Celcuity Inc. Aktie

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 do a lot happening in the company. But before we get there, I'm going to turn it to you for opening remarks.

Sure. So 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. And the pathway itself represents probably one of the most important oncogenic pathways overall, but also one of the most challenging drug. And 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 that it takes relative to the approved drugs in this class that have essentially narrowly targeted the inhibitor rather this pathway in a less efficacious way.

Fantastic. So the FDA granted priority review and you guys have a PDUFA date coming up very soon in that wild-type population. How is the commercial prep going for that? And how -- what does it take?

Sure. So you're referring to our Phase III study in second-line breast cancer, where essentially we evaluated patients who HER2 -- HR+HER2-negative advanced breast cancer, [indiscernible] PIK3CA mutations. So fantastic results, really unprecedented results. And we've anticipated success in this business, you have to plan for success. So we began building our commercial organization over 2 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. And then you guys have the mutant that you guys presented the data. What is the BLA submission timeline?

Sure. So this will be an NDA where we have a small molecule. And our plan is to submit what we will be a supplemental NDA sometime in the third quarter.

Okay. Great. And then in addition to breast cancer, I know is also being evaluated for prostate cancer. Can you talk about the rationale for prostate? And what is that opportunity, your -- the Phase Ib/II trial design and the status for that? And also when can we see data?

Sure. So prostate cancer is a similar underlying biology as breast cancer. They're both hormonally driven diseases. A lot of nonclinical work as well as some clinical studies have shown and demonstrated that this pathway, the PAM pathway is involved. But optimizing treatment of this pathway is critical to really inducing what we think is a necessary and clinically meaningful benefit.

And so we have a Phase Ib/II study that's ongoing. It's essentially dose finding. We've reported out results -- preliminary results for the first 2 doses that we evaluated, very encouraging results. We hope to update -- provide updated data with results from additional doses later this year at a medical conference. And so overall, we're optimistic. The population that we're treating are men who have metastatic castration-resistant prostate cancer. They progressed on a prior androgen receptor inhibitor, represents a population that's similar in size as those -- as the women that we're targeting and hoping to treat in breast cancer.

So a very sizable population. If you think about breast cancer and prostate cancer, they're 2 of the 3 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. And you guys guided runway into 2027. What does that include and not include?

Well, we actually just raised some additional money. We raised about $575 million recently. And so combined with the current cash, we think that takes us through '29 and at least through '29. So we think we have a long runway. I think that funds, obviously, our commercial launch, but also funds some 2 additional Phase III studies that we have, and we can talk about those in the advanced breast cancer space.

Right. And also the commercialization.

In the commercialization, exactly.

Okay. Fantastic. Let's dive deeper into GEDA in that second-line setting. So in that VIKTORIA-1 study, in that Study 1 for the wild-type patients, you guys performed, I think, subgroup analysis for that GEDA triplet and also the doublet. And then when you look at the mPFS, across the different subgroups, like geographic areas and then time for the disease progression and various other metrics, there seem to be some mixed data 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 go and try to sell the drug across different regions and like that?

So 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. And we think just based on analysis of dose reduction interruptions that were triggered for palbociclib, CDK4/6 inhibitor that are probably related to those countries less frequent or less used of CDK4/6 inhibitors. And so we think CDK4/6 pathway is important to inhibit, particularly in the wild-type setting. And so 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.

So that's great. And so 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. So we don't think that will have a big impact. We would want to commercialize there and make the drug available. But 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. And I think if that happens, you'd see more similar results across these different regions.

I see. Okay. Got it. And then at ASCO, very exciting. You guys presented that Phase III VIKTORIA-1 in the Study 2 population, the PIK3, the mutant population. Can you summarize the results there and the key learnings? And then it seems like the market did not seem a little disappointing and then hope to see a higher benefit. Is that a fair expectation?

Well, 2 things. One, the data was the first head-to-head trial of a drug comparing 2 PAM inhibitors. Ours is a multi-target inhibitor. We compared it to a PI3K-alpha inhibitor called alpelisib that Novartis has. We showed the highest median PFS ever reported in the second-line setting for therapies that include an endocrine backbone. So that's obviously fantastic.

And then we also showed the highest objective response rate for -- in breast cancer in the second-line setting for therapies -- regimens, including an endocrine therapy. So the results were, to be frank, great. We doubled PFS 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 expectations, implied expectations people had. But as you know, people can zero in on a single number and when they need to dial into 2, there were some assumptions made about what the study arm could do 12, 13 months. But again, they also were assuming about 7.5 months for the control.

Implied hazard ratio, if you do that analysis is in the 0.6 range. But 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, is because alpelisib only did 5.5 months, 5.6 months, we reported 11.1 and 11.3 months. And ultimately, you do Phase III studies to show the comparative benefit and 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. And so to show double the benefit between 2 drugs of the same class is typically -- is actually very unusual. And it really highlights how important the mechanism of GEDA is and when it's used, how much improved the outcomes will be for patient.

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 is targeting the mutation that the drug is designed to target, whereas the wild type is not excluded.

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 wild-type -- 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 5.5 months from existing approved therapy, whether it's an AKT inhibitor or whether it's a PI3K-alpha inhibitor and then 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, that's generally considered to be a home run. And that's certainly how the KOLs interpreted the data. So 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. We said, wow, we were hoping for 0.65 hazard ratio, and the fact that you were 0.5 is great. And so this will clearly establish a new standard of care. So the feedback from the clinical community has been unequivocally positive.

I see okay. And sometimes that's what matters.

Well, not sometimes, that is what matters.

Yes. Yes, exactly. So in that study, too, the GEDA 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? And then at this point, like how would you look at both regimens from the submission from the NDA filing? How do you think about that?

Sure. So 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 it really surprised to the good was the fact that GEDA, 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 the CDK4/6 still involves 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.

Whereas in the wild-type setting, where you don't have the mutation, you have these 3 pathways: ER pathway, CDK4/6 pathway, the PAM pathway that each are probably playing -- I don't want to say coequal, it's hard to tease that out, but playing a very important role, more balanced, I guess, you could think of and less balanced 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. And then in that subgroup analysis for Study 2, patients who received ribo in the prior line seem to benefit more compared to those who receive palbo. What's the implication there in terms of that ribo-palbo dynamic?

Sure. Well, 2 things. One, really, both sets of patients benefited significantly regardless of which CDK4/6 they had. And so in these subgroup analysis, 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. And we saw this in the wild type as well, where patients who had prior palbo, prior ribo got almost exactly the same benefit. I would say in mutant, you would say that they basically got essentially the same benefit.

And 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 I -- this patient may have received prior in the first-line setting, whether it was ribo or palbo, my patient is going to get a very meaningful benefit when I combine, get up with palbociclib and in this case, fulvestrant.

I see. Okay. So now with Study 1, Study 2, you kind of able to capture that entire second.

Exactly. And so essentially, I think our positioning is that now doctors will have -- I mean, we have a ways to go to get our submission for the mutant. But 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. And 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. And so giving doctors the option of selecting between a triplet, let's 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.

And that overall to us from a penetration standpoint is that we think it will 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 CDK4/6 for patients who may have essentially more compromised immune system. They can have confidence that the doublet -- to get a doublet will give a fantastic outcome for these patients or they can start off with the triplet and to the extent that there's some myelosuppression that they're concerned about, back off the palbo and continue with the doublet. And again, have confidence that the regimen will still -- will offer a meaningful benefit.

I see. Have you seen those patients, the ones that were on the triplet and then like maybe in the trial at some point, they come off the CDK4/6 or something like that. Have you seen like how those patients compare to patients who did not come off?

So essentially, you don't really see a very significant difference. I think what is that if you get some initial treatment with CDK4/6, you don't see -- again, these are small sample sizes. I mean, for instance, palbociclib discontinuation is in small percentages number. When you're trying to tease out too much information from these small sample sizes, you can kind of get a misleading interpretation. But you do know how well patients did who just got the doublet and the results are very favorable. For instance, the doublet in the wild type, for instance, if it weren't for the triplet, would have been the most favorable results relative to endocrine monotherapy ever reported in breast cancer. So by itself, the doublet would have been just unbelievably historic results and the triplet was even better. So again, those are 2 good options for these docs to have and the patients to have.

Right. Okay. So in that second-line setting, there's a lot of other therapies also being developed. And we have seen in the past where these next-gen SERD like Palazestrant, when you add that to a CDK4/6 like ribo, it showed like 13-month PFS in that median PFS in that all-comer setting. How do you view get a sublet competitive position for like these next-generation SERD that could be recommended on top of like CDK4/6 in the second line setting. Like even if it's not approved, it could be recommended in the NCCN guideline based on some of the use...

Maybe. I think the drug you're referring to is an investigational, so it's only Phase I data, we don't know. The 5 studies that we reported out Phase III data, though, that for oral SERDs have not shown a benefit relative to fulvestrant in patients lacking mutations. And so 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. So there will be some overlap in populations. We think we offer a clinical benefit relative to them, but that will be probably a more competitive segment in that 20%. 40% of patients are ESR1 wild-type, PIK3CA wild type. And again, we don't think they're fantastic options for patients today. We think GEDA will be positioned well as the clear standard of care.

And then 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. So 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 then in the patients that have ESR1 mutations, PIK3CA wild type, it will be more competitive, but that's fine.

Right. Okay. And then have you thought about doing any combination studies with GEDA and these next-gen SERDs instead of fulvestrant given the limitation for ESR1 mutation of fulvestrant. If you were to do a combo, which SERD would you use for that partner?

Well, ultimately, we think gedatolisib because of its 2 things. There's pathways involved in the disease independent of whether or not the patient has a mutation. That's our data has clearly shown that. And secondly, GEDA is able to address it effectively and more favorably than has ever been reported. And so we think GEDA will be a core backbone to any regimen that wants to offer standard of care benefit to their patients. And so it does make sense for us to evaluate these other therapies or class of drugs, oral SERDs, for instance. or other ones that might come up. And that will 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, 0.55, 0.57 range. And then essentially, you're going to get the physician preference. You'll see some differences in toxicity profiles that are in 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. But 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. And have you done any subgroup analysis in that ESR1 mutation versus wild-type setting? And do you see any differences between these 2 subtypes? And then also, what is the -- like in the VIKTORIA-1 study between the Study 1 and 2, how do these patients compare, the ESR1 mutation?

Sure. So 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% but we started the study before ESR1s has been a validated biomarker. So it wasn't an area of focus. And that actually is what occurred with the other drugs evaluating in our class, this population. So our results represent an agglomeration of results that include both ESR1 mutant patients as well as those with -- who have a wild type.

I see. But with ESR1 mutation measure, could you do that in the future? Could you do?

Going forward, certainly, we can. We just need to incorporate it in the protocol and have that analysis done. But 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 3 pathways, essentially as comprehensively as GEDA does, good can be good enough.

We saw, for instance, no difference between ribo and palbo and outcomes. Patients had prior ribo or palbo when patients got retreated with palbo. In studies that had evaluated patients who received prior palbo and then were subsequently retreated with palbo, but with a different endocrine therapy, saw no benefit. And so in our case, we saw a fantastic benefit with patients who had received prior palbo because you are controlling this pathway. And essentially, as long as that pathway was controlled effectively, you were going to get the benefit. And so we think the relative benefit may be more muted when you comprehensively shut down the pathway of PAM than when you're not. And so the mutation will play a more important role when the other pathways are not controlled.

I see. That makes sense. What is your view of the emerging class of the KAT6 inhibitors? So it seems to be complementary to the SERD. I think we saw some data from Pfizer. I think [ Olema ] is going to have the combination data coming out later this year or 2027. How do you see KAT6 as a potential emerging competitor?

Well, it's another target. We think the biology is well understood in breast cancer. You have 3 cooperative pathways, ER pathway, CDK4/6, PAM pathway and that directly inhibiting those, in our view, is likely to yield the most favorable benefit, hitting a different target that's more downstream, maybe a successful strategy to get something that could be better relative to endocrine therapy. And so it may be an approvable approach. I'm not sure it will be a better approach.

Right. Or potentially could be another combination agent for GEDA too.

Potentially. I mean, again, I think it's early days on that target. Yes.

And you mentioned that you guys are developing a subcutaneous formulation for GEDA. What is that timeline and the status for that?

Sure. And that program is essentially running in parallel with the Phase III study that we're running in patients, first-line breast cancer patients who are considered to be endocrine sensitive. And 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, median PFS of 48 months. So a very, very long duration of benefit early phase single-arm study. So we have to take it with a bit of a grain of salt, but very encouraging.

So 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. And so given the duration of treatment that these patients could potentially be on with our drug, we wanted to offer a subcu alternative. And so the development time line will run in parallel with our plan with the development and performance of that study. And so 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. And we think makes sense, that would certainly help optimize the penetration potential for that patient population. In the other settings that we're in, we 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.

So with that formulation, would that work for the second-line setting and also...

It would. Typically, the FDA wants you to demonstrate in one setting, if you're using the same molecule, equivalents, noninferiority. And if you do that, then the approval will allow you to use the formulations interchangeably in other indications.

For all settings.

For all setting.

I see. Okay. So let's switch gears to the front line. There's a lot of things happening there, too. You have the VIKTORIA 2 study. And then you also have Study 1 and Study 2; one for endocrine-resistant and one for endocrine-sensitive. So when I look at this VIKTORIA-2, it's almost like 2 studies...

2 different Phase III studies.

Right. So -- and then when you look at that, the study population, I think for the Study 1 is around 440 and then the other one is 740. So these are smaller, if I look at it individually compared to the frontline like persevERA, like SERENA-4, I mean how do you think about the size of the study? Is it too small? Is it extremely...

No, it's 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 [indiscernible] 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. And as we found, unfortunately, with the study with giredestrant wasn't meaningful enough.

When you're adding a new class of drug to address an untreated disease mechanism, the potential benefit is much greater. And 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. And so 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. So we're very confident that these studies are powered appropriately and essentially reflects what we think is the clinical benefit of controlling this pathway versus not compared to control.

Okay. Got it. And then you guys use palbo plus fulvestrant or palbo plus AI in the Study 1 and 2, respectively. But then you swap out the palbo for ribo in the comparator arm. What is the rationale for that?

Sure. So ribo is the standard of care because it had an OS benefit. And so 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 GEDA, 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 or even duration of benefit and palbociclib is generally considered and almost very widely considered than ribociclib. And so 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 will be getting equivalent efficacy that we would otherwise have gotten if we had used ribo. And so we elected to choose the more tolerable CDK4/6 inhibitor for our study arm.

Right. I see. Okay. And then what is the bar for efficacy and safety in that frontline population, given that the quality of life is important to patients that can run a trial for a couple of years. And then maybe remind us about your prior Phase Ib results in those 41 patients and how translatable are they into Phase III?

Well, certainly, small phase, a sample size of 41 is not necessarily 100% translatable. But what it provides is an important signal. The patients had 100% measurable disease. And so 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.

GEDA has been very well tolerated to date in the -- we found in the second-line settings. Discontinuation rates, which is kind of an uber metric for assessing tolerability was between 2% and 3%. So that's actually historically, if you were to look at other drugs evaluated in breast cancer, that's actually very low.

So we think net-net, patients can stay on GEDA. We have still patients. We have patients who've been on GEDA from our early phase studies for over 5 years, and they're continuing to come in and continuing to receive benefit, which is great for them.

And so if you can offer a clinically meaningful benefit, it is probably in the 5- to 6-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. And 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 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.

So when we look at persevERA, it did show about 5 months benefit in PFS, but that did not translate to typical...

And if you look at the hazard ratio, it was 0.89 hazard ratio. And so that's the number that matters. And again, that's, to be frank, is not even close.

Right. Yes. So do you -- how many months of benefit do you think it takes to?

Well, -- I mean, statsig is 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 trying to powering a study to detect a statistical difference when it's not going to be clinically meaningful. So we designed our studies to make sure that we're going to be able to detect a clinically meaningful difference. And again, in this setting, probably 5 to 6 months that's statistically significant, i.e., hazard ratio in that 0.75 range plus, I think, would be considered clinically meaningful.

Okay. Fantastic. We probably have time for one more question. So I want to ask you a more blue sky question. So as the adjuvant continues to trend towards 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 3, 5 years and the effect from that -- the changes in that adjuvant setting percolating to the front line to the second line plus?

It's going to have -- the short answer is it will have a nominal effect. The women who are getting treated in the adjuvant setting can typically expect most of them to not have the disease recur. 75%, 70% won't have the disease recur. And so these drugs are going to lower the recurrence rate by a few percentage, which is great for these women. But the downstream effect, it 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 with metastatic breast cancer are diagnosed de novo. They did not have diagnosis early disease, essentially it was diagnosed with metastatic. And 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.

So again, it's a very good option for patients to have a reduction of likelihood of recurrence. But 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. I really appreciate having you here at the GS conference, Brian, and then I'll turn it to you for final remarks.

Well, great. No, we're very excited. I mean we're kind of 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 a drug to patients. And we have 2 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. And 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, very meaningful benefit for those women. And again, that would be great.

Fantastic. Thank you again.

Good day, and thank you for standing by. Welcome to the Celcuity VIKTORIA-1 Trial call. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand the conference over to your speaker today, Brian Sullivan, Chief Executive Officer and Co-Founder of Celcuity. Please go ahead.

Good morning. Thank you for joining us today. I'm Brian Sullivan, CEO and Co-Founder of Celcuity. Before we begin, I must point out, and let's turn now to Slide 2, that some of the comments today contain forward-looking statements that are subject to risks, uncertainties and assumptions. In particular, our expectations around gedatolisib are uncertain and subject to change. Should our expectations fail to materialize, should our assumptions prove to be incorrect, actual company results could differ materially from these forward-looking statements. A description of these risks and uncertainties and assumptions is included in our SEC filings.

Let's now turn to Slide 3. Joining us today is Dr. Sara Hurvitz, the co-principal investigator of the VIKTORIA-1 study and the Senior Vice President of the Clinical Research Division of the Fred Hutch Cancer Center and President and Head, Hematology and Oncology at the University of Washington School of Medicine. Dr. Hurvitz will present the detailed results from the PIK3CA mutant cohort of the trial.

Dr. Sara Tolaney, Chief of Breast Oncology at Dana-Farber, will then join for a discussion about the treatment landscape in the second-line setting for patients with HR-positive/HER2-negative PIK3CA mutant advanced breast cancer.

Dr. Igor Gorbatchevsky, our Chief Medical Officer, will provide a few additional observations about these results, and we'll finish up with an update from Eldon Mayer, our Chief Commercial Officer, who will provide us a brief update on our preparations for a potential launch of gedatolisib.

Despite the importance of the PIK3CA or PI3K/AKT/mTOR pathway as a cancer driver, inhibitors targeting this pathway have had more limited impact than would have been expected when its importance was first discovered over 20 years ago. And this reflects the PAM pathway's complex structure, which requires multiple components to be inhibited to comprehensively blockade the PAM pathway's activity. When only a single component of this target, adaptive resistance arises and pathway shutdown is limited. Further complicating the challenge of drugging this pathway is the narrow therapeutic window that exists. There's a graveyard of drugs attempting to inhibit all of these components that were not efficacious, too toxic or both. Gedatolisib overcomes these challenges by over inhibiting all 4 Class I isoforms of PI3K and both mTORC1 and 2 with a potency and PK profile that patients can tolerate well.

Let's now turn to Slide 5. Today is an important day for patients with HR-positive/HER2-negative advanced breast cancer. Both gedatolisib regimens doubled the likelihood of a patient survival without disease progression or death compared to alpelisib plus fulvestrant. The clinically meaningful improvement in progression-free survival showed by both the gedatolisib-triplet and -doublet from the PIK3CA mutant cohort of our VIKTORIA-1 trial is now the second positive Phase III readout for gedatolisib, provides further demonstration of the clinical benefit comprehensive inhibition of the PAM pathway.

With positive Phase III results now in both the PIK3CA wild-type and mutant cohorts of VIKTORIA-1, we're well positioned to offer potential standard of care therapeutic combinations for all patients in the second-line setting. We believe these results also augur well for our 2 ongoing Phase III trials evaluating patients with HR-positive/HER2-negative advanced breast cancer in the first-line setting.

Let's now turn to Slide 6. As was the case with the data reported for the wild-type cohort of the VIKTORIA-1 trial, these results established several new milestones in the history of drug development for HR-positive/HER2-negative advanced breast cancer. First, VIKTORIA-1 is the first Phase III trial to demonstrate superiority of one PAM inhibitor versus another. And second, the greater than 11 months median progression-free survival for the gedatolisib-triplet and -doublet are the highest reported by any Phase III trial for a regimen, including endocrine therapy in the second-line setting. And third, the 49% objective response rate for the gedatolisib-triplet is the highest reported by any Phase III trial for a regimen, including endocrine therapy in the second-line setting.

Now let's turn to Igor Gorbatchevsky, our Chief Medical Officer.

Thank you, Brian. I'm very happy to introduce Dr. Sara Hurvitz with whom we are very happy to work for the last 5 years as a co-principal investigator for VIKTORIA-1 study. As Brian mentioned, Dr. Hurvitz is currently serving as the Senior Vice President of Clinical Research Division of Fred Hutchinson Cancer Center and Professor and Head of Hematology and Oncology at University of Washington School of Medicine.

So I will turn to Dr. Hurvitz to review results of VIKTORIA-1 Study 2 in patients with PIK3CA mutation-positive disease.

Thank you so much. It's my pleasure to be here. Good morning. By way of background, currently available therapies target a single component of the PI3-kinase/AKT/mTOR signaling pathway, which is a complex multicomponent signaling pathway that drives breast cancer growth and contributes to endocrine and CDK4/6 inhibitor resistance. These agents have modest efficacy and tend to be limited to biomarker selected patient subsets. These agents also as well as earlier therapeutic attempts to completely block the PAM pathway can produce significant toxicity. And so there is an unmet need for safer and effective PAM inhibitors.

As Brian told you, gedatolisib is a highly potent multi-target PAM inhibitor that targets all Class I PI3-kinase isoforms as well as mTORC1 and mTORC2 for comprehensive blockade of this important pathway. VIKTORIA-1 is a randomized open-label 2-part study designed to evaluate gedatolisib-based therapy in patients with hormone receptor positive/HER2-negative advanced breast cancer after progression on a CDK4/6 inhibitor and nonsteroidal aromatase inhibitor. Study 1, which was just published and was presented at the end of last year, enrolled patients with PIK3CA wild-type disease and demonstrated a statistically significant and clinically meaningful benefit compared to fulvestrant in patients with PIK3CA wild-type advanced breast cancer.

For the triplet, the median progression-free survival was 9.3 months versus 2 months for fulvestrant with a hazard ratio of 0.24, and the doublet had a median PFS of 7.4 months versus 2 months with a hazard ratio of 0.33. The safety profiles were generally consistent with the individual agents. So today, we present the first results for Study 2, which evaluated gedatolisib-based therapy in patients with PIK3CA-mutated disease.

Next slide. VIKTORIA-1 is a Phase III global open-label randomized 2-part clinical trial that assigned patients to Study 1 or Study 2, as I said, based on tumor PIK3CA status. Eligible patients had received prior CDK4/6 inhibitor and an aromatase inhibitor and experienced disease progression. Up to 2 prior lines of endocrine therapy were allowed, but no prior chemotherapy and no prior PI3-kinase pathway inhibitor was allowed. Our cutoff for HbA1c was 6.4%. Study 2 enrolled patients with a tumor PIK3CA mutation and randomly assigned patients in a 3:3:1 ratio to the triplet of gedatolisib-palbociclib-fulvestrant or alpelisib-fulvestrant or gedatolisib-fulvestrant. The primary endpoint was progression-free survival comparing the triplet, Arm D, to alpelisib-fulvestrant, which is standard of care for PIK3CA-mutated breast cancer.

Next slide. The primary efficacy analysis progression-free survival by blinded independent central review was performed on the intent-to-treat population of the gedatolisib-triplet versus the alpelisib-fulvestrant control arm. Key secondary endpoints were to be tested in hierarchical order. Although the overall survival data are not yet mature, an interim analysis was planned to coincide with the primary efficacy analysis, and those results will be reported today. Additional secondary endpoints comparing the gedatolisib-doublet to alpelisib-fulvestrant as well as objective response rates for all 3 treatment arms will also be presented.

Next slide. At the data cutoff, 362 patients had been assigned in a 3:1:3 ratio, and most patients in each arm received their allocated treatment. There were more patients who discontinued treatment with the standard alpelisib-fulvestrant than with the gedatolisib-triplet, and this was mainly due to disease progression. Moreover, there were more adverse events and treatment-related adverse events that led to treatment discontinuation as well as deaths in the alpelisib-fulvestrant arm compared to the gedatolisib arms. At the data cutoff, the median follow-up was 12.8 months.

Next slide. Baseline demographics and characteristics of the patients were generally well balanced across treatment arms. A large proportion of patients had liver and lung mets over approximately 3/4 of patients and about 15% of patients had endocrine-resistant disease as indicated by a short time to progression of 6 months or less. Consistent with real-world usage patterns, there were significantly more prior ribociclib and palbociclib treated patients relative to abemaciclib overall, and usage was similar for the gedatolisib-triplet and alpelisib-fulvestrant arms.

Next slide. Here are the progression-free survival data. VIKTORIA-1 Study 2 met its primary endpoint. The gedatolisib-triplet produced a statistically significant and clinically meaningful reduction in the risk of disease progression or death relative to alpelisib-fulvestrant. The hazard ratio was 0.50, meaning that we saw a 50% reduction in the risk of progression or death. To our knowledge, the 11.1 month median progression-free survival is the highest reported by any Phase III trial for a regimen, including endocrine therapy in second-line hormone receptor positive/HER2-negative advanced breast cancer following treatment with the CDK4/6 inhibitor. It is also notable that separation of the curves occurred early around the time of the first scan being performed.

Next slide. Subgroup analyses demonstrate that the clinical benefit of the gedatolisib-triplet was generally maintained across all subgroups. All hazard ratios were less than 1.0, although some of the confidence intervals at upper limits include 1.0. And as was seen in the wild-type cohort in Study 1, results were consistent across the different CDK4/6 inhibitor subgroups.

Next slide. The gedatolisib-doublet also produced a clinically meaningful reduction in the risk of progression or death. Although not part of the primary efficacy analysis, the hazard ratio was similar to that with the gedatolisib-triplet, so 0.51 versus 0.50, respectively, as was the median progression-free survival, 11.1 months here. The descriptive p-value of 0.0013 indicates the results are robust. These results suggest that when PIK3CA is mutated, the PAM pathway may play a more important role in tumor cell proliferation than in tumors lacking a PIK3CA mutation.

Next slide. Similar trends are seen in the subgroup analysis for the gedatolisib-doublet versus alpelisib-fulvestrant.

Next slide. Looking at overall survival, we see encouraging trends in the interim analysis with separation of the curves occurring at the outset. With 110 deaths total among 362 patients, the interim boundary for statistical significance was not yet met.

Next slide. The overall response rates, clinical benefit rate and disease control rates were all higher for the gedatolisib-based regimen than for alpelisib-fulvestrant. To our knowledge, the 49% objective response rate for the gedatolisib-triplet was higher than has been previously reported by any Phase III trial for a regimen, including endocrine therapy in second-line hormone receptor positive/HER2-negative advanced breast cancer. Additionally, nearly 3x as many patients in the alpelisib-fulvestrant group experienced disease progression compared to the gedatolisib arms.

Next slide. Gedatolisib-based treatments also produced a clinically meaningful duration of response as seen here for the gedatolisib-triplet on the left and the gedatolisib-doublet on the right, both compared to alpelisib-fulvestrant. The median duration of response was doubled with the gedatolisib-triplet, 15.7 months versus 7.5 months and tripled [ with gedatolisib triplet ].

Next slide. The safety profiles of each regimen were generally consistent with the individual agents within the regimen and no new safety signals emerged. Similar to the Study 1 wild-type data, there was a low rate of treatment discontinuation due to adverse events in the gedatolisib arms, 2.6% for the triplet and 3.8% for the doublet. In contrast, 7.1% of patients in the alpelisib-fulvestrant arm discontinued treatment due to AEs. There were 3 Grade 5 events seen related to treatment by the investigator, 1 in the gedatolisib-triplet and 2 in the alpelisib-fulvestrant. The safety profile of gedatolisib was generally consistent with that reported for Study 1 with the most common treatment-related AEs, including neutropenia in the triplet arm, which is likely or most likely related to the palbociclib and stomatitis in both arms, 61.4% Any Grade and 16.3% Grade 3 with the triplet and 5.8% Grade 3 with the doublet. Notably, rates of diarrhea and hyperglycemia, both considered class effects with PI3-kinase inhibition, were much lower in the gedatolisib arm than in the alpelisib-fulvestrant group.

In summary, gedatolisib, next slide, plus fulvestrant with or without palbociclib significantly improved progression-free survival compared with alpelisib-fulvestrant in patients with hormone receptor positive/HER2-negative PIK3CA-mutated advanced breast cancer in VIKTORIA-1 Study 2. Patients in the gedatolisib-triplet and -doublet groups were 2x as likely to survive without disease progression or death compared to alpelisib plus fulvestrant. Adverse events associated with the gedatolisib-based treatment were mainly Grade 1 or 2 in severity. Notably, hyperglycemia was low as was diarrhea, which is unexpected for a drug targeting the PAM pathway.

For alpelisib and fulvestrant, hyperglycemia was 58% and diarrhea was 40%. Stomatitis was the second and most -- and first most commonly reported treatment-related adverse event for the gedatolisib-triplet and -doublet, respectively, but study-treatment discontinuation due to these adverse events was 2.6% for the triplet, 3.8% for the doublet and higher in the alpelisib arm at 7.1%. Gedatolisib-fulvestrant with or without palbo represents a potential new standard of care for patients with hormone receptor positive/HER2-negative PIK3CA-mutated advanced breast cancer after progression on or after treatment with the CDK4/6 inhibitors. The combined results of VIKTORIA-1 Study 1 and 2 validate the PAM pathway as a molecular driver in hormone receptor positive/HER2-negative advanced breast cancer, regardless of PIK3CA-mutation status.

And with that, I will close.

Thank you very much, Sara, for this presentation and your leadership you provided for this program. I would like to provide a brief overview of these results in comparison to the current treatment landscape in a second-line setting for hormone-positive/HER2-negative advanced breast cancer.

Let's move to the next slide. As the results presented by Dr. Hurvitz confirm that gedatolisib regimens showed the strongest efficacy results, we compare them to reported results from other studies. And as you can see, both median progression-free survival and objective response rate high with a triplet reported 11.3 months -- doublet reporting 11.3, triplet reporting 11.1 and objective response rate of almost 50% for the triplet, 36% for the doublet. When it's compared to other agents in this class with the median progression-free survival, very similar between alpelisib and fulvestrant of 5.6 and 5.5 months and objective response rate of 26% in alpelisib-fulvestrant and capivasertib of 23% in previously reported studies in patients who previously received CDK treatment.

Let's move to the next slide. I would like to remind showing again the data that we presented last year, Dr. Hurvitz presented at ESMO in 2025 as the Study 1 met its primary endpoint, which was very statistically significant and the lowest hazard ratio ever reported in randomized Phase III study in advanced breast cancer for the triplet of 0.24 and for doublet of 0.33. Both regimens showed meaningful improvement in progression-free survival compared to standard of care.

Let's move to the next slide. When we look at the current landscape for treatment in patients with wild-type disease, we can see that changes in results when we compare to standard of care are very significant in gedatolisib treatment regimen. Median progression-free survival was improved by almost 5x with a triplet agent and almost 4x with a doublet agent in this disease. And as you can see, some of the products are already approved, some of them not yet approved and comparison is obvious.

Let's move to the next slide. Another way to compare efficacy and improvement for gedatolisib, as I already mentioned, triplet regimen in wild-type reported the lowest hazard ratio reported to date of 0.24% and the doublet 0.33%, which compares favorably to other studies reported in recent years.

Let's move to the next slide. Right now, I'm very happy to introduce Dr. Sara Tolaney, who is the Chief of Division of Breast Oncology at Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School. Dr. Tolaney kindly agreed to talk with us to provide her impression of the data that was shared with Dr. Hurvitz.

So Dr. Tolaney, in the first question, I would like to hear your initial impression of the results from Study 2 evaluating gedatolisib regimen in PIK3CA-mutated disease, especially when we compare to other agents in this class. What would be your initial impression?

Well, I'll say I was very impressed with the data. And I think this is a very challenging-to-treat patient population. These are patients post CDK4/6 inhibition who have an underlying PI3K mutation. And traditionally, we've been previously using fulvestrant-alpelisib. And in the U.S., we're often using fulvestrant-capivasertib. And what we're seeing with fulvestrant-capivasertib in a post-CDK population is a PFS of around 5.5 months. And so this, in essence, is doubling compared to control therapy, what we're able to achieve in terms of disease control. And so I think this is a very meaningful improvement for our patients.

Thank you, Dr. Tolaney. Another question, one follow-up on -- as we presented previously last year in Study 1 and as Dr. Hurvitz mentioned and we presented results from Study 2, treatment discontinuation due to adverse events was low in this study, below 4% for both triplet and doublet regimen across both studies. When we look at your already mentioned currently used agents in this disease, what's your initial impression about safety profile, low discontinuation rate and especially those side effects, as Dr. Hurvitz mentioned, related to PAM inhibitors, diarrhea, colitis and hyperglycemia? What's your initial impression of those results?

Well, I'll say we never get a discontinuation rate this low with a PI3K inhibitor. So it is very impressive. I mean, I think we are challenged right now in the clinic with using the current treatment. While capivasertib was certainly a step forward, I think, compared to alpelisib in terms of tolerability, it still requires monitoring. I have to do glucometer teaching with my patients, have them do finger sticks, which is challenging. The rate of diarrhea is over 70%. Patients are often using loperamide. So these drugs are not easy for us in the clinic and patients can often need to discontinue therapy due to rash. And so it has been a challenge. So again, to see a discontinuation rate under 5% is not something I've ever seen with the PI3-kinase inhibitor, so very impressive.

Thank you very much. And the last question. With this result that you saw, how do you think gedatolisib combination regimens will be positioned in a second-line advanced breast cancer following potential approval? What's your opinion?

Well here, I think combining the totality of the data across both studies within VIKTORIA-1, it does suggest that there's benefit for gedatolisib, honesty irrespective of PI3K mutation. I do think in the PI3K-mutant pathway, this is really an important step forward because, again, we're very challenged with our current treatment regimens. I think the PI3K wild-type population, as you pointed out, reviewing the current landscape, is a bit more complex in terms of thinking about various treatment options. But I think, again, this gives a very broad utilization in a post-CDK population, which is really nice for patients.

Thank you so much for your time. We really appreciate it.

So let's turn to the next slide. I will finish my part of discussions with a general summary of overall observations for this results. First, VIKTORIA-1 Study 2 evaluating patients in mutation positive disease did exceed statistical assumptions that we were set up before. As you see in both hazard ratio and based on assumed expected median progression-free survival, statistically significant improvement with hazard ratio of 0.5 and 0.51.

The next important point is that control arm in this study, alpelisib-fulvestrant actually represents today's most realistic real-world results for this therapy based on the number of points I would like to bring. The first, this is the largest randomized study comparing the study arm to alpelisib-fulvestrant when we look at the previously reported study with alpelisib. The higher number of sites participating and enrolling patients and significant proportion of patients with a significant tumor burden and a higher proportion of those who were endocrine resistant compared to previously reported results.

And the last point with that is that the low adverse event rate resulting in treatment discontinuation for alpelisib actually indicates that these efficacy outcomes are not associated with drug exposure and provide very realistic efficacy for alpelisib-fulvestrant combination in real world for patients with advanced breast cancer who were previously treated with cell cycle inhibitors.

And the last point to summarize that efficacy and safety profile of gedatolisib is explained by gedatolisib mechanism of action, PK profile and route of administration. All of those are responsible for significantly improved efficacy and safety compared to oral agent targeting a single component of the PAM pathway.

With 300x more potent activity, gedatolisib can be dosed infrequently, which results in significantly less frequent exposures of Cmax and lower systemic AUC. Also by passing initial GI tract metabolism, gedatolisib intravenous administration results in significantly lower number of immune-mediated and metabolic side effects such as diarrhea, rash and hyperglycemia.

I will be concluded with my part of presentation and turning back to Brian.

Great. Well, thank you, Igor. I'd like to now turn to Eldon Mayer, our Chief Commercial Officer. Eldon will provide a quick overview of the progress we've made establishing the commercial infrastructure for a potential launch of gedatolisib.

Thank you, Brian. Let's turn now to Slide 30. I'm pleased to provide an update on our commercial strategy and launch preparation. We're very enthusiastic about the opportunity ahead. We believe our data in both PIK3CA wild-type and mutant patient populations can position gedatolisib to become a best-in-class treatment option in the second-line setting. And our commercial and medical affairs teams have been executing with urgency to ensure we're ready for launch.

First, I'd like to take a moment to briefly review the exceptional leadership team that will drive the execution of this launch. Every individual here that is leading core functions of medical affairs, marketing, market access, commercial operations and sales has extensive industry and oncology experience. Over the past 2 years, they have each built highly experienced and deeply skilled teams designed to meet the specific market needs for launching gedatolisib. These leaders and their teams are seasoned, high-caliber people with a strong blend of industry know-how, commercial and clinical credibility and successful launch experience in both emerging biotech as well as large full-scale commercial stage organizations. And we're confident that together, we will deliver a successful launch that will create value for health care practitioners, for patients and for shareholders.

Let's turn now to Slide 31. Moving on to the market opportunity. Within the U.S., approximately 37,000 patients with HR-positive/HER2-negative advanced breast cancer receive second-line treatment each year following progression on CDK4/6 inhibitors. Of these, roughly 60% are PIK3CA wild-type and 40% are PIK3CA mutant. And importantly, approval for both indications would allow gedatolisib to address 100% of this market with the simplicity of a single PIK3CA agnostic treatment approach. This would be a major differentiator versus currently available drugs that are restricted to either wild-type or mutant patients.

There remains a significant unmet need in this market for therapies that deliver better efficacy without compromising safety. Gedatolisib's unique mechanism of action as a potent pan-PI3K/mTOR inhibitor, combined with its pharmacokinetic profile and IV route of administration provide a distinct efficacy, safety profile relative to existing oral agents. Taken together, we believe gedatolisib will offer a compelling value proposition, a unique combination of efficacy and safety that has the potential to become a new standard of care in this setting.

And finally, we estimate a $6 billion total served market opportunity across both PIK3CA wild-type and mutant patient populations.

Let's turn now to Slide 32. Moving on to the launch readiness and preparations for the PIK3CA wild-type launch. For market access and reimbursement, we have completed payer engagements, covering 90% of U.S. medical benefit lives. We've had multiple productive discussions with nearly all major payer and provider pathway organizations as well as 90% of 36 key strategic accounts and more than 50 local and regional accounts. Our NCCN submission pathway and compendia packets and AMCP dossier will be ready for submission within 72 hours of approval. And with regard to reimbursement, we expect prior authorization to label payer coverage, which is very important for a buy-and-bill IV therapy.

Let's turn now to Slide 33. Our sales force, field marketing and medical affairs teams are fully built and prepared. We have created a tenured sales organization that has an average of 24 years in pharma and 17 years in oncology experience. And every sales specialist has IV and buy-and-bill experience. Our medical science liaison team and field-based marketing team have been actively engaged with the breast cancer and oncology community. We began key opinion leader engagement and Advisory Boards in 2024 and have now reached a combined total of 1,000 community breast cancer experts, physicians that treat a high volume of breast cancer patients and key opinion leaders.

Let's turn now to Slide 34. On the broader marketing front, we launched the unbranded campaign, pampathway.com, which has already generated over 4 million digital impressions that highlight the importance of comprehensive PAM pathway inhibition. We've maintained a strong presence at all major oncology and breast cancer congresses and have developed a full array of promotional and educational materials and programs along with a digital media campaign that is ready to deploy immediately upon approval and launch.

Let's turn now to Slide 35. And finally, our distribution and patient support infrastructure is in place. We have secured our 3PL partner, our specialty distribution network, GPO contracts, specialty pharmacies and comprehensive patient and reimbursement support programs that are all ready to go live at approval. We have also built strong partnerships with Breast Cancer Patient Advocacy Groups.

In summary, we've built a strong launch team that is fully prepared to drive rapid adoption and establish gedatolisib as a new standard of care in the PIK3CA wild-type market and if approved for both indications across the entire HR-positive/HER2-negative second-line treatment patient population. We're confident that gedatolisib's differentiated clinical profile, combined with a high level of commercial readiness positions us for a strong and successful launch. I look forward to sharing more updates as we approach potential approval and launch.

Back to you, Brian.

Thank you, Eldon. And let's now turn to Slide 37. We're obviously very encouraged by these results and the implications for our 2 new Phase III first-line clinical trials and other potential future clinical development plans. And since gedatolisib has the potential to address a number of additional unmet needs in a variety of additional settings, we're thankful that our intellectual property position is very strong. We expect to have patent exclusivity with gedatolisib at least until 2042 with the potential to extend it further with the subcutaneous formulations we're developing. And this gives us a long runway to develop new potential indications and to expand the patient population we can treat with gedatolisib.

Let's now turn to the next slide. We have a number of several important milestones coming up in the back half of this year. First, we're expecting an approval decision from the FDA by a PDUFA date of July 17, 2026, for the VIKTORIA-1 PIK3CA wild-type cohort. Second, we have several data updates later this year. We expect to update data from our Phase Ib metastatic castration-resistant prostate cancer study in the fourth quarter and to provide updates from our VIKTORIA-1 wild-type and mutant studies later in the year as well.

And then finally, we have some important regulatory submissions we expect to file. First, we're targeting submission of a supplemental NDA to the U.S. FDA in the third quarter of this year. And secondly, we expect to submit the marketing authorization application, or MAA, to the European Medicines Agency in the fourth quarter of this year.

Let's now turn to Slide 39. So this concludes our presentation portion of the day. We'll now turn to a Q&A session. Thank you to those who have submitted questions, and we'll go from there. So operator, if you could open up questions, please.

[Operator Instructions] Our first question comes from the line of Maury Raycroft with Jefferies.

Congrats on the data and the strong PFS HRs in both the triplet and doublet. Given the similar PFS curves in the doublet versus triplet regimen, but differences in OS curves, how are you thinking about the potential labeling and commercial use? Will the triplet still be the predominant therapy across wild-type and mutant if CDK4/6 is not needed in the mutant setting? And can the doctors comment on whether they'll still test for PIK3CA mutations and whether they would use the triplet or the doublet?

Okay. Well, thank you, Maury. Both Sara, as it turns out, have commitments to present in other settings right now. So we were basically very lucky to get them at the beginning of this trial. So we'll be answering these questions, and Igor will be participating.

As far as the going-forward label, in the wild-type setting, we think there's a clear obvious distinction and benefit for the triplet versus the doublet. The research we've done, both quantitative and qualitative, indicates that physicians will likely prefer probably 5:1, the triplet versus the doublet. And part of that is related to the idea that with these patients in the second-line setting can provide a complete coverage of the disease pathways is very appealing. And also knowing that if for whatever reason, palbociclib is no longer appropriate for a patient or if it's not appropriate at the get-go, that they can use the geda-doublet with confidence that patients will receive an important benefit.

Now in the mutant setting, it is a little bit different. We are, to be frank, I mean, surprised that I think that doublet outperformed our expectations, and we think that's very encouraging because it basically indicates that in the mutant population, this pathway is playing more of a driver role. And you can think of the CDK4/6 pathway potentially as being more of a passenger. You do see differences in activity when you look at the objective response rate, 50%, 49% versus 37%. And you also see OS curves that might be a little more separated, but that's obviously early and not conclusive.

And so in the mutant setting, we think there'll be a similar perspective that controlling all pathways provides the potential most coverage of the tumor drivers. But certainly, we think there'll probably be maybe a higher preference for the doublet than in the wild-type setting. Overall, what we think this demonstrates is that both regimens are appropriate options for patients. And by having both regimens, we're providing flexibility to doctors. It's a very heterogeneous population. And so we think having options and having strong data for both potentially provides a lot of flexibility and optimization for the doctors to tailor the treatment that best reflects the patient's characteristics.

Our next question comes from the line of Tara Bancroft with TD Cowen.

So I guess with the doctors not here, Brian, my question is for you. So maybe thinking about the relative potencies and activity of hitting the single node like mutant specific versus the PAM pathway, does this at all change your expectations for future competition from the oral PI3Ks and where those can end up in Phase III?

Well, again, our view has been based on the underlying biology of these tumors and the role of this pathway. And ultimately, it's a complex pathway, multiple components that essentially allow cross activation to occur if one of the components is not inhibited. And I think if we go back 20 years, we see that this general biological imperative was well understood by every major pharmaceutical company. All the programs that were launched initially when this pathway was discovered as an important driver were pan-PI3K/mTOR inhibitors. And they took that approach for a reason that was understood and nonclinical work certainly reflected that, that comprehensive inhibition is required to optimize control this pathway and maximize potential antitumor control.

The switch or the shift towards single target inhibition really was just a reflection of the challenges of drugging and hitting these multiple targets, not necessarily an approach that was optimized according to the tumor biology. So our view is that single target inhibition is just fundamentally limited in the level of antitumor control that will be available just because of the structure and function of this pathway. We -- I think the results for the alpelisib arm probably represent real-world experience. Our nonclinical work and I think others' nonclinical work have shown that alpelisib and capivasertib in in-vitro models, and we've tested a lot of different tumor cell line models as well as in animal models show that the results for these 2 drugs are very, very similar. And so the results that we saw today actually don't surprise us.

And the fact that they're very consistent with capivasertib is kind of very consistent with the other data that we've seen. Igor explained some of the -- what we think the reason why in this robust Phase III setting, we probably got the best look at what alpelisib does in the real-world setting. And so again, I think single target inhibitors, particularly those that are focused on this alpha isoform. Again, are just going to be limited and probably alpelisib provides a very good demonstration of that. The fact that alpelisib's discontinuation rate is very low and that these patients were largely exposed to alpelisib continuously suggests that there was not a dose exposure.

I think there's been some question about the limitations of alpelisib because of its safety profile to provide a consistent treatment or exposure. 7% discontinuation rate is 1/4 of the level that had been reported previously. And so again, in this setting, seeing alpelisib utilized consistently kind of we think provides a demonstration of what its real potential or rather what its real efficacy is and the potential of inhibiting this alpha target.

Our next question comes from the line of Oliver McCammon with LifeSci Capital.

Congratulations on the data. I've 2 questions here. Just given where the alpelisib plus fulvestrant comparator arm landed, can you remind us of why it may be important to really look closely at the hazard ratios here?

And then on the second question, I'm curious if you can describe a little bit of how you see the read-through to the frontline endocrine-sensitive study plan as well.

Well, ultimately, we conduct randomized Phase III studies to compare the results from one regimen to another in a setting that ensures that all variables that could be related to differences in patient composition or the prior treatments are eliminated. And so a head-to-head comparison in a randomized setting really provides the best understanding of how one drug stacks up against another.

And it's unusual, to be frank, in a study that is comparing head-to-head drug from the same class to show this level of differentiation. And I think it again provides further demonstration of the importance of multi-target inhibition. So the hazard ratio of 0.5, to be frank, that's a fantastic result. I think it's the most relevant finding from the study. The fact that gedatolisib as a doublet was able to deliver that level of differentiation. I think, again, it's almost as good as it gets to show that differentiation, better than what we expected, to be frank. Our statistical assumptions were conservative. And so to exceed those statistical assumptions and then to see this over performance of the doublet really highlights just how effective and how important it is to shut down this pathway. And the hazard ratio really provides the most informed metric to establish that.

As far as how that reads to the endocrine-sensitive population, again, I think what we've shown is independent of the status of PIK3CA. This pathway, the PAM pathway is relevant. We've reported very encouraging results, preliminary results from our Phase Ib study, small sample size of 41 patients at least, 48 months median PFS, which compares very favorably to what's been reported previously of 24 months for other CDK4/6 letrozole combinations. And so again, showing in both settings, very, very, very strong efficacy, we think augurs well, and we think significantly decreases or increases rather the probability of success for that study as well as the endocrine-resistant study that we're fielding.

Our next question comes from the line of Andrew Berens with Leerink.

Just wondering, I think in the doublet arm, you saw much improved rates of mucositis. Wondering if there was anything in that arm that would explain it or it's just simply the low sample size.

Yes. Right. So the palbociclib induces some level of stomatitis. There's a little -- yes. And so the fact that gedatolisib-doublet didn't have palbo explains the difference in the stomatitis overall. And so there was a bit of an additive effect there.

Okay. And the patients were given the same mouthwash profile?

Yes. In other regimens, the prophylaxis were the same and very consistent between the wild-type and mutant population. I would say just Igor alluded to this, but the populations, baseline characteristics, demographics across the wild-type and mutant populations were very similar. Obviously, the major differentiation between the 2 was the status of PIK3CA. So we saw a very consistent population, roughly distributed in a similar fashion across geographies. And certainly, all the study procedures were the same, essentially as one protocol, screening patients and then just assigning them to different study arms. So there's really nothing different between the 2 studies in terms of how patients were treated and monitored.

Okay. Congrats on the progress, Brian.

Thank you.

Our next question comes from the line of Stephen Willey with Stifel.

Congratulations. Just curious as to why you think -- I know you talked about the alpelisib exposure, but why do you think there were much lower rates of hyperglycemia in this trial relative to EPIK-B5, just given that I believe it was the same HbA1c cutoff?

That's hard to explain. I mean there's always some variety from one trial to another. And so it's really not possible to provide a definitive explanation. And to the extent that the population we enrolled was able to stay on alpelisib, and I'd suggest that they may not have been as sensitive to hyperglycemia as the other studies, I mean, you just have to draw that conclusion from the data. But the fact that the patients were able to stay on the drug and receive essentially, for the most part, high proportion of the available dose indicates that patients were fully appropriately treated.

We didn't get the distortion that can occur when you have high dropout rates when 25-plus percent of the population drops out due to adverse events, that creates what can be characterized as a dropout bias or attrition bias. And essentially, you are not confident you're evaluating a representative population from the overall randomized pool. And so you eliminate that bias when you have patients who are able to stay on the drug without discontinuing. And so from our view, you get a real picture.

Now what's interesting is that the EPIK-B5 study reported, I think, around 0.5 hazard ratio relative to fulvestrant. And capi in its study, a similar population reported about a 0.5 hazard ratio. So those 2 drugs, when you look at them, even when you take into account potentially the different patient populations, reported very, very similar results. And so the fact that the study for capi reported 5.5 results and study for geda equated with VIKTORIA-1 for alpelisib reported essentially identical results is consistent with prior studies when you look at the hazard ratios that they both reported.

Okay. And maybe just a quick follow-up. As you think about the single node PIK3CA inhibitors following you into the frontline setting, how are you thinking about the need to prospectively generate some data to support sequencing opportunities in the second line?

I'm not sure I understand that question. I mean, obviously, to the extent that you can treat patients earlier, typically, that's found to be more favorable for the patients, prolong the progression and consequent morbidities that, that induces. So to the extent that we can offer an improvement in the progression-free survival period also creates an opportunity to potentially improve survival. I mean that's obviously the goal.

And so to the extent patients don't receive, if we're looking into the future, a gedatolisib regimen in the frontline setting, certainly, then the data supports use of geda in the second-line setting. And so we think long term that our studies read out the way we hope that geda will be part of nearly all patients' treatment regimen, whether it's in the frontline setting or the second-line setting.

Our next question comes from the line of Bradley Canino with Guggenheim.

Brian and team, congratulations. Now that we have the data, maybe some commercial questions. I guess with this profile, what do you think geda can achieve in the PIK3CA mutant group? Annualized capi sales look to be about $700 million in the U.S. geography, if I've got that right. What do you think that can grow into?

And then do you think the launch trajectories of prior oral therapies for second line are appropriate to think about for geda in the second half of this year? First quarter that was the full quarter for alp and capi achieved $40 million to $50 million. Is there anything to think about for an IV launch relative to these precedents?

So really 2 questions. As far as the potential, I think capi, as you can see with the numbers, has relatively low duration of treatment. It has a reasonably high level of discontinuation. And so it may not fully represent what the full potential is, to be frank, in this setting. We would expect, and I guess our internal projections expect higher peak revenues than what capivasertib has shown. And we think the overall safety profile, certainly the efficacy profile suggests that geda will become a new standard of care for these patients. As far as -- and then the implications for that will, we think, drive higher potential peak revenues as a result.

As far as the launch trajectory, I mean, certainly, those are good analogs. I mean, I think the way we think of the trajectory in general and how to estimate it is that we start off with a peak revenue assumption or rather peak penetration assumption, what we think is reasonable. Then we estimate a time to achieve that. If you look at first-time launches for companies, you typically see a 36- to 42-month time to peak revenue. And then you work backwards from there and say, okay, if we can get to x penetration in 36 to 42 months, essentially, the round numbers. I'm just going to use round numbers, not a projection here. But if the round numbers, you said, okay, you've got 42-month time to peak, and you're assuming 42% -- 40% penetration, essentially, you're assuming 1% a quarter penetration increase.

And then -- so the question is what does a percent represent of this population? That's kind of internally how we think about those numbers. Certainly, you can look at comparable numbers or rather launches and draw some conclusions with that. But AZ launching a drug into a space where they already had a significant presence, maybe not representative of what we can do. But again, we think there'll be very, very significant demand for this drug given its efficacy and safety profile. We've received very, very encouraging feedback as we've essentially begun meeting with docs with our medical affairs teams, getting their perspectives. And so again, I think there's always a triangulation to figure out what's possible. But we start off with base assumptions and work backwards from there.

Our next question comes from the line of Eva Fortea with Wells Fargo.

A quick one from us. Can you comment on the differences seen on duration of response between the geda-doublet and -triplet?

Eva, I had a little trouble understanding you. Could you repeat that question, please?

Can you hear me?

Yes, but you're muffled, sorry.

Oh. Is it better now?

Yes.

Okay. Can you comment on the differences seen on duration of response between the geda-doublet and -triplet?

Well, I think it reflects the fact that CDK is still playing a role in this disease and that controlling it induces improvement in overall tumor response. And the extended duration of response, so nearly 16 months versus alpelisib's 7.5 is very encouraging. And so again, I think it's a question of which pathway is driving in the setting. I think the data for the doublet demonstrates that this PAM pathway is the primary driver. CDK is playing a role and that you got potential improved tumor control when you include that in the regimen. And survival data suggests there may be some differentiation and latency benefit. And it's too early to say. But clearly, the CDK4/6 pathway is still an important component of the disease process, but just potentially not as prominent and as important as it is in patients with wild-type disease.

Our next question comes from the line of Gil Blum with Needham & Company.

Congrats on the advancement here. So specifically on the median OS arms crossing in the doublet, do you think this is a powering artifact?

Yes. I mean essentially, our biostats team has looked at that. And just with that small sample size, we don't believe it's necessarily relevant. I mean we think it kind of creates a bit of a distortion bias. The hazard ratio that's below 1 is the most important stat there, showing essentially no decrement. But again, when you're doing an OS analysis with small sample sizes, you're vulnerable to just a few patients that can swing the results.

And from a technical perspective, could you walk us through the process or whether there is a way to get the doublet data onto the label?

No, we expect in the wild-type setting, we believe we will -- I mean, our approach will be to seek approval for both the doublet and triplet. Essentially, with our sNDA, we'll be seeking an expansion of the label, essentially saying that these regimens can be used irrespective of the status of PIK3CA. And we think the totality of this data supports that. We had a significant number of consultations at the beginning of -- prior to initiating the study, getting aligned with the agency. And so the study design reflects an alignment with the agency on what would be required to support an approval.

Now -- it's early days. We haven't submitted the package. We haven't presented the data yet to the FDA. Those conversations will be coming soon. But we certainly think the data supports an approval of doublet or rather an expansion of the doublet to be used in patients irrespective of their PIK3CA status.

Our next question comes from the line of Kalpit Patel with Wolfe Research.

I have 2. Number one, the duration of treatment, how should we think about the average duration of treatment in this mutant patient population versus your wild-type population?

And then second, some individuals are going to make some cross-trial comparisons to some of the oral PIK3 inhibitors that are in development. So just curious on how you see the baseline patient population enrolled here versus competition?

Sure. As far as baseline duration of treatment, you don't get a full picture of duration of treatment with relatively short follow-up periods. And ultimately, the most relevant number is the average duration, and you don't get a full picture of that until you have a longer follow-up period. But typically, you'd expect that to mirror probably 90% of what you see -- 85%, 90% of what you see from progression-free survival because you're netting out some discontinuation. But when you take into account the full persistence of the population over an extended period of time.

As far as the kind of other studies that have been done, what's important, 2 things. When you have a randomized study, you're netting out any biases that could occur when you have different patient population. So you have the same population, and you're showing head-to-head how one -- in this case, class of drug, how one drug with different MOA compares to another drug targeting the same pathway. As far as how the single-arm studies that are done, it's always challenging to place much weight on those. They provide important signals. But in particular, with our study, you'd see that most of these patients had visceral mets, liver lung mets, very few patients had nonevaluable disease. In fact, they all were required to have evaluable disease as part of the screening process or eligibility process.

When you start to get in early phase studies, there's a tendency to see a lot of patients with nonevaluable disease, and that's fine. You're trying to enroll patients, you're trying to get a signal. But that's not necessarily representative of a population you'd see in a Phase III, where typically regulators require to only enroll patients with evaluable disease because the progression-free survival requires measurable lesions to assess whether progression has occurred or not. But when you do incorporate a population with significant measurable nonmeasurable disease, you create an upward bias in the numbers. I mean we've seen in our study, in the mutant arum and in the wild type that fulvestrant in PFS was 8 months with patients with nonevaluable disease.

Other studies that have evaluated fulvestrant and broken out the results for nonevaluable disease show that fulvestrant by itself, again, is in the 8- to 9-month range with nonevaluable disease. And so you create a much higher contribution from the endocrine component of a therapy, and that needs to be taken into account. So in that case, if your control is providing 8, 9 months, showing, let's say, 11 months in the study arm would obviously not be a very favorable result. And so again, our perspective is these single-arm numbers aren't very translatable and, to be frank, don't carry much weight. Ultimately, the drugs need to be compared to each other in a randomized setting. And we think the data for alpelisib probably is the most representative of what its true efficacy is able to induce.

And so we think ultimately, when you go head-to-head against another drug, like in this case, these alpha inhibitors, we'll be comparing head-to-head against another alpha inhibitor, then you're really measuring not necessarily mechanistic for the most part, difference, you're measuring differences that might be related to duration of level of exposure. And that's -- those are fine hypotheses, but I think it's much more powerful and the potential to improve efficacy is much, much more significant when your mechanism of action is aligned more closely with the underlying biological characteristics of the pathway.

We have time for one more question. Our last question comes from the line of Silvan Tuerkcan with Citizens.

Congrats on these great results. I just have a quick question on the discontinuation rates. So your control arm, the alpelisib plus fulvestrant, it performed -- the discontinuation was significantly better than, for example, in the EPIK trial. Is that just because you have a more moderate population here, larger population? Or is there -- were there learnings with respect to how to use that doublet? And what does that mean for your discontinuation rates being obviously much lower than that? But would they be roughly half of what alpelisib is today or how would you expect that?

Sure. Well, I think from alpelisib perspective, it's hard to really tease out exactly why that occurred other than the doctors were able to manage these patients effectively, able to the extent the patients require some medications if they require them to help manage any glucose increase that was done effectively. And I think, again, significant study, global study. So we had, we think, a very representative population. I can't really speak to how the other studies were conducted or what their protocols mandated. But we were mindful of essentially making sure patients were given the best chance to stay on their study drugs. And we think these results reflect that.

I think what's most interesting about our discontinuation rate results is that they're basically very consistent across the wild-type and mutant populations. And so we saw 2 different -- essentially 2 different populations, obviously, similar baseline characteristics. But we saw very similar discontinuation rates for geda. Safety profile was also very consistent. And again, we view that as further evidence of how well patients can tolerate this drug and stay on it. And that's a reflection of factors that Igor referenced, so PK profile, potency that requires infrequent dosing. So patients are only getting exposed 3 times a month versus, let's say, 28 times a month, correspondingly lower number of Cmax exposures, which, again, we think supports the overall well-being or rather enables patients' overall sense of well-being to be enhanced.

And so again, with these trials, you run these trials, you really see the results. And we think this was probably the most robust Phase III study done in the post-CDK setting for alpelisib. And you have to take these results face value. And certainly, the fact that they are consistent with capivasertib, which, again, single component inhibitor suggests the results are probably what you see in the real world.

Great. And maybe one last quick one. Do you think there's any way payers can bias use of doublet over triplet, obviously, because it will be cheaper...

I'm sorry, I couldn't quite make out what you're saying there.

I'm just asking if prescribers can jump or push towards the use of a doublet versus the triplet since the net would be cheaper for them, or would it be up completely to the prescribers?

No. Okay. Sorry, I understand. Well, palbo will be going generic next year. So the economic consideration will, I think, no longer be relevant. I think the primary factor they'll take into account is after assessing the patient's profile, determining whether including a CDK makes sense for them. Certainly, it's a different determination when at least the face value of the PFS is essentially the same. And so that gives them much more flexibility.

At the same time, I guess we've heard from a number of doctors that we've shown the data that they like the idea of, again, hitting all 3 pathways to minimize the risk of potential progression for these patients. But knowing that to the extent that the patients either aren't appropriate to receive -- shouldn't receive CDK4 or aren't tolerating it well, that they can back off, discontinue palbo and have great confidence that the doublet will induce a very important clinical outcome for their patients.

I'd now like to turn the call back over to Brian Sullivan for closing remarks.

Well, thank you for attending our call. We appreciate your participation. We look forward to catching up with you over the coming days.

This concludes today's conference. Thank you for your participation. You may now disconnect.

Good afternoon, ladies and gentlemen, and welcome to the Celcuity First Quarter 2026 Financial Results Call Webcast. [Operator Instructions] I would now like to turn the conference over to Jodi Sievers, Corporate Communications and Investor Relations at Celcuity. Please go ahead.

Thank you, Matthew, and good afternoon, everyone. Thank you for joining us to review Celcuity's First Quarter 2026 Financial Results and Business Update.

Earlier today, Celcuity released financial results for the first quarter ended March 31, 2026. The press release can be found on the Investors section of Celcuity's website. Joining me on the call today are Brian Sullivan, Celcuity's Chief Executive Officer and Co-Founder; Vicky Hahne, Chief Financial Officer; as well as Igor Gorbatchevsky, Chief Medical Officer; and Eldon Mayer, Chief Commercial Officer, who will also be available during Q&A.

Before we begin, I would like to remind listeners that our comments today will include some forward-looking statements. These statements involve a number of risks and uncertainties, which are outlined in today's press release and in our reports and filings with the SEC. Actual events or results may differ materially from those projected in the forward-looking statements. Such forward-looking statements and their implications involve known and unknown risks, uncertainties and other factors that may cause actual results or performance to differ materially from those projected.

On this call, we will also refer to non-GAAP financial measures. These non-GAAP measures are used by management to make strategic decisions, forecast future results and evaluate the company's current performance. Management believes the presentation of these non-GAAP financial measures is useful for investors' understanding and assessment of the company's ongoing operations and prospects for the future.

You can find the table reconciling the non-GAAP financial measures to GAAP measures in today's press release. And with that, I will turn the call over to Brian Sullivan, CEO of Celcuity. Please go ahead, Brian.

Thank you, Jodi, and good afternoon, everyone. Thank you for joining our first quarter 2026 operating and financial update conference call. We continue to make great progress as we prepare for the potential approval and commercial launch of gedatolisib in the third quarter.

Achieving these milestones would be a pivotal moment for the women with advanced breast cancer who need new therapeutic options. With the groundbreaking data we have previously reported from the wild-type cohort and the recent announcement of positive data from the mutant cohort of our VIKTORIA-1 study, we believe gedatolisib is well positioned to become the new standard of care second-line therapy for patients with HR-positive/HER2-negative advanced breast cancer. It's been an eventful past few months for Celcuity.

Last week, we reported positive top line results for the PIK3CA mutant cohort of the Phase III VIKTORIA-1 clinical trial, and we look forward to presenting detailed results at a late-breaking abstract oral session at the 2026 ASCO meeting on June 2.

Given the timing of our ASCO presentation, we'll not be answering questions regarding these results during the Q&A portion of our call. Second, this morning, we announced 2 important updates to our clinical development plan. First, we announced the expansion of our Phase III VIKTORIA-2 trial to include a second study evaluating gedatolisib as first-line treatment in patients with endocrine-sensitive HR-positive, HER2-negative advanced breast cancer. We're now positioned to evaluate nearly all patients in the first-line setting, irrespective of their endocrine sensitivity or PIK3CA status.

And this offers the potential to advance the standard of care for the approximately 90,000 women each year who are newly diagnosed in the U.S. with HR-positive/HER2-negative advanced breast cancer. And secondly, we also announced this morning that we are advancing the development of a gedatolisib formulation for subcutaneous injection and that we have submitted our first patent application to the U.S. Patent and Trademark Office.

The subcutaneous formulation is aimed at supporting potential future indications for gedatolisib regimens that may result in duration of treatment periods greater than several years. And finally, we remain optimistic about the outcome of the FDA's review of our NDA, assuming our NDA is approved, we intend to submit the FDA a supplemental new drug application based on the results of the PIK3CA mutant cohort, VIKTORIA-1 and to submit VIKTORIA-1 data for both the mutant and wild-type cohorts to other global regulatory authorities following the sNDA submission.

Turning now to the top line results for the PIK3CA mutant cohort. The primary efficacy analysis of gedatolisib combined with fulvestrant and palbociclib, which we refer to as the gedatolisib triplet, demonstrated a statistically significant and clinically meaningful improvement in progression-free survival compared to alpelisib, which is a PI3K-alpha inhibitor and fulvestrant.

The secondary endpoint of gedatolisib combined with fulvestrant, which we refer to as the gedatolisib doublet, which was not part of the primary efficacy analysis in a hierarchical order, demonstrated a statistically significant and clinically meaningful improvement in PFS compared to alpelisib and fulvestrant.

Both gedatolisib regimens were generally well tolerated with manageable safety profiles and no new safety signals. When considered alongside previously presented data from the VIKTORIA-1 PIK3CA wild-type cohort, the gedatolisib regimens have now demonstrated the potential to improve the standard of care in the second-line setting regardless of the PIK3CA status of a patient's tumor.

We believe the results from the VIKTORIA-1 study validate our pioneering approach to targeting cancers involving the PI3K/AKT/mTOR or PAM pathway. And researchers have sought for nearly 20 years to develop a drug that blockades this pathway comprehensively without inducing unacceptable levels of toxicity. VIKTORIA-1 represents the first Phase III study that demonstrate that comprehensively blocking the PAM pathway can significantly improve outcomes for patients with PIK3CA mutations compared to therapies only targeting a single component of this pathway.

Now as we've previously reported, the VIKTORIA-1 PIK3CA wild-type cohort set several new benchmarks for clinical trials evaluating patients with HR-positive/HER2-negative advanced breast cancer. The hazard ratios for the gedatolisib triplet and doublet were more favorable than has ever been reported by any Phase III trial for patients with HR-positive HER2-negative advanced breast cancer. 7.3 months incremental improvement in median PFS for the gedatolisib triplet over fulvestrant is higher than has ever been reported by any Phase III trial for patients with HR-positive/HER2-negative advanced breast cancer receiving at least their second line of endocrine therapy.

And the 17.5 months of median duration of response for the gedatolisib triplet and 31% incremental increase in the objective response rate relative to the control for the gedatolisib triplet are the highest reported for an endocrine therapy-based regimen in the second-line setting.

Now both regimens were found to have a manageable safety profile that was well tolerated by patients as evidenced by the 2% and 3% adverse event-related discontinuation rates for the triplet and doublet, respectively. We've also previously reported safety and tolerability-related analyses. In particular, for patients who experienced stomatitis, we reported that measures to mitigate it were generally effective.

The median time to improvement from first onset to a lower grade of stomatitis for patients with Grade 2 or Grade 3 stomatitis who received the gedatolisib triplet was 12 and 14 days, respectively. Now to characterize the overall tolerability of the gedatolisib regimens, we reported results from patient-reported outcomes that capture a patient's perception of their overall well-being.

A particular note was the stability of the patient's assessment of their well-being relative to their well-being prior to starting treatment with gedatolisib. Over the first 8 cycles of treatment with gedatolisib, patients reported no degradation in their sense of well-being, which we believe provides meaningful evidence that patients treated with gedatolisib tolerated it well. Now let's talk about our VIKTORIA-2 study.

Results from the PIK3CA wild-type mutation cohort of our VIKTORIA-1 study demonstrated the benefit of gedatolisib combination treatment in the second-line setting of HR-positive/HER2-negative advanced breast cancer. And these results confirm the role the PAM pathway plays in patients with or without PIK3CA mutations and the importance of multi-target inhibition of this pathway.

Additionally, results from our Phase Ib clinical trial provided strong evidence that the PAM pathway is also an important disease driver in treatment-naive patients with advanced breast cancer. In the early phase study that we performed, we evaluated gedatolisib plus palbociclib and letrozole as first-line treatment in patients with endocrine-sensitive HR-positive/HER2-negative advanced breast cancer.

Median progression-free survival or PFS was 48.6 months, which compares favorably to historical data of approximately 25 months for ribociclib plus letrozole and the objective response rate was 79%, which again compares favorably to historical data of 53% for ribociclib plus letrozole.

In light of the positive results for the PIK3CA wild-type and mutant cohorts of VIKTORIA-1 and the promising preliminary data for gedatolisib triplet in first-line treatment, we have high confidence that we can successfully develop gedatolisib triplet for nearly all patients in the first-line setting, irrespective of their endocrine sensitivity or PIK3CA status.

Successful development in the first-line setting would offer the potential to advance the standard of care for the approximately 90,000 women each year who are diagnosed with late-stage HR-positive, HER2-negative advanced breast cancer in the United States. So to achieve this goal, we amended several important elements of the VIKTORIA-2 study design. First, VIKTORIA-2 will now evaluate the safety and efficacy of patients with endocrine-sensitive HR-positive, HER2-negative advanced breast cancer in addition to those with endocrine-resistant disease. which was the original study. Endocrine-sensitive patients represent approximately 2/3 or 60,000 of the 90,000 women in the U.S. newly diagnosed with advanced breast cancer each year.

Current standard of care therapies for these patients provide median PFS of approximately 25 months. And patients will be assigned manually according to their endocrine sensitivity status to either study 1 if they're endocrine resistant or Study 2 if they're endocrine-sensitive and subsequently be randomized to a treatment arm.

Each study will have independent statistical analysis plans that will include separate primary endpoints. Second, the primary efficacy analysis for both Study 1 and Study 2 of VIKTORIA-2 will evaluate the entire intent-to-treat population enrolled in their respective study. Primary endpoints for patient cohorts based on their PIK3CA status are no longer included. And this revision of the primary analysis allowed us to reduce the sample size for Study 1. The endocrine-resistant study from 638 patients to 440 patients without affecting the power of the analysis. And third, the control arms for Study 1 and Study 2 will evaluate ribociclib combined with either fulvestrant for Study 1 or letrozole for Study 2. Study 1 will enroll patients with treatment-naive endocrine-resistant advanced breast cancer.

And these are women whose breast cancer progressed while receiving or within 12 months of completing adjuvant endocrine therapy. It's a more aggressive disease. The trial will evaluate the efficacy and safety of gedatolisib combined with palbo and fulvestrant in Arm A and compare that to ribociclib combined with fulvestrant in Arm B.

We expect to have top line data by the end of 2028 for this study. Study 2 is expected to enroll approximately 740 subjects with treatment-naive endocrine-sensitive advanced breast cancer. And these are women whose cancer relapse or progressed 12 months or more after completion of adjuvant endocrine therapy or those with de novo metastatic disease who've had no prior endocrine therapy exposure.

The trial will evaluate the efficacy and safety of gedatolisib combined with palbociclib and letrozole and compare itself to ribociclib combined with letrozole. The clinical trial primary endpoints for the VIKTORIA-2 clinical trial are progression-free survival for RECIST 1.1 criteria as assessed by blinded independent central review. And we expect top line data for the Study 2 in the endocrine-sensitive patients to be available by 2030.

And prior to finalizing this amended Phase III trial design, we conducted a Type B meeting with the FDA to obtain their feedback and to gain alignment on these planned amendments. Now knowing that our life cycle plan would eventually include indications that may offer several years of progression-free survival benefit, we initiated a program to develop a subcutaneous formulation of gedatolisib that would enable a patient to receive gedatolisib as an injection as an alternative to an infusion.

And this program is ongoing with the goal of demonstrating clinical equivalence to the current intravenous formulation of gedatolisib. And this work has resulted in a submission to the United States Patent and Trademark Office of our first patent application for an injectable formulation of gedatolisib.

Now let's turn to our Phase Ib/II trial that's evaluating gedatolisib in combination with darolutamide in men with metastatic castration-resistant prostate cancer. We presented data for the Phase Ib portion of the study at a poster presentation at ESMO last year. And in this portion of the trial, 38 patients were randomly assigned to receive standard doses of darolutamide twice daily and either 120 milligrams of gedatolisib in Arm 1 or 180 milligrams of gedatolisib in Arm 2.

The combination of gedatolisib and darolutamide was generally well tolerated in the trial and mostly low-grade treatment-related adverse events. No dose-limiting toxicities were observed in either arm and no patients discontinued study treatment due to an adverse event. For all patients treated, the 6-month radiographic PFS rate was 67% and the median radiographic PFS was 9.1 months. And these results compare favorably to historical results of a 40% 6-month radiographic PFS rate for patients with metastatic castration-resistant prostate cancer who were treated with an androgen receptor inhibitor as second-line treatment.

Now enrollment of patients in the dose escalation portion of the trial is ongoing. We expect to provide a data update at an upcoming medical conference. Now as we near what we hope is an FDA approval for gedatolisib in 2026, our efforts to prepare for the potential launch of gedatolisib continue to ramp up for our strategic launch plan, and we began laying the groundwork for a potential gedatolisib launch over 24 months ago.

Last call, we mentioned that we had largely completed building the commercial organization, except for the sales force. I'm excited to report now that we have since hired and onboarded all of our oncology sales specialists. They are a very experienced crew. On average, these individuals have 24 years of experience selling pharmaceuticals and 16 years of experience in oncology. They're an incredibly talented group of individuals who have a strong track record of successfully launching novel oncology therapeutics.

Key efforts today include continuing our extensive outreach across the country to payers, strategic accounts, which include health systems, integrated delivery networks and community oncology practices. We're also very encouraged by the results of research we continue to field to gauge the willingness of community and academic oncologists to prescribe gedatolisib should it get approved.

And these results make us optimistic about the possibility of establishing gedatolisib as the new standard of care in the second-line setting for HR-positive/HER2-negative advanced breast cancer in the wild-type patient population.

Now with positive results from our study with patients whose tumors have PIK3CA mutations, we expect the gedatolisib combination regimens to be uniquely positioned to provide second-line therapy for patients regardless of the PIK3CA mutation status. Based on the analysis of published epidemiological data, we estimate there are 37,000 patients in the U.S. receiving second-line treatment for HR-positive/HER2-negative advanced breast cancer. And using internal duration of treatment estimates and pricing assumptions consistent with currently available novel therapeutics for breast cancer, we estimate the total addressable market for gedatolisib in the second-line setting is more than $5 billion annually.

Given the significant penetration our research is suggesting we can achieve, we believe it's reasonable to estimate that a second-line indication for gedatolisib can potentially generate peak revenue of up to $2.5 billion annually. And so the progress we've made today is encouraging, and we look forward to providing you with updates over the next few quarters. Gedatolisib is well positioned to address critical needs in the second-line space with its unique mechanism of action and potential first-in-class and best-in-class safety and efficacy profile.

And this gives us an exciting opportunity to advance potential blockbuster indications in breast cancer and prostate cancer, while also aggressively preparing for and potentially launching gedatolisib commercially should we receive FDA approval. And now I'd like to hand the call over to Vicky to review our finances.

Thank you, Brian, and good afternoon, everyone. I'll provide a brief overview of our financial results for the first quarter 2026.

Our first quarter net loss was $52.8 million or $0.97 per share compared to a net loss of $37 million or $0.86 per share for the first quarter of 2025. Our non-GAAP adjusted net loss was $46.8 million or $0.86 per share for the first quarter of 2026 compared to non-GAAP adjusted net loss of $34.7 million or $0.81 per share for the first quarter of 2025.

Research and development expenses were $33.1 million for the first quarter of 2026 compared to $29.8 million for the prior year period. The $3.3 million increase was primarily due to a $3 million increase in employee-related and consulting expenses. The remaining increase was primarily due to a $5.4 million increase in manufacturing and other costs, partially offset by a $5.1 million decrease in clinical trial costs, which was primarily driven by decreased costs for the VIKTORIA-1 Phase III clinical trial.

Selling, general and administrative expenses were $17.4 million for the first quarter of 2026 compared to $6.3 million for the prior year period. The $11.1 million increase was primarily due to an $8.7 million increase in employee-related and consulting expenses, of which $6.6 million was due to commercial headcount additions and other launch-related activities. The remaining $2.4 million increase was primarily due to software costs, professional fees and other administrative costs.

Net cash used in operating activities for the first quarter of 2026 was $55.1 million compared to $35.9 million for the prior year period. The additional cash in operating activities quarter-over-quarter of $19.2 million was primarily due to non-GAAP adjusted net loss of $12.1 million and working capital adjustments of $7.1 million. Cash, cash equivalents and short-term investments were $387.1 million at the end of first quarter 2026. We expect cash, cash equivalents and investments and drawdowns on our debt facility to finance our operations through 2027. I will now hand the call back to Jodi.

Thanks, Vicky. Before we turn the call to the operator for questions, I'll remind you, we will not be answering questions related to the VIKTORIA-1 mutant cohort data being presented at ASCO on June 2 or providing additional guidance on our expectations for data at this time. Matthew, could you please open the call for questions?

[Operator Instructions] And your first question comes from Maury Raycroft of Jefferies.

Congrats on the progress. Maybe starting off, just wondering if you can provide any perspective into the nature of questions and interactions with the [indiscernible] FDA that you're getting ahead of the PDUFA date? And have you submitted a draft label? And are you in labeling discussions at this point?

Yes, we're not going to provide that level of detail about the interactions other than to say that there's nothing about the interactions to date that suggests that we will be off track for the PDUFA decision by July 17.

Got it. Okay. And then I wanted to ask about the subcu formulation as well. Wondering if there's anything more you could say about what you're seeing with preclinical data in respect to comparability on PK/PD and dosing frequency.

And can you talk more about time line to move this version into the clinic and whether there could be any bridging efforts as it relates to the VIKTORIA-2 study?

Sure. So as far as the internal work, I mean, we're not going to be providing a play-by-play of the internal work. But I can speak to the time line and the steps. I mean, obviously, the first step is optimizing the formulation itself. And it's required and you work with multiple candidates to ensure you've optimized it.

Then you have to transfer that to manufacturing, scale it, ensure you have stability, et cetera. And ultimately, you end up with PK studies, Phase I to confirm the PK profile and map its equivalents to the IV formulation.

And then finally, we expect the FDA to probably require equivalent study, Phase III study. They've laid out some guidance on that front. And so the goal is to have a subcu form available basically along the same time line that we would expect to get an approval or hope to get an approval for the endocrine-sensitive population.

And your next question comes from Tara Bancroft of TD Cowen.

So my question is not about the mutant data, more about some educational historical background. So because in thinking about the range for alpelisib and fulvestrant in 5 to 7 months, can you just -- from your view of historical trials, some context around the bookends of that range from BYLieve Cohort C to then Cohort A and [ EPICB5 ] in terms of patient characteristics that you think most contributed to the difference there, just to help us understand.

Yes. I don't want to speak directly other than to say that there's always a certain amount of heterogeneity between trials and the patient populations that get enrolled.

And so any time you're looking at potential results for a particular therapy, we think it's best to look at the range and not get overly fixated on trying to calculate the probability. It's just not practically possible.

And so the data that's been reported is really the only, we think, data that can be assessed to understand what the performance of a drug like alpelisib can do.

And your next question comes from Andrew Berens of Leerink Partners.

On the progress, Brian. Looking forward to seeing the data at ASCO in Chicago.

My questions are about the subcu announcement today. We've been trying to think of an analog of a small molecule that was given IV and then was changed to subcutaneous. Most of them are antibiotics and there's not really a benefit going subcu there.

Is there one that you could point us to, to get an idea of kind of the process, the regulatory process? And then also, would you expect that the PK and the Cmax would change when you go from intravenous to subcu. And we've heard some speculation about the mucositis maybe being related to Cmax. I'm just wondering if you think that would come down with the subcu version?

Okay. So as far as -- thanks for the question. As far as the regulatory process, I think there's a general process that FDA requires to assess drugs that are injected in some form, whether it's injected or infused.

And we expect that our process or our program will follow those requirements. And I outlined those in one of the prior questions, essentially where you have to characterize the PK profile for a variety of reasons, but then also then characterize the equivalence from an efficacy standpoint.

To date, it appears that when you are introducing a new formulation that has a different route, even if it's still being systemically administered directly. You need to demonstrate clinical equivalence. And based on some recent guidance, it appears that the FDA's position is that if you demonstrate equivalence in one indication that, that data will then in that approval will allow that new formulation to be used for any other indications that may exist. And so we expect that to be the path forward for us, and we'll take it from there.

Okay. And then what about the PK and the Cmax? Any insights on how.

No, I mean, obviously, from a development standpoint, I mean, the perfect world is you match PK profile as closely as you can or at least you kind of focus on certain ranges. As far as speculating about the stomatitis effect like that, it's just too premature to get into that. It's certainly, we think, a function of the Cmax but -- and the fact that concentration settles in after a few hours at a much lower concentration and basically remains stable.

And we think that's one of the reasons why patients have reported the drug to be very well tolerated, not affecting their quality of life. And so certainly, there's ways of thinking about administering the drug or formulating it that would allow you to try to optimize that. And those are all -- will be elements of the development program that we'll be evaluating.

Okay. Well, congrats again on continuing to move the needle.

And your next question comes from Stephen Willey of Stifel.

Congrats on the announcement today. I know that we've seen frontline market share in the endocrine-sensitive setting kind of largely influenced by longer-term OS data. So just curious as you were thinking about the sizing of VIK-2 Study 2, kind of how this factored into the design and whether you might be able to provide just any preliminary powering assumptions on either OS or PFS?

Well, OS becomes in effect, the way to break the tie when you have 3 regimens that offer almost equivalent progression-free survival. And that was the case with the CDK4/6 drugs.

And ribo then subsequently demonstrated that it offered a survival benefit. But we'll be comparing ourselves to ribo. And if we offer a progression-free survival period that's superior to ribo. And we show that there's no decrement in overall survival that would, in effect, achieve the goal of demonstrating that there's a clinical benefit for these patients.

Certainly, for any study you do, you'd like to show that there's a survival advantage relative to what you're comparing to. But if we achieve PFS and show no decrement in OS, we'll essentially satisfied certainly the regulatory requirements, and we think we'll satisfy the clinical expectations for a drug.

Certainly, the drug has to offer a meaningful increase in incremental PFS. 3 months on top of 10 is different than 3 months on top of 25. So we're mindful of that and then design the study to reflect the expectations that you need more than 3 months to demonstrate a clinically meaningful benefit.

And your next question comes from Brad Canino's of Guggenheim Securities.

Great to see the strong progress on my end as well.

For the subcu, and sorry if I missed this on the call, I missed some of the prepared remarks. Is the formulation completed? And have you conducted animal models with it yet? Or is this still in process?

Well, I mean, again, we're not going to give play by play on each stage of the program other than to say that we have multiple candidates that we're advancing, and we're in the middle of doing a variety of both stability studies to confirm and to characterize the formulation itself as well as evaluating the other nonclinical parameters, including animal studies and work like that.

Okay. And maybe it would be helpful, are there any certain properties about GEDA that support its translation to a subcu formulation that could give investors confidence?

Well, other than we're confident we'll be able to develop it. Every drug has its own challenges when it comes to converting it to a more concentrated form. And I think part of the advance that we've made is that it requires invention and which is good because it's not an obvious approach, and it's one that we think will certainly enhance our intellectual property position significantly.

But as far as signaling how to interpret the likelihood that we'll be successful, I would say we're very confident.

And then just anything you can say about what you're seeing so far about predicted dose, not so much disclosure of the dose, but how that might shape the specific device that you can use for the patient and the administration time?

I think you're referring to the volume. The dose itself will be the same, and it's just a matter of translating that dose into a smaller volume, so it's injectable.

We have targets internally. We have functional requirements that we're targeting. And so far, we fully expect to meet the functional requirements that would allow it to be an injectable form.

And your next question comes from Oliver McCammon of LifeSci Capital.

Just thinking about the endocrine-sensitive study, I'm wondering if there are any learnings to take from the PALOMA trial experience in terms of being thoughtful about patient follow-up and powering for OS.

There's a lot of learnings from the PALOMA-2 and also from the MONALEESA-2 ribo study. And believe me, we've taken in the learnings from the ribo study more than the PALOMA study. So we think there's certainly a way to design the study in a way that maximizes your opportunity to potentially demonstrate an overall survival advantage.

And your next question comes from Eva Fortea of Wells Fargo.

Congrats on the progress. Do you have any updated thoughts on the competitive positioning for GEDA versus other PIK3 inhibitors in development? And how do you see this evolving with a subcutaneous formulation coming online?

Well, I think details to follow, but we did report that GEDA doublet just been a head-to-head a replacement for an existing PIK3CA approved drug was statistically significantly and clinically meaningfully differentiated from a single target inhibitor.

And ultimately, what we think we've been saying has been confirmed, which is that multi-target inhibition of this pathway is required to optimize antitumor control and that single target inhibitors are going to be limited.

If you look at the data for alpelpsib and capivasertib, you'd see that the hazard ratios that they have reported in patients who had prior CDK treatment are very similar, roughly 0.5 compared to fulvestrant.

And so we've demonstrated that we're superior to that. And what we think that means is that the approach will be at a disadvantage going forward just from a benefit standpoint, we will not be able to -- that approach, we do not believe offers the potential to provide comparable efficacy.

And your next question comes from Gil Blum of Needham & Company.

Congrats on the progress and the impressive results, Brian. So just a couple of quick ones from us. One, as it relates again to the potential for a subcu formulation, is there any chance that would change kind of the -- you currently have a very specific schedule of dosing. Were there could be any changes to that? Or how do you view this? And I have a follow-up.

Sure. Those are factors that go beyond simply the formulation because it gets to the overall PK profile of GEDA and what's required to sustain sufficient target engagement.

And so I think that question is broader than simply subcu. I think it relates more generally to how to administer or rather how frequently it needs to be administered. And so how we answer that question, if it's different over time, will be the byproduct of studies probably involving the infused form because we have that now and we can evaluate that. And then to the extent that we find ways to potentially alter the administration schedule, that would be applied if that were to happen to a potential subcutaneous formulation.

Yes. That makes sense. And just interesting to hear your thoughts of recent news from one of your competitors, [indiscernible] decided to move away from a PIK3 selective mutant to an alpha specific, if you have any thoughts on that?

Well, I think, again, there's only so much biological potential that targeting the alpha -- [indiscernible] gives you.

And I think that's less a function maybe of the targeting and more a function of increasing the potential patient population that they're hoping to treat. They had a more selective approach that essentially meant that they would have a smaller patient population.

And I would imagine they found some results that indicated they didn't need to be that specific. And alpelisib generally targets and their indications include the 12 or 13 most common mutations.

And there's been some evidence of variation in response to those patients depending on their mutations. But I'm not sure that, that is this positive in how you think about developing for that population. So they've got data, I'm sure that is guiding their decisions. And again, it is in the context of what we think is limited biological potential to reduce a treatment effect when you limit targeting to the alpha isoform.

And your next question comes from Kalpit Patel of Wolfe Research.

One from us, another one on the subcu formulation. Would you characterize GEDA's antitumor effect as being Cmax-driven or AUC driven? And how does that inform your confidence on the subcu formulation that it can achieve clinical equivalence to an IV?

Yes. Those are -- I mean, those are good questions. And I think every drug company tries to tease that out. There's been a lot of work that people have done to try to kind of determine whether a drug is more Cmax versus total volume, total exposure.

I think an argument could be made that it's both, you've got to benefit the high Cmax and [indiscernible] and then the sustained target engagement.

So again, your road map is going to factor in what we've seen to date. So that's the best approach to take and see how close you can match that curve, knowing that it won't be exact, but there are other ways you can affect that. And we're taking those other factors into account.

And your next question comes from Silvan Tuerkcan of Citizens.

Congrats on all the progress and looking forward to ASCO. Maybe if I can ask around ASCO, not about the data, but in general, it seems it's a very important venue for you, especially with the PDUFA in the wild-type patients ahead. What's your strategy there to interact with doctors? What sort of events do you have planned? And what is your messaging on the wild-type population here ahead of the approval?

Well, we'll have an army of folks at ASCO with -- that are mostly there to medical professionals to be able to engage with doctors and exchange information. But there's a lot of other work that can be done as well. Certainly, it's a big venue, a lot of doctors will have good opportunity to communicate the results.

But no, we view it as a great staging ground to lay the groundwork for what we hope is a future launch over the summer. And so no, we're very excited about the timing of ASCO and its alignment with the schedule we're on, we hope, to get an approval.

Great. And have you done already some payer feedback discussions and kind of around coverage? Do you have any comments around that?

We've had a lot of discussions. We built our payer team, which includes a team focused on strategic accounts and then a team focused on payers, national accounts. And we've been engaging in great depth and length with them for almost a year and been very, very encouraged by the feedback we've gotten.

Their formal review really doesn't take place until you have an approval and you submit a dossier. But along the way, you can certainly get their input about their expectations. You can learn about the system and exactly what their requirements are and ensure that when it comes time to make decisions that everybody on these various committees is well informed and feels comfortable with getting and from their perspective, the proposition that it offers to their patients and to the relative reimbursement expectations.

And so no, we've made a lot of -- we're, I would say, very, very well along in laying that groundwork and being in a great, great position once the approval comes to really move expeditiously with the various accounts I described.

And your next question comes from Chase Knickerbocker of Craig-Hallum.

Just wanted to maybe just assess kind of your current kind of commercial readiness. In the past couple of months, there's been a couple of early oncology approvals relative to PDUFA date. So Brian, I just want to get your thoughts on kind of where you think you sit from an innings perspective is kind of having your team ready for a potential launch in wild-type.

Sure. Again, all of the situations with some of these early approvals are, I would say, situationally based. There was an approval recently for a drug that had a regular review, and it came in a few weeks early.

We have a priority review for a new drug, 6-month review period. And historically, RTOR reviews of drugs with priority designation occur pretty much in line with the PDUFA date.

And that's been our governing assumption. Now internally, we've identified a launch ready date that's before PDUFA. So we make sure that we are ready to roll when we hope the approval decision comes.

And there are no further questions at this time. I'd now like to turn the call back over to Brian Sullivan, Chief Executive Officer and Co-Founder, for closing comments.

Great. Well, thank you very much for your participation in our call. We appreciate the questions, and we look forward to seeing some of you at ASCO. Take care. Goodbye.

Ladies and gentlemen, this concludes today's conference. We thank you for participating and ask that you please disconnect your lines.

Good afternoon, ladies and gentlemen, and welcome to the Celcuity Fourth Quarter and Full Year 2025 Financial Call. [Operator Instructions] I would now like to turn the conference over to [ Jodi Sivers ], Corporate communications and Investor Relations at Celcuity. Please go ahead.

Thank you, John, and good afternoon, everyone. Thank you for joining us to review Celcuity's Fourth Quarter and Full Year 2025 Financial Results and Business Update. .

Earlier today, Celcuity Inc. released financial results for the fourth quarter and full year ended December 31, 2025. The press release can be found on the Investors section of Celcuity's website. Joining me on the call today are Brian Sullivan, Celcuity's Chief Executive Officer and Co-Founder; Vicki Hahne, Chief Financial Officer; as well as Igor Gorbatchevsky, Chief Medical Officer; and Eldon Mayer, Chief Commercial Officer, who will be available during Q&A.

Before we begin, I would like to remind listeners that our comments today will include some forward-looking statements. These statements involve a number of risks and uncertainties, which are outlined in today's press release and in our reports and filings with the SEC. Actual events or results may differ materially from those projected in the forward-looking statements. Such forward-looking statements and their implications may involve known and unknown risks, uncertainties and other factors that may cause actual results or performance to differ materially from those projected.

On this call, we will also refer to non-GAAP financial measures. These non-GAAP measures are used by management to make strategic decisions, forecast future results and evaluate the company's current performance. Management believes the presentation of these non-GAAP financial measures is useful for investors' understanding and assessment of the company's ongoing core operations and prospects for the future. You can find the table reconciling the non-GAAP financial measures to GAAP financial measures in today's press release. And with that, I would like to turn the call over to Brian Sullivan, CEO of Celcuity. Please go ahead.

Thank you, Jody. Good afternoon, everyone, and thank you for joining our fourth quarter and full year 2025 Operating and Financial Update Conference Call. The past year has laid the groundwork for what we expect to be a transformative year for Celcuity as we prepare for the potential approval and commercialization of gedatolisib. In 2025, we made remarkable progress, achieving a number of clinical and regulatory milestones while also significantly bolstering our balance sheet.

These achievements and the groundbreaking data reported to date are foundational to our goal of establishing gedatolisib as a new standard of care therapy for patients with HR-positive PER2 negative advanced breast cancer. Among the key clinical and regulatory milestones achieved recently, include: first, the FDA accepted our new drug application, or NDA, granted it priority review with a Prescription Drug User Fee Act, or PDUFA, goal date of July 17, 2026.

The NDA was submitted under the FDA's real-time oncology review program, which is utilized for drugs offering substantial improvements over available therapies in light of the unprecedented efficacy data from the PIK3CA wild-type cohort of the Phase III VICTORIA-1 clinical trial. We're optimistic about the outcome of the FDA's review of our NDA. Second, these data were presented at a late-breaking oral presentation at the European Society for Medical Oncology and San Antonio Breast Cancer Symposium in December.

More recently, these data were published a few weeks ago in a peer-reviewed manuscript in the Journal of Clinical Oncology. And third, we completed enrollment of the PIK3CA mutant cohort of our Phase III VICTORIA-I trial late last year, reporting results from this cohort of this Phase III trial will be another incredibly important milestone for Celcuity. We expect to announce these results in our top line press release in the second quarter and to present full results at a medical conference in 2026, where we also intend to host an investor call.

Given how close we are to this disclosure, we will not be answering questions about trial progress or offering additional guidance on expectations for the results of the PIK3CA mutant cohort during the Q&A portion of our call. We've discussed previously the historic nature of the results from the PIK3CA wild-type cohort of the VICTORIA-1 trial and the new milestones they achieved in HR+ HER2-negative advanced breast cancer. And just to recap, median progression-free survival, or PFS, for the gedatolisb triplet, palbociclib and fulvestrant was 9.3 months compared to only 2 months for fulvestrant and hazard ratio was 0.24.

Overall, these results set several new benchmarks for clinical trials evaluating patients in this disease setting. First, the hazard ratio for the gedatolisb triplet is more favorable than has ever been reported by any Phase III trial for patients with HR-positive HER2-negative advanced breast cancer. And second, the 7.3 months incremental improvement in median PFS for the gedatolisb over fulvestrant is higher than has ever been reported by any Phase III trial for patients with HR-positive, HER2-negative advanced breast cancer, receiving at least their second line of a regimen, including an androgen therapy.

And third, gedatolisb is the first inhibitor targeting the PI3K-AKT-mTOR pathway to demonstrate positive Phase III results in patients with HER2-positive HER2-negative, PIK3CA wild-type advanced breast cancer, which disease progressed on or after treatment with a CDK4/6 inhibitor. And fourth, the 17.5 months of median duration of response and the 31% incremental increase in the objective response rate relative to control for the fulvestrant triplet or the gedatolisb triplet are the highest reported for an endocrine therapy-based regimen in second-line HR-positive, HER2-negative advanced breast cancer.

Additionally, the results demonstrated that the clinical benefit of the gedatolisb triplet was consistent across all patient subgroups. One patient subgroup of note, patients enrolled in the United States or Canada achieved median PFS of 19.3 months to gedatolisb triplet versus 2 months for fulvestrant, which resulted in a hazard ratio of 0.13. Further analysis that included patients enrolled in the U.S., Canada, Western Europe and Asia Pacific, representing nearly 60% of those enrolled found that median PFS was 16.6 months, with a gedatolisb triplet versus 1.9 months for fulvestrant, which resulted in a hazard ratio relative to fulvestrant of 0.14.

Safety results showed that gedatolisib triplet is generally well tolerated in the trial with mostly low-grade adverse events. Study treatment discontinuation due to treatment-related adverse events was reported to 2.3 of patients treated with gedatolisib triple. In December, we presented additional safety analysis in an oral presentation at the San Antonio Breast Cancer Symposium. For patients who experience stomatitis, we reported that measures to mitigate it were generally effective in median time to improvement from first onset to a lower grade of stomatitis for patients with Grade 2 or 3 stomatitis who received the gedatolisib triplet was 12 and 14 days, respectively.

We also reported that gedatolisb did not induce meaningful changes in patient glucose levels, unlike other approved drugs targeting PI3K alpha, Gedatolisb, did not induce clinically relevant hypoglycemia and required no dose reductions or withdrawals due to hypoglycemia. To characterize the tolerability of the gedatolisib regimens, we also reported results from patient-reported outcomes to capture a patient's perception of their overall well-being. And these measures include a patient's assessment of their mobility, ability to care for themselves, ability to conduct their usual activities, their pain or discomfort and anxiety depression.

The result of these assessments is then summarized as the patient's time to definitive deterioration and changes in well-being relative to the measures we reported prior to the patients starting treatment on the trial. For the gedatolisib triplet, the median time to definitive deterioration was 23.7 months versus 4 months of fulvestrant with a hazard ratio of 0.39.

Additionally, for the first 8 cycles of treatment, patient's assessment of their well-being remained stable relative to their assessment prior to starting treatment with gedatolisib. And based on these assessments, we believe this provides meaningful evidence that patients treated with gedatolisib tolerated it well.

And let's turn now to our VICTORIA-2 study, which is a Phase III clinical trial evaluating gedatolisib plus a CDK4/6 inhibitor, fulvestrant as first-line treatment for patients with HR+ HER2-negative advanced breast cancer or endocrine therapy resistant. We're wrapping up the safety run-in, and we expect to provide an update on our final Phase III study design in the second quarter. We believe the positive results from the PIK3CA wild type cohort of our VICTORIA-1 study augurs well for the potential efficacy of gedatolisib triplet may induce in this patient population.

Now let's turn now to our Phase Ib/II clinical trial that is evaluating gedatolisib in combination with darolutamide in androgen -- receptor inhibitor we're evaluating this in men with metastatic castration-resistant prostate cancer. We present a detailed data for the Phase Ib portion of the study at a poster presentation at ESMO. And in this portion of the Phase Ib/II study, 38 patients were randomly assigned to receive standard doses of darolutamide twice daily in either 120 milligrams of gedatolisib in Arm 1 or 180 milligrams of gedatolisib in Arm 2.

The 6-month radiographic PFS or rPFS raised was 67% and the median rPFS for patients was 9.1 months both arms combined. And these results compare favorably to historical results of a 40% 6-month rPFS survival rate for patients with metastatic, castration-resistant prostate cancer who were treated with an androgen receptor inhibitor of second-line treatment.

The combination of gedatolisib and darolutamide was generally well tolerated in the trial with mostly low-grade treatment-related adverse events. No dose-limiting toxicities were observed in either arm and no patients discontinued study treatment due to an adverse event. We're continuing to enroll patients in the dose escalation portion of the trial to evaluate higher doses of gedatolisib to determine the recommended Phase II dose.

Now as we near what we hope is an FDA approval for gedatolisib in 2026, our efforts to prepare for the potential launch of gedatolisib continue to ramp up for our strategic launch plan. we began laying the groundwork for a potential gedatolisib launch nearly 2 years ago. And we've since largely completed building the organization, including our sales force and internal systems required to operate as a commercial stage company.

We're very fortunate to have attracted an incredibly talented group of individuals with strong track records of successfully launching novel oncology therapeutics. Key efforts today include extensive outreach across the country to payers strategic accounts and population health decision-makers in various treatment settings, including health systems, integrated delivery networks and community oncology practices. Each of these groups are expected to play a key role in providing oncologists access to gedatolisib for their patients.

We've made strong progress engaging with these decision makers, and we're very pleased with the feedback and the enthusiastic response. These efforts have yielded. We're also very encouraged by the results of research we fielded to gauge the willingness of community and academic oncologists to prescribe gedatolisib should it get approved. And these results make us optimistic about the possibility of establishing a gedatolisib as the new standard of care in the second-line setting for HR-positive HER2-negative advanced breast cancer in the wild type patient population.

In February, we report positive results from our study with patients whose tumors have PIK3CA mutations. The gedatolisib triplet will be uniquely positioned to provide second-line therapy for patients regardless of the PIK3CA mutation status. Based on analysis of published epidemiological data, we estimate there are approximately 37,000 patients in the U.S. with HR-positive HER2-negative advanced breast cancer. We've progressed after treatment as a CDK4/6 inhibitor and using internal duration of treatment estimates and pricing assumptions consistent with currently available novel therapeutic for breast cancer, we estimate the total addressable market for gedatolisib in the second-line setting is more than $5 billion.

And given the significant penetration, our research is suggesting we can achieve, we believe it is reasonable to estimate that a second-line indication for gedatolisib can potentially generate peak revenue of up to $2.5 billion annually. We're excited about the opportunity now that we're approaching potential launch to advance multiple potential blockbuster indications over the years in breast and prostate cancer, while also aggressively preparing for potentially launch of gedatolisib commercially, should we receive an FDA approval.

Gedatolisib is well positioned to address critical needs in the second-line space with its unique mechanism of action and potential first-in-class and best-in-class safety and efficacy profile. I'd like now to hand the call over to Vicky to review our finances. Well, Vicki is having trouble connecting. I can review the remarks that she was prepared to give. Operator, she no longer on the line.

Yes. She's reconnecting right now.

Well, why don't I continue?

Brian, I apologize, I think I'm back on.

Okay.

Well, good afternoon, everyone. I will provide a brief overview of our financial results for the fourth quarter and full year 2025. Our fourth quarter net loss was $51 million or $0.97 per share compared to $36.7 million net loss or $0.85 per share for the fourth quarter of 2024. Net loss for the full year was $177 million or $3.79 per share compared to $111.8 million or $2.83 per share compared to the same period in 2024.

Our non-GAAP adjusted net loss was $38.4 million or $0.73 per share for the fourth quarter of 2025 compared to non-GAAP adjusted net loss of $32.3 million or $0.75 per share for the fourth quarter of 2024. Non-GAAP adjusted net loss for the full year of 2025 was $150.8 million, or $3.22 per share compared to non-GAAP adjusted net loss of $101.9 million or $2.58 per share for 2024. Research and development expenses were $37.6 million compared to $33.5 million for the prior year period. Of the $4.1 million increase in R&D expenses, $8.6 million was related to increased employee and consulting expenses, of which $5.3 million related to commercial headcount additions and other launch-related activities. These amounts were partially offset by a $4.5 million decrease primarily related to costs supporting ongoing activities for the VICTORIA-1 Phase III trial.

R&D expenses for the full year 2025 were $145 million compared to $104.2 million for the prior year. Of the approximately $40.8 million increase in R&D expenses, $26.7 million was related to increased employee and consulting expenses, of which $13.1 million related to commercial headcount additions and other launch-related activities. The remaining $14.1 million increase was primarily related to activities supporting our ongoing clinical trials, a development milestone payment under the license agreement with Pfizer and other commercial launch-related activities.

General and administrative expenses were $11.6 million for the fourth quarter of 2025 compared to $3 million for the prior year period. Of the approximately $8.6 million increase in G&A expenses, $6.9 million was related to increased employee and consulting expenses, of which $5.4 million related to noncash stock-based compensation. The remaining $1.7 million increase was primarily related to professional fees, expanding infrastructure costs and other administrative expenses.

G&A expenses for the full year 2025 were $27.2 million compared to $9.1 million for the prior year. Of the $18.1 million increase in G&A expenses, $14.9 million was related to increased employee-related and consulting expenses of which $10.4 million related to noncash stock-based compensation. The remaining $3.2 million increase was primarily related to professional fees, expanding infrastructure costs and other administrative expenses.

Net cash used in operating activities for the fourth quarter of 2025 was $36.4 million compared to $27.8 million for the fourth quarter of 2024. Net cash used in operating activities for the full year 2025 was $153.3 million compared to $83.5 million for the full year 2024. Cash, cash equivalents and short-term investments were $441.5 million at the end of fiscal year 2025 and are expected to finance our operations through 2027.

I will now hand the call back to Jody.

Thanks, Vicki. Before we turn the call over to the operator for questions, I'll remind you, we will not be answering questions related to the progress or status of the mutant cohort of the VICTORIA-1 study or providing any additional guidance on our expectations for data at this time. John, could you please open the call for questions? .

[Operator Instructions] Our first question comes from the line of Maury Raycroft from Jefferies.

Congrats on the progress. Not sure if this fits within your criteria or not for a status update. But wondering if for the immune data, if you could say if the database lock is already in place, that's something you can comment on?

No, I can't comment on that.

Okay. Understood. And I know you've already commented on this in the past too, but if you could just recap how the disclosure is going to take place and what exactly you'll share in the readout?

Well, as I indicated, we'll provide top line data in a press release, and then we will provide details at an upcoming medical conference.

Got it. Okay. And then when thinking about when we could see more details at a medical conference, can you say if that's going to be like relatively soon? Or is it more likely going to be a second half update?

I think you'll just have to wait and see, Maurice more. Sorry, I can't provide any more details. .

Understood. Okay. Those were the questions.

Your next question comes from the line of Tara Bancroft from TD Cowen.

So I guess I'll shift to maybe a question on the launch. I was hoping maybe you could give us some feedback of what you're hearing from physicians on which segments may be treated immediately upon the wild-type approval and which ones may be more gradual? Just to get an idea of how you're planning ahead for Cadence once you receive approval?

So as we launch, we aren't going to be targeting or narrow casting our approach to doctors or patient segments. We believe gedatolisib regiments offer an opportunity to get the best option relative to what's available today. And so we would expect our sales force upon approval, assuming that occurs to retail generally to doctors and essentially help them understand how gedatolisib and the data can offer, again, what we believe is an improvement in the alternatives that are currently available. .

Okay. Great. And I guess in that feedback that you are hearing in these discussions with physicians, do you do you think or have any inkling whether they would be willing to potentially use it off-label and mutants ahead of a potential mutant approval if the data are positive?

Yes. That's just not something that we have any conversations with doctors about .

[Operator Instructions] Your next question comes from the line of Stephen Willey from Stifel.

Sorry to badger you, Brian, on the top line release of the data. But just curious if that will include any details just with respect to headline PFS numbers and risk reduction? Or will this just simply be a statement regarding the achievement of stat sig?

It will be the latter. I mean, we're mindful of embargo requirements to -- that we need to adhere to in order to be in a position to have podium presentation at one of these medical conferences. .

Okay. And then maybe just a question on prostate and then maybe just a quick one on on the second-line breast opportunity that you spoke to. So in prostate, just curious how high you think you can push dose kind of north of the 180 mg that is used in the VICTORIA trial. And then just curious, what metrics -- I mean obviously, there's a balance of safety and tolerability you need to consider in terms of nominating a recommended Phase II dose. But are there any efficacy metrics that you're going to be prioritizing? I know you've shown us the radiographic PFS data, but just curious how things like PSA response maybe even a [indiscernible] response for those patients with measurable lesions, how that kind of factors into [ dose denomination ].

Sure. Well, just to recap relative to what we announced previously, we were pleasantly surprised by the safety profile of the 180-milligram dose reported. No dose-limiting toxicities very limited Grade 3 adverse events. Hypoglycemia was consistent with our breast cancer. Stomatitis was significantly less frequent at that dose in these men. And so that's what led us to decide to increase the dose or rather to evaluate higher doses. And essentially, we're using some standard methodology to stepwise increase the dose and basically depending on achievement or levels of dose-limiting toxicities we'll keep going.

But we're in the midst of that, so I can't really comment on where we'll end up. But again, it's always a balance. We can't sacrifice tolerability to such an extent that it self-defeating. But to the extent that we believe there's a dose response that would lead to improved response at higher doses, we want to explore where that might take us. And so we would expect to have some look at that data by the end of this year or sometime early next year.

Okay. That's helpful. And then maybe just lastly, with respect to breast, I appreciate some of the color around kind of peak revenue opportunity here in the second line setting. I think you mentioned just kind of using historical pricing and duration of therapy. Obviously, the pricing is kind of readily available. But what's the duration of therapy estimate that you're using to inform the peak numbers that you mentioned?

If you just use a round number that of 10 months, and again, that's not a projection, that's just an assumption to drive an estimate. You would be consistent with how we're modeling the market.

Our next question comes from the line of Josh Bowen from Guggenheim.

This is Josh on for Brad. Just wanted to know, with most of the commercial build complete for second line, what is the key gating factor in getting the front-line endocrine-sensitive trial up and running.

Key gating factor is just completing the safety run and just to look back a little bit, we were evaluating, geda in combination with ravaciclib as a potential CDK4/6 option for doctors to use in the treatment arm. And because we haven't evaluated with geda with revaciclib before, we needed to evaluate it in a sufficient number of patients to make a decision about dosing and how to move forward. And so that's wrapping up. And based on those results, that we'll update study design accordingly, and we expect to kind of provide an update on the study design in the second quarter and proceed a pace to begin enrolling the Phase III study.

Our next question comes from the line of Gil Blum from Needham & Company.

I'll try to keep this brief. So a commercial question that we've gotten a couple of times is surrounding potential challenges in getting patients to come in for infusions. Can you discuss a bit how you plan to avoid these kind of challenges? Or are they actually challenges?

No, thanks for the question. We heard this question from investors. We do -- we've done a number of rounds of market research where we not only engage with doctors on a qualitative basis where we're able to have conversations and have it back and forth, but also quantitative setting where it's noninteractive and doctors are essentially going stepwise through information prompts that we provide. And they both allow us to gauge probably interpret the data, how they think about that data relative to other regimens are currently available. What factors they like, dislike how strong a factor that is on a neutral on different factors.

And 1 thing that's very clear when we reviewed the results of that research is that, a, the efficacy is clearly the most important factor for them as they're evaluating the regimen; and b, the IV administration, it shows up as a negative factor and meaningfully less than 10% of the responses we have in this research.

Secondly, we also do research with patients. And again, that's primarily qualitative. And again, except in cases where we believe there's a geographic limitation for a patient simply clinics too far, or if there are some other considerations in their mobility, we do not expect that there will be significant patient pushback on the IV. I mean we have some interesting anecdotes from these conversations that suggest that women take very seriously their obligation for their family to do everything they can to maximize the time that they can be with their family and to use what they believe are the best drugs that they may have an option to take.

So we think all in, it just reinforces what we believe, which is in certainly a terminal disease like metastatic breast cancer, the most important criteria that's going to guide selection of therapy by both the physician and then the preference for the patient is going to be related to the efficacy that the regimen can induce. And then also to how well tolerated the regimen is and the feedback we've received again is very positive on that front as well. And so finally, as it relates to the administration route, again, we think that's going to be an [indiscernible] issue for only a small number of patients for the reason I mentioned. And we don't believe that is going to restrict preference for physicians to prescribe the therapy.

And maybe as a follow-up, can you help us understand the commercial advantages of having get a label across metastatic breast cancer subtypes.

Sure. Well, has anybody that's followed this space, no one word that gets used to describe the landscape is it's very complex, a lot of activity. And so what we hope to be able to provide and the way we expect to position the drug is that we can simplify the decision-making process for these physicians by giving them an option that we believe for any patient subgroup that they may be treating the best potential risk benefit relative to the alternatives. .

Now it doesn't mean there aren't available options that some doctors may select or prefer in certain patient segments. But we think, overall, we'll be in a very strong position by being able to offer essentially a biomarker-agnostic alternative that doesn't require them to evaluate some complex decision-making around biomarker subgroups. Anything ultimately that hitting the easy button isn't to diminish the importance of the decision for the doctors. But particularly in the community setting, the challenges of keeping up with the alternatives can make it difficult for them to make the right decisions in some cases.

And so to the extent we can leverage the data that we have now, and we hope to have with the mutant setting, we think that will be a very significant advantage.

Our next question comes from the line of Oliver McCammon from LifeSci Capital.

So switching gears a little bit. We're roughly 1.5 years into the launch of enavalisib for the PIK3Ca mutant endocrine therapy resistant setting. I'm curious if there are any learnings from the launch, the label and/or KOL feedback that you think are supportive of the positioning of geda in the VICTORIA-2 trial?

So they reported very good data. And unfortunately, though, the patient population that really is appropriate to treat with that drug is fairly limited. The study only enrolled patients who essentially were metabolically healthy, patients who had an [indiscernible] level below 6 and essentially ruling out patients that were either prediabetic or diabetic type 2 diabetes. .

And there has since been several [ dear doctor ] letters for very significant adverse events that have been reported and the label requires fairly extensive glucose monitoring, both by the physician as well as the patient while they're at home. And so overall, just based on our assessment of the claims data. it appears those restrictions are having an impact on the usage in the clinic to date. So from a learning standpoint, for us, I mean, essentially, highlights just how unique a drug geda is, a, we're addressing this pathway. But more importantly or rather very importantly, we're not inducing the levels of system disruption that can lead to hypoglycemia that requires significant management or any management at all, actually. And we do not believe that patients who have -- were prediabetic or type 2 diabetes will be restricted in their ability to receive treatment with gedatolisib.

And so it really goes back to the drug and the overall safety profile. And when you don't have a safety profile like geda when you hit this pathway, you run challenges and really being to able to treat a broad group of patients or to treat patients in a way that does create some potentially significant adverse event risk.

Very helpful. And just one sort of.

Very helpful. And just one sort of frontline follow-up. Given the Percepta results we saw recently, your prior Phase Ib data that you've shared in frontline patients, as well as the number of oral PI3K inhibitors looking at the frontline setting, I'm curious what your level of interest is in a frontline endocrine-sensitive study.

Well, it would be very logical given the very favorable data that we've reported in that setting in our Phase Ib study. And just as a reminder to folks, in that study, sample size of 41, we reported median PFS of over 48 months and an effective response rate of 79% with gedatolisib combined with palbociclib in that result. So those those really compare very favorably to what's been published to date for currently approved therapies. So I think there's a very strong case to be made for us in conducting a study in that space. And we will keep people posted on our thinking.

Our next question comes from the line of Eva Verdejo from Wells Fargo.

A quick 1 from us. Do you have any updated thoughts on the European commercial strategy for gedatolisib in terms of like timing for a potential update or approach to partnering? Or how do you expect EU to sequence versus the U.S?

So our current plan, if our grand plan comes to fruition is that if we have as we hope and expect a positive readout in our mutant cohort, we would then follow up with a supplemental NDA, assuming we get the initial approval for gedatolisib. And then once that NDA is complete -- the sNDA package is completed, we would then utilize the documents and essentially most of the documentation will translate, but essentially use the information from both the wild-type and mutant data sets and the NDA modules overall to create an [ MAA ] submission in the fourth quarter this year. That's roughly a 3-month process to potentially get it accelerated, but 13 months with a regular review.

And so in the meantime, after we submit, that would be the window of time that we would use to explore finding partners to collaborate with launching not only in Europe but potentially globally. Simultaneously, we've also been engaging with the regulators in Japan to identify the regulatory path forward for submission in Japan. We think we've got gained alignment so far on that front. And so even though we haven't identified a partner at this time, we are not -- we're proceeding at pace with regulatory activities in the most significant markets, which would include the major 5 European countries as well as Japan. And so we will in this window have ample time to find the right partner without delaying at all our ability to have get a launch in those markets.

Our next question comes from the line of Kalpit Patel from Wolfe Research.

one from us on the mutant update, do you need to hit both the doublet and triplet arms to file later in the year? Or can you file on a successful hit on triplet alone?

Well, without getting into any more detail, I'll just limit it to the study design. The study design primary endpoint is a comparison of the triplet to Alpelisib. And so that is the primary endpoint and that would form the basis for any potential regulatory submission .

The analysis comparing the doublet to alpelisib is an exploratory analysis or secondary analysis .

Our next question comes from the line of Chase Knickerbocker from Craig-Hallum.

We'll be curious what you and your market access team have heard in your early prelaunch discussions with payers on a number of items around the profile of geda in wild type. Maybe kind of foremost amongst them, how that's solidified or altered any of your thoughts around potential pricing?

I guess, just the overall reception to the information that we've shared with payers and strategic accounts, which you're able to do on a safe harbor basis health care providers has been very, very positive. I think it's interesting to get the feedback they provide. They're in the business of helping ensure the individuals who they are ensuring have access to therapies are ultimately responsible for treating and have access to the right therapies.

And so we've been very pleased with how they've reacted to the data, and they're collaboration to how I would say it and working with us to lay the groundwork to ensure that as early as practically possible, get a rather patients would have access to this -- to this drug and the resident.

Maybe just as a follow-up around the competitive environment, we saw recently another acquisition of a mutant selective PI3K alpha inhibitor. Can you just refresh us on your thoughts on potential future competition for you from that angle? And then just kind of generally on kind of the next-generation assets coming up in competition here?

sure, Thank you. Again, I think there's been -- since alpelisib received its approval, I guess, 7 years ago, there have been a number of companies that have sought to potentially provide an alternative that would be safer than alpelisib. And that's a worthy project. But the underlying biological assumption that's really driving those projects, we think is not necessarily current.

[indiscernible] and the approach we've taken of inhibiting all Class 1 [indiscernible] isoforms as well as Mtor 1 and 2 is the approach that's required to optimize anti-tumor control to provide maximum antitumor control. And so we just think there's a biological limit on the benefit that a single target inhibitor like a PI3K inhibitor can induce. And having more, as we've seen with SERDs, doesn't necessarily yield different results. I think 5 Phase III reports later. I think we've seen very, very similar results.

Now in this case, with this in this setting, I think it's reasonable to expect that based on the way these drugs are distinguishing their targeting between the mutant form of PI3K alpha and the wild-type form, they can improve upon safety profile relative to alplisib, but I think that seems pretty reasonable. But ultimately, I think there's going to be limited biological potential to induce an optimal outcome for efficacy. And I think the results today for geda certainly, we think, demonstrate the value and importance of providing comprehensive inhibition of this pathway as opposed to selective inhibition of this pathway. So as far as impacting us, we actually -- we think, again, that targeting approach will be obsolete. If the data we hope to report out soon is what we hope and expect.

There are no further questions at this time. I will now turn the call over to Brian Sullivan, Celcuity's Chief Executive Officer, for closing remarks. Sir, please go ahead.

Well, thank you for participating in our call today for your ongoing support and look forward to reporting back to you soon. Take care. .

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.

All right. Good afternoon, everyone. I'm Andy Berens, senior biotech analyst at Leerink Partners. Thank you for joining us on day 2 of our Annual Miami Healthcare Conference. We're very excited to have with us Brian Sullivan, CEO of Celcuity. Thank you for joining us.

Your welcome, Pleasure.

You've got a lot going on, Brian. Thank you for making time for us.

We do, no, this is what I need to do.

For those that don't know Celcuity, can you give an overview of the company?

Sure. Well, I started the company a while ago now to initially develop a platform with our Chief Science Officer, to isolate the activity and quantify the activity of live patient tumor cells so that we can help identify patients who might be responsive to particular targeted therapies.

We began working the PI3K space and identified what we felt was a fantastic drug, gedatolisib, pan-PI3K/mTOR inhibitor and began developing that drug in '21. Now we have essentially completed 1 Phase III study. We have another 1 we will report out soon in the second-line setting in breast cancer. We also have a first-line study in process. I'm sure we'll talk about that as well in breast cancer. And then we have an early phase study in process in prostate cancer.

Okay. Great. Well, you guys entered a very dynamic space with a lot of moving parts. And since you started your program, a lot has transpired and lot of pieces have fallen into place, others have fallen out of place. How would you say HR-positive breast cancer looks today, first-line, second-line adjuvant? What are you forsee? What's different, I guess, today than it was when you started your program?

Well, I think the most important data set to be reported to be frank is ours because we've validated the importance role this pathway plays, independent irregardless of whether there's a PIK3CA mutation. Our early phase data demonstrated the important role this pathway plays in patients who are treatment-naive, who've never received treatment in the late-line setting.

And so I think if I look at the landscape going forward, I think essentially, GEDA will change it. And we hope to have studies that would demonstrate the activity of GEDA in the frontline setting for women who have endocrine-sensitive disease as well as endocrine-resistant disease. We've already shown essentially unprecedented levels of efficacy in the second-line setting in patients who lack mutations. And we hope to kind of close the loop with our data set in the next few months when we report out our mutant setting.

I think all the other studies have essentially been trying to optimize existing targets. I think the PAM pathway has really been kind of very, very suboptimally targeted to date, and really have only shown modest efficacy in a subset of patients. And we think our drug has the promise of offering optimal tumor -- antitumor control, irrespective and in both front and -- frontline and second-line settings.

Okay. There certainly seems to be something, I'm going to use the word magical for lack of another term, but when you hit the PAM pathway with both a PI3K drug as well as an mTOR inhibitor versus what you would see with individual, would you agree? I mean, what is causing the better efficacy?

So 1 of the key features -- the 2 key features of this pathway. One is it plays a critical role in regulating glycolic system in a tumor cell, which essentially means it's regulating the uptake of glucose which is the energy source or primary energy source for tumor cells. They're particularly dependent on glucose that consume 100x more of glucose in a healthy cell.

And so it's a very relevant pathway. And that's why GEDA has shown its ability to work independent of the mutation. But because it's so important, it seems to have built in these redundancy mechanisms. And so you have multiple targets that are required to be addressed to control it to comprehensively shut it down, the 4 Class 1 isoforms of PI3K, mTORC1 and 2.

And that unless you control all of those or inhibit all those targets and shut down this pathway, essentially this pathway can continue to function. Now drugs that hit a single target have shown activity when the tumor has a mutation. But absent that, they really haven't shown as meaningful activity. And so that's been the riddle, how can you essentially address this pathway in light of its complexity and also because of some of the safety challenges associated with this pathway because it does regulate such important physiological activities, depending how you hit it, how often you hit the concentration required to address it. It can induce unacceptable levels of toxicity.

Right. Okay. And then obviously, there's been a lot of attempts for people to improve upon fulvestrant, and that's falling short. We just had the announcement yesterday that another oral SERD was disappointing in the front line this time which I think for you guys, I think it's a double-edged sword in some ways. I think it was good in that it gives some stability to the front line. We have the same stability, I guess, in the second line, meaning the fulvestrant is not going anywhere. It doesn't look like AIs going anywhere, at least in the near term. So I guess how do you view kind of the news about another oral SERD?

Well, look, you never root against another drug, right? To the extent that there's an opportunity to improve outcomes for patients, you want that to work. But the fact it didn't work certainly creates clarity around how to think about improving the outcomes for those patients because you know what the components of a regimen would be, what the components of the control would be.

And that makes it very straightforward to take the next step. And again, if you think of breast cancer 3 pathways, you need to close that circuit. And we think GEDA is the only drug under development that we think can effectively close that circuit and create, we hope, based on our early Phase III results, we think we have a very good chance to do that and create a very meaningful treatment benefit in the frontline setting.

Okay. Can you talk a little bit -- look, let's go through the data you showed in the second line, and in the wild types and then the trial that's about to read out in mutants.

Sure. And so we reported out 2 primary endpoints. We reported out data for GEDA plus palbociclib and fulvestrant compared that to fulvestrant, reported 9.3 months median PFS compared to 2. So a 7.3 month delta. That was the biggest delta ever really reported with an endocrine therapy before in the second-line setting. The hazard ratio 0.24 was the most favorable hazard ratio is ever been reported in breast cancer. So it was really unprecedented level of efficacy.

And that again, just reflects the importance of the target and how well GEDA does in mitigate or inhibiting that activity. We also saw a very significant activity for GEDA combined with fulvestrant, so a doublet versus fulvestrant.

Again, absent the triplet, it would have been the best results reported in the second-line setting. So we think that help validate our hypothesis that it's important to control this pathway comprehensively. And then if you do, it can induce a very, very significant benefit, again, irrespective of the mutational status of PIK3CA.

Okay. And then the data that are coming in the mutant population?

So we haven't -- we expect to report that data end of this quarter, sometime next quarter. We've reported early phase data that is quite promising. Reported in a cohort of patients in a Phase Ib study, about 14.5 months median PFS.

And so that would be a great result if we reported that. But to be stat sig in this study, based on the results that have been reported to date for our control, which is alpelisib and fulvestrant. 10 months would be stat sig. And it would also be clinically relevant because the true standard of care today in the mutant -- the patients with PIK3CA mutations is capivasertib and fulvestrant. And in the setting that we in, that drug reported about 5.5 months median PFS. And so even if we just squeak over the line with the stat sig study, we've been nearly double with that drug has been able to offer patients. And so we think it would be very clinically meaningful, given our early phase data, certainly, we think the odds of being positive are high. And we think they're also high of hopefully doing better than that, but we'll see.

Right. Now over 9 though, in the wild types and now you're adding in a tumor that should get an added benefit. So you would think that, that -- plus the data that you've shown. And then I think if I recall in that Ib reanalysis, there was actually a smaller group that actually did even better that was similar to which the way you're seeing it now.

Right. No, I just want to manage expectations. That was great data. It was 19 months median PFS in patients that have mutation. Small sample size, so you have to really caveat that. But I think what it just shows is, GEDA -- all the results we've reported today for GEDA, either the early phase or a later phase setting have shown very, very good results. And again, just demonstrates the relevance of the pathway and capability of GEDA.

Now I mean, obviously, large pharma has spent a tremendous amount of effort to broaden the oral SERDs as broad as they can get them, and they've run into some difficulty beating fulvestrant in the second line, except for an ESR1-mutant patients. And now we haven't seen the data yet, but as I said there was a numerical but not statistical trend in the frontline beating AI. So would it be possible hypothetically to run the trial with GEDA plus an oral SERD and use that to beat fulvestrant or AI?

It would be challenging because you have 2 changes to the study arm. So you would need to control for both. And especially if 1 drug has already failed the comparison and not shown to be active statistically in meaningful way, it would make the trial design very complicated.

Okay. So you have to run like a 3-arm trial?

Right.

I see, but you've done a 3-arm trial?

Yes. Once you've done it once, you want to avoid it if you can.

We've done 2 of them.

Right again. But if you can avoid it, you want to avoid it.

Okay. Let's talk about the front line.

Sure. So we have a Phase III in patients who are HR-positive, treatment-naive, but are considered to be endocrine resistant. And these are patients who didn't really get much benefit from their adjuvant endocrine therapy, essentially at early breast cancer and the disease recurred either while they were receiving a tamoxifen or within 12 months after. So it's a tough group of patients, unfortunately. Current standard of care for the most part that they get only gives them about 7 months median PFS. So in some ways, it feels a little bit like a second-line study in terms of the outcome that they're currently getting.

And that population is comparable in size of the second-line population we're treating. It represents about 1/3 of all women who are treatment-naive. And we've been doing a safety run and to evaluate GEDA with ribo, ribociclib, and we expect to report out the results of that and then any updates to the study design in the near term.

And what would be -- so one of the advantages of that subgroup is that it wouldn't be like a 4 or 5-year.

Right. No, exactly. And that's why we prioritize that, a, biggest unmet need and in turn, that also typically corresponds to a relatively short trial, whereas the endocrine-sensitive population, which is roughly 60,000 women who are either well beyond their time of treatment with an adjuvant endocrine therapy or de novo metastatic. They weren't diagnosed with early breast cancer. They just present with metastatic disease.

The women treated with current standard of care CDK4/6 plus letrozole get about 25 months. So that's a longer study, right? Your control -- that's your control and then your study arm and hopefully, in our case, be a lot longer than that. But it's an important opportunity, we think, to help these women just stave off progression as long as possible. And earlier, you can do that, we think ultimately, it's better for patients.

And the Ib trial that you cited that had 4 arms. What did you see in the naive that...

So actually, these were really good results. We reported 48 months median PFS, 79% objective response rate. So very, very favorable and encouraging. And that's why we think, ultimately, it will make sense for us to launch a study in that setting.

Okay. What's the gating factor for that now?

Just we have a lot of stuff going on, and we're getting ready to launch a drug. We expect to get an approval decision, PDUFA date is mid-July. And so we're sorting through things, and we'll keep people updated.

Alright. What preparations have you made? How big a sales force do you need?

So we've largely completed the build-out of the organization, except for the sales force. So essentially, you need market access several teams in market access and marketing team, customer operation -- or rather commercial operations team, medical affairs. So all those teams are built, the sales -- head of sales, regional team, regional management team is built.

And we'll bring on the sales force beginning in the second quarter. There are a lot of infrastructure systems and process-wise that need to be built, other organizations, other suborganizations within different departments also need to be created, essentially to handle the requirements of being a commercial organization. And so that's well on its way. So we're kind of close to being ready to go and targeting, hopefully, an approval date mid-July.

And what size sales force do you think you need?

So we haven't disclosed that yet, but if you were to benchmark other companies that have drugs in the breast cancer space, you'd see they typically have around 90. So it's a very manageable side -- manageable sales force in terms of how to reach the docs.

Okay. And the fact that it's intravenous would mean you can target a smaller group of...

Well, no. I mean, actually, pretty much every practice because, for instance, breast cancer, the largest drugs, most significant drugs are all IV. So every doc that treats breast cancer patients has to have a connection to an infusion center, just because a good chunk of their patients will be on infused -- will need infused drugs. And as it turns out, that's an important component of, particularly in the community setting, an important part of their practice.

So they're well organized and they have the infrastructure to do that. And to be frank, economically, it helps support their practice as well. From a market access standpoint, medical infused drugs are considered to be medical benefit, tends to get less challenging reimbursement pathway than oral drugs. So there are a lot of factors that are to the good for us by having an IV drug. And we think, ultimately, that will actually be a favorable factor for our launch.

Okay. And the feedback, I mean, as you've been doing your commercial assessments has been strong for the IV?

It has. I mean, you do a lot of different testing of messages, of appeal. We present data -- you do a lot of quantitative research, essentially without any prompt just essentially giving information to docs and allowing them to evaluate the data and draw some conclusions from it.

And all of that research has been very favorable in terms of what at least we're seeing for preference for use of GEDA versus the current alternatives and the low impact, we think, having the drug administered as an IV will have on that preference.

Okay. Do you want to talk about the prostate program?

Sure. So it's interesting. The biology -- underlying biology of prostate cancer is some parallels to breast cancer, both are hormonally driven tumors. HR positive breast cancer is. And then these hormone pathways in prostate cancer, the androgen receptor pathway has been shown nonclinically and clinically to interact with the PAM pathway.

So in a way that essentially could be considered similar to what you see with breast cancer. And so we have a study that's evaluating GEDA combined with very good androgen receptor inhibitor called darolutamide in men whose disease has progressed after they've received frontline or, a, androgen receptor inhibitor.

And so we hope to show that we can improve the outcomes for these patients, these men. Early results for 2 different doses were favorable. We think we showed that we can induce a meaningful treatment effect. The safety data actually was very encouraging. It was surprising, it was better than we expected. It seems men have a different safety profile than women that received GEDA and so we thought it was important to evaluate potentially another dose to make sure we haven't ruled out that prematurely. And so we should expect -- we expect those results sometime by the end of this year.

Okay. And the combination partner, you said it is what?

Darolutamide. That's a drug owned by Bayer. And it's the most potent androgen receptor inhibitor, and it's also the best tolerated. Essentially, if you stack these up, it's really the best partner drug for GEDA. And because it's not used as widely as the 2 standards of care enzalutamide or abiraterone, you're going to switch all these patients, say, well, have received this drug. And so it makes it a very good alternative to combine with.

Okay. And are there any other tumor types that do you think?

So there's been interesting work done in endometrial cancer. GEDA actually reported very favorable data in endometrial cancer as monotherapy, and there's been some other -- there have been some other studies that have shown some activity. Hormonally driven roughly 80% or ER-positive endometrial tumors or are HR positive.

It's confounded a bit because the PD-1 drugs have become a standard of care for many of these patients in the frontline setting, not 100% clear how that may change the potential responsiveness to targeted therapy because that typically you move on to chemo after PD-1 drugs.

So that's an unknown. But there are other tumor types that were other drugs have shown activity, but potentially didn't develop further because of safety issues. And so we think we overcome those safety issues. And so there's some interesting threads to pull on outside of breast or prostate.

Can we talk a little bit about the IP? And then obviously, I know you think the IV formulation is going to be -- it's going to support the commercial launch for the reasons you mentioned. But is there any thoughts about subcutaneous version?

Yes. So I'll talk about the IP. We think we'll have patent term exclusivity through 2042 based on the dosing patent that's critical to optimize outcomes. It's a 3-week on, 1 week off schedule. You have other patents that are shorter duration. And as far as the potential for a subcu, we don't think it's relevant, meaning necessary to optimize penetration in the second line or in the endocrine-resistant population.

Certainly in a setting with patients who are endocrine-sensitive where you could potentially be offering 36 months or so of progression-free survival. It would make a lot of sense to think about a subcu form.

You could get meaningful penetration. It's a very large market, long duration of treatment. So there's a -- there are independent of whether you have subcu with -- and you only have IV. But you could potentially optimize penetration in a way that you wouldn't really have much impact on these other patient populations.

Okay. Are there any difficulties formulating it?

Well, we haven't really gotten into detail yet on the status of any of those efforts, and we'll update people in the future.

Okay. Outside the U.S., what's your thoughts there? Whether the doctors may not have as much incentive to use IV drugs?

Well, I mean, incentive to try to improve the outcomes of their patients. I think that's usually the primary criteria for selecting a drug for a patient. It's not the convenience. It's really the outcome for them and knowing that the patient is getting a drug.

Ex U.S., we won't market ourselves. We're obviously preparing to launch in the U.S. We felt it's important to hold off having any discussions with a potential partner we've had a lot of discussions, but to actually move anything forward until after our data in the mutation cohort is available. But in the meantime, we're laying the groundwork to submit an MAA. That's the equivalent of an NDA in Europe. Soon after, we have our mutant data submission to the FDA or what would be a supplemental, and we would submit that as a joint combined package.

And we've also gained alignment with Japanese regulators on what additional data they would expect in addition to what we already have with VIKTORIA-1. And so we're essentially in the major markets, the 5 major EU countries as well as Japan that comprises the bulk of ex U.S. revenue. And so we are marching down the path without delay to get those drugs hopefully approved.

And then the partner discussions can fall within that time period, and we think we could wrap that up. And that's Europe, 13-month review cycle. So you're really talking about an approval late '27 at best. Japan will be longer because you're generating additional data. So we have time to optimize our approach there and hopefully find the right partner, right overall approach.

Okay. Let me see if there's any questions from the audience. Any questions?

You asked all the right of questions.

Well, you guys have been very visible. So big news.

Yes, all good, Well, thank you.

Thank you.

We're going to get started. Hi, everyone. I'm Tara Bancroft. I'm one of the senior biotech analysts here at TD Cowen, and thank you for coming to TD Cowen's 46th Annual Healthcare Conference. For our next session, we have a fireside chat with Celcuity. And from Celcuity, we have the CEO and Co-Founder, Brian Sullivan.

Thank you so much for being here, Brian. It's such a privilege to have you.

That's my pleasure.

[Operator Instructions] So Brian, I guess, to start off, can you just give us some high-level thoughts and a general overview before we get into details?

So Celcuity is a clinical stage company focusing on development of drugs that address the PAM pathway, PI3K/AKT/mTOR pathway. It's one of the most important pathways in oncology. We have 3 trials underway currently, Phase III trial evaluating GEDA in combination with palbociclib and fulvestrant in women who've progressed on their prior CDK. We have data that we'll be reporting out -- a second set of data reporting out in the next few months.

We have a first-line study in process with the same drug combination in women who are treatment naive, who have endocrine-resistant metastatic breast cancer. And then we have a third study at an earlier phase investigating data in combination with an androgen receptor inhibitor in men with castration-resistant prostate cancer.

And a lot of other stuff going on as well. So we'll talk about that.

You sure do. Okay. So let's start with talking about launch preparation. You had the NDA acceptance, PDUFA date in July. So as that review is ongoing, I know you have the RTOR designation. So maybe you could start by talking about the various benefits of that. I know it's a somewhat uncommon thing to get. So maybe you could familiarize us with the benefits of that package.

Sure. So RTOR stands for real-time oncology review. Essentially, it's really only given or used for drugs that in the FDA's view offer a promise of changing the standard of care landscape for patients. And we weren't surprised by getting it because we had breakthrough designation and the breakthrough designation reflects results from earlier phase studies.

The benefit of RTOR program is that it allows you to begin submissions prior to your completion of your formal submission of your final submission. So we started providing the FDA data sets within a month after we had our data and then provided that on a rolling basis.

We have a priority review. So essentially, PDUFA will be 6 months after they accepted our NDA. And we think it's unlikely that the review will come in prior to that PDUFA date. And I say that because of the 20 or so RTOR reviews that have been done in the past 5 or 6 years since they put this program in place, drugs that have a profile similar to ours, first-time submission, priority review, full approval, not just an accelerated approval.

For the most part, have gotten an approval decision along the line at the PDUFA date. Where you'll see the real advantage in terms of short time frames is for supplemental NDAs. And so if our mutant data, which we expect to report out end of this quarter, early next -- sometime next quarter, is what we hope, then we would file a supplemental NDA. We would also seek RTOR and hopefully, in that case, we would see a shorter approval time line.

Okay. Great. And maybe just briefly, we exist in a pretty volatile FDA environment. So maybe a little bit on your thoughts on confidence in approval in this kind of environment.

We haven't seen any change in our -- the type of interactions, the quality of the interactions, the timing of the interactions over the past year. We've been interacting with the same group, same people for the past 5 years. And relationship has been very collaborative and all the meetings we have regular interactions with the agency.

All the interactions typically are scheduled, i.e., they're supposed to occur within a certain time frame. There has been no diminution or delays that have occurred. So from our standpoint, we wouldn't know there was an issue just based on what we're seeing.

So we don't expect any anomalous outcome that could be influenced by some of this other stuff that's going on.

Okay. Great. Okay. So how about launch preparation? Where are you at with that? Maybe some numbers on sales force, MSLs, anything else that you...

So we actually began preparation for the launch about 2 years ago when we brought on our Chief Commercial Officer. And in turn, that led us to build out the senior team reporting to him that would be responsible for key functions in the commercial department.

But we also developed essentially a company-wide launch plan that not only involves building out the team over time and have a plan for that and the projects associated with establishing your infrastructure commercially, but also laying out the projects required for all of your other departments, whether it's IT, a huge number of systems you need to put in place that involve IT.

Your safety department has to substantially change to be ready for commercial reporting of safety events. HR, finance, every function essentially gets affected. So we had a company-wide launch plan or have one, and then we've been implementing against that.

We've pretty much completed the hiring of the commercial organization by the end of last year, except for the sales force. We did hire the regional sales managers prior to that. And so now we've identified -- we know how many we need.

We've already identified the great bulk of those that we would be making offers to, and we would expect to begin bringing the sales reps on second quarter. And so I would say we're directly absolutely on track to being able to launch effectively around the time of the PDUFA date.

Okay. And then maybe a little on launch expectations, the cadence of what use could look like in the beginning because you're in a little bit of a unique situation where you expect to get approval in one segment, but a little bit later in another. However, the data is going to be out for that. So just curious what types of patients and then how many you think it could be used right away.

Sure. So you can think of this market as having 3 fairly discrete segments. Obviously, the most common one or rather the broadest one is just to use PIK3CA status as the determinant, right? PIK3CA wild-type patients are roughly 60% of patients. So that's what we'll focus on.

We'll have data in the mutant cohort. That data will actually, we think, be available, be public prior to launch of GEDA. So that will certainly be wind at our back if it's what we hope it is for the launch. And so we'll be focusing on women who are PIK3CA wild type. Our data is very favorable relative to drugs that are currently available.

And we think we've done a very effective job at being able to analyze the physician health care practitioner profile, so we are able to prioritize where we should put our efforts, how to design the sales territories, how to define the call patterns that we want the reps to use and also then how to build out the messaging and how to make these individuals effective proponents of GEDA and recognize that these doctors are used to alternatives.

So part of our job will be to help them understand the context of GEDA and how it relates to what they've done or what they might do in the future.

Okay. I do want to get into a little bit more on which segments and types of patients that it can be used in and that you have confidence it will be used in. But I think everyone in this room and listening probably wants to hear expectations for the mutant data.

So the first question that I have is with the late Q1, Q2 guidance, we're really coming up on that very, very shortly. So what can you say about your confidence that, that time line will not be delayed? Are you very close or have reached events already?

We haven't changed our guidance, and I don't think we will be changing our guidance with our quarterly call. So we're confident that that's the time bucket that we'll have data to report.

Okay. Got it. All right. So expectations, I think let's first start with the control arm. I know we have some benchmarks with BYLieve and EPIC-B5 in the 7.3, to 7.4 range, but maybe talk about your expectations for what we could see in the control arm using those benchmarks and others.

So there's always a question of is there a risk that the control arm could overperform relative to whatever assumptions you were and how would that impact you? We think just based on data that's been reported with those 2 studies that reported almost exactly the same results. We think it's unlikely that there would be a surprise on the high side of that. Also, if you look at the data for another drug that hits this pathway called capivasertib, that drug reported 5.5 months in a similar population.

And it also had a control fulvestrant that was about the same level that we would expect in the mutant population with our study. And that drug has a similar hazard ratio as alpelisib, roughly 0.5. And so that would be an example or rather, that would be a case to say, okay, well, that further buttresses the idea that it's unlikely to be outperforming what that drug has done previously.

So that's one -- that's the base case -- rather that's the foundation for any assumption you make about our drug. And so there's really kind of 2 aspects of expectations. One is what do we need to be successful. So that's a statistical benchmark. And just based on how the math works, roughly 10 months or so median PFS would be Statsig. And that would only be 10% or less better than what we reported in the wild-type population. So we think from a probability standpoint, that seems like a highly probable outcome to at least hit that threshold.

Now then the question is the clinical significance, -- how meaningful is that number? Well, alpelisib is no longer really being used very frequently. It's market has primarily moved towards Capi, Capi reported 5.5 months median PFS.

And so if we're offering at a minimum 10 months relative to 5.5 months, we think that's a great advantage. We think our safety profile will also be an advantage. And certainly, anything better than 10 months would be better. One frame of reference is the Phase Ib data that we reported at ESMO. And this Phase Ib study evaluated a very similar patient population as what we're evaluating now.

And in the wild-type population, it reported 9.1 months for wild-type. And that was almost exactly what we reported in the Phase III study, which was 9.3 months. In the mutant portion of that study, patient population, we reported 14.6 months. And so we all know what we're going to see in the Phase III, but at least it gives us confidence that the 10-month number is highly probable.

Essentially, it just leads you to kind of put a high number for your probability of success and gives a sense of what your range could be. I'm not assigning probabilities to other numbers, though.

Yes, of course. I mean within that range, though, I mean, 14 to 19 months, it's quite a range. So maybe which of those different segments, do you think that the Phase III population most closely mirrors?

Well, I would love it if it mirrored the 19-month one, but we'll see, right, in a few months. But we'll see. I think it's a reasonable enough sample size that it gives a sense of what's possible. There's also one other number independent of our study that is useful to reflect on is that with all the other studies done evaluating inhibitors of this pathway where they've generated data, patients who lack mutations versus those that have mutations.

They've seen significant difference in outcomes for patients, i.e., better outcomes for patients that have mutations versus those that don't. And so alpelisib in this setting reported the same results as we reported in the wild-type setting.

And so it's very much the case that it's reasonable, we think, to think that the drug will do better in the mutant than wild-type. That's what our Phase Ib data showed. So all those factors, I think, give us reason for optimism about what the outcomes will be.

Okay. And how about making a comparison to mutant-specific inhibitors? I mean, do you need to be over that 11- to 12-month range to be competitive with them and gain comfort.

To be competitive with a 5.5-month Capi.

I'm more so talking about relay, [ Scorpion.]

Again, those drugs, maybe they get approved, maybe they don't 3 or 4 years from now. So it's not top of mind. I think there's -- ultimately, when you're assessing the potential for a drug, it's really a function of what the relevance is of the target, right? And typically, there's only so much biological potential for inducing antitumor effect associated with the target.

And we saw with the SERDs that -- what is it the book eternal optimism or something, where every SERD coming down that was reporting data was going to be the one that reported positive wild-type result. And after 5 or 6, you'd start to think that optimism would dim and it doesn't seem to.

And I'm not being critical of those SERDs other than to say, this is an example where lacking a mutation there's only so much potential you can get out of hitting that target. You can't get more than 100%. And so there's only so much potential, I think, that you can get when you hit the component of this pathway.

And certainly, to optimize the impact of inhibiting this pathway, you should comprehensively inhibit it. And we've shown non clinically very clearly what the benefit is, and then we've shown clinically what the benefit is.

So I think whatever our drug can do, I think it would be better than whatever a single target drug could do.

Got it. And then I still want to dig in a little bit more on what that mutant specific target is. I mean, I know we've seen Phase II data, but maybe you could tell us a little bit more about the impact of baseline with measurable, nonmeasurable disease and how much that actually impacts...

Well, I think when you're looking at data sets, particularly early phase data sets, when you're trying to project what that might imply for a future readout in the Phase III setting, you need to pay attention to the composition of that population. And one factor that can have a big impact on PFS is whether or not the patient has bone-only disease versus measurable disease.

And in pretty much every study that I've seen that has an endocrine therapy component or monotherapy, the results for patients that have bone-only disease can be typically 3x to 4x better than the results in patients that have measurable disease.

So for instance, PALOMA-3 broke out that data sort of wow, 3x better results for patients with bone-only disease. We saw that, although a very small sample in our own study where the baseline was 2 months, bone-only was 8 months.

And so if you have a population in an early phase study that has a high proportion of patients with bone-only disease, then you need to factor in the impact that, that would have. If you've got a cohort of patients that are generating 8 months of benefit from fulvestrant.

Well, that's going to goose your numbers and can potentially make them not representative of what you'd see in a Phase III study. And so again, as you -- as people think about what the biological potential is of a single component inhibitor of the PAM pathway, the prior results are probably more instructive than in those Phase III studies than anything else.

Okay. Great. So I want to move on to safety. And before I ask more specific questions, I do feel like we came out of ESMO in San Antonio with a little bit of misunderstanding. And not -- I'm not talking about from the Street and investor perspectives, but really among KOLs on the impact of the safety profile that you saw in GEDA's data. And so maybe you could give us some context there on.

Well, we were able to put some specifics. I think one of the big surprises for doctors was that GEDA induces very, very little hyperglycemia. So drugs in this class are typically associated with inducing high levels of hyperglycemia, can turn oncologists into endocrinologists.

It's very tricky to manage patients. It's particularly important in this setting because roughly 50% of women with advanced breast cancer are either prediabetic or diabetic.

And so they're particularly sensitive to any impact on the glucose system, metabolic system. And we reported less than 10% overall, 2% grade 3. Alpelisib induces 80% hypoglycemia.

So orders of magnitude difference. So that was a surprise to the good. And I think the -- on the other side, stomatitis was higher than we had expected to be frank, we thought the dexamethasone would have a bigger impact.

But then as we dug into the data and then presented some of those results at San Antonio, we saw that, okay, this kind of makes sense. If you get stomatitis, it's going to manifest quickly, first 2 doses, days 1 and 8. And then it resolves to a lower grade within a couple of weeks.

And you don't really almost have any grade 3 by the end of a second cycle in your overall population. And that was -- the fact that the stomatitis was really not impacting patients' perception or experience of treatment burden was really demonstrated in the quality of life patient-reported outcomes that we were able to report.

And so probably the best metric for assessing how a drug is impacting a patient's sense of well-being is this one score that essentially asks patients to rate how they're feeling in 5 different parameters associated with their health and general sense of well-being.

And we showed no degradation over an 8- cycle treatment period, which was a follow-up period in that score. So essentially from baseline to end, there was no change. And so if you had an adverse event that was seriously impacting their quality of life, their sense of well-being, you see a diminution in that, and we did.

And then when you see only a 2% discontinuation rate, which is what we had for this -- which we read out, that essentially says patients can stay on this drug. And then qualitatively, we've heard from investigators that have said their patients will say unprompted, I don't feel like I'm on a cancer drug. And this relates to the PK profile of the drug.

We're only needing to drug these patients 3 times a month. Drug stays at sufficient concentration to induce antitumor effect during that off period. So 25 days out of 28, they're not getting the drug, which means they're only getting that hit with that Cmax concentration of drug 3 times a month.

And whereas an oral drug is hitting the patient every day typically or at least 30 times -- 20 days a cycle -- 20 times a cycle. And that is what induces the sense of burden that a toxic anticancer drug can impose on a patient.

And so that's why we think the quality of life data is what it is, is that essentially for 25 days out of 28, you're not on this drug, so to speak, physiologically, the concentration is below a level, below the IC50 level for healthy cells. It's above the IC80 level for tumor cells. And that's this very specific window that GEDA is able to fit in.

And in turn, that's what we think leads to a very, very favorable safety profile. We think we'll absolutely win on that basis.

Okay. Great. And any reason to believe that mutant and wild-type data would look any different?

No. I mean in the early phase data, we kind of looked at that. That was part of our NDA submission, providing that analysis. And there's no reason for it to be different physiologically, but there wasn't from an actual readout standpoint.

Okay. Great. Okay. Now I want to talk about the overall market. And aside from the few months that it's going to be on the market with wild-type, potentially without mutant yet, let's maybe -- I think it's easier to talk about segmentation of patients in everybody. So there's a lot of mutations and PIK3CA, AKT, ESR1. Can you break down your assumptions for what the peak use could be based on those segments?

And in particular, I'm curious what you're hearing and what you think about priority of mutations, like if a patient has PIK3CA and AKT and ESR1, like which mutation gets treated first?

Right. So we've obviously done a lot of research with doctors, quantitative and qualitative to get a feel for how they think about this and then in turn, prompt us to dig in and do some quantitative evaluation of those comments.

And what's very clear is that doctors do, at least today, prioritize the PIK3CA as the treatable mutation that they'll use to make a decision. And so that's the 40% bucket that I mentioned earlier. Now with ESR1 mutations, you get a further bucketization of the segmentation of this group. ESR1 wild-type, PIK3CA wild-type patients. So essentially, they lack biomarkers.

That represents about 40% of the population. And so essentially, 80% of the population is one where we think we have a very, very compelling advantage. For patients who lack mutations of any type or those mutations, there really aren't great alternatives and GEDA really does offer a very, very meaningful benefit for them relative to what's available.

So where you get more potential competition is in the patients that have ESR1 mutations and lack PIK3CA mutations. That's about, again, 20%. There'll be some drugs that are likely approved or some regimens by the end of this year. And we think our data stacks up very well against their data, but there'll be more relative competition.

And so I guess I would say we have clear advantage, clear advantage in 80% of the market. And in the 20% of the market, we'll have a bit of a dog fight.

And even then, any idea of potential third line use? What have you heard about...

No. I mean, obviously, doctors can decide to sequence the therapy. There's no reason why -- if they elected to use an alternative regimen, why they wouldn't necessarily consider it as an alternative in the third line.

I would say one other observation that's pretty clear from the research is that doctors do want to spare patients from chemotherapy as long as possible if there's an appropriate and efficacious -- sufficiently efficacious endocrine alternative. We think our drug regimen offers that efficacious endocrine alternative.

So even if it isn't used in the second line, we think the data would warrant use of it prior to, let's say, in HER2 or some other chemo.

Okay. Great. And I know you also have this frontline trial that's ongoing. So maybe you could talk about what your assumptions for use there are. And in that, there's a lot of discussion and debate about LIDERA and persevERA and how those regimens can impact potential getter use in the frontline and even potentially second line. So maybe...

Okay. Right. Okay. So you have really talked about 3 different groups of patients. There are patients that are early breast cancer getting adjuvant treatment. That was the LIDERA study. Really won't have any downstream effect on advanced breast cancer.

Over time, you might see some diminution in the number of women who progress or rather who recur to metastatic disease. But you also have a countervailing factor, which is the increase in overall incidence of breast cancer. So net-net, I think it should be 10 years before you might see any effect. And if you do see any effect, it would be nominal.

So then the other population, the 2 populations of women who present with metastatic disease. The larger group, it's about 60,000 women a year, present with either endocrine-sensitive disease. These are women who got their adjuvant -- rather got their adjuvant tamoxifen or whatever, and it was years before they recurred, at least more than a year or the de novo.

They just were diagnosed for the first time with metastatic disease. They didn't have early breast cancer. The second group, it's about 35,000 patients, similar in size actually to the second-line population are women who have what's considered to be endocrine resistant. And these are women who didn't get much of a benefit from their adjuvant endocrine therapy.

They progressed while they were either receiving it or within 12 months. That's the study that we're doing right now, VIKTORIA-2. And so we're evaluating these women who today, if they're getting a CDK4/6 and fulvestrant, which is the standard of care for most of these patients, only get about 7 months median PFS.

So it's almost like a second-line study in some ways. We have data from the endocrine-sensitive population in our early phase study that was very, very promising. The women who are endocrine-sensitive, we kind of delayed recurrence from early breast cancer when they are given the standard of care, which is a CDK4/6 and letrozole, get about 25 months median PFS.

We reported 48 months median PFS in that patient population. Small samples, I mean, 41 patients, not nothing, but at the same time, just a single arm, 80% response rate. So clearly, we think it demonstrated, if nothing else, that this pathway, the PAM pathway is relevant intrinsically in this disease. It's not an adaptive response to prior treatment. And that's consistent with the mutational pattern that you see.

The percentage of patients with PIK3CA mutations really is no different in the first line versus the second line, i.e., it's an intrinsic mutation. And this pathway, because of its role, we think, is intrinsically involved in the disease.

Okay. Great. Kind of a tangent, but I kind of want to ask you, do you think persevERA is going to work?

So if you were placing bets, I think you take into account 2 other studies. I mean one would be a study with a SERD that had a similar hypothesis using -- combining an oral SERD with a CDK4/6 inhibitor and comparing it to CDK4/6 and letrozole. And that study didn't get through interim analysis. And the interim efficacy analysis resulted in the study being discontinued due to futility.

So that obviously suggests that it's not a slam dunk. Now not all oral SERDs are the same, but they all are in the same class, and there's only so much potential that you can get out of a target, even if one is better than the other.

Second data set relates to -- what was my other second data, was PARSIFAL study where they compared palbo fulvestrant versus palbo letrozole. The hypothesis was, well, more direct engagement of the target, hitting ER directly with the SERD would be more efficacious than the indirect effect on estrogen with aromatase inhibition.

And numerically, the letrozole CDK palbo did better than fulvestrant, not statistically significantly different. But it suggests that just having a good oral SERD or rather good SERD doesn't do much.

And the other, I guess, third set of data that you'd point to would be that in patients, tumors lacking mutations, there really is no difference between oral SERD and fulvestrant in terms of efficacy. And that's the patient population that you're treating in the first-line setting. And the question is, does the delay in onset yield a meaningful benefit.

And that's what we'll see. [ SOLAR ] study didn't show it, but we'll see. But certainly, it's a bit of a bank shot.

Okay. One more question before we go, but what do you think is the most underappreciated aspect of Celcuity?

I think if people really step back and understood the size of the patient population that we think we'll eventually be able to treat, right? We have 37,000 patients that will be eligible in the second line. I think ultimately, we will progress with trials, and we think high probability of success in these trials in the first-line setting.

And if you do the math on the potential impact in terms of treating that number of patients and the revenue that we generate, I mean, we have $10 billion plus higher potential peak revenue with this drug just in breast cancer.

And so I think if people understood that and just fast forwarded what the implications are of having effective drug that treats 1 of the 3 critical disease drivers, that would potentially change their current view.

All right, Brian. Well, thank you so much for your time and insights, and thanks, everyone, for listening.

Thanks, everyone, for continuing to join us here at the Guggenheim Healthcare Conference. My name is Brad Canino. Very happy to be sharing the stage with Brian Sullivan, CEO of Celcuity. Brian, thank you so much for joining us.

Good to see you. Thank you.

Transformational last couple of quarters for Celcuity with positive Phase III data in breast cancer. You just announced that you had the NDA accepted with a PDUFA date. So I guess just overview for people in the audience and listening in the time lines for bringing GEDA to market in the PIK3CA wild-type population in breast cancer and then expanding its opportunities beyond that.

Sure. So with the PDUFA date set for July 17, later this year, we would expect to -- the decision is positive to launch the drug soon after that approval is received. And in the meantime, we expect to receive data for the mutant cohort of our VIKTORIA-1 study sometime either later this quarter or sometime in Q2. And so going into the launch, we'll have a full data set for all the patients, PIK3CA wild-type and PIK3CA mutant available to physicians as they evaluate GEDA for the first time.

Okay. What is your expectation for review time lines with the RTOR program and the potential for that to come in a bit earlier than the July date?

Sure. So we looked at all the RTOR approvals that have taken place over the past few years since this program was established. And we looked at those reviews that were very similar to ours, first-time drugs, an NDA, priority review and a full review approach. And of the drugs that fell into that category, which is our category, for the most part, I think everyone was approved pretty much at the same time as their PDUFA date.

To the extent that RTOR does lead to an acceleration of an approval decision, it appears just based on our review of the data that it is isolated to those drugs that are filing a supplemental NDA. Essentially, they've already been reviewed by the agency, comfortable with the data, and it's a much more limited data set to review. And so our expectation is that the most likely timing for an approval decision would be the PDUFA date.

Okay. And then if you have to be ready to launch the drug in 5 months from now, what commercial infrastructure has already been built? And what do you still need to build up in the interim between then?

Sure. So we brought on our Chief Commercial Officer, Q1 '24 and began laying out the plans to essentially prepare for launch with a midyear '26 goal in mind or '26 time line in mind. And so in '24, we built out the initial senior leadership of the commercial organization. We also identified all the infrastructure and other effects that -- or other organizations within our company that would be affected.

And then '25, we further fleshed out the commercial organization and largely completed hiring of the individuals who are in the marketing, customer commercial operations, market access area as well as medical affairs. The only group really left to hire are our field sales reps. We do have the sales management VP and their sales managers in place.

At the same time, we've recognized and part of what happens when you transition from a preclinical to a commercial stage company or from a clinical to a commercial stage company is that it affects every department in your company. And so we've needed to install and implement systems and processes and add people. to the IT, safety, HR, other administrative functions to ensure that we can effectively operate as a commercial company.

Okay. Now you've been to in the last quarter, multiple medical meetings showing your data, meeting physicians there, key opinion leaders. How would you describe the way the GEDA data have evolved the understanding of the PAM pathway and the way to inhibit it that's different from the available options?

Well, I think we should go back to 20 years ago when the pathways role was first discovered as a cancer driver. And 20 years ago, this led almost every major pharmaceutical company to develop pan-PI3K/ mTOR inhibitors because the biological imperative required that. You have 4 PI3K isoforms, Class I isoforms, mTORC1 and 2. And they recognize that these components of this pathway serve as redundancy mechanism. So this pathway can continue to function and perform its metabolic role regulating glucose uptake even if one of these components is inhibited.

Unfortunately, those drugs were too toxic. They never made it out of the clinic and the focus deviated or shifted towards developing drugs that only hit single components. Unfortunately, it doesn't address the activity of this pathway. And certainly, the results to date have shown that you will not get effect in patients who lack PIK3CA mutations.

And so the -- I think surprise to docs, and it's not their fault, is that the history of development in this industry wasn't on their radar and the imperative of comprehensively inhibiting it wasn't viewed as relevant, i.e., C mutation hit mutation was an effect -- approach that had been considered to be the only practical one to pursue. And as we've now had an opportunity with our MSLs who we've deployed as well as some of the other work that we're doing to educate clinicians and physicians on the role this pathway plays as a key metabolic regulator.

Just go back to the discoveries 100 years ago with tumor cells and as we started to understand kind of how unique they were relative to healthy cells, the Warburg effect, tumor cells consume 100x more glucose than normal cells. a sense that's their energy source. The PAM pathway regulates that energy source. So if you inhibit that, you're essentially blowing up a key power plant within the tumor cells.

And so the mutation isn't necessarily the most relevant feature of the pathway. The pathway is what's relevant, but controlling it requires this broad inhibition. And so I think as we've explained that, it's been very, very illuminating. And I think people appreciate how important comprehensive inhibition of this pathway is.

And as you've had those conversations and more broadly with just physicians that you've gone out and started to talk about it, how do the clinicians frame back to you how they see the GEDA efficacy and safety profile comparing to their available options in second line?

Sure. Well, I think the data was -- as we viewed it, is similar to how they viewed it. It's unprecedented. We reported a hazard ratio of 0.24, which translates to a 76% reduction of risk of progression or death. And that level of benefit had never been seen before compared to endocrine therapy. The incremental improvement in PFS or multiple relative to endocrine therapy of nearly fivefold was unprecedented as well.

And so I think if you stack up other therapeutic options to those results, it's hard not to view GEDA as potentially the best alternative for their patients. And so the reaction that we've received to date from most doctors has been very, very favorable. I think some doctors will want to try it themselves. It's expected. But the doctors who have worked with the drug, investigators, are unbelievably optimistic about the role this drug can play. And I think a lot of perspectives that people have who haven't used the drug, they're always formed by their prior experience with other drugs. That's just reality.

And so that's why you have a sales force. That's why you have MSLs, you educate folks and get them to understand better not only the efficacy profile, but also the tolerability profile, which we think is a huge feature and a unique characteristic of the drug.

And what do these clinicians tell you about their ability to uptake a triplet regimen, which does include 3 visits a month for a week for an IV and then uptake it at a high volume in their practice?

Well, it's interesting that this question comes up because if you really dig into the oncology space, you'd find that the largest drugs are all infused drugs, whether it's pembrolizumab, the poster child of cancer drugs. And then if you look at breast cancer, in particular, you'd see that Herceptin, Perjeta, Trodelvy and HER2 are all multibillion-dollar drugs. And so they've essentially built their practices around treating patients who have -- or treating patients with drugs that are infused. And these drugs create a favorable economic outcome for their practices. So they've appropriately built out their capabilities and infrastructure and are certainly not averse to having more patients come to the clinic.

One of the other benefits that accrues to patients who are on infused drugs is that the doctors know and the patients are getting the therapy. One of the big challenges in treating patients, particularly in later line settings is that you may not have the compliance that you'd like or certainly that the patients should have with taking their medicines. So the doctors know their patients are receiving the therapy, and that's obviously critically important to getting treatment benefit.

Okay. And at San Antonio, you presented a really thorough characterization of the stomatitis side effect. Can you talk about the patient experience on the drug and how patients are able to stay on the drug long term even with that side effect?

Sure. So a couple of things about stomatitis. I mean it certainly manifests a high proportion of patients. But a couple of interesting observations. First, if patients get stomatitis with our drug, it occurs in the first couple of weeks of treatment, first 2, in effect, infusions. The incidence after that is almost nominal. And secondly, it tends to resolve within 2 weeks to a lower grade. And so that by the time end of the second cycle, very few patients will have Grade 3 stomatitis.

The other aspect of stomatitis translates back to the general sense of well-being that we found patients experienced and reported themselves when they were on gedatolisib. We had an extensive quality of life endpoints to evaluate patients' view of the drug and their experience on it. And I think one of the most important outputs of those or rather the most important endpoint was one that measured the sense of well-being. Essentially, there's a 5 score questionnaire, very specific that asks patients to assess how they're feeling relative to where -- today and you compare it against how they felt before they were taken into the study. And we found no degradation of" "their sense of well-being" from the baseline uptake versus the eighth cycle.

And so then the question is, well, why is it that patients are tolerating this drug so well even if they do have stomatitis. And I think this gets back to the PK profile of GEDA. GEDA is unbelievably potent, 12 nanomolar, a fraction, 300-fold less drug can inhibit and block this pathway. And what that means is that you can only dose it 3 times a month, and you can be at an IC80 level concentration of drug throughout that dosing window, but below the IC50 level, it would affect healthy cells. So essentially, we're able to have the drug concentration for 25 days out of 28 in this window.

And as most of you know, if you're taking a daily cancer drug, you're hit every day with a Cmax concentration of the drug. That Cmax concentration is what tends to essentially cause or induce adverse events and also create a sense of treatment burden. And anecdotally, we heard from a number of physicians who commented on the fact that patients didn't feel like they were on a cancer drug. And so we think as physicians use the drug and they start to see how well their patients tolerate it, that will become an incredibly important component of the value that physicians will see in the drug.

Okay. And now in the PIK3CA wild-type patients, do you think you will be reserved for patients with an ESR1 wild-type status? Or could GEDA be used over oral SERD mono or combos in the ESR1 mutant patient populations as well?

Well, I think our data compares favorably to those regimens. And I think if you're making decisions on the basis of the data and outcomes, then you'll select GEDA. And additionally, if you're looking at tolerability, for instance, the regimen that's, I think, under review by the FDA, an oral SERD with everolimus, I think you'd also select GEDA independent of this ESR1 status.

Obviously, the more people in the market, you're going to have just a more crowded space. But we think over time, as we do our job educating physicians and then using this drug and seeing how their patients respond to it, we think that it will sort out to the case where GEDA is viewed as the second-line alternative that can be used independent of ESR1 or PIK3CA status or independent of HbAC1 levels for their patients.

And that's going to be very attractive, particularly in the community setting, where the complexity that can occur when you essentially are trying to manage this 4-box equation of ESR1 mutant versus and PIK3CA mutant, yada yada, makes it very hard for them to manage their practice. And we think we'll allow them to hit the simple button and give their patients, more importantly, the best option irrespective of those other factors.

Okay. And how do you weigh a full go-it-alone strategy with potential strategic options to commercialize GEDA?

Sure. Well, 2 things. It's -- we're very confident about our ability to execute the commercial launch of this drug. And we've essentially 100% on our marks for accomplishing the infrastructure build organizational build to do that. At the same time, you're building a business, starting a business as I've done a couple of times, the only thing you can really control is what you can control. And so what we can control is launching this drug and doing it very effectively.

What we can't control are potential external events or external factors. And so if you take care of what you can control, other things can happen. But if you are waiting for external events to occur, I think you can run into trouble. And we think we will provide the appropriate focus and effort that will play big dividends in being able to maximize the penetration of this drug.

Okay. Now let's flip to the mutant Phase III readout that we have coming up imminently late 1Q, 2Q. What got you to that time point of the catalyst reading out then in terms of enrollment and how events have come in versus expectations?

Well, there are always kind of 2 factors that were -- many factors, but maybe 2 or 3 factors that can really drive a delay in being able to report data. One is enrollment. If the enrollment took longer, obviously, it takes longer for the events to accrue. That wasn't the case with the mutant population. We pretty much hit to the week our enrollment target. So the enrollment was very consistent and wasn't a variable.

The other factor is obviously how long patients are on either the control or the study drug. And so we monitor pretty much on a quarterly snapshot basis using the calendar quarter, the event rates and then use that and project forward to what we project to be the -- or what's required to be the event threshold -- target threshold. And that slowed down in Q3, just is what it is, and you then roll that forward and that pops out a date when you think the event threshold will be met and then correspondingly, the database locked and top line results available.

Then the question is, is it due to the control of the study arm. We are blinded. We don't know. But there have been some recent results out for the control that we're using. We're using alpelisib/fulvestrant as a control in the study. A Phase III study was reported out at San Antonio just in December called EPIK-5, reported, I think, 7.4 months, 7.3 months median PFS for alpelpsib and fulvestrant, which is consistent with the assumptions we used going into the study because of the BYLieve study had reported almost exactly the same results.

So there seems to be a fairly consistent result for alpelisib when treated in a population similar to ours. And that suggests to us that we're unlikely to see us get surprised on that end. But again, until we report the data, we don't know.

Okay. And then you have Phase I data that suggests 14 and change median PFS up to 19 and change. As you think about this Phase III, though, what is the PFS bar for success at a median? And maybe you can delineate that between statistical significance and commercial relevance.

Well, there's always what we'd like to have and what we need to have, right? So certainly, we'd love to recapitulate those numbers from the Phase Ib. But what we need to have, and really you alluded to this is beat 2 benchmarks. One is the statistical benchmark, right? We have to beat alpelisib. And based on the math, essentially a 3-month delta relative to alpelisib roughly 10 months or so for median PFS with our study arm would be statistically significant. And so first things first, you want to have a positive study.

Now as it turns out, a positive study would also be clinically meaningful because even though alpelisibs are controlled, they're no longer relevant clinically. They've been superseded as the go-to standard of care by an AKT inhibitor called capivasertib, TruCap. And that drug reported about 5.5 months median PFS in the same population we're treating, patients who had prior CDK. And so even with a 10-month median PFS, we'd be essentially offering almost a double relative to what is currently available for these patients.

Now certainly, more is better. We're not trying to suggest that's what we'd like. But it does say, given the results we had in our early phase studies, we've got a pretty good margin for error, which in turn, we think corresponds to a high probability of success.

Yes. We just saw TruCap is now $600 million annualized in the U.S. So maybe let's talk a little bit about the commercial opportunity for GEDA because that's just in the mutant population for them. As you think about how you size the opportunity with the profile of GEDA, what do you think that is in just the U.S. alone? And how do you think about what a reasonable penetration is that GEDA could achieve into that?

So TruCap just provides somewhat of a benchmark. It's got some limitations as a drug because of its tolerability profile and also relatively short duration of treatment. But if you normalize that for the whole population, so 40% of PIK3CA mutations, it translates to roughly $1.7 billion. It's actually roughly $700 million now run rate based on the last quarter. So roughly $1.7 billion in the market as a whole.

We think this overall market has a potential of over $6 billion. This is a second-line wild-type mutation. And that represents -- or let's assume roughly 37,000 women are eligible to receive treatment. Duration of treatment is, call it, 10 months just on average, just to have a number that our pricing is comparable to what's currently being achieved with, like, say, a drug like TruCap. And so even -- I think the way to think about that is not so much focus on what we'd like, what our goal is, which is high, is to say, well, what's the value of this drug if we're even just at 30% penetration, which is -- would translate to roughly more than a couple of billion dollars in just a second-line indication, not taking into account what we think is equal opportunities or larger opportunities in the first-line setting.

And so we think it's highly probable, I mean, based on the math I just shared that we can build a multibillion-dollar drug in this setting, second-line setting. And that if we have success in rolling out and achieving positive results in the 2 first-line populations, endocrine-sensitive patients, endocrine-resistant patients, we could build a drug, $5 billion to $10 billion drug in just breast cancer.

Okay. So let's talk about that a little bit, how you're bringing GEDA it to the front line. Maybe explain the key features and status of the first initial frontline trial you've got ongoing.

So we're initially focused on the treatment-naive population, women who are considered to be endocrine resistant. These are women who are on their adjuvant hormonal therapy for early breast cancer and progressed or they progress within 12 months after finishing up that course. So they have a rough prognosis. With standard of care drugs, let's say, CDK4/6 plus fulvestrant, they're only getting about 7 months median PFS.

And so we're enrolling in that population now. We're doing a safety run-in. The study is designed to give physicians the option of ribociclib and palbo as their CDK combination partner for both the study and control arms. And to -- essentially before we could initiate Phase III, we needed to do a safety assessment with ribo. That will be wrapping up soon. And then once that's done, we would expect to begin enrolling in the Phase III portion of the study soon after that.

And how would you describe the probability of success for the ongoing endocrine-resistant frontline trial and why investors should credit it today?

Sure. Well, I think the results that we reported in VIKTORIA-1 are -- really were outstanding. You saw the data even in patients who had prior CDK reported very, very significant incremental benefit with just the doublet, fulvestrant and GEDA. And then we were able to resensitize these patients to CDK4/6 treatment. I mean it was interesting that the patients in the wild type who had palbo -- prior palbo had 16 months median PFS with retreatment with palbo and GEDA and fulvestrant.

So we think that suggests that the combination of these 3 inhibitors essentially are addressing the important -- the disease drivers of women with this type of cancer. And that if you do that with a drug that comprehensively inhibits this PAM pathway, then you can have a significant outcome irregardless of your stage of treatment. And in effect, the harder hurdle to overcome is demonstrating clinical benefit in patients who've already received 2 components of the triplet, the hormonal therapy and prior CDK. So we're optimistic.

And also, I just should point out that we did have data in treatment-naive patients who are endocrine sensitive. And these are patients who have a much better prognosis. They will get 25 months median PFS with a CDK4/6 and letrozole, which is an AI inhibitor. In our study, which is a single-arm study, but 41 patients were enrolled. We reported 48 months median PFS, which is obviously a very, very promising result. And so what we think that demonstrated is that irregardless of whether you've had prior treatment with hormonal therapy, this pathway plays a role and is important and really one of the 3 components -- 3 pathways driving the disease.

Okay. Maybe we'll just close it out because still running a lot of clinical trials, building out commercial, what is the cash runway and access to capital as you see it because you do have some debt facilities as well.

Sure. So we had $450 million of cash at the end of Q3. We also expanded our term loan facility last year so that we now have access to up to $500 million of cash off that term loan. We've only pulled down $125 million so far. We're not going to lever ourselves up ridiculously, but it does give us flexibility. And certainly, with this market cap and hopefully, positive data coming up, we think we'd have some options to augment our balance sheet further.

Okay. Great. Well, Brian, thank you so much for joining us. Thanks, everyone, for listening in. Exciting year ahead.

Thank you.

Good afternoon, ladies and gentlemen, and welcome to the Celcuity's Third Quarter 2025 Financial Results Webcast and Conference Call. [Operator Instructions]

I would now like to turn the conference over to Apoorva Chaloori with ICR Healthcare. Please go ahead.

Thank you, operator, and good afternoon to everyone. Thank you for joining us to review Celcuity's Third Quarter 2025 Financial Results and Business Update. Earlier today, Celcuity Inc. released financial results for the third quarter ended September 30, 2025. The press release can be found on the Investors section of Celcuity's website.

Joining me on the call today are Brian Sullivan, Celcuity's Chief Executive Officer and Co-Founder; Vicky Hahne, Chief Financial Officer; as well as Igor Gorbatchevsky, Chief Medical Officer, who will be available during Q&A.

Before we begin, I would like to remind listeners that our comments today will include some forward-looking statements. These statements involve a number of risks and uncertainties, which are outlined in today's press release and in our reports and filings with the SEC. Actual events or results may differ materially from those projected in the forward-looking statements. Such forward-looking statements and their implications involve known and unknown risks, uncertainties and other factors that may cause actual results or performance to differ materially from those projected.

On this call, we will also refer to non-GAAP financial measures. These non-GAAP measures are used by management to make strategic decisions, forecast future results and evaluate the company's current performance. Management believes the presentation of these non-GAAP financial measures is useful for investors' understanding and assessment of the company's ongoing core operations and prospects for the future. You can find the table reconciling the non-GAAP financial measures to GAAP measures in today's press release.

And with that, I would now like to turn the call over to Brian Sullivan, CEO of Celcuity. Please go ahead.

Thank you, Apoorva. Good afternoon, everyone, and thank you for joining our third quarter operating and financial update conference call. Past few months were busy and fruitful ones for Celcuity. We made significant progress achieving a number of clinical and regulatory milestones while also significantly bolstering our balance sheet. These achievements lay the groundwork for us to potentially establish gedatolisib as a new standard of care second-line therapy for patients with HR-positive, HER2-negative advanced breast cancer.

Amongst the key clinical and regulatory milestones achieved, first, we released top line data results from the PIK3CA wild-type cohort of the Phase III VIKTORIA-1 study and then subsequently presented detailed efficacy and safety results for this study at a late-breaking oral presentation at the European Society for Medical Oncology, or ESMO Congress. We also presented at this ESMO Congress updated clinical results from the Phase I portion of a clinical trial evaluating gedatolisib in combination with darolutamide in men with metastatic castration-resistant prostate cancer.

And third, we completed enrollment of the PIK3CA mutant cohort of the Phase III VIKTORIA-1 trial, and we now expect top line data in late Q1 '26 or during Q2 '26.

And fourth, the FDA accepted our request to submit our New Drug Application, or NDA, under their real-time oncology review program for gedatolisib based on the results from the PIK3CA wild-type cohort of the VIKTORIA-1 trial, and we expect to complete the submission this quarter.

And then fifth, to strengthen our balance sheet, we completed concurrent offerings of convertible notes, common stock and prefunded warrants, which resulted in net proceeds of approximately $287 million. We also amended our term loan facility with Innovatus Capital Partners and Oxford Finance to increase the total term loan facility size to $500 million, including $350 million in committed capital and up to $150 million at the mutual discretion of Celcuity and its lenders. Future draws of committed capital under the facility are subject to the achievement of certain milestones.

The most consequential milestone of the quarter for Celcuity was, of course, the release of positive data from the PIK3CA wild-type cohort of the VIKTORIA-1 trial. And we've discussed previously the historic nature of the results and the new milestones they achieved in HR-positive, HER2-negative advanced breast cancer.

But to recap, median progression-free survival, or PFS, for the gedatolisib triplet, which is gedatolisib, palbociclib and fulvestrant was 9.3 months compared to only 2 months for fulvestrant, which is a 7.3-month incremental improvement in median PFS. The hazard ratio was 0.24. For the gedatolisib doublet, which is gedatolisib and fulvestrant, median PFS was 7.4 months versus 2.0 months with fulvestrant, a 5.4-month incremental improvement in median PFS. And the hazard ratio was 0.33. These results set several new benchmarks in HR-positive, HER2-negative advanced breast cancer. The hazard ratios for both the gedatolisib triplet and doublet are more favorable than have ever been reported by any Phase III trial for patients with HR-positive, HER2-negative ABC. The 7.3 and 5.4 months incremental improvements in median PFS with the gedatolisib triplet and doublet over fulvestrant, respectively, are higher than have ever been reported by any Phase III trial for patients with HR-positive, HER2-negative advanced breast cancer receiving at least their second line of endocrine therapy. And gedatolisib is the first inhibitor that targets the PI3K/AKT/mTOR pathway to demonstrate positive Phase III results in patients with HR-positive, HER2-negative PIK3CA wild-type breast cancer, whose disease progressed on or after treatment with a CDK4/6 inhibitor.

Now as a follow-up to the release of the top line data in July, additional data were released at a late-breaking oral presentation in October at ESMO. Now in this presentation, we reported, among other things, that the objective response rate of the gedatolisib triplet was 32% compared to 1% with fulvestrant and the median duration of response was 17.5 months and that the objective response rate of the gedatolisib doublet was 28% and the median duration of response was 12.0 months. The median duration of response for fulvestrant was not determinable because there was only one objective response. And these results also established new benchmarks. The median duration of response and the incremental improvement in the objective response rate relative to control for the gedatolisib triplet and doublet are the highest reported for an endocrine therapy-based regimen in second-line HR-positive, HER2-negative advanced breast cancer.

Additionally, the results demonstrated the clinical benefit of the gedatolisib regimens was consistent across patient subgroups. And one patient subgroup of note, patients enrolled in the United States and Canada, achieved median PFS of 19.3 months with the gedatolisib triplet and 14.9 months with the gedatolisib doublet. The ESMO presentation also provided detailed safety results that showed the gedatolisib triplet and doublet were generally well tolerated in the trial with mostly low-grade treatment-related adverse events. Study treatment discontinuation due to treatment-related adverse events was reported in 2.3% of patients treated with the gedatolisib triplet and 3.1 months of patients with the gedatolisib doublet.

Now in the presentation of results from the PIK3CA wild-type cohort of the VIKTORIA-1 study at ESMO, additional data from a Phase Ib clinical trial that evaluated gedatolisib in patients with HR-positive, HER2-negative advanced breast cancer was included. And the analyses reported efficacy data from patients who are treated with the same drug regimen evaluated in the VIKTORIA-1 study, gedatolisib combined with fulvestrant and palbociclib. Now these patients were included from the escalation Arm B and expansion arms B, C and D of the Phase Ib study. Median PFS and the objective response rate, or ORR, were assessed in subgroups of patients according to their PIK3CA status. For the 30 analyzed patients with PIK3CA mutant tumors, median PFS was 14.6 months and the ORR in response of evaluable patients was 48%. For the 60 patients with PIK3CA wild-type tumors, median PFS was 9 months and the ORR in response evaluable patients was 41%.

Now let's turn over to our VIKTORIA-2 study, which is a Phase III clinical trial evaluating gedatolisib plus a CDK4/6 inhibitor and fulvestrant as first-line treatment for patients with HR-positive, HER2-negative advanced breast cancer who are endocrine therapy resistant. We dosed the first patient for this study in late July and enrollment is ongoing. We believe the positive results from the PIK3CA wild-type cohort of our VIKTORIA-1 study augurs well for the potential efficacy of gedatolisib triplet may induce in this patient population.

Now let's turn to our Phase I/II clinical trial that is evaluating gedatolisib in combination with darolutamide in men with metastatic castration-resistant prostate cancer. We presented detailed data for the Phase I portion of the study at a poster presentation at ESMO. And in this portion of the Phase I/II study, 38 patients were randomly assigned to receive standard doses of gedatolisib in either 120 milligrams of gedatolisib in Arm 1 or 180 milligrams of gedatolisib in Arm 2. Among the 38 patients enrolled, 61% had received 1 line of prior systemic therapy and 39% had received at least 2 or more lines of prior therapy. The Phase I data set utilized in August 15, 2025 data cutoff and median duration of follow-up was 9 months.

The 6-month radiographic PFS, or rPFS rate was 67% and the median radiographic progression-free survival for patients was 9.1 months from both arms combined. For patients treated with 120 milligrams of gedatolisib, the 6-month rPFS rate was 74% and the median rPFS was 9.5 months. For patients treated with 180 milligrams of gedatolisib, the 6-month PFS rate was 61% and the median rPFS was 7.4 months. And these results compare favorably to historical results for patients with mCRPC who were treated with an androgen receptor inhibitor as second-line treatment. The combination of geda and darolutamide were generally well tolerated in the trial with mostly low-grade treatment-related adverse events. No dose-limiting toxicities were observed in either arm. The only Grade 3 treatment-related adverse events for patients from both arms combined included rash in about 5.3% of patients, stomatitis in 2.6% of patients and pruritus in 2.6% of patients as well. No Grade 3 hypoglycemia was reported. Additionally, no patients discontinued the study treatment due to an adverse event.

Now as we near what we hope is an FDA approval for gedatolisib in 2026, our efforts to prepare for the potential launch of gedatolisib have ramped up per our strategic launch plan. Foundational to these efforts was the additional cash we raised and the enhanced financial flexibility, our $500 million term loan facility provides us. We began laying the groundwork for a potential gedatolisib launch 18 months ago, and we've since made significant progress building the organization and internal systems required to operate as a commercial stage company. Now as planned, once the VIKTORIA-1 wild-type data was in hand, our commercial launch preparation efforts significantly accelerated. Except for the field sales force, we've mostly completed hiring of the individuals needed to execute the launch, and we're very fortunate to have attracted an incredibly talented group of individuals who have a strong track record of successfully launching novel oncology therapeutics.

Our sales management and customer operations groups have defined our regional and sales territories and our go-to-market objectives for each one. The medical science liaison and KOL engagement teams have done a great job of exchanging scientific information with key opinion leaders and community practice leaders and obtaining important insights and feedback from them.

Now key efforts today include extensive outreach across the country to the payers and population health decision-makers in various treatment settings, including health systems, integrated delivery networks and community oncology practices that will play a key role in providing oncologists access to gedatolisib for their patients. We've made strong progress engaging with these decision-makers, and we're very pleased with the feedback and enthusiastic response these efforts have yielded. We're also very encouraged by the results of research we have fielded to gauge the willingness of community and academic oncologists to prescribe gedatolisib should it get approved. And these results make us optimistic about the possibility of establishing gedatolisib as the new standard of care in the second-line setting for HR-positive, HER2-negative advanced breast cancer in the wild-type patient population.

Now in light of this feedback, we believe obtaining majority market share in this setting appears not only achievable, but potentially too conservative. Based on analysis of published epidemiological data, we estimate there are 37,000 patients in the U.S. with HR-positive, HER2-negative advanced breast cancer who've progressed after treatment with a CDK4/6 inhibitor. Using internal duration of treatment estimates and pricing assumptions consistent with currently available novel therapeutics for breast cancer, we estimate the total addressable market for gedatolisib in the second-line setting is $5 billion to $6 billion. And given the significant penetration our research is suggesting we can achieve, we believe it's reasonable to estimate that a second-line wild-type indication or second-line indication in general for gedatolisib can potentially generate peak revenues of $2.5 billion to $3 billion.

The progress we've made to date is encouraging and exciting. We look forward to providing you updates over the next few quarters. We believe the resources we've raised will enable us to advance multiple potential blockbuster indications in breast and prostate cancer while also aggressively preparing for and potentially launching gedatolisib commercially should we receive FDA approval.

Gedatolisib is well positioned to address critical needs in the second-line space with its unique mechanism of action and potential first-in-class and best-in-class safety and efficacy profile.

I'd like to now hand the call over to Vicky to review our finances.

Thank you, Brian, and good afternoon, everyone. I'll provide a brief overview of our financial results for the third quarter of 2025.

Our third quarter net loss was $43.8 million or $0.92 per share compared to $29.8 million net loss or $0.70 per share for the third quarter of 2024. Our non-GAAP adjusted net loss was $37.2 million or $0.78 per share for the third quarter of 2025 compared to non-GAAP adjusted net loss of $27.6 million or $0.65 per share for the third quarter of 2024.

Research and development expenses were $34.9 million for the third quarter of 2025 compared to $27.6 million for the third quarter of 2024. Of the approximately $7.3 million increase in R&D expenses, $5.6 million was related to increased employee and consulting expenses, $3.2 million of which related to commercial headcount additions and other launch activities. The remaining $1.7 million increase was primarily related to activities supporting our ongoing clinical trials.

General and administrative expenses were $7.9 million for the third quarter of 2025 compared to $2.5 million for the third quarter of 2024. Of the approximately $5.4 million increase in G&A expenses, $4.9 million increase was related to increased employee and consulting expenses. Of this increase, $4 million was related to noncash stock-based compensation. The remaining $0.5 million of the $5.4 million increase primarily related to professional fees, expanding infrastructure and other administrative expenses.

Net cash used in operating activities for the third quarter of 2025 was $44.8 million compared to $20.6 million for the third quarter of 2024. We ended the quarter with approximately $455 million of cash, cash equivalents and short-term investments. As Brian mentioned earlier, in July of 2025, we conducted a concurrent public offering of 2.75% convertible senior notes due in 2031 common stock and a prefunded warrant offering. The net proceeds from the combined offerings were $287 million after deducting underwriting discounts, commissions and the company's operating expenses. In September 2025, the company entered into an amendment to its existing senior secured term loan facility with an affiliate of Innovatus Capital Partners and Oxford Finance and certain of its affiliates. The amendment increases the total term loan facility size to $500 million, including $350 million in committed capital and up to $150 million at the mutual discretion of Celcuity and its lenders.

In connection with the release of the positive top line data from the PIK3CA wild-type cohort of the VIKTORIA-1 Phase III clinical trial, Celcuity achieved the Term D milestone and was eligible to draw an additional $30 million under the term loan facility. In connection with the amendment to the term loan facility, the Term D loan was disbursed and Celcuity received net proceeds of $27.8 million. The upsized facility strengthens Celcuity's ability to manage its capital structure efficiently while providing additional funding to support commercial launch preparations for gedatolisib and other strategic initiatives.

Also triggered by the release of the positive top line data was the 75-day expiration date for warrants that were issued pursuant to a private placement that closed on December 9, 2022. Warrants that were exercised generated cash proceeds of $12.8 million. We expect cash, cash equivalents, investments and drawdowns on our current debt facility to fund operations through 2027.

I will now hand the call back to Brian.

Thank you, Vicky. Operator, could you please open the call for questions.

[Operator Instructions] Your first question comes from the line of Maury Raycroft from Jefferies.

Congrats on the progress. You're planning on having additional data at the San Antonio Breast Cancer Symposium Conference. Maybe talk about what the main focus of the presentation is going to be? And do you anticipate sharing more detailed subpopulation data related to ESR1 wild-type and mutant in the near future?

Thanks, Maury. We'll present the data when it's presented. Typically, these presentations that follow the detailed initial presentation include additional subgroup analyses for efficacy, additional data that might relate to certain safety or quality of life aspects of the study. And we expect to follow that approach with the data we released in San Antonio.

Okay. Understood. And maybe a question just related to the frontline setting. Wondering if you can comment on whether enrollment in VIKTORIA-2 has been positively impacted by the second-line data? And is there anything additional you can say on time lines? And also wondering if you're considering expanding to first-line endocrine-sensitive patients with the current formulation.

Thanks for the question. No, enrollment is on track. I mean, certainly, investigators who are participating in the VIKTORIA-2 study were very excited about the results. And I think that, of course, would impact the visibility for their patients and the credibility of the study itself. So we think it will have a favorable effect.

As far as additional Phase III studies, I mean, certainly, we have a long-term life cycle development plan. And over time, as we make progress fleshing that out or making some decisions about timing and approach, we'll announce those, but we're not ready to do that yet.

Your next question is from the line of Andrew Berens from Leerink Partners.

This is [ Samantha ] on for Andy. So for the real-time oncology review submission process to the FDA, you're guiding to completing that in fourth quarter. We're just kind of trying to figure out the wild-type submission will be complete from the -- completely separate from the mutant submission. Are there any implications to this? Do you also expect the mutant submission to be a real-time oncology review? Any color would be helpful.

Sure. So we're on track, as I indicated, with the submission for the wild-type cohort completed by the end of this quarter. And we've had specific conversations about the approach that we're taking with this NDA and the RTOR submission and that was ultimately approved by the FDA, reflected that we'll just be submitting and seeking an NDA for the wild-type population. So we're in sync with the FDA on that front.

We would, depending on the data, request a real-time oncology review for the mutant data, but it's always a function of the data. These real-time reviews are typically only granted when the data is very, very clear and the potential for a new standard of care is possible. And so, we hope that's the case. But until we have the data, we can't necessarily commit to that.

Next question is from the line of Tara Bancroft from TD Cowen.

So I'm hoping you can maybe expand a bit more on what you believe the eventual duration of therapy will be, especially in the commercial setting for the triplet based on the data that you've seen so far?

And then separately, I'm wondering if you could tell us what assumptions would go into your pricing strategy and what are some good comps to look for there?

Okay. As far as the duration of therapy, I mean, there's a couple of ways to think about that because there -- we did find variation in the outcomes according to region. And in the U.S., for instance, we reported that PFS was 19.3 months, which was significantly longer than the intent to treat. And so, we have an internal estimate of what we think is reasonable yet. We will do some further analysis before we might share that externally, and that will be a function of providing additional subgroup analyses over the coming months.

As far as assumptions for pricing, there have been drugs launched recently that are novel therapeutics targeting, in this case, the PI3K pathway. I think the wholesale acquisition cost for one therapeutic or several therapeutics that are in this HR-positive, HER2-negative space are in the range of, let's call it, $25,000, plus or minus. And so, that's a reasonable benchmark. You also have to factor in potential discounts that would be associated with distribution of the drug. Oral drugs typically will have probably closer to a 30% discount, gross to net of 70% discount. And then medical benefit drugs like geda would probably only have a 20% discount. So you could potentially get a better price in this market just by virtue of being a medical benefit on a net basis with the same wholesale acquisition cost price. Now we're doing research in this area now. We haven't made a final decision on our pricing approach. But for purposes of trying to estimate what the addressable market value is, we think it's reasonable to use the numbers that I just shared.

Your next question comes from the line of Brad Canino from Guggenheim.

Just one question for me. What is the plan to bring gedatolisib to patients outside the U.S.?

Sure. I think we've discussed in other calls or at least we've mentioned that we expect to commercialize in the U.S. and as I discussed on the call, and then find a partner or partners to commercialize the drug ex U.S. And we are holding off finalizing or really moving forward with intense discussions on that until we have our mutant data available and until we've submitted what we hope is an sNDA for the mutant population. And coincident with the submission of the sNDA for the mutant population, if all goes according to plan, we would soon after expect to file an MAA to the European medical authorities that would comprise both mutant and wild-type patient data.

Additionally, we've also been working with the Japanese health authority to identify their requirements for a submission. We think we're aligned with them on an approach that makes sense to us. And so, we're moving forward on a regulatory path that will allow us to stay on track with as rapid commercialization as possible, even without the -- rather a marketing partner. And we would expect to start engaging those discussions once, I would say, the middle of next year once our data was available and the regulatory submissions were on their way.

Next question is from the line of Stephen Willey from Stifel.

Can you hear me?

We can.

This is Dara Azar on for Steve. Brian, you announced plans to develop gedatolisib for endocrine-resistant frontline well before the VIKTORIA-1 readout. I'm curious, has your thinking around the type of frontline population to be enrolled changed at all now that you have Phase III data from the wild-type population, you have this interesting signal from Phase Ib subgroup analysis. And I'm assuming you have KOL feedback, investor feedback. So what is your philosophical view around the need to conduct endocrine-sensitive trial in the frontline setting?

No, thank you for the question. Well, I mean, certainly, we believe that there's an important opportunity to help patients delay their progression for even longer than is possible with the current CDK4/6 letrozole regimens. And we base that view on the data that we obtained in our Phase Ib study in treatment-naive endocrine-sensitive patients. Now the standard of care CDK4/6 letrozole regimens, the 3 of them offer patients, at least as reported in their Phase III studies, about 25 months, plus or minus median PFS. In our Phase Ib study, which, again, only 41 patients, single-arm study, so you have to caveat it, but a meaningful enough population that is probably not a random result. But we reported about 48 months median PFS. So that we think helps establish or certainly provide preliminary evidence that this pathway is an important driver in treatment-naive hormone receptor positive breast cancer. And in effect, it kind of confirms our hypothesis certainly helps demonstrate that this pathway, the PAM pathway is really 1 of 3 driver pathways promoting breast cancer, the PAM pathway, CDK4/6 and endocrine therapy, or ER pathway. And so, we think there's a very, very strong rationale to develop this drug for that population. It's a long study, given the potential progression-free survival of both the control and study arm and probably a fairly sizable number of patients as well.

And so, again, we are wanting to step back, as you suggested, given the results we have here where we really saw a profound effect in wild-type patients and be very thoughtful about how we would design that study in light of the current study in endocrine-resistant patients.

So yes, we believe it's an important opportunity to help patients further. It represents probably 2/3 of women who are treatment-naive in the metastatic setting. And so, we think would be an important thing for us to do. And we think there's a lot of strong rationale to do it. And over time, we will provide updates on our thoughts on that.

Your next question comes from the line of Oliver McCammon from LifeSci.

I'm just curious if you can speak to the potential impact of a favorable overall survival trend in the second- and third-line setting, caveating that we've seen interim OS data so far. And also curious if you can speak to potentially what role these data could play in the regulatory process as well.

Sure. And so, in conjunction with the primary analysis, our stats plan and typically is required, but our stats plan performed an interim OS analysis to demonstrate or hopefully to reveal what, if any, effect you might have on overall survival for these patients. The requirement from a regulatory standpoint is that, you don't show any evidence that you're reducing patients' likelihood of survival, i.e., you have to have a hazard ratio that's below 1. And in the case of the interim analysis for our study, the hazard ratio was, I think, 0.69 for the triplet and about the same for the doublet, which, again, we believe is a favorable trend. And we think that, that supports our submission for drug approval and supportive of that.

As far as the impact of an overall survival positive readout, certainly, we think, impactful. But that's -- it has been a very high bar to beat in second-line setting. There hasn't been a drug yet in the second-line setting that has showed an OS advantage. And that's just because of the nature and heterogeneous nature of the patients and the subsequent drugs they receive. But we'll see. I mean, certainly, we look forward to reporting out those numbers. But when you have a study of our size with the sample size, you have a relatively small number of events that you're using to characterize what is only a certain effect size. And so, it's a high bar to beat with a small sample size, but we'll see. And certainly, if successful, it will be very impactful.

Your last question comes from the line of Chase Knickerbocker from Craig-Hallum.

This is Jake on for Chase. In light of this administration's focus on domestic manufacturing, could you just remind us where geda is manufactured?

Sure. We have several sites for manufacturing, and we have an approach that we think allows us to have flexibility in how we manufacture, where we manufacture the drug. We haven't really announced where we're manufacturing the drug. But based on our kind of inventory approach and also our approach to finding second sources, we're basically taking the steps necessary to make sure our supply chain is as bulletproof as you can make it.

There are no further questions at this time. I would like to turn the call back to Brian Sullivan for closing comments. Sir, please go ahead.

Well, thank you for attending our call, and I look forward to providing further updates in the future. Goodbye.

Ladies and gentlemen, this concludes today's conference call. Thank you very much for your participation. You may now disconnect.

Hello, and thank you for standing by. My name is Bella, and I will be your conference operator today. At this time, I would like to welcome everyone to Phase III VIKTORIA-1 Additional Results Presentation. [Operator Instructions]

I would now like to turn the conference over to Brian Sullivan, CEO and Co-Founder of Celcuity. You may begin.

Good morning. Thank you for joining us. Dr. Igor Gorbatchevsky, our Chief Medical Officer, will also be joining us today. We're excited to discuss the detailed data that was presented over the weekend at the ESMO Congress in Berlin for the PIK3CA wild-type cohort of our VIKTORIA-1 Phase III clinical trial.

Let's now turn to Slide 2. Before we begin, though, I must point out that some of our comments today contain forward-looking statements that are subject to risks, uncertainties and assumptions. In particular, our expectations around gedatolisib are uncertain and subject to change. And should our expectations fail to materialize or should our assumptions prove to be incorrect, actual company results could differ materially from these forward-looking statements. A description of these risks and uncertainties and assumptions is included in our SEC filings.

Let's turn now to Slide 3. The PI3K, AKT, mTOR pathway, which we'll refer to as the PAM pathway, is one of the most important oncogenic pathways. It plays an important role in a number of critical cell functions, including cell metabolism, cell growth, proliferation and survival. And the PAM pathway also cross regulates other oncogenic pathways and impacts immune competent cells in the tumor microenvironment. Multiple studies have demonstrated that the PAM estrogen receptor and CDK4/6 pathways play important roles in promoting tumor cell proliferation. Additionally, there are interdependent drivers of HR+/HER2- advanced breast cancer, and this process is not dependent on PIK3CA mutation stats.

To maximize the efficacy, the evidence suggests simultaneous blockade of all 3 pathways is very important. It's especially important to provide complete blockade of the PAM pathway. Doing so prevents cross activation of the PAM pathway when both the estrogen receptor and CDK4/6 pathways are inhibited. And it can also restore our enhanced sensitivity to both endocrine therapy and CDK4/6 inhibitors. Because of the critical role in oncogenesis, the ability to interact and cross regulate other oncogenic pathways, we believe that the PAM pathway represents one of the most important targets in oncology.

Let's now turn to Slide 4. The challenge is that it's very hard to safely and efficaciously inhibit the PAM pathway. It is multiple components, each of which need to be inhibited to comprehensively blockaded. Otherwise, if only a single component is targeted, adaptive resistance arises and the pathway shutdown is limited. Further complicating the challenge of drugging this pathway is the narrow therapeutic [indiscernible] window that exists. There is a graveyard of drugs attempting to inhibit all of these components that were not efficacious to toxic or both.

The failures of these early generation PAM inhibitors, led drug developers to target single components of the pathway, such as PI3K-alpha, AKT or mTORC1, as a strategy to avoid toxicity. However, by compromising on the biological imperatives that requires comprehensive blockade of the pathway, the resulting drugs have typically only demonstrated efficacy in patient populations that have pathway mutations. As we initiated our development for gedatolisib, we hypothesized that the pathways relevance of the cancer driver was not a function of the presence or absence of a mutation. This meant that an inhibitor that could comprehensively shut down the pathway could potentially be efficacious in patients lacking common mutations such as PIK3CA.

Our second hypothesis was that a highly potent drug that avoided overexposure in key organs such as the liver and GI tract and was only dosed 3 times a month could potentially limit the incidence of the side effects associated with the pathway, such as hypoglycemia or diarrhea.

Let's turn now to Slide 5. Gedatolisib's differentiated mechanism of action and pharmacokinetic profile as a comprehensive TAM inhibitor results in a highly potent therapeutic that is shown in nonclinical models that it can achieve effective pathway shutdown with low nanomolar concentrations of drug in tumor cell models with or without PIK3CA mutations. And this opens up the opportunity to address an important unmet need for improved therapeutic options for the 37,000 patients with HR+/HER2- advanced breast cancer, whose disease progressed on or after treatment with a CDK4/6 inhibitor.

The need for better options for these patients makes, we believe the results for the gedatolisib triplet and doublet especially important. 76% and 67% reduction, respectively, in risk of disease progression or death and the 7.3 and 5.4-month improvement, respectively, over fulvestrant for the gedatolisib triplet and doublet were unprecedented. And with these results, we believe the gedatolisib regimens have the potential to establish a new standard of care for these patients.

Let's turn now to Slide 6. It's my pleasure now to introduce Dr. Igor Gorbatchevsky, our Chief Medical Officer. Igor will review the results that were presented on Saturday at the ESMO Congress in Berlin.

Thank you, Brian. Let's turn now to Slide 7. VIKTORIA-1 is a randomized open-label global Phase III study in patients with hormone positive/HER2- advanced breast cancer. VIKTORIA-1 study included patients with both PIK3CA mutation positive and wild-type disease. Today, we will be focusing on study design and review of the results that were presented for patients with PIK3CA wild-type disease.

Main eligibility criteria included both men and women, and patients who had disease progression on or after treatment with CDK4/6 inhibitor in combination with nonsteroidal aromatase inhibitor. Up to 2 lines of hormonal therapy was allowed, prior treatment with agent targeting PAM pathways was prohibited as well as prior chemotherapy for advanced breast cancer.

However, treatment with chemotherapy in neoadjuvant or adjuvant setting was allowed. Patients must have had measurable disease according to RECIST criteria and patients with endocrine resistant therapy was also eligible for this study. And then 392 patients were randomized in an equal manner 1:1:1 to receive therapy into 2 study arms and one control arm. Patients received target doses of palbociclib and fulvestrant. Gedatolisib was given at 180 milligrams intravenously over short infusion period on days 1, 8 and 15. These intermediate schedules, 3 weeks on and 1-week off provides in essence 2 weeks of therapy for patients, one patient can take time off between day 16 and 29 when the next cycle of treatment starts.

In Arm A, patients received triplet regimen of gedatolisib combined with palbociclib and fulvestrant. And in Arm B patient received doublet regimen where gedatolisib was combined with fulvestrant. In a controlled Arm C, patients received standard treatment fulvestrant.

The primary objective of this study was efficacy, which was assessed by comparing median progression-free survival between 2 treatment arms and control, Arm A versus Arm C and Arm B versus Arm C. Patients who were assigned to Arm A or Arm B received prophylactic therapy with mouth wash based on steroid water-based prophylactic therapy. And prophylactic non-sedating antihistamine treatment was recommended but not mandated in this study.

Let's turn now to Slide 8. 392 patients were randomized in this study. Most patients in the gedatolisib treatment arms received allocated therapy. 8 patients who were assigned to fulvestrant therapy did not receive it, and 95% of patients in a control arm who receive fulvestrant ultimately discontinued treatment due to disease progression.

Radiologic disease progression was less common in gedatolisib treatment arm. A small number of patients in each gedatolisib group discontinued study due to one or more adverse events that were assessed by investigator to be related to any of the treatment regimen.

Let's now turn to Slide 9. Demographics and baseline characteristics of patients were generally well balanced between all 3 treatment arms. All patients had advanced disease, 100% of patients who enrolled in the study had stage 4 disease with 80% of patients having liver and lung metastases. Additionally, patients who received less than 6 months of benefits on their prior endocrine therapy were eligible and accounted to 15% of patients enrolled in this study. This patient are often referred as endocrine therapy resistant and often excluded from studies evaluated in recent studies with SERD treatment. As expected, more patients in each arm received ribociclib than either palbociclib or abemaciclib as their prior CDK4/6 inhibitor.

Let's now turn to Slide 10. As we have previously announced, the gedatolisib triplet regimen produced a statistically significant and clinically meaningful improvement of 7.3 months in median progression-free survival over results achieved with the standard of care fulvestrant. So the triplet regimen median progression-free survival was 9.3 months, which results in hazard ratio of 0.24 meaning that we saw 76% reduction in the risk of disease progression or death. This level of efficacy has not been seen before in patients who were previously treated with CDK4/6 inhibitor. Unlike in most other trial settings, the initial steep drop in PFS curves that results from rapid early disease progression appears have to be accumulated in this study, as you can see in the Kaplan-Meier curve.

The median progression-free survival of 2 months for fulvestrant arm is similar to that has been reported in multitude of recently randomized Phase III studies. The gedatolisib doublet regimen also produced a statistically significant and clinically meaningful improvement of 5.4 months over standard of care fulvestrant. The hazard ratio was 0.33%, which means we saw 67% reduction in the risk of disease progression or death. And again, this level of efficacy has not been previously reported in patients who have been treated with cell cycle inhibitor.

Let's turn to Slide 11. Subgroup analysis demonstrates the clinical benefit of triplet was maintained across all subgroups that were predefined for analysis. All hazard ratio were less than one, and none of the confidence intervals overlapped one, notably with the patients who were enrolled in the United States and Canada, median progression-free survival was 19.3 months for gedatolisib triplet, and as you will see later, 14.9 months for gedatolisib doublet regimen. Additionally, efficacy was observed regardless of which prior cell cycle inhibitor was used for treatment of these patients.

Patients who received prior palbociclib benefited as much or more than those who had prior ribociclib or abemaciclib. This is the first time when randomized Phase III study, the data shows the benefits over treatment with palbociclib.

Let's now turn to Slide 12. Similar finding are seen for gedatolisib doublet regimen comparing this combination with standards of care fulvestrant. All point estimates for hazard ratio were less than 1. However, the upper limit of confidence interval included 1 in several characteristics group, most notably for those patients or disease progression occurred within first 6 months of treatment on their most recent therapy before including on the study.

Let's turn to Slide 13. When we compare triplet regimen and doublet regimen results for different subgroups of patients, there are several that show differences in median progression-free survival and hazard ratio comparing those 2 regimens. For example, it includes patients in pre and perimenopausal status, where median progression-free survival for triplet regimen was 11.1 months and 5.6 months for doublet regimen and resulting in hazard ratio of 0.13 for triplet and 0.33 for doublet. For patient who were enrolled in North America, United States and Canada, medium progression-free survival was 19.3 months for triplet and 14.9 months for doublet regimen with hazard ratio being 0.13 and 0.35, respectively.

Those patients who had visceral metastases at the beginning of the study median progression-free survival was 10.7 months for the triplet regiment and 7.3 months for the doublet with hazard ratio reflected in 0.214 triplet and [ 0.3 ] for doublet regiment. In those patients who had disease progression occurred within first 6 months of treatment on immediate prior therapy before inclusion in the study, median progression-free survival was 7.4 months for triplet regimen and 5.6 months for doublet regiment, which resulted in hazard ratio of 0.24 for triplet and 0.98 for doublet. Those patients who received palbociclib as their prior treatment, median progression-free survival was 16.6 months for triplet regiment and 7.6 months with the doublet, which resulted in hazard ratio of 0.21 for the triplet and 0.39 for the doublet.

While definitive conclusion cannot be drawn from a subgroup analysis. These results may reflect the contribution of CDK4/6 inhibitor in palbociclib containing triplet regimen compared to the doublet, providing additional clinical benefits in certain patient subgroups who may have more difficult-to-treat disease.

Let's turn to Slide 14. Promising trends for both the triplet and doublet regimens were seen in the interim overall survival analysis. However, the data is immature with almost 67 patients or 48% of a prespecified 140 events occurring at this time. These results are especially encouraging since the analysis includes 63 patients who crossed over from a control arm of fulvestrant to receive therapy with either triplet or double regimen, 80% of patients received triplet regimen and the rest of patients receive doublet of those who crossed over.

Let's turn to Slide 15. When we censored at the time of crossover, those patients who received treatment with gedatolisib, the overall survival curves have even greater separation with a trend towards significance in the interim analysis in both gedatolisib treatment arms.

Let's turn to Slide 16. Further assessment of efficacy with the objective response rate for the gedatolisib triplet was 32% compared to 1% for control with fulvestrant and the median duration of response was close to 18 months, exactly 17.5 months for triplet regimen. So the gedatolisib doublet regimen response rate was 28.3% and the median duration of response was 12 months. The median duration of response and incremental improvement relative to the control for gedatolisib triplet and doublet regimen are the highest reported for the endocrine-based treatment regimen in the second-line patients with hormone positive/HER2- advanced breast cancer.

Let's turn to Slide 17. The gedatolisib triplet and doublet regimens were generally well tolerated in this trial and resulted in discontinuation of study treatment due to treatment-related adverse events in the very few patients, 2.3 patients in a triplet regimen and 3.1 patients in the doublet regimen group compared to 0% of patients in the control arm.

Safety profiles were generally consistent with individual agents with no new safety signals observed in this study. Most of patients experienced adverse events of very low Grade 1 and 2 severity and few experience Grade 3 adverse events, except of the patient who experienced dermatitis neutropenia. Grade 4 adverse events only included neutropenia, which is as stated with treatment with palbociclib. It is important to note that there was no increase in number of neutropenic adverse events with the gedatolisib triplet regimen compared to historical data for palbociclib combination with fulvestrant. There was this very minimal changes in neutrophil levels for patients in a doublet regimen, only 2% of patients which confirm further previously reported data that gedatolisib does not induce neutropenia.

All grade hyperglycemia levels were low with 9.2% observed in triplet regimen and 11.5% in doublet regimen with all grade diarrhea of 16.9% in a triplet and 12.3% in a doublet regimen also was low and majority of those events were of a low grade. And each of this results quite unexpected for drugs that target PAM pathway.

Let's turn to Slide 18. In conclusion, this finally validates further the PAM pathway as a molecular driver in -- even in the patient with PIK3CA wild-type disease and support comprehensive PAM blockade with gedatolisib-based therapy as a potentially new standard of care for patients with advanced breast cancer.

Thank you, and I turn back to you, Brian.

Thank you, Igor. Let's turn now to Slide 19. Gedatolisib is addressing a significant unmet need for patients who have progressed on a prior CDK4/6 inhibitor. This is a significant patient group. We estimate there are roughly 37,000 patients who move on to second-line treatment after they've received treatment with a CDK4/6 inhibitor. And roughly 60% of them are PIK3CA wild-type and this is a very large opportunity. It was also a very real and very important need here. Current second-line treatment for these patients are limited in terms of added progression-free survival benefit. And our market research shows that oncologists are hungry for options that are more effective and have a safety profile they can manage.

And with such a large underserved market, we see a chance to build a strong presence for Celcuity. In light of the clinical benefit offered by the gedatolisib triplet and doublet, we're well positioned to address critical needs in this space. And a couple of points on market dynamics. IV administered drugs like gedatolisib fall under the medical benefit category, which means typically smoother reimbursement process compared to oral drugs under pharmacy benefits where payers tend to manage claims more heavily.

Additionally, unlike oral drugs, IV therapies offer the opportunity for practices to recover costs, which is particularly important in the community setting. And finally, breast cancer community is active, engaged and well supported by patient advocacy groups, which will help create awareness for new treatments such as gedatolisib. Based on our projections, this patient population represents a potential $5 billion addressable market.

Let's turn now to Slide 20. We have 3 important milestones coming up. First, we expect to submit a new drug application for the VIKTORIA-1 PIK3CA wild-type cohort indication this quarter. As we've previously disclosed, the FDA approved our application to the real-time oncology review program. And this program allows sponsors to submit data on a rolling basis so that the FDA can begin its review more quickly. We've already provided 2 pre-submissions to the FDA, and we expect to complete our NDA submission this quarter.

Second, we expect to present additional data at a major medical conference later this year. And third, we hope to report top line data for the VIKTORIA-1 PIK3CA mutation cohort by late Q1 or Q2 2026.

Let's now turn to Slide 21. As we started getting ready to report results on the PIK3CA mutant cohort of the VIKTORIA-1 trial, we analyzed data from patients who are treated with the same drug regimen evaluated in the VIKTORIA-1 study, gedatolisib combined with fulvestrant and palbociclib. This included a total of 90 patients from escalation arm B and expansion arms B, C and D of our Phase Ib study.

Patients in escalation arm B and expansion arms D and C received a 180-milligram dose of gedatolisib once weekly, while patients in expansion arm D received the same dose of gedatolisib but only on days 1, 8 and 15 of a 4-week cycle, which was the same intermittent dose regimen patients in the VIKTORIA-1 study received. Overall, 72% of these patients have received prior treatment with a CDK4/6 inhibitor and 71% received a weekly versus intermittent dose of gedatolisib.

For all patients with PIK3CA mutant tumors, median PFS was 14.6 months and the objective response rate or ORR in response evaluable patients was 48%. Median PFS was 19.7 months and the ORR was 64% in patients with PIK3CA mutant tumors who received the intermittent dose of gedatolisib. For all patients with PIK3CA wild-type tumors, median PFS was 9 months, and the objective response rate in response evaluable patients was 41%.

For patients with PIK3CA wild-type tumors who received the intermittent dose of gedatolisib median PFS was 9.1 months and the ORR was 53%. We're very encouraged by the median PFS at 14.6 months found in the entire PIK3CA mutant subgroup, particularly given the high proportion of patients who receive gedatolisib weekly, which we believe is a less effective dose schedule than the intermittent schedule.

And while the sample size is small, median PFS from patients whose tumors had PIK3CA mutations and who received the Phase III intermittent gedatolisib dose is promising and consistent with the results from the overall group. And we're looking forward to reporting Phase III data for this patient subgroup in 2026.

If we report positive results from the PIK3CA cohort, as we hope, we believe we'll be well positioned to offer an all-comer therapeutic option that oncologists can consider for patients independent of the PIK3CA, ESR1 or diabetic status. And again, on the importance of the PAM pathway, the breadth of patients gedatolisib can potentially treat. Gedatolisib has the potential to become the new backbone drug required to optimize outcomes for patients. This will position us well as we consider additional clinical development opportunities such as combinations with oral SERDs and indications in earlier lines of therapy.

Let's now turn to Slide 22. Well, that ends the presentation portion of our day, let's now turn to the Q&A session.

[Operator Instructions] Your first question comes from the line of Maury Raycroft with Jefferies.

Congrats on the update. I was going to ask one on just the hyperglycemia. So in the Phase III, you're showing a lower rate than in the Phase Ib study. What do you think accounts for this difference? And we're wondering if the 2 studies use the same protocol and grading criteria?

No, thanks for the question, Maury. They did use the same criteria -- same criteria used to evaluate diabetes and any changes in glucose. As far as the reason for the difference, it really is hard to say. I mean this is a larger study. So I think you placed more weight on the results from this study. It's a global study. So potentially, you had fewer patients that may have been obese or had glucose issues which are obviously associated with many patients in the U.S. But other than that, I don't think we can pinpoint a specific reason for the results we showed for diabetes or rather for hypoglycemia in the study.

Got it. Okay. And then I'll ask one more and then hop back in the queue. Just there was a lot of discussion around Roche's evERA data before ESMO. Now that we've seen the data, how do you think physicians would potentially use their regimen versus your regimen? Maybe if you can just comment on that.

Well, I think the data showed that the drug was effective in patients who had ESR1 mutations and that the drug didn't add a benefit relative to its control in patients who lack those mutations. And so based on that data, I would say that, that drug will be an option that physicians consider. I think a lot of these physicians will have experienced treating patients with everolimus, and they'll be familiar with that profile. I think the patients that regimen would address, which would be patients who are ESR1 mutant, PIK3CA wild-type, who are endocrine-sensitive, comprises roughly 15% of the total patient population.

And the reason why we think that is the population that, that drug would be mostly limited to, just as based on, I guess, our belief that we will show favorable results in the PIK3CA mutant pathway that would exceed those reported here. And then in the ESR1 wild-type patients we think our regimen is clearly differentiated results relative to those therapies. And so even with this regimen there, which is great, it's another option for patients.

We think we have the opportunity because we can, we think, more effectively address the needs of patients, roughly 85% of patients. We think we have the opportunity to become the go-to option for all these patients because we offer comparable efficacy in that small subgroup as the other regimen. But we think the familiarity and the experience that doctors will gain working with our regimen for the great bulk of their patients will, we would believe, likely lead them to rely on this regimen for all -- or for most of their patients.

Your next question comes from the line of Tara Bancroft with TD Cowen.

Congrats on the great data and the great feature at the conference. So my question, I guess, is if you could maybe elaborate a little bit more on the stomatitis events that you're seeing, like the timing of them, time to resolution? And I think with such a low discontinuation rate, I mean, it clearly [indiscernible]. I'm curious to hear also how it's managed and if it resolves while the patient stays on therapy and maybe -- or if it necessitates some kind of dose reduction anything along those lines?

Thanks, Tara. So we'll be reporting out more details on kind of safety profile of geda to future medical conference, including stomatitis. But in the meantime, we can say that we were a little surprised, to be frank, by the Grade 3 stomatitis. We did expect it to be lower based on some results from prior studies. It's hard for us at this point to pinpoint the reason for that, although we think probably the leading contender for that would be potentially a lack of compliance upfront with patients using the regimen.

One disadvantage when -- with our regimen for patients using prophylaxis is unlike with an oral drug that they might be using every day, there's not a daily reminder to use that prophylaxis. However, based on the analysis we did in our Phase Ib study, we found that even patients who -- most of those patients didn't receive any prophylaxis. But the dexamethasone mouth rinse was -- which is used to treat stomatitis, was found to be effective in reversing stomatitis, again, which is, we think, one of the reasons why patients are able to stay on therapy even with that incidence of stomatitis because ultimately, it resolves to a lower grade that allows them to stay on the treatment.

We also think because geda only dosed 3 times a month and only exposing patients to a Cmax concentration of drug 3 times during that month. But the general incident will be potentially less severe during the dosing window because essentially the gedatolisib concentration is reduced substantially over that dosing window stays well above the IC80 level needed for target engagement. And so we think the average dose level the patient is exposed to throughout the treatment cycle is lower and less likely to initiate or to aggravate adverse events. And so that while stomatitis manifests, we think it's treatable and reversible.

But we also think the general level of aggravation is one way to characterize it, the dermatitis may expose the patient to somewhat self-resolved because of the lower concentration that the patient sees during -- for the most part throughout the treatment period.

Your next question comes from the line of Andrew Berens with Leerink Partners.

Congrats on the results and execution, Brian. A couple of questions. I was wondering if you could comment on the agency's preference for BICR in an open-label trial. And if you think of evERA's use of local reads for their primary endpoint could become a regulatory issue for them?

And then another one on the stomatitis. One thing we noticed was -- it seems like the rate was higher with the triplet in this trial versus the doublet and also higher than that seen in the prostate trial. I'm wondering if this is something that's magnified by the CDK4/6 or choice of combination partner?

And then just a question on the IT, because I've gotten a lot of questions on it from investors. Just can you run through what you currently have for geda? And what potential strategies you're using to extend the runway?

Okay. Okay. Andy. Okay. So the first question relates to BICR, blinded independent central review. It's the guidance of the FDA as well as the European Medicines Agency that studies that are open label where the investigators and physicians know what therapy they're prescribing or they're treating the patients with should use a blinded reviewers of the scans to limit or eliminate the potential bias that could accrue to investigators who know which treatment they're providing. And so with a blinded independent review, you eliminate that bias, which obviously is why the FDA and EMA look for that.

It is surprising to us when there are open-label studies that use investigator-assessed PFS. Based on our interactions with the agency, we received very, very -- I guess, firm recommendations that we use blinded independent central review. So I can't explain what other sponsors do and what the rationale was, but I do know that we followed the agency's recommendations.

Regarding stomatitis and being higher in the triplet and doublet. And we do think there is some stomatitis that accrues to palbociclib. If you look at their Phase III studies, PALOMA-2 and 3, you see that there is some incidence of stomatitis. So that's probably one area where there's a bit of an overlap of adverse events between geda and palbo.

It's interesting you pointed out the results we reported in prostate cancer, where there was very little stomatitis overall. And so we think that there seems to be some greater sensitivity for women with breast cancer than there is for men with prostate cancer, which, again, is at this time, hard for us to explain.

One further follow-up to the question that Tara asked regarding stomatitis. I would say one of the reasons why we were surprised by the stomatitis results is that we didn't hear much commentary from investigators throughout the course of the study. And again, we've been working with investigators for over 2 years now, treating patients and our medical team regularly interact with physicians, providing a follow-up and questions. And we just did not hear very much about stomatitis at all. And so again, over the course of the study, you get exposed to questions about safety, how to mitigate adverse events. And really, there just was not much dialogue on that.

So that somewhat is consistent with what we observed in the Phase Ib, which is that just the overall pharmacokinetic profile of geda, results in maybe a less difficult to -- or easier to manage, I guess, type of stomatitis or incidence of stomatitis than maybe the case with drugs that are prescribed on a daily basis, such as an oral drug where you're hitting Cmax every day.

I guess, and finally, the third question you asked regarding intellectual property. So we have a series of 3 patent families that we think will ultimately help extend exclusive period for geda to sometime in 2042. The first layer of protection for exclusivity relates to our [ ATI ] patent in the drug substance product patent, and that patent will provide exclusivity through the end of 2034. We have a composition of matter patent related to our dosing formulation or rather a drug formulation. And that involves a functional excipient, which essentially is what's required to ensure stability of the drug. And so it's not substitutable. Essentially, if functional excipient performs a role that's required to achieve the necessary parameters for it to be reliably produced and used in the clinic. And so that patent will expire sometime in 2041.

And then we also received earlier this year a patent for the dosing schedule that used -- that we used in this trial, 3 week on, 1 week off. And that's schedule will be incorporated on the label, and that would be included on the orange -- in the Orange Book. And so we think that patent will serve to prevent the agency from granting approval to any ANDA submission as a result, essentially, these dosing patents are very strong and really serve as effective barriers to generics coming in.

And so a combination of those patents as well as other work that we're doing that could further extend the exclusive period, give us confidence that we have a very long runway, at least until 2042 to develop gedatolisib for additional indications.

Okay. Does the actual work that you're mentioning is that potentially include a subcutaneous version?

We're working on a lot of different things that we think will have the opportunity to improve the ability of gedatolisib to provide a benefit to patients. And if we're successful in launching those, then we think the -- one of the results would be that we would extend the exclusive period as well.

Your next question comes from the line of Brad Canino with Guggenheim Securities.

This is [indiscernible] on for Brad. Congrats on all the ESMO update. So just regarding the observed positive OS trend for VIKTORIA-1 at the interim analysis? And how have you designed study to ensure that it has the ability to demonstrate statistical significance with more mature follow-up? And then what is the competitiveness of an outcome in the treatment setting?

You were fading a little in and out. Could you just maybe repeat a bit about your question regarding the overall survival data?

Sorry. I guess for the -- regarding the positive OS trend, how have you designed the study to ensure that it has the ability to demonstrate stat sig with more mature follow-up and what is the competitive significance of that of reaching an outcome in this treatment setting?

Okay. So the primary endpoints were PFS and the FDA requires a time of primary analysis that you do an interim look at overall survival to confirm or rather to determine whether there's any decrement to patients' overall survival. One of the thresholds that they make very clear, you need to not trip is showing any decrease in the likelihood of survival for patients on the study therapy. We showed in this interim analysis, very favorable trend. I mean, obviously, it's immature and so not going to achieve statistical significance. We're also encouraged by the sensitivity analysis that excluded the patients, stat sig patients who had crossover.

And so again, with overall survival analysis in the second-line studies, you haven't seen before positive OS data. You've seen favorable trends. One of the challenges to getting -- reaching to statistical significant is that the number of events that -- and the size of the studies in the second-line setting in breast cancer tend to be smaller. And so the delta needed between -- to show and survival between the study arm and control arms tends -- needs to be bigger as a result, not -- and so it's more of a statistical hurdle, not necessarily a therapeutic hurdle.

But one strategy that we did employ though, to maximize the chance of potentially achieving statistical significance is that we had a statistical design that analyzed all the endpoints in a hierarchical manner. And the reason for that is that by testing and then only proceeding to the next analysis upon positive achievement of the end point. In the prior analysis, you preserve your alpha. And so the benefit of that then with the results that we've reported is that we'll have the full alpha available when the overall -- final overall survival analysis is performed, which we estimate would be sometime in early 2027.

Your next question comes from the line of Stephen D. Willey with Stifel.

And apologize for the background noise. Congrats on [indiscernible]. I was just curious, I know Igor kind of spoke to it in his review of the data. But just curious if you have any thoughts or hypotheses around what appears to be preferential activity of geda occurring in patients post-palbo. I think you see it in the triplet, you see in the doublet. I think the inverse is true for abema. And just curious if you think that, that's a byproduct of the CDK4/6 inhibitor itself? Is that a byproduct of just where these drugs are being used geographically in site enrollment? Just curious if you have any thoughts there. And just have a quick follow-up.

Right. Well, I think it's hard to tease out the difference there. I mean I think we can look at different patient characteristics. It's unlikely in a randomized study that we would see much difference in these patient characteristics unless there were starting physicians targeting treatment with palbociclib for different patients in a way that may be different than the population that receive ribo, but we think that's unlikely.

Yes, I would point out that the hazard ratio for both ribo and palbo 0.22 and 0.21 were very similar. I think the median PFS was much higher with palbo. And again, that can potentially just be a bit of a statistical quirk because you're dealing with a smaller subgroup of data. I think the main takeaway is that I think there hasn't been before any data that is shown, you can retreat patients with palbo with a different endocrine therapy and induce a benefit.

And so with this data kind of confirms is that there's a general role that the CDK4/6 pathway continues to play despite the patient's progression while they were on CDK4/6. Essentially, if the tumor seems to adapt to reliance on other pathways. And so that by blockading the PAM pathway and continuing to blockade the ER pathway. Our nonclinical models suggest that reactivates the CDK4/6 pathway and those resensitizes patients with CDK4/6 inhibitors. And this data suggests that there's -- it's a class effect. It doesn't really matter with CDK4/6 inhibitor patients will have received.

Now I suppose the caveat would be abemaciclib. Although the treatment -- the hazard ratio for abemaciclib was still very, very good. I forget the number off the top of my head, but it's still very, very favorable relative to what's been reported previously. I think those results tend to be consistent with other drugs that follow abema. There seems to be some difference in how patients who received abema respond to subsequent therapy compared to ribo and palbo. And I'm not sure that is something that we can readily explain.

Understood. And then maybe just a follow-up on the prostate trial. I think it was noted that there's an intention to add, I think, 2 higher doses protocol. And just curious as to, I guess, a, what you're trying to achieve with the higher dose? And then b, whether or not the PSA data that you may or may not have seen from that trial seems to suggest that there is indeed a dose-dependent effect. I think there was a little bit of a step down in radiographic PFS at the higher dose. I know small patient numbers populated like Kaplan-Meier curve. Just curious on the higher dose strategy and your...

Sure. No, I think that's a great question. That's a question we're asking ourselves, which -- what -- how do we best identify the most appropriate dose. And so on the one hand, the numbers said that the lower dose did better than the higher dose, small sample numbers, sample sizes. And so you want to be careful about drawing too firm a conclusion. Given how well tolerated the combination was in these patients, almost no diarrhea, hypoglycemia, stomatitis. We felt that it was important to explore higher doses because essentially when you're going into a new tumor type, you can't make assumptions that how patients respond or the dosing will be recapitulated in prostate in this case versus breast cancer.

Clearly, there seems to be a different response to geda from an AE standpoint for the men in prostate and the women in breast. Additionally, prostate cancer presents mostly as bone-only disease. Only roughly 20% of patients have any form of visceral metastases, which is the inverse of breast cancer, where most of these patients have some form of visceral disease they may have a fair amount of bone disease participating, but there's infrequent, probably 20% of women who only have bone-only disease, no visceral mask. And so because of that different presentation, we, again, want to make sure we fully analyze or in a position to analyze the potential relationship of dose to response.

And so going to a higher dose would potentially allow us to tease out whether there is a dose response or not. We don't want to make a decision just on the basis of the 2 arms we evaluated. And in drug development, the last thing we want to do is go to a Phase III with a suboptimal dose. And so we just concluded that it's really important to make sure we step back answer some questions now before you get to the Phase III and really be confident that we have a valid data set to support selection of what we hope, depending on the results would be the dose used in the Phase III study.

Your last question comes from the line of Gil Blum with Needham & Co.

Allow me to also have my congratulations on the results. Maybe going back to the Roche data. Just what do you think would be required assuming there would be changes to the standard of care with the addition of oral SERDs. Currently all the studies are against fulvestrant. And would you think any additional studies would be required for slotting here? Or this would be label dependent?

Gil, I'm not sure I quite understood the question. Are you asking me for a general comment on SERDs or are you asking a question as it relates to gedatolisib?

As it relates to gedatolisib and the changes -- potential changes in the standard of care as it relates to oral SERDs?

Okay. Well, we think the data that we have will support registration. There's not going to be a look back on what therapies were used in the study. As far as going forward, there's a bit of a to-be-determined aspect to this. On the one hand, it's always important to demonstrate that a drug like geda can be safely combined with the various SERDs. So that would be one step to take just to ensure that physicians wanted to consider use of one oral SERD and combined with geda they had data -- they would need data to confirm that we save for their patients for that to occur.

And as far as the regulatory strategy and how to incorporate a SERD into a geda regimen that's -- there's some complexity around that, and we're obviously still thinking that through with our Phase III data in wild-type. We want to see what we see in mutant. I mean, we feel confident about that. But until you get the data, you don't know. And that will allow us to kind of more fulsomely understand how to think about the opportunity to do some work with oral SERDs and potentially create additional options for patients.

Great. And as it relates to the additional data disclosures from the VIKTORIA-1 study, what the proportion of ESR1 mutant patients be disclosed at some point or at a later stage?

We'll be reporting additional data and those types of subgroup analysis are on the list.

Great. And congrats again.

That concludes our Q&A session. I will now turn the call back over to Brian Sullivan, CEO and Co-Founder of Celcuity for closing remarks.

Well, thank you for joining us today. We appreciate your interest in Celcuity, and I look forward to speaking with everyone at some point in the future. Take care. Goodbye.

Ladies and gentlemen, thank you all for joining, and you may now disconnect. Everyone, have a great day.

Good afternoon, ladies and gentlemen, and welcome to the Celcuity Second Quarter 2025 Financial Results Webcast and Conference Call. [Operator Instructions]

I would now like to turn the conference over to Apoorva Chaloori with ICR Healthcare. Please go ahead.

Thank you, operator, and good afternoon to everyone. Thank you for joining us to review Celcuity's Second Quarter 2025 Financial Results and Business Update. Earlier today, Celcuity, Inc. released financial results for the second quarter ended June 30, 2025. The press release can be found on the Investors section of Celcuity's website.

Joining me on the call today are Brian Sullivan, Celcuity's Chief Executive Officer and Co-Founder; Vicky Hahne, Chief Financial Officer; as well as Igor Gorbatchevsky, Chief Medical Officer, who will be available during Q&A.

Before we begin, I would like to remind listeners that our comments today will include some forward-looking statements. These statements involve a number of risks and uncertainties, which are outlined in today's press release and in our reports and filings with the SEC. Actual events or results may differ materially from those projected in the forward-looking statements. Such forward-looking statements and their implications involve known and unknown risks, uncertainties and other factors that may cause actual results or performance to differ materially from those projected.

On this call, we will also refer to non-GAAP financial measures. These non-GAAP measures are used by management to make strategic decisions, forecast future results and evaluate the company's current performance. Management believes the presentation of these non-GAAP financial measures is useful for investors' understanding and assessment of the company's ongoing core operations and prospects for the future. You can find the table reconciling the non-GAAP financial measures to GAAP measures in today's press release.

And with that, I would now like to turn the call over to Brian Sullivan. CEO of Celcuity. Please go ahead.

Thank you, Apoorva, and good afternoon, everyone. Thank you for joining our second quarter financial results conference call.

Past few months have been eventful ones for Celcuity. We achieved several significant milestones, and we believe these milestones lay the foundation for us to potentially establish gedatolisib as a new standard of care therapy for patients with HR-positive, HER2-negative advanced breast cancer.

The first and most importantly, of course, was the positive top line data we reported from the PIK3CA wild-type cohort of our Phase III VIKTORIA-1 clinical trial. In patients with HR-positive, HER2-negative, PIK3CA wild-type advanced breast cancer, gedatolisib plus fulvestrant and palbociclib or the gedatolisib triplet and gedatolisib plus fulvestrant or the gedatolisib doublet met the study's 2 primary endpoints by demonstrating statistically significant and clinically meaningful improvement in progression-free survival or PFS versus fulvestrant. The reported hazard ratios and improvements in median PFS are unprecedented in HR-positive, HER2-negative advanced breast cancer.

We believe these data validate our hypothesis that the role of the PI3K, AKT, mTOR or PAM pathway as a cancer driver is not solely a function of the presence of a pathway mutation. The implications are profound for patients with HR-positive, HER2-negative advanced breast cancer as we seek to advance gedatolisib as a therapeutic option for patients with or without PIK3CA mutations in both the second-line and first-line settings.

Second important milestone achieved was the dosing of the first patient in our Phase III VIKTORIA-2 clinical trial. This trial is evaluating gedatolisib in combination with a CDK4/6 inhibitor and fulvestrant as first-line treatment for patients with HR-positive, HER2-negative advanced breast cancer.

The third milestone was the announcement of favorable preliminary top line results from 2 early-phase clinical trials. One, evaluating gedatolisib and darolutamide in men with metastatic castration-resistant prostate cancer, and a second one that evaluated gedatolisib and trastuzumab biosimilar in patients with HER2-positive, PIK3CA-mutated metastatic breast cancer.

Fourth milestone was the extension of our patent exclusivity for gedatolisib into 2042 with the issuance of a new dosing regimen patent for gedatolisib.

And finally, we raised around $287 million through public offerings of convertible notes, common stock and prefunded warrants that provide the funding that should allow us to aggressively prepare for and launch gedatolisib should we get FDA approval next year.

I'd like now to turn to the VIKTORIA-1 trial. Last month, we announced top line results from this trial. Median progression-free survival or PFS for the gedatolisib triplet was 9.3 months compared to only 2 months for fulvestrant, 7.3 months incremental improvement in median PFS. The hazard ratio was 0.24, which translates to 4.2x higher likelihood of survival without disease progression for the gedatolisib triplet than fulvestrant.

With the gedatolisib doublet, median PFS was 7.4 months, again, compared to only 2 months for fulvestrant, a 5.4-month incremental improvement in median PFS. The hazard ratio was 0.33, which translates to 3x higher likelihood of survival without disease progression for the gedatolisib doublet than fulvestrant.

Now these results established several new milestones in the history of drug development for this patient population. First, the hazard ratios reported for both the geda triplet and doublet were the most favorable ever reported by any Phase III trial, first line, second line or third line in this population. And second, the incremental improvements in median PFS for the triplet and doublet, 7.3 and 5.4 months, respectively, were the highest ever reported by any Phase III trial for this patient population receiving at least their second line of therapy for advanced disease. And third, gedatolisib is the first PAM inhibitor to achieve a positive Phase III data result in patients with PIK3CA wild-type tumors and whose disease progressed on or after treatment with a CDK4/6 inhibitor.

And for comparison purposes, it's important to note that several Phase III studies in this patient population have reported data recently. In these studies, the incremental improvement in median PFS ranged from 1.7 to 3.9 months and the hazard ratios ranged from 0.55 to 0.73. Both gedatolisib regimens exhibited a favorable safety profile, including lower rates of hypoglycemia and stomatitis, and the rate of discontinuation of all treatment due to a treatment-related adverse event was lower than was reported in a Phase Ib study in this patient population.

In light of the favorable safety profile, more favorable hazard ratios and longer incremental PFS with the gedatolisib regimens than the other currently available or investigational agents, we believe both the gedatolisib triplet and double each have the potential to establish a new standard of care for these patients. We're on track to submit a new drug application to the FDA in the fourth quarter of 2025 for geda based on data from the PIK3CA wild-type cohort, and we're looking forward to presenting the full data set later this year at an upcoming medical conference. Additionally, we expect to release top line data for the VIKTORIA-1 PIK3CA mutation cohort by the end of 2025.

Moving on, I want to share just a quick overview of the market landscape we see for gedatolisib and how we're gearing up for a potential launch should we get FDA approval. We think the market looks very promising for gedatolisib. We estimate there are 34,000 patients moving to second-line treatment after progressing on a CDK4/6 inhibitor, and roughly 60% of them are PIK3CA wild type. That's a very large opportunity.

And there's also a significant need for more efficacious therapies than those currently available. Currently approved therapies only offer 2 to 4 months of median PFS. With gedatolisib's unique mechanism of action, corresponding clinical benefit, it's well positioned to address critical needs in the second-line space. And this unmet need has been verified in our market research, which shows that oncologists are hungry for options that are more effective and have a safety profile they can manage. And as we've discussed on prior calls, efficacy and safety are the 2 primary criteria oncologists use to select therapies for their patients. This is also consistent with the criteria used by treatment guidelines, such as NCCN, to determine recommendation categories for drug treatments.

Additionally, as an IV-administered therapy, we believe gedatolisib will be very well received in the community practice setting where over 80% of patients are treated. Gedatolisib will fall under the medical benefit category, which means typically a smoother reimbursement process compared to oral drugs that fall under the pharmacy benefit category. For oral drugs, payers tend to manage claims more heavily, resulting in a more cumbersome prescribing and reimbursement process for practices. And unlike oral drugs, IV-administered therapies also allow physicians to recover costs associated with the purchase and administration of therapy and to better ensure patient compliance with the treatment regimen.

And finally, the breast cancer community is active, engaged and well supported by advocacy groups, which will help create awareness for new treatments in general and we think for gedatolisib specifically.

As a result, we believe Celcuity has the opportunity to build a strong presence amongst medical oncologists to address this large underserved patient population. And based on our projections, we believe the addressable market potential for a standard of care second-line therapy to treat this patient population is roughly $5 billion.

I'd like now to turn to our Phase III VIKTORIA-2 trial. Last month, we announced that we dosed the first patient in VIKTORIA-2 that's evaluating gedatolisib plus a CDK4/6 inhibitor that the investigator may choose and fulvestrant as first-line treatment for patients who have endocrine therapy-resistant, HR-positive, HER2-negative advanced breast cancer.

The standard of care first-line treatment for most endocrine therapy-resistant patients includes any 1 of 3 approved CDK4/6 inhibitors combined with fulvestrant. And results from a recent trial suggests the median progression-free survival period for patients receiving one of these 3 regimens is only about 7 to 8 months and highlighting the significant need for more efficacious frontline therapy for these patients. We believe the positive top line data from the PIK3CA wild-type cohort of our VIKTORIA-1 study augurs well for the gedatolisib triplet in this patient population.

I'd like now to turn to our Phase Ib/II clinical trial that's evaluating gedatolisib in combination with darolutamide in men with metastatic castration-resistant prostate cancer. In late June, we announced encouraging Phase Ib preliminary efficacy and safety data from this study, which enrolled 38 prostate cancer patients who were randomly assigned to either receive 80 milligrams of darolutamide twice daily combined with either 120 milligrams of gedatolisib in arm 1 or 180 milligrams of gedatolisib in arm 2. And gedatolisib was administered once weekly for 3 weeks and then 1 week off in both arms.

The preliminary analysis for the combined arms show the 6-month radiographic PFS rate was 66%, which compares favorably to published data for androgen receptor inhibitors in this setting. Additionally, the data highlighted the favorable safety profile of this novel combination. There were no treatment-related discontinuations, and less than 3% of patients experienced grade 3 stomatitis.

These data indicate that the optimal gedatolisib dose for this patient population may not yet have been reached. And we believe it's important to explore additional dose options for gedatolisib. As such, we amended the clinical trial protocol to enable exploration of additional doses in the Phase Ib portion of this clinical trial to determine the recommended Phase II dose.

In addition to announcing encouraging preliminary data from our prostate cancer trial, we also announced encouraging data from an investigator-sponsored Phase II clinical trial. In this trial, 44 patients with HER2-positive, PIK3CA-mutated breast cancer were treated with gedatolisib plus standard doses of trastuzumab biosimilar. No prophylaxis for stomatitis was administered. The median number of prior anti-HER2 therapies enrolled patients received in the metastatic setting was 4 or more, 86% of patients that received at least 3 prior anti-HER2 therapies. So these patients were heavily pretreated.

The overall response rate was 43%, and no patients discontinued gedatolisib due to a treatment-related adverse event. Achieving 43% overall response rate in patients receiving a fourth or fifth line of anti-HER2 treatment for their disease is very encouraging and compares favorably to published data for other available therapies in this group of patients. It also suggests gedatolisib in combination with HER2-targeted therapy may be an effective and well-tolerated therapeutic option for patients with HER2-positive metastatic breast cancer.

Now I'd like to turn to a few corporate updates. First, U.S. Patent and Trademark Office issued Celcuity a new patent covering the clinical dosing regimen for gedatolisib in HR-positive, HER2-negative breast cancer patients. The patent extends gedatolisib's patent exclusivity in the U.S. into 2042. And with this added patent exclusivity, we expect to have a long runway to optimize development of gedatolisib.

And last but not least, we also completed concurrent offerings of convertible notes, common stock and prefunded warrants with net proceeds of $286.5 million at the end of July and beginning of August. With our current resources and other financing arrangements, we believe we are well positioned to advance multiple blockbuster indications in breast and prostate cancer and to aggressively prepare for and launch gedatolisib commercially should we receive FDA approval.

I'd like now to hand the call over to Vicky Hahne, our CFO, to review our finances.

Thank you, Brian, and good afternoon, everyone. I'll provide a brief overview of our financial results for the second quarter of 2025.

Our second quarter net loss was $45.3 million or $1.04 per share compared to $23.7 million net loss or $0.62 per share for the second quarter of 2024. Our non-GAAP adjusted net loss was $40.5 million or $0.93 per share for the second quarter of 2025 compared to non-GAAP adjusted net loss of $22.2 million or $0.58 per share for the second quarter of 2024.

Research and development expenses were $40.2 million for the second quarter of 2025 compared to $22.5 million for the second quarter of 2024. Of the approximately $17.7 million increase in R&D expenses, $6.6 million was related to increased employee and consulting expenses, $6.1 million was related to increased research and development costs primarily attributable to activities supporting our ongoing clinical trials, and $5 million is related to an anticipated development milestone payment under the license agreement with Pfizer.

General and administrative expenses were $3.8 million for the second quarter of 2025 compared to $1.8 million for the second quarter of 2024. Of the $2 million increase in general and administrative expenses, $1.6 million was related to increased employee and consulting expenses. The remaining $0.4 million of the $2 million increase resulted from professional fees, expanding infrastructure and other administrative expenses.

Net cash used in operating activities for the second quarter of 2025 was $36.2 million compared to $18.1 million for the second quarter of 2024. We ended the quarter with approximately $168.4 million of cash, cash equivalents and short-term investments. However, on a pro forma basis, taking into account the net proceeds of our financing activities in Q3, cash, cash equivalents and short-term investments as of the end of Q2 2025 was approximately $455 million.

Additionally, existing financing arrangements are expected to give us access to an incremental $160 million of cash over the next few quarters, $80 million from our current term loan agreement and $36 million from the exercise of soon-to-expire in-the-money warrants. As a result, we believe we have the resources and financing in place to fund our operations through 2027.

I will now hand the call back to Brian.

Thank you, Vicky. Operator, could you please open the call for questions?

[Operator Instructions] Your first question comes from the line of Maury Raycroft from Jefferies.

This is Amin on for Maury. Congrats on all the progress. A couple of questions from us. First, regarding the upcoming full data presentation later this year for PIK3CA wild-type portion of the Phase III study, can you elaborate on what we should expect to see? Specifically, will you be sharing subgroup analysis, such as PFS analysis for ESR1 wild type and mutant cohorts there? And then I have a follow-up.

Sure. So we'll be focused on our initial data presentation on the primary analyses, the primary endpoints. And then we would expect to present data at subsequent meetings, additional subgroup analyses.

Okay. Sounds good. And for the PIK3CA mutant population, how are you thinking about the benchmarks for success here? Is there a specific hazard ratio or PFS delta that you are considering a meaningful threshold there and could be considered clinically meaningful?

So I think there are 2 thresholds to consider when we're reviewing the data in that cohort. The first is the comparison to the control, which in this case is alpelisib/fulvestrant. As it turns out, given what we think is the likely outcome based on historical data for alpelisib in this population of between, let's say, 7 to 8 months, a statistically significant result would also be a clinically meaningful result of a little less than 3 months. So we think if we have a positive study, we'll also be reporting clinically meaningful results.

Additionally, because alpelisib is probably no longer the primary option that physicians are relying on, we think from a practical standpoint, the benchmark data that physicians will consider will be the data for capivasertib, an AKT inhibitor. And [ capi data's ] reported data in the post-CDK population of about 5.5 months of median PFS. So if we're able to report positive results relative to alpelisib, those will be especially positive relative to our capivasertib.

Your next question is from the line of Tara Bancroft from TD Cowen.

This is Frances on for Tara Bancroft. So just one question on our end. So since the full safety data isn't broken out in the top line, is there any more detail you can offer ahead of it? If there's better rates observed, was that overall rates or just grade 3 stomatitis and...

Sure. So we'll be providing that data at the upcoming conference. We were really only at this stage able to provide a general summary of what we saw, but the additional detail will be forthcoming.

Your next question is from the line of Andrew Berens from Leerink Partners.

This is Eason on for Andy. Congrats on all the progress. Just a 2-parter if I can. So we noticed across various pivotal trials in the HR-positive, HER2-negative breast cancer space, it's been mixed whether the PFS primary endpoint was based on BICR, as is the case in VIKTORIA-1, or based on investigator assessment. So first question is, can we expect the PFS analysis based on investigator assessment to be presented at an upcoming meeting later this year?

And then second, what is the company's understanding on the concordance between BICR versus investigator assessment based on what we've seen in prior HR-positive, HER2-negative trials as well as how is this aspect evaluated by FDA and other regulatory agencies?

Sure. No, thanks. So the selection of BICR for our study as the assessment method was a function of our study being an open-label study, and that just reflects that gedatolisib is an IV-administered drug and you can't really have a plausible placebo, and you use blinded assessment of the scans to ensure that you're eliminating the potential for investigator bias. And that's why you saw -- see that the trials for the recent oral SERDs, the EMERALD trial and the VERITAC-2 trial were also BICR studies because, again, not plausible to create a placebo for fulvestrant.

And so BICR is the method that the FDA actually encourages or recommends when you do have an open-label study for that purpose. And so in this case then, the investigator data is really simply collected as part of ongoing assessment. And it's more for exploratory sensitivity analysis. And so it's not a fundamental analysis, and we'll be reporting data, as I indicated earlier, in the sequence as we move from one conference to another.

But -- and to your question regarding concordance, I think I saw one study that showed the concordance between the hazard ratios. A BICR PFS and the investigator-assessed PFS were -- I think, correlated well over 90%. It may even have been 95%.

And so we do not expect to have any issues on that front. We've -- in the process as we prepare for NDA doing sensitivity analysis, many of which were prescribed by the FDA in our discussions with them about our statistical analysis plan. And all the sensitivity analyses are indicating that our data is very robust, and we're very comfortable and confident about the package that we expect to submit to the FDA.

Your next question is from the line of Stephen Willey from Stifel.

I was just wondering how you're now thinking about launch-readiness. You're going to be filing an NDA here in the fourth quarter. You've got breakthrough. Presumably, there's an RTOR pathway you can leverage. So what are some of the comps, I guess, that you look to in terms of the requisite amount of infrastructure build that you need? And how do you think about scaling that infrastructure here over the near term and as we get into '26?

Sure. No, that's a great question. So a couple of points to highlight. First, we began building our team last year. We hired our Chief Commercial Officer, Eldon Mayer, in first quarter 2024. And then he in turn brought on board a head of marketing, head of market access, head of commercial operations. And they focused on projects that have a long lead time, and there are a variety of those that can take up to 18 months to get done.

And so essentially, we've been working back from a launch date. You have to assume an earlier launch date or you're kind of aggressive on when you think that will occur just so you're not blindsided and you're ready under any circumstance. And now as we've gotten closer to launch these past few months, we've begun hiring the individuals who report up to the heads of these various departments, and in turn, they have been taking on more projects.

Now that we have our data, we have what we think is a clear path to an approval decision, which we can kind of -- where we can define with some degree of confidence a launch date, we'll be taking that next step. And so that will involve additional infrastructure associated in the commercial operations area to support sales force, to supporting MSL force. There's activities in the market access area engaging with payers, strategic accounts in ways that are appropriate at this stage. And then in turn, you start to build out your sales force management structure, starting with head of sales and then regional management, which in turn requires you to define sales territories, number of territories, the geographic alignment, et cetera. So all those projects are on track.

And as far as how are we doing and what is our benchmark, we've been very deliberate about hiring folks in all of these key positions, people who have been involved in first launch of a company's -- first drug launch for a company. And that's critical because there's so much infrastructure, operational support activities that are required to be effective as a commercial organization. It's not a plug-and-play if somebody coming from big pharma has never had to set up all of this infrastructure or to establish these processes and these functions from scratch.

So I think we've been very, very fortunate. We've hired a great team, incredibly experienced, very focused. And I think we're absolutely on track to having what we think -- we're optimistic about the launch and our ability to be very, very effective in communicating the benefits of or what we believe are the benefits of geda to medical oncologists.

Your next question is from the line of Gil Blum from Needham & Company.

This is Gil Blum on for Gil. So just a couple from us. Can you put into context the practical ramifications for physicians now that they may have optionality with both a doublet and triplet? And I have a follow-on.

Well, I think the primary, I think, goal of all these physicians is to optimize and delay as long as possible the progression of a patient's disease, and the triplet offers that to these doctors. Now the triplet, because it includes palbociclib, also induces some myelosuppression, which for patients who could be elderly or have immune -- an immune system that may be more compromised, they may consider not to be appropriate. And so they'll have the option of still getting very, very, we believe, extended incremental benefit in PFS.

And so what we think having either regimen available does is allow us to have access to as broad a range of patients as possible. And that's always great. And then I think as we get into and describe results for different subgroups, I think that will help guide some of the decision-making for different subgroups for physicians and how they might want to think about the doublet versus the triplet as an example.

Very helpful. And just as a follow-on to Steve's question, is there any consideration on commercial partnering strategy for a launch? I mean it looks like it might be a very large investment just given the size of the market.

No, we're expecting and planning to launch ourselves. We think we understand what's -- we know what's required. We have a very, very detailed operating plan and operating budget. We know what the head count is and why we need to bring them on. The investment is not insignificant, but it's not ridiculous, to be frank. And relative to the size of the opportunity, it's very manageable.

And so we've financed ourselves accordingly. That's the other part of the equation, obviously, is having sufficient capital to invest aggressively in the launch. And we think we've set ourselves up very well with our balance sheet to do that. And so just purely from a financial perspective and financial return perspective, it makes absolute sense for us to be launching this ourselves and not to be partnering with somebody.

Your last question comes from the line of Chase Knickerbocker from Craig-Hallum.

Maybe, Brian, just to start, can you kind of just give us your general thoughts on kind of the competitive landscape in the mutant population? There's obviously some other actionable mutations in there with ESR, et cetera. So can you just give us your general, too early thoughts as far as the competitive environment there and how you see kind of geda fitting in?

Right. So I think 2 things. I mean for PIK3CA mutation patients, we'll be reporting out that data later this year. Obviously, if our data is positive and shows benefit relative to alpelisib, we think that will position us very well to establish geda as a new potential standard of care. So we'll be taking -- we think that will kind of speak for itself.

As far as the ESR1 mutations, we just don't think they'll be as relevant given the nature of the drug combination that we have. In the absence of inhibition of, let's say, CDK4/6 or the PAM pathway potentially in ESR1 mutant patients, I mean data suggests that you can get some incremental benefit if you use an oral SERD to address that pathway. And at the same time, we think if you are addressing the PAM pathway and CDK4/6, the relative difference in outcomes between the ESR1 mutant and wild-type patients is unlikely to be meaningfully different.

Got it. Mainly -- maybe just on the mutant side, to dig in a little bit there, obviously, the most recent approval there with Itovebi, I mean can you just give us some thoughts as far as kind of how the market has changed in the last kind of 10, 12 months and any relative comparisons there?

Sure. So I kind of still use the generic name inavolisib. That drug is an alpha -- PI3K-alpha inhibitor. It's approved for treating patients who have a PIK3CA mutation in the first-line setting for women who have endocrine treatment-resistant disease, advanced disease. And that's actually the patient population that will be -- that we're addressing in our VIKTORIA-2 study.

So that population doesn't overlap at all with the population that we'll be addressing with the VIKTORIA-1 study results. And so the data does provide confirmation that in the frontline setting, treatment-naive patients have involvement of the PAM pathway in their disease and they'll benefit. In this case, this drug has only shown activity and favorable activity in patients that have a PIK3CA mutation. That drug also has some -- induces levels of hypoglycemia that can potentially limit its use to patients who are healthy metabolically, which means they are not prediabetic or not diabetic at all.

And we would hope, and that's what our trial will evaluate, that geda can be effective in treating patients independent of their PIK3CA status and independent of their metabolic status and independent of their hbA1c levels or glucose levels. And so ultimately, if our data from wild type recapitulates in the VIKTORIA-2 study and we show activity generally, we think we have another opportunity to establish geda as a potential standard of care.

And maybe just one more if I could sneak it in. On the CMC portion of your filing, when you submit it in Q4, can you just remind us your manufacturer there, any specifics you're willing to give as far as your kind of confidence around your CMC package?

We're very confident about the CMC package. We have all the data. Our modules are complete for CMC. There's a very prescribed set of studies that are expected, analyses to be performed, kind of number of demonstration of consistency of your process, and that's all been done. So we're very confident just based on the robustness of the package that we've built and the data that we've generated that we should satisfy the FDA's requirements.

And we've also engaged directly with the FDA and ensured that there aren't any open questions based on an outline that we've provided to them of the data we expect to provide. And so we think we should be in good shape on that front.

There are no further questions at this time. I'd like to turn the call back to Mr. Brian Sullivan for closing comments. Sir, please go ahead.

Well, thank you for participating in our call today, and thank you for your ongoing support. And I look forward to catching up with you at various conferences along the way. Take care.

Ladies and gentlemen, this concludes today's conference call. Thank you very much for your participation. You may now disconnect.

Good day, and thank you for standing by. Welcome to the Celcuity Phase III VIKTORIA-1 Top Line Results Investor Call. [Operator Instructions] Please be advised today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Brian Sullivan, CEO and Co-Founder of Celcuity. Please go ahead.

Good morning. Thank you for joining us today. Let's now turn to Slide 2. Before we begin, I must point out that some of our comments today contain forward-looking statements that are subject to risks, uncertainties and assumptions. In particular, our expectations around gedatolisib are uncertain and subject to change. Should our expectations fail to materialize or should our assumptions prove to be incorrect, actual company results could differ materially from these forward-looking statements.

A description of these risks, uncertainties and assumptions is included in our SEC filings. Let's now turn to Slide 3. Today is an important day for patients who have HR-positive/HER2-negative advanced breast cancer. A clinically meaningful improvement in both progression-free survival primary endpoints from the PIK3CA wild-type cohort of Phase III VIKTORIA-1 trial was unprecedented in this disease setting. Dr. Igor Gorbatchevsky, our Chief Medical Officer, will be joining us today to present these exciting results.

We're also pleased to have Dr. Rachel Layman, Professor of Medicine at the MD Anderson Cancer Center, join us to provide an overview of the treatment landscape for HR-positive, HER2-negative advanced breast cancer. And Eldon Mayer, our Chief Commercial Officer, will provide a brief update on our preparations for a potential launch of gedatolisib should we get FDA approval. Let's turn now to Slide 4. We founded Celcuity because we believed that a functional analysis of the signaling pathways in tumor cells could yield important insights that weren't available from genetic analysis alone.

When we turned our attention to the PI3K-AKT-mTOR or PAM pathway about 5 years ago, I couldn't reconcile 2 facts. First, the PAM pathway has long been recognized as one of the most important cancer drivers. And second, at the same time, very few patients were benefiting from drugs that targeted this pathway. It made no sense to me that there weren't any blockbuster PAM inhibitors. And we learned that the primary reason why PAM inhibitors have had limited impact despite the importance of the PAM pathway is because it is very difficult to safely and efficaciously inhibit this pathway.

And there's multiple components, each of which need to be inhibited to comprehensively blockade the PAM pathway's activity. Otherwise, if only a single component is targeted, adaptive resistance arises and pathway shutdown is limited. Further complicating the challenge of drugging this pathway is the narrow therapeutic window that exists. There is a graveyard of drugs attempting to inhibit all these components that were not efficacious, too toxic or both. The failures of these early generation PAM inhibitors led drug developers to target signal components such as PI3K-alpha, AKT or mTORC1 as a strategy to avoid toxicity.

However, by compromising on the biological imperative that requires comprehensive blockade of this pathway, the resulting drugs have typically only demonstrated efficacy in patient populations that have pathway mutations. Eventually, we developed 2 hypotheses that led us to gedatolisib. First, we didn't think the pathway's relevance as a cancer driver was a function of the presence or absence of a mutation. It became clear, at least to us, that PAM pathway's role as a cancer driver and its overall importance was independent of any specific pathway variants or mutations.

And this meant that an inhibitor that could comprehensively shut down this pathway could potentially be efficacious in patients lacking common mutations such as PIK3CA. Second hypothesis was that a highly potent drug that avoided overexposure in key organs such as the liver and GI tract could potentially limit the incidence of the side effects associated with this pathway, such as hypoglycemia or diarrhea.

Let's now turn to Slide 5. Until today, we're very thankful that the data from the PIK3CA wild-type cohort of our Phase III VIKTORIA-1 clinical trial has validated our hypothesis. In patients with HR-positive/HER2-negative PIK3CA wild-type advanced breast cancer, gedatolisib plus fulvestrant and palbociclib and gedatolisib plus fulvestrant met the study's 2 primary endpoints by demonstrating statistically significant and clinically meaningful improvement in progression-free survival or PFS versus fulvestrant. Median PFS for the gedatolisib triplet was 9.3 months compared to only 2 months for fulvestrant, a 7.3-month incremental improvement in median PFS.

The hazard ratio was 0.24, which translates to 4.2x higher likelihood of survival without disease progression than fulvestrant. Median PFS for the gedatolisib doublet was 7.4 months, again, compared to only 2 months for fulvestrant, a 5.4-month incremental improvement in median PFS. The hazard ratio was 0.33, which translates to 3x higher likelihood of survival without disease progression than fulvestrant. Let's now turn to Slide 6. I have to say we were genuinely amazed at these results. They're unprecedented and established several new milestones in the history of drug development for HR-positive HER2-negative advanced breast cancer.

First, the hazard ratios reported for both the gedatolisib triplet and doublet were the most favorable ever reported by any Phase III trial, first line, second line or third line in this population. Second, the incremental improvements in median PFS for the triplet and doublet were the highest ever reported by any Phase III trial for this patient population receiving at least their second line of therapy for advanced disease. And third, gedatolisib is the first PAM pathway inhibitor to achieve positive Phase III data in patients who have PIK3CA wild-type tumors and whose disease progressed on or after treatment with a CDK4/6 inhibitor. In light of this data, we believe the gedatolisib triplet and doublet each have the potential to establish a new standard of care for these patients.

Let's turn now to Slide 7. We're obviously very encouraged by these results and the implications for our now enrolling Phase III first-line trial and our other potential future clinical development plans. Since gedatolisib has the potential to address a number of additional unmet needs in a variety of additional settings, we're thankful that our intellectual property position is very strong. With the recently issued patent, we expect to have patent exclusivity with gedatolisib until 2042.

Let's turn now to Slide 8. It's my pleasure to introduce Dr. Igor Gorbatchevsky, our Chief Medical Officer. Igor joined us at the outset of our clinical development program for gedatolisib. He's done a fantastic job of building and leading the clinical development team that has delivered these trial results. Igor, you're up.

Thank you, Brian. Let's turn to Slide 9. Well known that most common type of advanced breast cancer is hormone-positive HER2-negative disease, and approximately 60% of patients will have PIK3CA wild-type breast cancer. Unfortunately, the currently approved therapies offer very limited efficacy with median progression-free survival ranging from 2 to 4 months only. As Brian mentioned, the PAM [ PI3K/mTOR ] pathway is one of the most important oncogenic pathways. It plays an important role in a number of critical cell functions, including cell metabolism, cell growth, proliferation and survival.

The PAM pathway also cross-regulates other oncogenic pathways and impacts immune competent cells and tumor microenvironment. Multiple studies have demonstrated that PAM, hormonal and cell cycle pathways play important roles in promoting tumor cell proliferation. Additionally, they are interdependent drivers for hormone-positive HER2-negative advanced breast cancer, and this process is not dependent on PIK3CA mutation status. To maximize the efficacy, the evidence suggests the simultaneous blockade of all 3 pathway is very important. It is especially important to provide complete blockade of the PAM pathway.

Doing so will prevent cross-activation of PAM pathway when both hormonal and cell cycle pathways are inhibited. It also can help to restore or enhance sensitivity to both endocrine and cell cycle targeting therapies. Because of this critical role in oncogenesis and ability to interact and cross-regulate other oncogenic pathways, we believe that PAM pathway represents one of the most important targets in oncology today. Let's please turn to Slide #10. Gedatolisib is a very potent inhibitor and very potently inhibit all 4 isoforms for Class I PI3K and both mTORC1 and mTORC2. This enables gedatolisib to provide complete and comprehensive blockade of the whole PAM pathway.

This means that there is a limited potential for adaptive resistance when a single target inhibitor is used, for example, when someone target just single either for PI3K like alpha isoform or just AKT or just mTOR. In several preclinical studies, gedatolisib inhibitor effect was 300x more potent compared to those targeted a single PI3K isoform form or AKT or mTOR. This potency was the same in tumor cell lines regardless of PIK3CA mutation status. Preliminary data with gedatolisib also found that patients with or without PIK3CA mutations had objective response rates well over 50%.

Let's turn to Slide 11. VIKTORIA-1 is a randomized open-label global Phase III study in patients with hormone-positive and HER2-negative advanced breast cancer. VIKTORIA-1 included patients with both PIK3CA mutation positive and wild-type disease. Today, we are focusing on design and review of top line results for Study 1, which included patients with PIK3CA wild-type disease. In this study, both men and women were eligible for enrollment. Patients must have had disease progression on or just right after treatment with CDK4/6 inhibitor in combination with nonsteroidal aromatase inhibitor.

Up to 2 lines of hormonal therapy was allowed and prior treatment with agents targeting PAM pathway was prohibited as well as chemotherapy for patients advanced breast cancer. However, patients could have received chemotherapy as part of their treatment regimen in neoadjuvant or adjuvant setting. Patients also had to have measurable disease according to most recent RECIST version 1.1. In total, 392 patients were randomized equally 1:1:1 in 3 study arms. 2 of them were treatment study arms and 1 controlled study arm. Patient received standard doses of palbociclib in Arm A and B. It's 125-milligram daily for 21 days with 7 days of treatment window.

Fulvestrant in all 3 arms also was given as a standard dose of 500 milligram twice during cycle 1 and every 4 weeks thereafter. Gedatolisib was given in the standard dose of 180 milligram intravenously once weekly on days 1, 8 and 15. This 3 weeks on and 1 week off schedule provides patients with virtually 2 weeks break in treatment. For example, from day 15 to the day 1 of subsequent cycle, patients will have 2 weeks of break. In Arm A, patients received triplet regimen of gedatolisib combined with fulvestrant and palbociclib. In Arm B, patients received doublet regimen of gedatolisib combined with fulvestrant.

And in the control Arm C, patient received fulvestrant alone. It's important to notice that patients in Arm C who had confirmed disease progression were able to cross over and receive active treatment with either gedatolisib triplet or doublet regimen. The primary objective of the study was efficacy assessed by comparing median progression-free survival between treatment arms. We had 2 co-primary endpoints. First one comparing efficacy in Arm A versus Arm C and second, Arm B versus Arm C.

Let's turn now to Slide 12. As Brian mentioned, both primary endpoints were met. Each shows statistically significant and clinically meaningful improvement in progression-free survival relative to fulvestrant alone. For patients in Arm A who received gedatolisib triplet regimen, median progression-free survival was 9.3 months compared to 2 months for the patients in Arm C who received fulvestrant alone. This resulted in a hazard ratio of 0.24 and a very narrow confidence interval with a p-value less than 0.0001. This translates to 4.2x higher chance of surviving without disease progression. These results are very clinically meaningful with 7.3 months incremental improvement in median progression-free survival for triplet regimen.

Let's now proceed to Slide 13 and review results of the second co-primary endpoint. For patients in Arm B who received gedatolisib doublet regimen, median progression-free survival was 7.4 months compared to 2 months for patients in Arm C who received fulvestrant alone. This resulted in a hazard ratio of 0.33 and a narrow confidence interval with a p-value less than 0.0001. This translates to a 3x higher chance of surviving without disease progression for patients who received doublet regimen. These results are also very clinically meaningful with a 5.4 incremental improvement in median progression-free survival for those who received gedatolisib in combination with fulvestrant.

Let's turn to Slide 14. Obviously, we are very excited. This efficacy result was so favorable. But we're also pleased to report that both gedatolisib triplet and doublet were well tolerated and the side effects were easily managed with available standards of care. The discontinuation of therapy due to treatment-related adverse events was lower in both gedatolisib triplet and gedatolisib doublet regimens compared to those results observed in Arm B from our Phase Ib study in advanced breast cancer that we presented in prior years.

Additionally, the safety profile for both regimens was better than observed in the overall Phase Ib study we presented earlier, including lower rates for stomatitis and hyperglycemia. Finally, the overall survival analysis shows positive trends and was favorable for both triplet and doublet regimens. Although the data is immature at this time, we are very encouraged about this because a very significant portion of patients in Arm C crossed over to receive active therapy, as I mentioned earlier.

So patients in Arm C upon disease progression were able to receive either triplet or doublet gedatolisib regimens. Full results of VIKTORIA-1 PIK3CA wild-type cohort will be presented at the upcoming scientific symposiums later this year, and we are anticipating NDA submission in the fourth quarter of this year. We thank all patients, investigators and site staff for participating in VIKTORIA-1 study. And now I'll turn it back to you, Brian.

Thank you, Igor. Let's turn now to Slide 15. It's my pleasure now to introduce Dr. Rachel Layman, Professor of Medicine at MD Anderson. Dr. Layman provides a unique perspective. She was one of the top enrollers in both our Phase Ib breast cancer study and the VIKTORIA-1 study. So she has a deep level of experience treating patients with gedatolisib. Let's turn now to Slide 16. And Rachel, the floor is yours.

Thank you so much, Brian. Today, I'll be presenting the current treatment landscape for patients with hormone receptor positive HER2-negative advanced breast cancer following prior treatment with endocrine therapy and a CDK4/6 inhibitor, and I'll be focusing on cancers without PIK3CA mutations. Unfortunately, after patients are treated with a first-line endocrine therapy combined with the CDK4/6 inhibitor, subsequent endocrine-based treatment regimens have not performed well. In an effort to improve outcomes for this patient population, multiple clinical trials of novel therapies have been performed. I will start by reviewing the data for novel endocrine therapy agents.

This slide shows the oral SERDs, which have been in development for years. Although the expectations were high, Phase III studies evaluating oral SERDs against standard of care endocrine therapy showed no significant benefit for cancers that do not harbor ESR1 mutations. The Phase III studies with positive readouts are shown here. This data only includes the ESR1 mutation population regardless of PIK3CA mutation status as this is the population that benefited from therapy.

The hazard ratios were similar for all 3 drugs, ranging from 0.55 to 0.66 with lower hazard ratios being more favorable. Elacestrant is the only oral SERD currently FDA approved. The EMERALD trial improved the median progression-free survival by only 1.9 months. In the VERITAC-2 study, vepdegestrant improved median progression-free survival by 2.9 months. And finally, the Phase III EMBER-3 study enrolled patients with or without prior CDK4/6 inhibitor therapy. 30% of the study population did not receive a CDK4/6 inhibitor. Despite this, imlunestrant only improved progression-free survival by 1.7 months compared to standard endocrine therapy.

Let's go to Slide 17, please. Another approach to improve outcomes following first-line therapy was to continue a CDK4/6 inhibitor combined with a different endocrine therapy. The Phase III postMONARCH clinical trial randomized patients to receive fulvestrant with or without the CDK4/6 inhibitor, abemaciclib. All patients received a prior CDK4/6 inhibitor combined with an aromatase inhibitor in the metastatic setting and had any PIK3CA and ESR1 status. The results were positive with a hazard ratio of 0.73. However, there was less than a 1-month improvement in progression-free survival with abemaciclib.

The EMBER-3 study evaluated the oral SERD imlunestrant with and without abemaciclib. The study population in this trial was more diverse with only 65% of patients receiving a prior CDK4/6 inhibitor, and the study enrolled patients in the first, second and third-line treatment settings. EMBER-3 also yielded positive results with a hazard ratio of 0.57 and absolute progression-free survival improvement of 3.9 months.

Let's go to Slide 8, please -- slide 18, please. Here, we will move to the PAM pathway targeting therapy. To date, no prospective clinical trial in the post-CDK4/6 inhibitor setting has demonstrated benefit in cancers without a PIK3CA mutation. The most recently approved PAM pathway drug is capivasertib, an AKT inhibitor. However, no benefit was observed with the addition of capivasertib to fulvestrant in patients with PIK3CA wild-type breast cancer patients who had received a prior CDK4/6 inhibitor. Alpelisib is a PI3 kinase inhibitor, which is approved for the treatment of hormone receptor positive breast cancer with a PIK3CA mutation.

The study leading to the approval of alpelisib was performed prior to wide availability of CDK4/6 inhibitors. And so most patients on this study did not receive a CDK inhibitor. Even so, patients without PIK3CA mutations did not benefit from the therapy and thus are excluded from the FDA approval of this drug. Everolimus is an mTOR inhibitor. Results from Phase III studies were published more than a decade ago prior to the availability of CDK4/6 inhibitors, among other therapies.

Slide 19, please. Now let's look at how gedatolisib containing regimens stack up against the current treatment landscape. First, I will show the median progression-free survival of the gedatolisib regimens, along with the approved regimens for which we have Phase III data in the second-line setting, again, for patients with hormone receptor positive, HER2-negative and PIK3CA wild-type breast cancer following CDK4/6 inhibitor therapy. Fulvestrant provides a progression-free survival of only 2 months, while elacestrant has a 3.9 progression-free survival when limited to the ESR1 mutant population.

The 2 gedatolisib containing regimens studied far outperformed the standard of care therapies with a median progression-free survival of 7.4 months when combined with fulvestrant and 9.3 months when combined with both fulvestrant and palbociclib. Slide 20, please. Now let's include regimens with available data that are not FDA approved at this time. This slide shows the absolute improvement in median progression-free survival with each regimen when compared to standard endocrine therapy.

Gedatolisib clearly provides the highest incremental progression-free survival with a 5.4-month improvement with doublet therapy and a very impressive 7.3-month improvement with triplet therapy. Incremental improvement in the other regimens range from 0.7 to 3.9 months. Slide 21, please. This slide shows the same data shown by hazard ratio. The lower the hazard ratio, the better the treatment efficacy compared to control, which is standard endocrine therapy in this case. The hazard ratio for the triplet gedatolisib regimen is 0.24, and the doublet regimen has a hazard ratio of 0.33. These extremely favorable hazard ratios are rarely seen in oncology clinical trials and are unprecedented in this treatment setting. Up to this point, hazard ratios for this population in the second-line setting have ranged from 0.55 to 0.73.

Slide 22, please. This data supports the potential for gedatolisib to become the standard of care drug for second-line hormone receptor positive HER2-negative and PIK3CA wild-type advanced breast cancer. Gedatolisib is highly efficacious. It is associated with the highest incremental improvement in median progression-free survival over endocrine therapy that has ever been reported in this patient population. The hazard ratio for triplet therapy of 0.24 and doublet therapy of 0.33 are the most favorable reported for any study in hormone receptor positive HER2-negative advanced breast cancer.

Additionally, gedatolisib is associated with preserved quality of life. Patients tolerated both gedatolisib-containing regimens well with very low discontinuation rates. In addition, the safety profile for triplet and doublet therapy was more favorable than that previously reported in the Phase Ib advanced breast cancer study. Of note, intravenous administration was not a barrier to use. Thank you very much. We can now go to Slide 23, please.

Thank you, Rachel, for your very helpful summary of the treatment landscape. Let's turn now to Slide 23. It's my pleasure to introduce Eldon Mayer, our Chief Commercial Officer. Eldon joined us last year, and he's done a great job of assembling a talented team and laying the groundwork for a potential commercial launch sometime next year. Eldon, please go ahead.

Thank you, Brian. Let's now turn to Slide 24. I want to share a quick overview of the market landscape we see for gedatolisib, what we're doing to get ready and how we're gearing up for a potential launch should we get FDA approval. So let's start with why we think the market looks promising for gedatolisib. First off, this is a sizable patient group. We estimate there are 34,000 patients moving to second-line treatment after CDK4/6 inhibitors and roughly 60% of them are PIK3CA wild-type. That's a very large opportunity.

There's also a real need here. As we heard earlier on this call, current second-line treatments for HR-positive/HER2-negative advanced breast cancer are limited in terms of added progression-free survival benefit. Our market research shows that oncologists are hungry for options that are more effective and have a safety profile they can manage.

With such a large underserved market, we see a chance to build a strong presence for Celcuity. And with gedatolisib's unique mechanism of action and corresponding clinical benefit, it is well positioned to address critical needs in the second-line space. And a couple of quick points on market dynamics. IV administered drugs such as gedatolisib fall under the medical benefit category, which means a typically smoother reimbursement process compared to oral drugs under pharmacy benefits where payers tend to manage claims more heavily.

Plus, the breast cancer community is active, engaged and well supported by advocacy groups, which can help create awareness for new treatments. Based on our projections, this could represent a $5 billion served market revenue potential. Let's turn now to Slide 25. All right. Let's talk about how we're preparing for a potential launch in this market. Our experienced teams are hard at work getting ready, and we're on track for a strong market entry if we receive FDA approval. We've been gathering valuable insights from key opinion leaders and now with our clinical data in hand, we'll be investing more in those conversations to dig deeper into what these results mean for physicians and patients.

Market access is a major focus for us to ensure patients have access to gedatolisib with a quick and seamless process when a physician orders it, and we're actively engaging with health systems, payers, pathway decision-makers, group purchasing organizations or GPOs. We're also working hard to educate and build excitement around the importance of comprehensively blocking the PI3K-AKT and mTOR or PAM pathway.

That includes having a strong presence at key oncology conferences and continuing to educate and raise awareness about these issues within the breast cancer and oncology community. And we're tackling the major long lead time initiatives such as setting up distribution, reimbursement and building patient support systems to name a few. So we're ready to execute these at launch. Let's turn now to Slide 26. And finally, let's touch on our launch planning and infrastructure. With the teams we've built, we're refining our strategic and tactical plans, especially now that we have Phase III clinical data to work with. The most critical piece is having a seasoned skilled team to execute, and we're ready to ramp up hiring quickly to make that happen.

We're also staying close to oncologists through ongoing market research and working with key opinion leaders to ensure we're aligned with what oncologists and patients need so we can position gedatolisib as effectively as possible. And we're making great progress on the operational side across our company, building out critical infrastructure such as supply chain, IT systems, data and analytics, field support and much more to ensure operational excellence. All in all, we've made major strides in getting ready to become a commercial stage company, and we're pushing forward confidently to be fully prepared for a potential launch. Brian, back to you.

Thank you, Eldon. So let's now turn to Slide 28, please. We have 3 important milestones coming up the back half of this year. First, we'll present the full data at a major medical conference later this year. Second, we expect to submit a new drug application or NDA for VIKTORIA-1 PIK3CA wild-type cohort indication in the fourth quarter of 2025. And finally, we hope to report top line data for the PIK3CA mutation [ cohort ] of the VIKTORIA-1 study by the end of 2025.

Let's turn now to Slide 29. So this ends the presentation portion of our day. We'll turn now to the question-and-answer session. Thanks to all of you who did send in questions. And I should just mention that Rachel Layman will have to attend to patients in just a few minutes, and we'll have to lead during Q&A. Hopefully, she'll be available for your questions. So let's open it up to questions, please.

[Operator Instructions] We will now start with our first question, and this is from Maury Raycroft from Jefferies.

Much congrats on the data update. Wondering if you can provide additional context to the 2-month PFS data observed in the control arm. Do you believe this patient population exhibits greater endocrine resistance compared to recent trials in the same setting? And what implications might this have for gedatolisib's effectiveness in a more sensitive population?

Thanks, Maury. So on one hand, we weren't surprised by the results for the fulvestrant arm. There've been, I think, 4 fairly recent clinical trials, prospective trials randomized that reported 1.9 to 2.1 months median PFS for fulvestrant. And there have been some outlier trials, but those really -- those results were really driven by differences in patient populations relative to a registrational study. So this, we think, represents the current state that -- and representative of what patients can experience in the setting.

And so what that means, I think the translation is that these patients are not going to respond to much endocrine therapy that essentially they're untreated disease mechanisms, which we think we demonstrated in the VIKTORIA-1 trial. As far as the sensitivity, we had data in our frontline -- in our Phase Ib study for endocrine-sensitive patients. And in that study was preliminary data, but in a sample size of 41 patients, we reported a median PFS of 48 months with gedatolisib, palbociclib and letrozole. And so that's obviously very encouraging data. Our VIKTORIA-2 study, which we're currently enrolling, is focused on enrolling patients who are considered to be endocrine treatment resistant.

And these are patients who progressed almost immediately after or during their treatment -- endocrine treatment for early breast cancer. Big unmet need for these patients that -- most of these patients are only getting therapies that offer them about 7 months median PFS. And so we're encouraged by the results here. Obviously, we have to get the results for the VIKTORIA-2 study to see what the effect is. But certainly, the data we have today is encouraging for us and makes us optimistic about those future results.

Got it. That's helpful.

Go ahead, sorry.

Yes, maybe one other question just on -- wondering if you could talk more about the favorable overall survival trend, what that means. Does that mean the trend is positive? And even though it's immature and with crossover, can you add any more context to how your OS data compares so far relative to competitors at the same stage?

Sure. Well, I think what was very encouraging to us was that patients with the triplet showed a favorable trend, even though in the control arm, a significant number of these patients crossed over to receive gedatolisib therapy. And while favorable OS -- positive OS is not required or hasn't been a benchmark that the FDA requires, we certainly expect to see no detriment to the overall survival trend for patients.

And there was a recent study that reported encouraging progression-free survival data, which showed a fairly significant negative trend. And so I guess everybody is more sensitive to the overall survival data as a result. And so in that context, we're particularly encouraged by what we've seen with the overall survival data.

We'll now take the next question. This is from Tara Bancroft of TD Cowen.

Congrats on these fantastic data. I was hoping you could talk more about the balance of the arms across mutational status and what consistency you might be seeing in those, especially in ESR1 mutant patients and if you could compare those relative to EMBER-3 data specifically?

Thanks. All that data, that type of data would be presented at later medical conferences. But what we can say is that the demographic data, baseline characteristics data that we've reviewed suggests that these arms were all well balanced. We had stratification variables or factors that ensured for critical factors that these populations or the arms were consistent and representative. So we don't expect to see any anomalies or anomalous accrual according to mutational status or differences between arms.

Okay. Great. And then I guess for that full data, are you thinking more on the ESMO time line or San Antonio time line or something else?

Just stay tuned.

We'll now take the next question. This is from Andrew Berens from Leerink Partners.

Congrats on the transformational results. Just wanted to ask a couple of questions on the future plans for the program. Can you just run through the rationale for the frontline trial, specifically the decision to target endocrine-resistant population with fulvestrant? Just trying to put the results of the prior Phase Ib in context with that program.

And then it really seems to me a large opportunity could be to combine GEDA with the oral SERDs and help those drugs beat fulvestrant in a broader population, which as the doctor ran through, none of those agents have been able to do it. So are you considering running those trials? It really seems like that could unlock a lot of fundamental and strategic value.

Okay. Thanks, Andy. So as far as the rationale for the first-line trial, we initiated work to get this trial going last year around middle of the year. And as we reviewed the unmet needs, we concluded that this population, in particular, was particularly underserved and with median progression-free survival outcomes in the first-line setting for most patients only being 7 months. And so from a practical standpoint, that means you can enroll a study and get data from that study in a fairly reasonable time line.

And so, a, we're addressing unmet need; and b, it just is a practical population to evaluate for a company at our stage of development. The endocrine-sensitive population gets a median PFS of roughly 25 months. And so it would be a much, much longer study. And one, over time, we think would be appropriate to potentially go after because, again, the preliminary data we showed in the endocrine-sensitive population was very, very encouraging.

And so VIKTORIA-2 then, in some ways, mirrors, you could say, the population we enrolled here endocrine resistant. And so again, we're encouraged by these results, and we'll have to wait and see how that translates into VIKTORIA-2, but certainly gives us reason to be optimistic. And then as far as future development opportunities, certainly, we think GEDA has shown that it can extend progression-free survival period when combined with hormonal therapy.

And to the extent that there are better ways or different ways of offering patients an oral SERD, we want to certainly explore that. It'd be premature for us to really comment more specifically. But as we look longer term, we want to make sure that we position gedatolisib to be combined with as many appropriate drugs as possible so that we give patients the best opportunity to get the best efficacy and safety profile possible.

And we move to our last question today. This is from Oliver McCammon from LifeSci Capital.

Congrats on the data. Just considering some of the baseline characteristics in VIKTORIA-1, like prior CDK4/6 inhibitor use, measurable disease, et cetera, can you remind us how heavily pretreated this patient population is versus some of the reference studies we've seen in the second or third-line setting? I'm thinking specifically of things like EMBER-3 and CAPItello-291.

Well, because of the -- thank you, Oliver. Because of the enrollment criteria, we I think -- and we'll disclose this data when we present the full data. But we've clearly enrolled mostly a second-line population and some third-line patients. We did not allow patients who had prior chemo in that setting. Some of the other studies, for the most part, mirror this -- to be frank, all these studies largely mirror this population. The EMBER-3 study had, as Rachel alluded to, a very diverse population. In some ways, you can think of them as having 4 subgroups of patients, first line and then second line with or without prior chemo or rather prior CDK. So it's really hard to kind of assess directly.

But again, the hazard ratio comparison provides a way to kind of evaluate the relative contribution of the study drugs on top of hormone therapy. And so what's particularly interesting about this space is that for the most part, every study that's been run over the past, I'll pick a number, 20 years, has essentially compared itself to endocrine monotherapy. And so you have the ability to kind of draw a beat on what the reasonable expectation is for these patients with endocrine monotherapy.

And then what you'll see are some variations depending on whether patients are enrolled without measurable disease, which will happen in nonregistrational studies or patients may have received a more prior chemo. But for the most part, I think these populations really line up, except in cases where they're combined with first-line patients or patients who've not had CDK. And that really is a very small proportion of patients today. So really the most representative trials and the ones most relevant are ones that really isolated patients with prior CDK.

Well, that wraps up our day. We appreciate you guys attending, and we look forward to providing these results in greater detail at an upcoming conference and to continuing our work to get ready for an NDA submission and to be able to get back with everybody with results from our mutant cohort. So look forward to chatting some of you over the upcoming months. Thanks again.

Thank you. This concludes today's conference call. Thank you for participating, and you may now disconnect.