and 11.3 months. Ultimately, you do phase III studies to show the comparative benefit- Right show how on a relative basis, when you control for all the other factors that could influence outcomes, how much difference there is between one therapy and another. To show double the benefit between two drugs of the same class is typically, actually very unusual, and it really highlights how important the mechanism of GETA is and when it's used, how much improved the outcomes will be for patients. Right. Well, I think another way to see it is that if you compare study 1 result and study 2 Should there be a higher benefit because now your study 2's targeting the mutation that the drug's designed to target, whereas the wild type is not excluded though? Well, I mean, the results were better in the mutant, so I'm not quite sure I'm tracking here. The results were better in the mutant population. They were 11.1 months versus 9.3, double. In the case of the PIK3CA mutation patients, they actually have worse prognosis, right? They're only getting five and a half months from existing approved therapy, whether it's an AKT inhibitor or whether it's a PI3K-alpha inhibitor. To offer those patients who really had no other options double the benefit. In oncology, if you're offering double the benefit relative to standard of care. Right That's generally considered to be a home run. That's certainly how the KOLs interpreted the data. We were able to meet with obviously a lot of KOLs over the course of the ASCO meeting, and we previewed the data with them on a confidential basis just to get their reaction and get their thoughts, and it was overwhelmingly positive. They said, "Wow. We were hoping for 0.65 hazard ratio, and the fact that you were 0.5 is great, this will clearly establish a new standard of care." The feedback from the clinical community has been unequivocally positive. I see. Okay. Sometimes that's what matters. Well, not sometimes. That is what matters. Yeah. Exactly. In that study too, the GETA, the triplet, and the doublet show similar- median PFS and also the hazard ratio. Why didn't the triplet show more benefit- compared to the doublet? Sure. At this point, how would you look at both regimens from the submission Sure from the NDA filing? How do you think about that? Sure. I think what was surprising to us, we didn't have data for the doublet going into the study, so it was an unknown for us. I think what was surprising, and I think a really surprise to the good, was the fact that GETA, when combined with fulvestrant, carried the weight in effect. It doubled the benefit relative to alpelisib in a pure head-to-head setting. I think our interpretation then is that the PAM pathway plays a particularly important role, as you'd expect, in patients in tumors that have this mutation, and that CDK4/6 is still involved because if you look at some of the additional data that we reported, clearly CDK4/6 is playing a role, but less prominent. You think of it as more of a passenger rather than a driver of the disease at that point. In the wild-type setting where you don't have the mutation, you have these three pathways, ER pathway, CDK4/6 pathway, the PAM pathway, that each are probably playing, I don't want to say co-equal, it's hard to tease that out, but playing a very important role. More balanced, I guess you could think of. Less balance maybe in the mutant setting, which just highlights how important, to be frank, having a multi-target inhibitor is for these patients. Okay. Got it. In that subgroup analysis for study 2, patients who received ribociclib in the prior line seemed to benefit more compared to those who received palbociclib. What's the implication there in terms of that ribociclib/palbociclib dynamic? Sure. Well, two things. One, really both sets of patients benefited significantly, regardless of which CDK4/6 they had. In these subgroup analyses, you'll see somewhat minor differences in hazard ratios, and you don't want to tease too much out of that. What really we think is most important is the fact that irregardless of what prior CDK4/6 you had, you're getting a very meaningful benefit. We saw this in the wild type as well, where patients who had prior palbociclib, prior ribociclib got almost exactly the same benefit. I would say in the mutant, you would say they basically got essentially the same benefit. That, we think, highlights the benefit that occurs just by keeping the pressure on that pathway, and then when you comprehensively inhibit it, so that essentially doctors can approach this and say, "Okay, independent of what this patient may have received prior in their first-line setting, whether it was ribociclib or palbociclib, my patient's going to get a very meaningful benefit when I combine Geta with palbociclib and, in this case, fulvestrant. I see. Okay. Now with study 1, study 2, you kind of able to capture that entire second- Exactly. Essentially, I think our positioning is that now we have a ways to go to get our submission for the mutant. If we fast-forward, let's say, a year from now, we fully expect that doctors will have an approval for these regimens, and doctors will have the option of selecting and optimizing, really, selection between the doublet and the triplet because it's a very heterogeneous population. Typically, drugs have one option, one size fits all. In the case of breast cancer, it's probably more heterogeneous than many diseases, where you can have a woman who's 35 premenopausal with very aggressive disease, and you can also have a 75-year-old woman who has more indolent disease. Yeah. Giving doctors the option of selecting between a triplet, let say, and a doublet and factoring in the clinical characteristics of their patients will actually, we think, be hugely helpful to them because it allows them to more precisely dial in what they think the best treatment will be for those patients. That overall, to us, from a penetration standpoint, is that we think it'll actually help us expand or certainly optimize the potential penetration because we won't have this dilemma where doctors are concerned about potentially continuing on a CDK4/6 for patients who may have essentially a more compromised immune system. They can have confidence that the doublet, the geta doublet will give a fantastic outcome for these patients. They can start off with the triplet and to the extent that there's some myelosuppression that they're concerned about, back off the palbociclib and continue with the doublet. Again, have confidence that the regimen- Right will still offer a meaningful benefit. I see. Have you seen those patients, the ones that were on a triplet and then maybe in the trial at some point they come off the CDK4/6 or something like that? Have you seen how those patients compare to patients who did not come off? Essentially, you don't really see a very significant difference. I think if you get some initial treatment with CDK4/6, again, these are small sample sizes. For instance, palbociclib discontinuation is in the small% number. When you're trying to tease out too much information from these small sample sizes, you can kind of get a misleading interpretation. You do know how well patients did who just got the doublet. The results are very favorable. For instance, the doublet in the wild type, for instance, if it weren't for the triplet, would've been the most favorable results relative to endocrine monotherapy ever reported. Right In breast cancer. Right. By itself, the doublet would've been just unbelievably historic results, and the triplet was even better. Again, those are two good options for these docs to have and the patients to have. Right. Okay. In that second-line setting, there's a lot of other therapies also being developed. We have seen in the past where these next gens are like palbociclib. When you add that to a CDK4/6-like ribociclib, it show 13-month PFS in that medium PFS, in that all-comer setting. How do you view gedatolisib's doublet competitive position for these next generation third Sure that could be recommended on top of a Yeah CDK4/6 in the second-line setting? Right. Even if it's not approved, it could be recommended in the NCCN guideline based on some of these- Maybe. I think the drug you're referring to is investigational, so it's only phase I data. We don't know. The five studies that we reported out, phase III data, though, that are for oral SERDs have not shown a benefit relative to fulvestrant in patients lacking mutations. Their approvals to date, and we think going forward, are going to be limited to treating patients who have ESR1 mutations, and that's an important subgroup. Patients who have ESR1 mutations and are PIK3CA wild type represent about 20% of the population. There'll be some overlap in populations. We think we offer a clinical benefit relative to them, but that'll be probably a more competitive segment in that 20%. 40% of patients are ESR1 wild type, PIK3CA wild type. Again, we don't think there are fantastic options for patients today. We think Geta will be- positioned well as the clear standard of care. With the mutant data, we think we've established a new standard of care for patients that have a PIK3CA mutation, and that's about 40% of the patients. If we think about the 80% of patients that I just described, we think we've set a significantly higher new bar for standard of care and that in the patients that have ESR1 mutations, PIK3CA wild type, it'll be more competitive, but that's fine. Right. Okay. Have you thought about doing any combination studies with Geta and these next-gen SERD instead of fulvestrant, given the limitation for ESR1 mutation of fulvestrant? Right. If you were to do a combo, which SERD would you use for that partner? Well, ultimately we think gedatolisib, because of two things. This pathway is involved in the disease independent of whether or not the patient has a mutation. Our data's clearly shown that. Secondly, Geta is able to address it effectively and more favorably than has ever been reported. We think Geta will be a core backbone to any regimen that wants to offer standard of care benefit to their patients. It does make sense for us to evaluate these other therapies or classes of drugs, oral SERDs, for instance, or other ones that might come up. That'll be just part of our life cycle plan, is to evaluate those. As far as which of those SERDs would be optimal, I think there's very little differentiation between them. If you look at the results on a comparative basis, you'd see that they all offer hazard ratios in this mid 0.5 or actually 0.55, 0.57 range. Essentially you're going to get to physician preference. You'll see some differences in toxicity profiles that are, on the scheme of things, relatively small. Certainly elacestrant was the first drug that was approved, has done a great job of developing, from what I can tell, the market, to their credit. The other companies are following. Again, from an efficacy standpoint, you really don't see differentiation. The only differentiation I think you'll see is just in potentially the indications where they're trying to develop their drugs. I see. Okay. Have you done any subgroup analysis in that ESR1 mutation versus wild-type setting? Do you see any differences between these two subtypes? Also, in the VIKTORIA-1 study, between the study 1 and 2, how do these patients compare the ESR1 mutations? Sure. In our study, we did not break out subgroups and did not end up, unfortunately, generating data for ESR1 mutational status. We enrolled ESR1 mutant wild-type patients just because they're part of the population, typically find between 35%-40%. We started the study before ESR1 had been a validated biomarker, so it wasn't an area of focus. That actually is what occurred with the other drugs evaluating in our class, this population. Our results represent an agglomeration of results that include both ESR1 mutant patients, as well as those who have a wild type. I see. Was ESR1 mutation measured? Could you do that in the future? Oh, going forward? Yeah, certainly we can. We just need to incorporate it in the protocol and have that analysis done. We wouldn't expect, just because ultimately when we found this with CDK4/6, it tends to be a class effect. If you're inhibiting all three pathways, essentially, as comprehensively as Geta does, good can be good enough. We saw, for instance, no difference between ribociclib and palbociclib in outcomes where patients had prior ribociclib or palbociclib when patients got retreated with palbociclib. In studies that had evaluated patients who had received prior palbociclib and then were subsequently retreated with palbociclib but with a different endocrine therapy, saw no benefit. In our case, we saw fantastic benefit with patients who had received prior palbociclib because you're controlling this pathway, and essentially, as long as that pathway was controlled effectively, you were going to get the benefit. We think the relative benefit may be more muted when you comprehensively shut down the pathway of PAM than when you're not. The mutation will play a more important role when the other pathways are not controlled. I see. Yep. That makes sense. What is your view of this emerging class of the Caspase-6 inhibitors? It seems to be complementary to the SERD. I think we saw some data from Pfizer. I think Lilly is going to have this combination data coming out later this year or 2027. How do you see Caspase-6 as a potential emerging competitor? Well, it's another target. We think the biology is well understood in breast cancer, yet you have three cooperative pathways, ER pathway, CDK4/6, PAM pathway, that directly inhibiting those, in our view, is likely to yield the most favorable benefit. Hitting a different target that's more downstream may be a successful strategy to get something that could be better relative to endocrine therapy. It may be an approvable approach. I'm not sure it will be a better approach. Right. Potentially could be another combination agent for Geta, too. Potentially. Again, I think it's early days on that target. It's early, yeah. Yep. You mentioned that you guys are developing a subcutaneous formulation for Geta. What is that timeline and the status for that? Sure. That program is essentially running in parallel with a phase III study that we're running in first-line breast cancer patients who are considered to be endocrine sensitive. These are women who, on the current standard of care therapies, are getting roughly 25 months median PFS. We reported in that segment, in an early-phase study, a median PFS of 48 months. A very long duration of benefit, early-phase single-arm study. You have to take it with a bit of a grain of salt, but very encouraging. Clearly at least demonstrating in our view that this pathway is intrinsically involved irregardless of mutational status or prior treatment, or independent of prior treatment. Given the duration of treatment that these patients could potentially be on with our drug, we wanted to offer a subcu alternative. The development timeline will run in parallel, the sub plan, with the development and performance of that study. That at the time things go the way we hope, we get favorable results and get an indication to treat those patients approved, we would have a subcu alternative formulation available to those patients. We think makes sense. That would certainly help optimize the penetration potential. Right for that patient population. I see. Okay. In the other settings that we're in, we've found our research indicates that the current IV formulation doesn't create a barrier to infusion, or rather to achieving what we think are the appropriate penetration targets in those segments. Would that formulation, would that work for the second line setting? It would setting as well? Typically, the FDA wants you to demonstrate, in one setting- Yeah If you're using the same molecule, equivalence, non-inferiority. If you do that, then the approval will allow you to use the formulations interchangeably- Right in other indications. For all settings? For all settings. I see. Okay. Let's switch gears to the front line. There's a lot of things happening there, too. You have the VIKTORIA-2 study. Yes. You also have study one and study two. Yeah. One for endocrine resistant and one for endocrine sensitive. When I look at this VIKTORIA-2, it's almost like two studies. It is like two phase III studies. Two different phase III studies, yeah. Right. Then when you look at that, the study population, I think for the study one is around 440. 440, yeah. Then the other one is 140. These are smaller. If I look at it individually compared to the front line- Right like PERSEVERE, like SERENA-4. Right. How do you think about the size of the study? Sure. Is it too small? Is it- No, it's actually appropriately sized. I mean, essentially, the number of patients you enroll is a function of what your underlying assumption is about the effect size difference you'll see, i.e., what do you think will be for receiving, in this case, our regimen versus the control. The larger the projected effect size is, that difference, smaller number of patients required to detect that difference in a statistically significant way. In the case of these other studies, where essentially they're replacing one therapy of a particular class for another, like one hormonal therapy versus another- Typically, the effect size potential is much smaller. As we found, unfortunately, with the study with uncertain, wasn't meaningful enough. Yeah. When you're adding a new class of drug to address an untreated disease mechanism, the potential benefit is much greater. As we showed in our early phase study, it would potentially double the outcomes for these patients. Well, if you're offering that magnitude of benefit, the number of patients required to detect it, again, is correspondingly smaller. To be frank, we're relatively overpowered, we think, in the endocrine sensitive population relative to the benefit we expect, and similarly in the other study. We're very confident that these studies are powered appropriately and essentially reflect what we think is the clinical benefit of controlling this pathway versus not, compared to control. Okay, got it. Then you guys use palbó plus fulvestrant or palbó plus AI- Yep in the study 1 and 2, respectively. Right. You swap out the palbociclib for ribociclib in the comparator arm. Yes. What is the rationale for that? Sure. ribociclib is the standard of care because it had no less benefit. That was clear that from a comparator standpoint, that we need to offer patients the standard of care. Now, when you combine a CDK4/6 inhibitor with a drug like gedatolisib, we think the differences that are potentially available to patients are essentially not going to be meaningful. If you look at a PFS standpoint, palbociclib and ribociclib offer identical profiles in terms of hazard ratios, even duration of benefit. palbociclib is generally considered and almost very widely considered than ribociclib. Given the duration of treatment, we're optimistically hopeful that patients' experience in the triplet in the first-line setting, we think tolerability is actually more important and that essentially we'll be getting equivalent efficacy that we would otherwise have gotten if we had used ribociclib. we elected to choose the more tolerable CDK4/6 inhibitor for our study arm. Right. I see. Okay. what is the bar for efficacy and safety in that front line- Sure population, given that the quality of life is important to patients- Sure can run a trial for- Yeah a couple of years. Right. Maybe remind us about your prior phase I-B result in those 41 patients, and how translatable are they? Sure To phase III? Well, certainly, a sample size of 41 is not necessarily 100% translatable. What it provides is an important signal. The patients had 100% measurable disease. They had essentially a significant tumor burden for that setting. When you see a delta of 2X relative to what has been reported for historical studies with the same population, that's obviously encouraging. gedatolisib has been very well tolerated to date. We found in the second line settings, discontinuation rates, which is kind of an uber metric for assessing tolerability was between 2% and 3%. That's actually historically, if you were to look at other drugs evaluated in breast cancer, that's actually very low. We think net-net, patients can stay on Geta. We have still patients who've been on Geta from our early-phase studies for over five years. They're continuing to come in and continuing to receive benefit, which is great for them. If you can offer a clinically meaningful benefit, it's probably in the five- to six-month range relative to control in this setting, proportionately hazard ratio 0.75, just as an example. I think the challenge for the oral SERDs that we're evaluating this population is that the clinical benefit was not achieved. As a result, again, that just reflected the lack of benefit of replacing one drug with a different, rather having an alternative from the same class of drug- Right might not be the way to optimize outcomes for those patients. You need to inhibit what is an untreated disease mechanism, in this case, the PAM pathway, to take the leap in improvement for these patients. When we look at PERSEVERE, it did show about five-month benefit in PFS, but that did not translate to statistical significance. if you look at the hazard ratio, it was 0.89 hazard ratio. 0.89. that's the number that matters. again, that's, to be frank, not even close. Right. Yeah. how many months of benefit do you think it takes to- Well, stat sig, typically can be achieved less than what's clinically meaningful in these studies. That's always the trick is to make sure you're not just powering a study to detect a statistical difference when it's not going to be clinically meaningful. we design our studies to make sure that we're going to be able to detect a clinically meaningful difference. again, in this setting, probably five to six months. That's statistically significant, i.e., hazard ratio in that 0.75 range. Yep I think would be considered clinically meaningful. Okay, fantastic. We probably have time for one more question. Sure. I want to ask you a more blue sky question. Sure. As the adjuvant continued to trend toward the CDK4/6 combination compared to just AI monotherapy, and then you saw the giredestrant success with lidERA, how do you see the treatment paradigm changing in the next three to five years and the effect from that? Sure in that adjuvant setting percolating to the front line, to the second line plus? The short answer is it'll have a nominal effect. The women who are getting treated in the adjuvant setting, we can typically expect most of them to not have the disease recur. 75%, 70% won't have the disease recur. These drugs are going to lower the recurrence rate by a few percentage, which is great for these women. The downstream effect will take a decade, and unfortunately, as the incidence of breast cancer increases, I think the number of women that get ultimately diagnosed with metastatic disease will probably, even with the benefits from the use of these adjuvant therapies, will be offset by just the increase in overall incidence. For instance, roughly 40% of women who are diagnosed metastatic breast cancer are diagnosed de novo. They did not have a diagnosis of early disease, essentially was diagnosed with metastatic. That number has been increasing. I don't think scientists understand what's driving that, but that's a patient population that isn't at all affected by potential treatment in the early disease setting. Again, it's very good option for patients to have the reduction of likelihood of recurrence. Again, it's going to be almost an intangible or rather not a significantly detectable difference in the populations that we'll be treating with our drugs. Fantastic. Well, we're out of time. It's been a very interesting conversation. Really appreciate having you- You're welcome. Here at the GS conference, Brian, I'll turn it to you for final remarks. Well, great. No, we're very excited. We're a few weeks away from what we think will be a positive approval decision from the FDA. We're really excited about being able to offer our drug to patients. We have two additional phase III studies to treat roughly 90,000, we hope, to develop the therapy for the 90,000 women a year who are diagnosed initially and require that first-line treatment. Data we've received in the second-line setting certainly gives us a lot of encouragement and optimism that we could potentially extend gedatolisib to offer a very meaningful benefit to those women. Again, that would be great. Fantastic. Thank you again. You're welcome.