Yep.
Okay. Morning, everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. It's with great pleasure that I'd like to welcome the CEO of Celcuity, Brian Sullivan. Thanks so much for joining us today, Brian.
Oh, you're welcome.
We're going to do fireside chat format. Maybe for those who are new to this story, if you can give a one-minute intro to Celcuity.
Sure. I started the company initially to develop a platform that could quantify the signaling activity in a patient's live tumor cells. We have since migrated to developing therapies that target the PI3K/AKT/mTOR pathway, or PAM pathway. This pathway, PAM pathway, is probably one of the most complex and also important pathways in cancer. That has led it to be probably, we think, the largest untapped development opportunity in oncology.
We have three current programs that are active: two in breast cancer, one in prostate cancer. The ones in breast cancer are both phase III. we are currently expecting to read out soon results from a phase III study. In the second line for women who have HR positive, HER2- negative advanced breast cancer, we have two cohorts. We will be reporting a cohort of patients that are PIK3CA, wild-type in the next few months.
Second cohort, PIK3CA-mutant patients, we'll be reporting out sometime by the end of this year. The second breast cancer study is a phase III study in women with first-line advanced breast cancer, HR positive, HER2 negative. The third study we have is at an earlier phase in prostate cancer. It's evaluating men who have metastatic castration-resistant prostate cancer in the second line.
Got it. Yeah, it's a great overview. You mentioned a big near-term catalyst. Your VIKTORIA-1 phase III study in second-line wild-type patients. That's guided to have enough events by June, with data expected in the third quarter of this year. Can you confirm whether the June event threshold has been met and if the data lock has occurred yet?
We're on track. We expect to be able to report data in the third quarter. All things are going according to the schedule we laid out previously.
Got it. Okay. You still expect to meet the event threshold in June, then?
Yes.
Okay. Got it. What are your latest thoughts on what will be included in the top-line readout event, and what would be reserved for a medical meeting presentation or publication?
Sure. We would expect to report out the median PFS for the three-arms, t he three-arms, a triplet with gedatolisib, palbociclib, and fulvestrant; another arm with gedatolisib, fulvestrant; and the third arm, the control with fulvestrant. We'd report out the median PFS for each of those arms, as well as the hazard ratio. There are two primary analyses: one comparing the triplet versus fulvestrant, and then the second primary endpoint is comparing the doublet versus fulvestrant.
Got it. Okay. Wondering, have there been any safety interim analyses from the wild-type cohorts, and have you had visibility into the safety signal from each specific arm?
Sure. Our protocol required four interim safety analyses performed by an independent data monitoring committee. We did not get any feedback from those, which is generally favorable, nor did we get any requests to modify the protocol based on any safety signals they may have seen. Overall, we interpret that as favorable, but it is not very specific.
Got it. Okay. There have been a few adjustments to the readout timeline, and you previously mentioned having visibility into the number of events every couple of weeks. Can you clarify if you only have visibility into the total number of trial events, or do you have specific visibility into each treatment pair?
Sure. We're blinded to the event data for the individual arms, as we're blinded to everything else. We only see the event totals in aggregate for all three-arms. From that, we try to correlate that to the two different event thresholds that we have to meet. One is for the A versus C analysis, triplet versus fulvestrant analysis, and then a separate one for the doublet versus fulvestrant analysis. Both thresholds have to be met, and that would trigger our ability to perform the primary analysis.
Got it. You do not have any specific insight into those individual thresholds?
No, no, we don't.
It's kind of extrapolated.
Right. We get told from a statistician that's independent of us, that's associated with the independent data monitoring committee, the IDMC. When that threshold's hit, he alerts us.
Got it. Okay. And then regarding OS data, when do you expect to see, in early trends from the three-arms, and what is the expected timeline for mature OS data?
Sure. At this stage of a study, the overall survival data is typically immature. You just do not have enough events. There have not been enough deaths to draw any real statistical confidence in what the results mean. FDA typically is looking at interim OS data to, in effect, confirm that there is not a detriment in the study arm relative to the control in overall survival.
It takes typically at least a couple of years for that data to mature. That is why you see a significant lag factor with survival data relative to the initial study reports. In the second-line setting, the overall survival data has not typically been weighed heavily because it is confounded by subsequent therapies and changes in therapies used. It is really just a check for the most part.
Got it. So basically, no detriment is kind of what you want to demonstrate?
Exactly. Exactly.
Got it. Okay. With multiple SRDs being developed in both the second-line and front-line settings, it seems likely that more are going to be approved in those lines. What are your thoughts on the SERENA-6 study presented at ASCO and generally the SRD landscape?
Sure. The SERENA-6 study is really a first-line study. Basically, these patients were continued treatment without a progression. The only change in their treatment was switching from letrozole to that SRD. We would not expect it to have any impact on us because those patients will progress eventually, and they would become eligible for our treatment, assuming everything works out the way we want. I think the biggest impact probably would be on oral SRDs because we have heard from a number of KOLs, ASCO just wrapped up, and we had a lot of meetings with KOLs, and that question came up.
There are two issues with that study. One is just the practicality of it. I think there is some question about how widely deployed that regimen would be or that protocol. Secondly, I think there'll be a question in some oncologists' minds whether they want to retreat with a subsequent oral SRD if they've already given an oral SRD in the first-line setting. I think the impact, if there is any, would likely be confined to the different oral SRDs that are being developed.
Got it. Digging deeper into that, do you think there's going to be potential for SRDs to be used in the ESR1 wild-type population in the second line, especially in light of Arvinas Management's 1Q Earning' s Comments, where they said they believe ER therapies will be restricted to patients with ESR1 mutations?
I think these therapies, I mean, they had great promise. I think everybody had high expectations, but I think we're 0 for 5 in oral SRDs being evaluated in this setting for ESR1 wild-type patients. I think it would be very, very surprising, I guess, and you'd have to assign pretty low probability to them demonstrating activity or improvement in activity relative to fulvestrant in ESR1 wild-type patients. My sense is that's going to be the population. It's roughly 30%-40%, depending on the study, of patients who have that mutation. That's likely where those drugs will primarily be used in the second line, at least.
Got it. With the EMBER-3 study, we see a difference between the blinded independent central review and then the investigator assessment. In the VERITAC-2 study, we're not really seeing that difference. T hat data was just presented at ASCO recently. Can you discuss the trade-offs and historical differences in breast cancer outcomes between a BICR analysis and investigator assessed measures?
Sure. Blinded independent central review, BICR, is typically required when the investigators, the oncologists, are not blinded to which treatment is being used. The reason why they want blinded assessment is they want to eliminate the bias that could come from interpretation of progression or not by these investigators. You saw with another SRD, elacestrant, the EMERALD study, as well as VERITAC-2, both had blinded independent review, BICR-assessed PFS as their primary endpoint.
You tend in those studies not to see a wide discrepancy between the BICR result and the investigator-assessed PFS. It was interesting to us that the EMBER-3 study used investigator-assessed PFS as their primary endpoint. When you have BICR as essentially a secondary endpoint, essentially it is used as a confirmatory endpoint of the investigator-assessed, you can have a less rigorous imaging charter. Without seeing the details of that charter, it's hard to really explain why they see that discrepancy.
Because, again, there shouldn't be much discrepancy. If they have, for instance, they don't in our charter, for instance, as an example, you have multiple reviewers of the scans. You have an adjudication if there's a discrepancy between the two reviewers' conclusions. You really confirm in a rigorous way whether there's been a progression. Charters may have less substantive control over those assessments, or rather less rigorous requirements for those assessments if it's not the primary endpoint.
Got it. Anything else about the charter that you can say for yours? I guess, is there a good benchmark in this space?
No. I mean, I think you basically comply with what's expected. Now, if you have a primary endpoint, you're not inventing these charters. You're using convention, and you want to make sure you're not deviating from what the FDA expects. In our case, the FDA was pretty clear that given the different routes of administration, the investigators unblinded to the treatments, they expected us. Essentially, they always recommend, that's the FDA's way of saying, "Do it this way," that we use the BICR assessed PFS as our primary endpoint.
Got it. Okay. Interesting. Is variability between these two different measures a key reason why you're focusing on hazard ratio to compare data sets, or are there other factors?
No. The hazard ratio focus isn't really at all related to this BICR versus investigator-assessed PFS. That gets more to study conduct and other factors.
Got it.
The hazard ratio really is a reflection where we think the relevance of the hazard ratio is important, particularly when you're trying to compare results, which physicians have to do when they're trying to select a therapy, between studies that have pretty substantial differences in the patient populations. Up until recently, you had fairly consistent homogenous populations that allowed you to just more easily compare the results side by side.
Recently, EMBER-3 is a good example. You had multiple subgroups being evaluated in one study. You had patients who were first line and second line, CDK, not prior CDK, and one primary endpoint that's kind of, in effect, combining the analysis for all those patients. Very hard to interpret just the top-line number because the control result is not possible to interpret. It is important to evaluate the relative benefit that you get to control. Hazard ratio allows you, in a very rigorous way, to assess that reduction in risk.
Another kind of poor man's hazard ratio is just to look at the ratio of the study drug result versus the control to compare that ratio, in effect, the potential multiple improvement relative to control. Certainly, investigators will look at the difference in PFS benefit from the control to the study drug. They will do a holistic assessment. Hazard ratio is probably just the most rigorous way to really assess that reduction in risk, which is the whole point of these studies, is to demonstrate that the study drug reduces the risk of progression for these patients in a statistically significant way.
Got it. Yeah. It makes a lot of sense. You got hazard ratio to account for the different subgroups within the study. You could also look at the PFS delta as a good indicator.
Exactly. The ratio, right? Four-month delta on top of five months is not as good as a four-month delta on top of two months, as an example. On a relative basis, you really look for how that control did relative to the study drug.
Makes sense. Okay. And then given that VERITAC-2 reported a median PFS of 3.6 months for the fulvestrant arm with BICR analysis, do you think it's reasonable to assume a median PFS of 3-4 months for the control arm in your VIKTORIA-1 study?
I do. I think it's important to note that the VERITAC-2 study excluded patients who are endocrine resistant. These are patients who had less than six months median PFS on their prior endocrine therapy. They enriched essentially for endocrine-sensitive patients. Our study doesn't have that exclusion criteria. We essentially have an all-comer when it comes to endocrine sensitivity status. That would introduce probably an upward bias in the median PFS in that study.
Interestingly, at ASCO, another phase III study was reported in a patient population very similar to ours. It was the FINER study. It compared an AKT inhibitor versus fulvestrant. That study reported 1.9 months median PFS. That's consistent with some other studies that have been performed. EMERALD study, for instance, for elacestrant was 1.9 months. Three other randomized studies have shown results in that 2-2.5 month range. We'll see soon enough. Probably south of 3 would, based on those studies, be more likely than north of 3.
Got it. Okay. Interesting. Another area of debate is the doublet arm. Do you expect to see meaningful differences between the two active arms based on your pre-clinical and clinical observations?
We would expect to see a difference. That's primarily because our non-clinical data has shown, and other non-clinical data from other researchers has shown, that an inhibitor of this pathway, PAM pathway, can resensitize tumor cells to CDK inhibitors if those tumor cells had previously stopped responding to CDK4/6 inhibitors. The inclusion of palbociclib in our study arm A is intended to essentially block the activity that gedatolisib could induce, i.e., reactivating that CDK4/6 inhibitor, and t hen palba will block that activity. As a result, we would expect to see a delta between arm A versus arm B.
Got it. Also on safety, how are you evaluating the tolerability trade-offs between the triplet and doublet arms?
Sure. In the early phase study with the phase III dosing, we reported treatment discontinuation rate due to adverse events of roughly 4%, which is very good. Essentially, if you were to compare it to trials that just evaluate CDK4/6 and fulvestrant or letrozole, you'd see discontinuation rates above 6%. We're not saying we're better than that, but we're saying it's unlikely gedatolisib adds, or at least that data suggests, adds incremental level of toxicity that prevents patients from staying on the regimen.
We think the only difference in outcome in safety-related outcomes between the doublet and the triplet arms will likely just be associated with palbociclib. gedatolisib is a very stable molecule, doesn't metabolize. Drug-drug interaction is really nominal, and very little overlap between the different drugs in terms of their toxicity profiles. You'd have to justify use of palbociclib on the basis of incremental efficacy. We don't think the safety delta will be that relevant in comparing the two, depending on the patient.
Certainly, if they're more immune compromised, if they're elderly patients, potentially use of a CDK inhibitor, which potentially can just induce some myelosuppressive adverse events. Doctors may like to have that option of not including palbociclib in the regimen. For otherwise patients that have stronger immune systems, they're more generally healthy. If the data warrants it, the efficacy data warrants it, I don't think the safety of the triplet would be a barrier.
In fact, we would hope the safety of our triplet, at least with the early phase data, suggests we could be safer than the other doublets that are being offered or more tolerable, I want to be careful, more tolerable than the doublets that are being developed in this space.
Got it. If both the triplet and the doublet succeed, you get both of those in the label, and the doctor would have the option whether they would be CDK4.
Yeah. Potentially. Sure.
Okay. Going back to the prior question, if you think the control arm comes in south of 3 months, potentially, just based on how long the study has been going, that implies that the treatment arms could be doing really well unless I'm missing something? I guess, what are some of the other variables that?
I just can't really speculate at this stage. We'll see. The data is going to come out in just a bit, and it'll be what it is. I can't hope what it'll be. We think with all the data out there for the control arm, you can draw a reasonable estimate of what you think that's likely to be and then draw your own conclusions about the implications for the study drug.
Got it. Okay. Assuming a positive wild-type readout, how soon after top-line disclosure do you expect to file the NDA? Will you pursue the real-time oncology review or priority review based on the strength of the PFS and hazard ratio data alone?
Sure. We would like to be able to submit an NDA before the end of this year. Obviously, it depends on the timing of when our data is available. We are working towards that. We have essentially been preparing the NDA and the various modules and the various documents required for the past year and laying the groundwork for that. As far as the regulatory pathway, we will request a real-time oncology review.
It is up to the agency's discretion, somewhat dependent on their workload. We will provide a data package that will become the basis for their determination whether or not we qualify for that. Again, somewhat dependent on their workload. If we do not get accepted into that pathway, certainly we would request a priority review. Both pathways, again, depending when our NDA is submitted, we think would lead to an approval, or at least we would work towards an approval mid-year 2026.
Got it. For the real-time oncology review, what do you need to demonstrate to justify eligibility?
Sure. It's somewhat similar to the criteria used to determine whether you qualify for breakthrough therapy designation. Our regimen qualified for breakthrough therapy designation in 2022 on the basis of our early phase data. Those determinations are a function of the agency's perception of the unmet need and the potential benefit that our regimen would offer those patients. If on the basis of the data, they think it's important to advance as quickly as possible the regulatory review, they would grant us, I mean, that would be the expectation.
At least that would be the hope. Again, it is somewhat workload-dependent because this puts a burden on the agency right away. Essentially, within weeks of getting, let's say, we qualify and they accept our request, you start submitting data. The review begins almost immediately. The agency has to be ready and have reviewers in a position to keep up with the submission of data.
Got it. Okay. As it comes to commercial adoption, can you talk about launch prep and strategy for driving adoption in community oncology settings where familiarity with IV PI3K inhibitors for wild-type patients may be limited?
Sure. We began initial preparation when we hired our Chief Commercial Officer last year and then senior people under him. We developed a launch plan. We've begun work on a variety of components of that plan that have long lead time items. We're essentially tracking towards, let's say, a launch mid-year next year, working back from that. That work has included, among other things, interviews, research, blinded research with different types of oncologists, KOLs, community docs. One of the questions we ask is what impact, if any, does gedatolisib's route of administration, intravenous administration, have on their likelihood of using the drug?
What's important to note is that the guidelines, as well as just obviously intuitively, these oncologists are focused on their priority as finding the therapy or therapeutic regimen that offers the most efficacy, what's going to increase the likelihood of or reduce the risk of progression or death as much as possible. Then safety, how well can these patients tolerate it? Is there a decrement in their quality of life? Then convenience.
Convenience, if let's say it's an oral therapy, is most relevant if these other two variables, i.e., safety and efficacy, are the same. If it's not the same, if let's say our regimen offers incremental efficacy benefit and is well tolerated, the route of administration from what we've heard won't be a barrier at all in community docs to using gedatolisib as an intravenously administered drug. In fact, for a lot of these docs, it's actually an advantage. An infused drug is considered a medical benefit. It has a much easier pathway for reimbursement purposes. Medical benefits do not involve co-pays that patients may be responsible for.
You have less financial risk for the patient. These doctors are able to recover costs. They see these patients. There is a benefit to that, just ensuring that the patients are using the drug, etc. It is also important to point out that the largest drugs in breast cancer, or amongst the largest drugs, are infused drugs. KEYTRUDA and HER2, Herceptin, PERJETA, this whole class of, or rather this tumor type, has really been advanced on the basis of infused therapy. These doctors are very comfortable treating patients with drugs like gedatolisib that have that route of administration.
Got it. Makes sense. Based on reimbursement, they're somewhat incentivized to use the infused drug.
Potentially. Yes, exactly.
Okay. Maybe shifting gears to the mutant part of the phase III study. Those results are expected in fourth quarter of this year, by the end of the year. Will the mutant-type top-line disclosure mirror the wild-type format with showing PFS and hazard ratio, or are you going to have more details in there?
It's a little early for us to commit to any particular disclosure strategy since it'll be somewhat dependent on the proximity to a major medical meeting. Certainly, we understand the importance of being able to provide an update as soon as the data is available. It's somewhat circumstantial or situational.
Got it. Okay. What are the expectations for this readout? What delta in median PFS would you consider clinically meaningful?
It's somewhat similar to what we've heard from oncologists in the wild-type setting. Essentially, if you can offer patients and the physicians incremental benefit of 3 months median PFS, they'll consider that practice changing. That would lead them to motivate them to prescribe that for their patients. Mutant would have a similar delta expectation.
Got it. Okay. Is enrollment now complete for the mutant-type cohort? Do you expect the end-of-year readout timing to hold, or what are the key risks to the timeline?
Sure. No. Enrollment's on track and ongoing. We're kind of monitoring the event threshold as we go. We're still on track to reporting data out before the end of this year. To the extent it pushes out, just based on the current enrollment trends and kind of consistency of those, we think it would be related just to delays in recording events.
Got it. Okay. Makes sense. I wanted to ask about the front-line study. Enrollment for the VIKTORIA-2 study is expected to start second quarter of this year. Have you started opening sites, and how long do you anticipate full enrollment could take for this study?
Sure. We have started opening sites, activating them. We expect to activate roughly 200 sites in 20 different countries. That process has begun. We have a number of active sites now. Enrollment, again, early to try to estimate that. I think it would probably be similar to the enrollment period for VIKTORIA-1, a couple of years.
Got it. Okay. Maybe you talk about this study and expectations for PFS and the control arm here and also active arms. Do you expect learnings from VIKTORIA-1 to influence any adjustments or how you view the probability of success for the front line?
Sure. A study was done in the front line for this patient population by Genentech. They used as a control, palbociclib and fulvestrant. A study had not really been done that evaluated these patients. These are patients who are receiving their first treatment for metastatic disease, but they are considered to be endocrine resistant. They did not get a significant benefit from their adjuvant endocrine therapy.
They progressed either while they were receiving it or within 12 months. They reported about 7 months median PFS for that control. That provides good foundation for our control assumption. It also happens to be about the same number, same median PFS that alpelisib, for instance, which is our control in our VIKTORIA-1 study, reported. In some ways, this first-line study, given the patient population, has the characteristics of a second-line study in terms of duration and control assumptions.
Got it. So you've got a good benchmark there to help you.
Yes. Yes, we do.
Got it. Okay. And do you find the INAVO120 phase III study, which tested inavolisib, palbociclib, and fulvestrant, do you find that to be a proper benchmark here? But this is only in the PIK3CA-mutant.
I think it provides a proof of principle of what we're doing. I'm not sure it'll be a benchmark because that study and that drug is only approved for patients that have PIK3CA- mutations. It's not going to treat the 60% of patients that lack PIK3CA- mutations. Secondly, that drug has very similar characteristics as alpelisib in terms of its ability to induce hyperglycemia. In the study to essentially manage that, they excluded patients who were either prediabetic or were type 2 diabetics.
They had to have very low A1C levels, glucose levels, for patients to enroll. We won't have those exclusions. We'd essentially, if the trial works out the way we hope it would, be able to essentially treat all comers, independent of PIK3CA status, independent of glucose status. As a result, we think our results, assuming we show benefit relative to control, would stand on their own and offer doctors a single regimen that they could use to treat all their patients.
Got it. That front-line Genentech study that you just referenced, was that a phase III study? Any.
Which one? The AKT study?
The palbociclib fulvestrant.
Yes, that was the INAVO120 study.
Oh, got it.
Yeah.
Okay. Got it. Yeah. Let's shift gears to prostate cancer.
Sure.
You're testing gedatolisib and darolutamide in combo at two different doses in a phase 1b with 18 patients in each cohort, followed by a dose expansion at 12 patients at the recommended phase II dose. What should we expect from the readout there expected by the end of this quarter? Will you disclose safety and our PFS data?
Sure. The two primary endpoints in that study, one are safety endpoints. Essentially, you're assessing whether there are any dose-limiting toxicities. We would expect to report a high-level summary of safety, as well as the efficacy endpoint, which was PFS rate at 6 months, essentially a landmark analysis at 6 months. We would present a more detailed, more complete data set at a subsequent medical meeting.
Got it. Okay. How are you thinking about the role of PSA response in this setting, given gedatolisib's non-AR mechanism?
Right. We do not think it will be relevant. I mean, certainly, it is one of the secondary endpoints. We will look at that. Other studies that have been done with PI3K inhibitors and with androgen receptor inhibitors have not necessarily shown significant deltas. We will see. I mean, obviously, the most relevant clinical characteristic is whether or not these patients' diseases, the progression of it, is being delayed. That is why PFS is the primary endpoint. PSA is an interim analysis that allows you to get a quick read on potential drug activity, confirms mechanism. In our study, PFS will be what determines the activity or allows us to assess the activity of the drug regimen in that patient population.
Got it. And quickly, for VIKTORIA-1, are you going to announce when the database is locked and then a quiet period? Maybe just talk about the logistics.
You'll see a press release cross the wire when we have the data. That'll include the top-line results we just discussed.
Got it. Okay. Maybe just to close out, if you can comment on cash position and key callouts ahead that you want to highlight.
Sure. We ended Q1 with around $206 million in cash that would take us through the end of 2026 with our clinical programs. Several key milestones, just talked about the wild-type and the second-line patient population. We think that's going to be a big deal, significant patient population, big unmet need. Preliminary data gives us a reason for optimism, but we'll see. We'll have subsequent data in this study, another phase III readout for the mutant population end of this year. We'll have an update with our prostate cancer study this quarter. We'll have a fair amount of data for people to assess gedatolisib.
Got it. Look forward to these updates. Thanks so much for joining us today.
You're welcome.