Celcuity Inc. ($CELC)

Good morning, everyone. I am very excited to host Celcuity. 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.

Oh, sure. So I guess the most important thing to understand about Celcuity is that we're focused on treating diseases that involve 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 1 of the most important oncogenic pathways overall, but also one of the most challenging to drug and the real advance that gedatolisib is demonstrated so far, and I'm sure we'll get into that, is the superior efficacy and better tolerability 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 day 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+ R2 negative advanced breast cancer, LACT mutations, but 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 time line?

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

Okay. Great. And then in addition to breast cancer, I don't get 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 designs and the status for that? And also when can we see data?

Sure. So prostate cancer is a similar underlying biology is 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 a woman that we're targeting having 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. 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 perform, I think, subgroup analysis for that get a triplet and also the doublet. And then when you look at the PFS, across the different subgroups, like geographic area and the 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, the CDK4/6 inhibitor that are probably related to those countries less frequent or less use 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, 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 PIK3CA, 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 compare it to the PIK3CA inhibitor called alpelisib that Novartis has. We showed the highest median PFS ever reported in the second-line setting for therapies that included an endocrine backbone. So that's obviously fantastic. And then we also showed the highest objective response rate for breast cancer in the second-line setting for therapies regimens, including in 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 0 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. Well, 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 have only been 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 so how, on a relative basis, when you control for all the other factors that could influence outcomes, how much difference there is between 1 therapy and another. And so to show double the benefit between 2 drugs of the same classes, typically, it was 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. Right?

Well, I think another way to see it is that if you compare Study 1 results Study 2, should there be a higher benefit because now you're 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 a 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 PIK3CA inhibitor and then to offer those patients who really have 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 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 2, the GEDA, the triplet and the doublet show similar median PFS and also the hazard ratio. Why did 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 is -- it doubled the benefit relative to palbociclib a pure head-to-head setting. And 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 involved because if you look at some of the additional data that we reported, clearly, CDK4/6 is playing a role, but less prominent. You think about 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, your pathway, CDK4/6 pathway, the PAM pathway, that each are probably playing -- I don't want to say co-equal it's hard to tease that out, but playing a very important role, more balanced, I guess, you could think of and less balanced maybe in the mutant setting, which just highlights how important to be frank, having multi-target inhibitor is for these patients.

Okay. Got it. And then in that subgroup analysis, for Study 2 patients who received ribociclib in the prior line seem to benefit more compared to those we see received palbociclib, what's the implication there in terms of that ribociclib palbociclib dynamic?

Sure. Well, -- 2 things. One, really, both sets of patients benefited significantly regardless of which CDK4/6 had. And so in the 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 palbociclib, prior ribociclib almost exactly the same benefit. I would say in mutant, you would say 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 this patient may have received prior in their first-line setting, whether it was ribociclib or palbociclib, my patient is going to get a very meaningful benefit when I combine GEDA 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 the doctors we'll 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 1 option, 1 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's more indolent disease. And so giving doctors the option of selecting between a triplet, let's say, in a doublet and factoring in the clinical characteristics of their patients. Well, 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 a 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, I have confidence that the regimen 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 compared to patients who did not come up?

So essentially, you don't really see a very significant difference. I think 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 the small percentages numbers. When you're trying to tease out too much information from the 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, a doublet in the wild type, for instance, if it weren't for the triplet, would have been a 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 trip was even better. So again, those are to 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 are like places when you add that to a CDK4/6 rival, it showed like 13-month PFS in that median PFS in that outcome setting. How do you view get us doublet competitive position for like the next generation third. That could be recommended on top of like CDK 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 in, relative to fulvestrant in pancaking 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 our PIK3CA wild type represent about 20% of the population. So there will be some overlapping populations. We think we offer clinical 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 there are fantastic options for patients today. We think that 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 that in the patients that have ESR-1-mutations well 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 next-gen set of fulvestrant given the limitation for ESR1 mutation of fulvestrant. If you were to do a combo, which third would you use for that partner?

Well, ultimately, we think gedatolisib because of its -- 2 things. This pathway is involved in the disease independent of whether or not the patient has a mutation. That's our data has clearly shown that. And secondly, you've got is able to address it effectively and more favorably than has ever been reported. And so we think data 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 classes of drugs, oral service, 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 be would 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- at 0.55, 0.57 range. And then essentially, you're going to get to physician preference, you'll see some differences in toxicity profiles that are in the scheme of things, relatively small. Certainly, fulvestrant 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 say, okay. And have you done any subgroup analysis in that ESR1 mutation versus wild-type setting? And do you see any differences between subtypes? And then also, what is the -- like in the VIKTORIA-1 study, between the Study 1 and 2, how do these compare the ESR-1 mutations?

So in our study, we did not -- we did not break out subgroups and did not end up unfortunately generating data for ESR1 mutational status. We enrolled OS-1 mutant wild-type patients just because they're part of the population typically find between 35%, 40%. But we started the study before you sort ESR-1 have been a validated biomarker, so it wasn't a focus -- and that 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 cells with -- who have a wild type.

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

Going forward, certainly, we can. We just need to incorporate 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 ribociclib or palbociclib and outcomes, patients had prior ribociclib or palbociclib when patients got retreated with palbociclib. In studies that had evaluated patients would receive prior palbociclib and then were subsequently retreated with palbociclib, but with a different endocrine therapy, saw no benefit. And so in Arcus, we saw a fantastic benefit with patients who had received prior palbociclib because you are controlling this pathway. And essentially, as long as that pathway was controlled effectively, you're going to get the benefit. And so we think the relative benefit may be more muted when you have comprehensive shutdown the pathway. -- than 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, yes. That makes sense. What is your view of the emerging class of the CAT 6 inhibitors? So it seems to be complementary to the third. I think we saw some data from Pfizer I think Lima is going to have the combination data coming out later this year or 2027. How do you see CAT 6 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, not sure it would 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 already that target Yes.

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

Sure. And that program is essentially running in parallel. -- with a Phase III study we're running in patients first-line breast cancer patients who are considered to be endocrine sensitive and these are ones 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 very, very long duration of benefit early phase single-arm study. So you 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 of our plant, 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 it 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 the current IV formulation doesn't create a barrier to infusion 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.

So typically, the FDA wants you to demonstrate in 1 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 setting.

For all settings.

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, 1 for endocrine resistant and 1 for endocrine-sensitive. So when I look at this VIKTORIA-2, it's almost like 2 study.

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 1 is 740. So these are smaller. If I look at it individually compared to the front line like Persevera like Serena 4, I mean, how do you think about the size of the study -- is it too small as a...

It's appropriately sized. I mean, essentially, the number of patients who enroll is a function of what your underlying assumption is about the effect size difference you'll see, i.e., what do you think will be for paving 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, essentially, they're replacing 1 therapy of a particular class for another, like 1 hormonal therapy versus another. Typically, the effect size potential is much smaller and as we found unfortunately, with the study with your adjustment wasn't meaningful on. 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, we 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 to be frank, we're relatively overpowered, we think, in the under 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 reflect what we think is the clinical benefit of controlling this pathway versus not compared to control.

Okay. Got it. And then you guys view palbo plus fulvestrant or palbo plus AI in the study 1 and 2, respectively. But then you swap out the palbo for rival in the comparator arm. what is the rationale for that?

Sure. So ribo is a standard of care because it had no less benefit. And so that was clear that from a comparative 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 pretty meaningful. If you look at a PFS standpoint, palbociclib and ribociclib offer identical profiles in terms of hazard ratios or even duration 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 we'll be getting equivalent efficacy that we would have otherwise have gotten if we had used ribo. And so we elected to choose the more tolerable CDK 4/6 inhibitor for our study arm.

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

Well, certainly, small size of 41 is not necessarily 100% translatable. But what it provides 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 relative to what has been reported for historical studies with the 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, 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 1 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 and improvement for these patients.

So when we look at evERA it did show about a 5-month benefit in PFS, but that did not translate to set.

Look at the hazard ratio, it was 0.89 hazard ratio. And so that's the number that matters. And again, that's not even close.

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

I mean stats typically can be achieved less than what's clinically meaningful in these studies. That's always the trick is to make sure you're not just powering a study to detect a statistical difference when it's not going to be clinically meaningful. So we design 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 statistically significant, i.e., hazard ratio and 0.75 range plus I think, would be considered clinically meaningful.

Okay. Fantastic. We probably have time for 1 more blue sky question. So I want to ask you a more blue sky question. All the Jared esterases with Ladera, -- how do you see the treatment paradigm changing in the next 3 to 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 answer is it to have a nominal effect. The women who are getting treated in the adjuvant setting, we can typically expect most of them to not have the disease recur. 75%, 70% won't have the disease recur. 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, if 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 incidents. For instance, roughly 40% of women who are diagnosed metastatic breast cancer or diagnosed de novo, they did not have a diagnosis of 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 the 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. While we're out of time. It's been a very interesting conversation. We appreciate having you here at the GS conference Brian, and then I'll turn it to you for a final remark.

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 our 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 to those women. And again, that would be great.