Hi, everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. Thanks for joining us today. I'd like to welcome our guest, Brian Sullivan, the CEO of Celcuity. Thanks so much for joining us today, Brian.
You're welcome. Thank you for having me.
We're going to do fireside chat format. Maybe to start off, for those who are new to the story, if you can get a one-minute intro to Celcuity.
Sure. So we're focused on treating cancers that involve the PAM/PI3K/AKT/mTOR pathway. Our lead candidate is gedatolisib, which is equally potent at low nanomolar concentrations or subnanomolar concentrations against the Class I PI3K isoforms, as well as mTORC1 and mTORC2. Our current development focus is on HR-positive, HER2-negative breast cancer and metastatic castration-resistant prostate cancer. We have a current Phase III study in breast cancer, which I'm sure we'll talk about, one that we expect to initiate early next year in frontline patients as well in breast cancer. And then we enrolled our first patient in a Phase Ib study in metastatic castration-resistant prostate cancer.
Got it. Yeah, that's a great summary. Maybe to start off, if you want to set the stage for the Phase III study and talk about the design for the study.
Sure. So essentially, we're enrolling all comers, women who've progressed on their prior CDK4/6 and letrozole combination. The design is intended to randomize according to PIK3CA status. So we have separate primary analysis for patients who are PIK3CA wild type and a different control. So we use fulvestrant as a control in that cohort of patients. Patients who have a mutation of PIK3CA will receive alpelisib fulvestrant as the control. In the patients who are wild type for PIK3CA, we have two primary endpoints tested hierarchically. We'll compare the triplet, gedatolisib, palbociclib, fulvestrant versus fulvestrant. If that is positive, we'll test hierarchically the combination of gedatolisib, fulvestrant versus fulvestrant.
Got it. Yeah, it makes sense. You announced 50% completion of enrollment in the wild type cohort on your fourth quarter earnings call. Just a quick clarification on whether the milestone was reached in first quarter of this year or fourth quarter of last year. What are your latest views on how enrollment is going and when you think enrollment would complete the wild type?
We hit the 50% threshold in the wild type population during the first quarter. We announced that, I think, early first quarter. Then enrollment continues to track. So we remain on track to report data by the end of the second half of 2025 for the wild type population.
Got it. OK. And then I think you said the primary analysis is event-driven. Other Phase III studies in similar settings have reported between 70% and 80% maturity at data readout. Can you say how your stats plan compares to these historical precedents? And could your healthier patient population affect timing of the readout?
Sure. I think the threshold is actually closer to 60%. Actually, the two studies that were just read out at ASCO, Phase III studies in breast cancer, their event threshold relative to total patients enrolled was about 60%. You might see it as high as 70%. And we're within those thresholds, those precedents. And the second part of your question?
For your healthier patient population, how could that affect timing of the readout?
Well, we think the assumptions we've made for the control are very conservative, to be frank, higher than has been reported in the population that we're evaluating for fulvestrant in prior studies. Obviously, there's always variability around what you expect for your study therapies. We've made some assumptions about what we expect, and our projections reflect that. But to the extent that the timing is affected, it would solely be, we think, a result of more favorable and longer duration on the median PFS of the study arms.
Got it. OK, makes sense. And for this study, you've got over 200 sites open in more than 20 countries, which is a significant number of sites to manage. Can you talk about how you're using CROs and talk about the process of coordinating between sites?
Sure. Well, I mean, like every sponsor, I think almost every sponsor in this space, you rely on a CRO to essentially do the day-to-day work associated with managing the sites, setting up the sites, coordinating a lot of the activities, performing the monitoring. We obviously have responsibility for oversight of the study. We have a team that's dedicated to, in effect, overseeing the study, coordinating with the CRO, conducting audits of sites. But what is most important as far as tracking the effectiveness of your CRO and also the sites is your monitoring plan. Again, we're following standard guidelines. Our monitors are in every couple of weeks. Their primary focus is ensuring study data is entered timely into the electronic database. They will also be required to do verification of that data.
Then finally, they'll work with and meet with site personnel, A, to answer any questions that may come up. If there's any questions about eligibility criteria or anything about the study itself, they're available and present. Secondly, they'll review the study documentation they have, ensure that they're using the appropriate documentation, and that the procedures that we prescribe and the protocol are being followed so that we're able in real time to make sure that sites are operating as expected and required by our protocol.
Got it. Makes sense. That's helpful. For patient baseline characteristics for the study, I'm just wondering if you're seeing any patterns or trends that may be different from the literature or your initial expectations.
Well, we have very specific eligibility criteria. For instance, the most important ones are that they're women who've progressed in their prior CDK4/6 and letrozole. We're not going to have any deviation on that. We exclude patients who have had prior chemo. We wouldn't expect deviation from that. We are allowing patients who are bone-only who have a lytic or blastic lytic lesion that's measurable to enroll. Other Phase III studies have reported between 15%-20% of the population includes that type of bone-only patient. There's nothing about the criteria that we're enrolling that would suggest we would see any deviation from that. And so we would expect the population to be consistent with the enrollment criteria and that's also consistent with what's been reported in other Phase III studies.
Got it. OK. In the geda safety appears to be another key differentiator versus other PAM inhibitors with only about 4% discontinuation due to AEs in the Phase 1B Arm D study. Are there other reasons for this besides the better dosing schedule? We know that for alpelisib, several AEs tend to show up early, typically within a couple of weeks. Can you remind what the AE kinetics are like for geda?
Sure. So this pathway, PAM pathway, is associated with one particular adverse event, hyperglycemia. Hyperglycemia is induced as a function of primarily inhibition of PI3K alpha isoform, but with the PAM pathway in general as well. And that pathway can be disrupted with inhibition of mTOR or AKT. And so geda has a couple of advantages relative to some of the other drugs that are targeting this pathway. One is its route of administration. It's administered intravenously. That's important because it avoids the liver. And that's important because the activity that PI3K regulates, among other things, is gluconeogenic function. And when that's disrupted, that's what leads to increased glucose levels, hyperglycemia. That activity primarily takes place in the liver.
So if you can avoid the liver on first pass, which what an IV drug does compared to an oral drug, which obviously is processed through the liver, you can minimize exposure in the liver and, as a result, have a correspondingly reduced level of hyperglycemia. Secondly, the PK properties matter, in particular, volume of distribution. Volume of distribution allows you to assess the relative distribution in tissue versus plasma. Ideal, I think, is generally considered to be balanced, which is what geda is. If you have a volume of distribution that's very high, it implies then that you are getting potentially overexposed in tissue. In particular, with these drugs, it can be the liver. And there's been examples of an IV-administered drug that had very, very high volume of distribution, 50 times greater concentration or exposure in the liver relative to plasma, and do similar levels of hyperglycemia.
So we think gedatolisib through its route of administration of PK properties, at least with hyperglycemia, is able to avoid this exposure in the liver, which in turn directly correlates to a more favorable hyperglycemia profile.
Got it. And what's the reference drug you were just talking about there?
Oh, for the IV drug, copanlisib, which was for heme indication, since been discontinued, but the data we think is relevant.
Got it. OK. Yeah, makes sense. For second line, HR-positive, HER2-negative breast cancer, it's clearly a large market opportunity. What's your estimate of the total market opportunity in the split between the United States and ex-US markets?
Sure. So if we look at data, epidemiological data, and then estimate, and from that, we can estimate the number of women who receive CDK4/6 inhibitors as frontline therapy and are endocrine treatment sensitive and then are eligible for subsequent second-line therapy, that's in the 30,000-35,000 range in the U.S. If you assume that we are pricing geda at a price that's consistent with the pricing for recently approved drugs, and you assume we have comparable duration of treatment to what we saw in our early Phase study, that translates to an addressable market of over $5 billion. Obviously, to drive a peak revenue estimate, you include some penetration assumptions. But you can be pretty conservative on your penetration assumptions and end up with a multi-billion dollar peak revenue estimate.
As far as the rest of the world, if you look at the EU5 countries and Japan, this roughly corresponds a little bit higher number of patients relative to the U.S. So essentially, a little bit more than doubles the total addressable population. Different pricing dynamics there, so the market potential is lower, but a very significant number of patients.
Got it. OK. Yeah, makes sense. And you mentioned that geda is IV administered. And for patients, they come in for a weekly injection while most other PAM inhibitors are daily orals. Can you remind how geda's PK lasts for a week? And is there a risk the drug concentration could drop below efficacious concentration toward the end of the week?
So one of the most important features of geda is that, A, it's a PAM, PI3K, mTOR inhibitor. That's relevant because by inhibiting all these nodes equal potently and simultaneously, you're preventing cross-activation of uninhibited nodes. And that translates into a very high potency. And so we assess the various single-node inhibitors and geda in breast cancer cells and assess their effect on cell proliferation rate and found that geda is at least 300-fold more potent inhibitor of tumor cell proliferation than these single-node inhibitors. And we think that reflects the mechanism of action, among other things. And so in humans, when we look at the plasma concentration of geda at the end of the dosing window, and we compare that to PD studies that have shown that at a corresponding concentration, we're above 80% level inhibition of the pathway.
We think during the dosing window, that 7-day window, we're at or above the threshold level of geda required to induce 80% inhibition of pathway activity.
Got it. And that's comparable with the competitor drugs as well.
Yes.
Got it.
Well, I can't necessarily speak for what the level of inhibition is of the pathway, but I can speak to ours.
Got it. OK. And how does drug exposure or AUC compare to other PAM inhibitors over multiple doses? And what have you learned from your non-clinical in vivo studies about the correlation between efficacy and dose?
Sure. So we think the animal studies kind of provide reasonable proxy. I mean, you have to always kind of look at these as part of the entire data set. But we've compared geda to the single-node inhibitors as inhibitors in animal studies, mouse xenografts, and found that geda is more potent, more induces a greater level of antitumor effect than these other drugs. And these studies were done using doses in animals that were comparable to the doses that they would be exposed to in humans. And there's an algorithm that's well understood that allows you to ensure you're using appropriate doses. And so we think that provides some validation of the relative in-human dose and antitumor effect, taking into account some of these PK properties. So geda is dosed intermittently in these animal studies. The oral drugs are obviously administered daily.
And so we think the PK profile is similar in the mice, where we try to simulate that as we do with the other drugs. And then by using, in effect, comparable doses as seen in humans, you're able to draw a bead on the relative antitumor control.
Got it.
We think gedatolisib is, at least the data that we've reported, has shown a more effective antitumor control, tumor regression, than these other compounds.
Got it. OK. Makes sense. There's been a lot of discussion around what to expect with the Phase III and the different arms of the studies. In your study, you've got patients you're enrolling that tend to be healthier and will be chemo naive. What are some scenarios on how this could influence the fulvestrant control arm, which historically has been in the approximate 3-month PFS range?
Sure. No, I mean, that's obviously a very fundamental assumption. We've been conservative in our design of the study in terms of what we assume for the control. There have been studies that have ranged from 2 months to 3.5 months for fulvestrant in a roughly comparable population. CAPItello-291 study with capivasertib was probably the most comparable population, reported about 3.5 months. They had 10% of their patients didn't have measurable disease. We would expect 100% of our patients have measurable disease. And that's relevant because patients with non-measurable disease, which essentially means they don't have a lesion that can be measured and assessed for progression, will tend to have a longer duration of PFS than patients with measurable disease. And we found that with the postMONARCH study.
PostMONARCH was the study that compared in patients who had progressed on their prior CDK, abemaciclib, fulvestrant versus fulvestrant. The population they enrolled really isn't necessarily one that would be enrolled in a registration study because they allowed patients with non-measurable disease. A third of their patients essentially had non-measurable disease. If you look at other studies, PALOMA-3 would be a good example. You'd see that the patients with non-measurable disease, where you're essentially relying on bone scans as opposed to a target lesion, have much longer, i.e., at least 2 times greater PFS than patients who have measurable disease. So we don't think that data was necessarily representative of the population that we're enrolling. So we think that 3-3.5 range, based on the data, is kind of reasonable expectations. And then we were more conservative than that in our control assumption.
Got it. OK. Makes sense. And the postMONARCH data, that's data that came out recently.
Recently at ASCO. Right. And so people, I'm sure, have seen that or might be eventually looking at that data. And we dug into that and think that, again, the PFS that was reported was greatly influenced by the composition of the inclusion of a significant proportion of patients with non-measurable disease.
Got it. And I've got a complex question for you. So you showed similar or better tumor inhibition with 15 mg/kg geda versus 2 mg/kg everolimus in preclinical data. And we know that in the TRINITI-1 study, everolimus plus ribo plus exemestane showed a notable 9-month PFS signal in PI3K wild-type patients post-CDK4/6, where the doses were below full dose. So how do you compare your dose in your Phase III study versus the everolimus dose in TRINITI-1? And do you expect deeper mTOR and CDK4/6 inhibition with your Phase III dose, which should lead to better PFS?
I'm sorry. Can you repeat that? Just a joke. No. So I think, no, that was an interesting study. And we think it's actually encouraging and somewhat validates what we're doing. So with our study, we were using what we would call our standard dose, 180 mg, and the standard dose of palbociclib, which is 125 mg. And that study, you relied on essentially, I think everolimus was 25% of standard dose. Ribo was 50% of standard dose. So it was able to report meaningful treatment, antitumor effect, despite having substandard doses. I think the fact that we're using full doses and have essentially a more potent compound and more active compound is encouraging to us that they were able to get those results despite these substandard doses, which we think reflects the benefit of simultaneously inhibiting these three pathways.
As we've talked previously, the estrogen receptor pathway, CDK4/6 pathway, the PAM pathway are interdependent. And in activation, or rather inhibition of one, can lead to cross-activation of the other. So simultaneous blockade of those three pathways, we think, is the best opportunity to get the most effective or optimal tumor control. What that data suggests is that you don't need necessarily optimal dosing to achieve a meaningful effect. What was also interesting is that they reported in patients who had more than 12 months median PFS on their prior CDK, roughly twice as long 13-month PFS as in patients who had less than 12 months duration on their prior CDK4/6 inhibitor.
If you think about that population, roughly 70% of women, again, if you just assess the Kaplan-Meier curves from the various studies, roughly 70% of women would be expected to be on a CDK4/6 inhibitor and letrozole for more than 12 months. That study under-enrolled that patient population. So again, we would expect to kind of probably follow what the overall population is. And again, another encouraging facet of that study.
Got it. Really helpful. Just based on the learnings from TRINITI-1 and your understanding of some of the powering assumptions for your Phase III VIKTORIA-1 study, how are you setting expectations for this initial wild-type readout?
Well, I mean, obviously, we would hope and we think it's reasonable to think that our Phase I data could be replicated. There's always questions about the replicability of early Phase data into later Phase settings. We have a couple criteria or composition of our patient population that is probably more favorable relative to the population re-enrolled in the early Phase study, including bone-only patients with lytic lesions, excluding patients with prior chemo. Those patients tend to have a better prognosis, theoretically, or at least based on data from other studies suggest that they would be more responsive to therapies. So to the extent that you have the unknown unknowns that can confound or rather affect the Phase III results relative to Phase I results, we think these other factors could be considered as potentially offsetting those.
But I think in general, if you were to speak to KOLs or community docs, for them to be interested in using a new therapy, they would want to see at least a 3-month effect size difference benefit relative to what the alternative is. And that's a threshold. That's obviously not our goal or our expectation. But that's the threshold you need to beat. And our early Phase data was substantially better than that, depending on what you use for your control assumption. We reported in the early Phase setting nearly 13 months median PFS. So a very significant difference relative to whatever you want to assume for fulvestrant.
Got it. Makes sense. I know you've got alignment with FDA to get approved based on the Arm A comparison versus Arm C, which is monotherapy fulvestrant. But is there any regulatory risk with FDA if Arm B performs the same as Arm C, raising questions around the contribution of palbo versus geda in Arm A?
Sure. So the most important arm is Arm A and the treatment effect that we induce. Obviously, the FDA in any study is always, as they say, looking at the totality of data to make their decision. geda contributes to the antitumor effect, we think, in two ways. One, by controlling or rather blockading the PAM pathway. But two, by resensitizing patients to CDK4/6. I think it's been pretty consistently found that retreating patients with CDK4/6 induces a very nominal benefit in patients. But with geda, by reactivating the CDK4/6 pathway, that in turn would resensitize patients to CDK4/6 inhibition. So you get a twofold contribution from geda that wouldn't be available, for instance, unless geda was part of the regimen. And that'll be part of the analysis that's done and that we'll provide and that is prescribed in our stats plan.
OK. Understood. And let's see. So in the remaining time, definitely want to talk about your frontline study, which you recently disclosed they're going to pursue. Maybe just talk about the trial design and how the study could look.
Sure. So the most important aspect of that study is that we're hoping to create a new option for women who have endocrine therapy resistant disease. These are women who, on their adjuvant endocrine therapy, progressed while they were receiving that therapy or within 12 months. And their prognosis is very unfavorable. Women who are endocrine therapy sensitive will get median PFS of 25 months or so. Patients who are endocrine therapy resistant only get 7 months. So big unmet need. And that really only became apparent when data was announced at San Antonio last year in this patient population. So it really allowed us to zero in because we had very, very favorable data, preliminary data in treatment naive women. And so we thought, wow, we need to figure this out. But we can't go after the endocrine sensitive patients.
But we didn't know how to define the population or at least the control assumptions in this resistant population. This INAVO120 data really made that possible. And so we thought it was important to do it as quickly as we could for obvious reasons. And the study is fairly straightforward. It's geda plus investigator's choice of CDK4/6, ribo, palbo, plus fulvestrant, and comparing to investigator's choice, ribo, palbo versus fulvestrant. We are assigning and randomizing according to PIK3CA status into two different cohorts so that we can perform independent primary analysis of those two groups of patients and do that in a way that spares alpha and doesn't require hierarchical testing. So we think that's favorable. And we had a very productive and good meeting with the FDA to review the study design. So we think we're aligned on that.
We've kind of checked that box, ensured that what we're doing makes sense to them. And so now it's a matter of getting the work done and doing the feasibility and site selection and then site activation work.
Got it. I look forward to that. And we're out of time. But maybe if you just want to talk about the prostate cancer study as well, and cash position, and highlight anything else you want to.
Sure. So the prostate cancer, interesting. It's also a hormonally driven tumor type, androgen receptor in this case. A lot of nonclinical data, as well as several clinical studies, have shown that the PAM pathway is involved in promoting androgen metastatic castration-resistant prostate cancer. So based on that data and the activity of geda, we thought it was important for us to assess and evaluate geda in those patients. Phase 1B, we enrolled our first patient in February and would hope to create another opportunity for geda to help an important group of patients who don't really have very good options post-androgen receptor therapy these days.
Got it. OK. Thanks so much for joining us today, Brian.
It's my pleasure.