Morning, everyone. I'm Ken Shields, Vice President of Equity Research at Leerink Partners on the Targeted Oncology team. I have with me today Celcuity, Brian Sullivan, CEO and Co-founder of the company. Nice for you to be here.
Oh, I appreciate the opportunity to introduce you to Celcuity.
Yeah, sounds like a great story. So why don't we just start off a little bit with the background of the company, the origin, you are the founder, and how it came to be?
Sure. No, so I founded the company about 10 years ago, initially with the goal of developing a platform that could quantify signaling pathway activity in live tumor cells. And that ultimately led us to the PI3K pathway, which ultimately led us to gedatolisib. Gedatolisib was owned by Pfizer. We had a relationship with them because of a collaboration, ended up in-licensing the drug early 2021, and then took over development at that point.
Okay. Yeah, that's great. And I guess could you provide a background on that molecule, its mechanism? I mean, obviously it's a pan-PI3K inhibitor, so maybe you can talk about that.
Sure. So the pathway, PAM pathway, PI3K/AKT/mTOR pathway, is probably one of the most important pathways in cancer. Most of you probably know that. But it's also one of the most challenging pathways to drug. And so despite its importance, relatively small impact on the patient populations that are particularly relevant, breast and prostate cancer. And the challenge relates to the structure of the pathway. There are four class I isoforms that interact with each other, as well as two mTOR complexes, mTORC1 and mTORC2, and then AKT thrown in the mix is somewhat of a paradoxical target. And so to really address this pathway or dysregulated pathway activity, you need to comprehensively blockade it. And that's a challenge because the pathway is involved in metabolic processes. It can affect the immune response by regulating the tumor microenvironment. It also controls, greatly affects tumor cell proliferation.
To optimize development of a drug for treatment of pathways that involve this pathway, you'd like to comprehensively blockade it. To date, that has been a challenge. When this pathway's role was first discovered 20 years ago, almost every major pharmaceutical company launched a pan-PI3K-mTOR drug program because they understood biologically that that was the imperative, that this pathway's complexity required comprehensive blockade because essentially it has built-in redundancy given its important role as a metabolic controller. None of them made it out of phase I. They're all oral drugs. That really highlighted the challenge of safely addressing this pathway. It also highlighted the challenge of having an oral drug addressing this pathway. Gedatolisib, you can walk through that, addresses those challenges with its mechanism as well as its PK profile.
Yeah. Why don't we dive more specifically into.
Sure. Sure. And I can show a slide here just to give you some PowerPoint experience, just to highlight kind of the differential mechanism of action. So you have four class I isoforms. You have mTORC1 and 2. Gedatolisib has low nanomolar or subnanomolar potency [that] addresses all of those subunits or nodes, as we call it, compares very favorably to alpelisib when you look at IC50 values against PI3K-alpha, more active against mTORC1 than everolimus, also address[es] mTORC2. And even though we don't directly, gedatolisib doesn't directly address AKT, it's actually more effective as an inhibitor of AKT-related activity than capivasertib. And the real assessment, though, of the relevance of the mechanism can be seen when you look at these drugs in using a growth rate proliferation assay because this assesses essentially the drug's effect on the whole cell and its ability to continue to function.
So if we look at the potency, which essentially just to get a sense of how generally active it is, gedatolisib low nanomolar IC50 values, roughly 12 nanomolar, and independent of the PI3K status, PIK3CA status, which essentially is as the pathway intended. Essentially, this pathway is ubiquitously involved in some of these tumors, and it's not simply dependent on a particular activating mutation. Whereas if you look across the way at the right-hand chart, you can see that gedatolisib is 300 times more potent than these other inhibitors. They're just essentially inhibiting a single node, and that gedatolisib is the only one that is cytotoxic. The others are cytostatic. And again, this essentially helps demonstrate non-clinically the importance of the mechanism of action.
Okay. Obviously, you guys have generated some compelling data in the clinic. Maybe we can look at what's been shown, the early studies.
Sure. So the cancer types, there are two tumor types that have a significant amount of data, both clinically and non-clinically, that demonstrate the role the PAM pathway plays: breast cancer, HR-positive breast cancer, and metastatic castration-resistant prostate cancer. Our phase III program, we have a phase III program in breast cancer. We're treating patients who have progressed on their prior CDK4/6 inhibitor and have HR-positive, HER2-negative advanced breast cancer. And our second program is a phase I, phase II study we're currently enrolling where we are evaluating men who've progressed on their prior androgen receptor signaling inhibitor. And so we hope to report initial data in our phase III study sometime at the end of this year, by the second half of this year, and then report early data, preliminary data, in the castration-resistant prostate cancer study first half 2025.
Okay. And the previous data, I think, in phase II, can you walk through sort of the efficacy that was shown there?
Sure. No, I'll give you more slides. Yes. So in the woman that had received prior CDK4/6, we reported 12.9 months median PFS and a 63% response rate. And just to put that in context, hold on a sec, the alternatives available for women today in this setting are offering, for women who have PIK3CA mutation, between 5 and 7 months PFS if they receive alpelisib in combination with fulvestrant. Drug was just approved recently, an AKT inhibitor, capivasertib, Truqap, reported 5.5 months in patients who have PIK3CA or AKT mutations who've progressed on their prior CDK4/6. And then for patients who have ESR1 mutations, as you're all, I'm sure, aware of following the SERD space, the first one got approved, and then those patients showed roughly 4 months median PFS.
And then for women who don't have those mutations, they can expect 2-3 months benefit from fulvestrant. So clear need, significant unmet need to improve that, and our early phase data suggests we have a good shot at that.
Okay.
Just maybe just highlight one other set of the data. So we also evaluated women who were treatment naive in the advanced breast cancer setting and reported 48.6 months median PFS, which is really a very promising number, and then 79% objective response rate. So basically what we did in that setting was add gedatolisib to standard of care palbociclib letrozole. And here you can, this slide is helpful because it helps demonstrate the role that each of these pathways plays. So if you inhibit the estrogen receptor pathway with letrozole, you get very significant treatment benefit, 14.5 months, very active antitumor control. You add a CDK4/6 on top of that, you almost double median PFS, again, clearly an important driver of this disease.
And then when you add on top of this, and again, this is cross-trial comparison, have to take it with a grain of salt. But the level of activity shown, at least in this early study, 41 patients, suggests that, again, this pathway is ubiquitously involved. It's not involved simply as a post, as a result of activation of mutations that resulted from prior treatment, essentially that you will induce significant effect if you blockade all three pathways simultaneously. And that's ultimately our goal, would be to hopefully demonstrate success in the second-line setting and bring this to the clinic as a first-line drug option as well.
Yeah, it does seem impressive that this was addressing basically an overall population. It wasn't segmented by mutation.
Exactly. Only of the 41 patients, only 20% had PIK3CA mutations. And then if we looked at the, in the second-line setting, we had, again, comparable efficacy. Roughly 49% of patients who lacked PIK3CA mutation were progression-free at 12 months, whereas 60% of patients who had a PIK3CA mutation were progression-free at 12 months. So essentially, you'd say comparable, obviously a little arithmetic difference, and similar comparability in response rates, roughly 60% in the wild-type population, 73% in the patients who lacked, who had the mutations. And again, that's a function of its mechanism and addressing it comprehensively rather than just with a single node.
Okay. And then maybe we can touch on safety. What's safety profile?
Sure. So the third rail for this category, if you've been following this space, has been safety. And that reflects the role that the pathway plays as a controller of key metabolic processes, particularly your glycolytic function. And your glycolytic function takes place primarily in the liver where we're regulating glucose. And so when you inhibit PI3K-alpha in particular, you can induce very high levels of hyperglycemia. Alpelisib, for instance, which was approved in 2019, reported nearly 40% grade 3, grade 4 hyperglycemia in its randomized study. Roughly 26% of patients had to discontinue treatment. So a tough, tough setting. Gedatolisib, as a single agent, reported 1% grade 3, grade 4 hyperglycemia. So very, very nominal level of hyperglycemia, which then begs the question, well, why is that, right? Because there's typically an association with on-target potency versus grade level of associated adverse event.
One thing that's really important to understand is that what drives this toxicity is the exposure of the drug in the target organ, in this case, the liver. This activity that's regulating your glycemic function takes place in the liver. Oral drugs first pass or are processed in the liver, and as a result, you're going to see very high levels of hyperglycemia. Whereas Geda is intravenously administered, which is a necessary but not sufficient condition to avoid the toxicity. Geda also has a very favorable PK profile, so it doesn't get overly, essentially retained in the liver, has a balanced volume of distribution, which essentially means it's distributed somewhat evenly in tissue as in plasma. And as a result, it avoids overexposure in the liver. And also because it's intravenously administered, it avoids the gut on first pass.
That has been a challenge for some other PI3K inhibitors is GI-related toxicities, which again, we have nominal levels of that.
Okay.
And so for those of you who remember beer commercials, great taste, less filling, gedatolisib is able to essentially comprehensively address this pathway, affect in a very, very effective way without inducing the levels of toxicity that have prevented prior generations of pan-PI3K inhibitors from advancing in the clinic.
Okay. And then you mentioned the phase III data that's coming up, second half. Could we talk about the design there? I mean.
Sure.
There's been other studies like capivasertib, which showed a benefit in the overall population, but they ended up getting a restricted label.
Right. And sorry, I'll eventually find the slide here. Oops, going backwards. I need to, sorry. It's here someplace. Yeah. And so the FDA has made it very clear that if you have a drug that hits a particular mutation, they want you to demonstrate activity in, if you want to get an overall label, you need to demonstrate activity both in the patients who have mutations as well as those who lack them. And so capivasertib's study didn't independently power an endpoint for the wild-type population. Now, as they did the exploratory analysis, they found there really was nominal, there wasn't any activity in that subgroup. And that's what we would expect based on kind of the nature of the drug and the data that we've had, we've generated from a non-clinical perspective.
And so essentially taking FDA's direction, we work closely with them on several type C meetings to ensure that our design was consistent with their expectations. So we're evaluating, we're enrolling all comers, assess their PIK3CA status, and then assign them based on their status to either arms A through C or if they're mutated arms D through F. The control, if you lack mutations, is fulvestrant. We have two primary endpoints. We're comparing gedatolisib, fulvestrant, palbociclib to fulvestrant, and then comparing gedatolisib, fulvestrant to fulvestrant. We're testing A, C, and B, C hierarchically, so we're spending alpha. And then in the mutated patients, we'll be comparing to alpelisib, fulvestrant as the control. That's an independent statistical analysis. So again, doesn't take alpha, and we report that out independently. And we'll be comparing the triplet versus the alpelisib, fulvestrant doublet.
Now, because there are twice as many patients who lack mutations as have mutations, we will enroll the wild-type subgroup more quickly. And that's why that data will be available by the end of the first half this year, whereas the data in patients who have a PIK3CA mutation will be available first half of 2025.
Okay. So the wild-type population will be second half.
No, yeah, wild-type is the second half, right?
Okay. Yeah, and it looks like you definitely have all the different components, so it'll be able to show contribution of parts.
Exactly. Exactly. And that's important to do as well. And then if you are trying to assess probability of success or how do these various controls compare to our early phase data, this slide, which again, you can check out on our investor presentation later, but highlights the wide separation between the results we've reported in our early phase study versus fulvestrant as the control, and similar type of separation between the control alpelisib, fulvestrant versus what we've reported in our early phase study.
Okay. So yeah, we'll be eagerly waiting those results. Maybe you could talk about your second program, the prostate.
Sure. So prostate cancer, again, a lot of parallels between prostate cancer and breast cancer mechanistically. Both are driven by hormonal pathways, the androgen receptor pathway in the case of prostate cancer, and both involve the PAM pathway. That's been well demonstrated in a variety of both non-clinical and clinical studies. The challenge has been having the right PAM inhibitor because these pathways are interdependent, and inhibition of one can cross-activate the other. And so we are evaluating initially 2 different doses, essentially reflecting FDA's Project Optimus to reconfirm your dose in a new tumor type. And so that portion of the study is currently enrolling. And then once we settle on recommended phase II dose, we will enroll additional patients. So we'll have at least 30 patients that we'll be able to assess. And the primary endpoint for this study is progression-free survival rate at 6 months.
That's relevant because currently standard of care in the second-line setting in castration-resistant prostate cancer is about six months. So essentially we have designed the study to be able to show, we hope, significant effect size difference between these historical controls.
Okay. This is also essentially a broad population as well.
Yeah. So these are men who've received prior androgen receptor signaling inhibitor independent of when they received it. So they could have received it in the hormone-sensitive setting. But they need to be at a stage, though, where they're castration-resistant. And so we could enroll a combination of first and second-line patients in the metastatic setting.
Okay. And then so data, you said first half 2025.
Yes, early, preliminary data, just because it'll take us time before the data matures.
I imagine there'll be some PSA response or PSA 50 or.
Well, that's one of those secondary endpoints, but we think the primary objective, since we're not hitting the androgen receptor inhibitor, is to demonstrate tumor control. And so that's why our PFS is a primary endpoint.
Okay. Yeah, can you talk about any preclinical or other rationale for the problem?
Sure. So what's interesting is that similar to the data that we generated in prostate and breast cancer, we found non-clinically that gedatolisib is hundredfold more potent than other inhibitors that have been evaluated in this space as an inhibitor of growth rate activity, growth rate proliferation activity. And then similar results in animal models. But there have been a couple of clinical studies done with drugs that have since been discontinued that address this pathway that was favorable. These drugs had properties that didn't lend themselves to advancing in the clinic, but they demonstrated when combined with an androgen receptor signaling inhibitor, meaningful activity. And so essentially we're following those breadcrumbs. I mean, fortunately for us, there have been a huge number of trials with a variety of different drugs that have evaluated different patient populations.
Most of these drugs had flaws that prevented them from advancing, but in some cases, they indicated or reported very promising results, which we think with gedatolisib's properties, we would hope to at least replicate or exceed.
Okay. So that is prostate. I mean, was there a basket study and a histology of?
There was. So when Pfizer had the drug, they didn't necessarily focus initially on the tumor types that we think were most relevant, which would be tumor types that involve hormonal pathway. Endometrial cancer is another tumor type, for instance, that there's been significant reports of potential effect or benefit of combining PAM inhibitor with an estrogen receptor inhibitor. So that's sort of been where they went, but they really were focusing more on essentially colon cancer, pancreatic cancer, which have significant unmet needs, but there's not a very strong biological rationale.
Pretty tough.
Yeah. Exactly. So our focus has really been on these tumor types where there's clear evidence of activity of this pathway and clear unmet need, so relatively low bar to beat from just a strategy standpoint, and also very significant populations. I mean, so each of our indications, second-line breast cancer, first- and second-line prostate cancer. And the major markets, U.S., major European markets, Japan, have over 40,000 or 80,000 patients that could potentially be treated. And so each indication, we have a ways to go, has the potential to be a blockbuster, generate potentially in peak revenue $1.5 billion-$2 billion, which is just a fraction of its served market potential.
Yeah. As you guys grow, I know it's a little early and we're still waiting the pivotal data, at least breast. Are you building out or thinking about commercialization already?
We are. We brought on a chief commercial officer last month. Typically you require a 2-year runway to prepare, lay the groundwork for commercialization. So we've begun that work and tentatively would plan on an early, late 2025, early 2026 launch if, A, the data is available when we're currently projecting and we are able to and eligible for a priority review.
Okay. So do you think that you could potentially even file for the full population before the mutant arm?
Yes. So the plan would be to file for the wild-type initially, since the study is essentially independently powered and independent statistical analysis plan. And so essentially we're just following the FDA's guidance initially when we designed the study. So that is our plan, to file initial NDA for the wild-type population. Things go according to plan, we would get an approval, and around the time that we were getting an approval, we'd have the data for the wild-type, we'd be in a position to submit an sNDA for the mutated population.
Okay. And the hope would be priority review. Do you guys have any regulatory designations?
We have a breakthrough status for breast cancer because we had clinical data. We don't have clinical data for prostate. Hopefully we generate that and would get some form of priority designation then for prostate cancer.
Okay. And just in terms of those, I guess, early commercialization efforts or planning, what are the sort of considerations? I mean, have you guys thought about pricing? Have you guys.
Well, it's interesting. This market is, because of the unmet need and the nature of the disease, the market supports meaningful pricing. I mean, so the wholesale price for these drugs is significant, $27,000 a cycle. Now, obviously, your net revenue is a fraction of that, probably 70% of that. And so we think we'll show more value than those drugs, or at least that's what the data suggests. If we do demonstrate that, we think certainly we could support a price that's consistent with the prices that have already been established. And it's interesting, the two drugs that have been most recently launched, capivasertib and elacestrant, all have very similar level of pricing. So we think there's a good precedent for pricing along those lines.
Okay. Just in terms of competition, do you see any other programs that are emerging?
Well, clearly there's a lot of activity in the SERD space. And to essentially provide an alternative, to date, the results have suggested there'll be significantly more benefit in the ESR1 mutated patients, but other ones are under development. So it's still unknown what the potential could be in wild-type patients. Our view is that essentially, all things being equal, if you're treating effectively an untreated disease mechanism, in this case the PAM pathway, and you're also controlling where the other pathways involved, and again, in this case, CDK4/6 and estrogen receptor pathway, you have potential to induce greater treatment effect by controlling an untreated mechanism than by optimizing treatment of an already treated mechanism. There's more room to potentially improve anti-tumor control or likely more effect. And we'll see.
But we think ultimately, given the mechanism, the most effective and optimal control of the tumor in breast cancer, at least, would involve comprehensive blockade of all three of those pathways.
Yeah. Okay. I guess in terms of early pipeline efforts, is there anything else that you would point to or how do you think about it?
Yeah. We'll report those when we're ready to go. So we're not really previewing anything that we might be doing. Although I can say, given the favorable data we have in the frontline setting in breast cancer, it's an obvious place for us to go. Because again, the level of activity we showed relative to reported data for the current standard of care suggests that we would have pretty significant margin for error relative to what we reported and still potentially have the chance to provide a very significant treatment benefit for these women.
Okay. Yeah. Could you remind us your cash position and any potential partners you may have, how you're thinking about partnering?
Sure. So we had in December, $185 million of cash, which would take us through essentially into 2026, allow us to report out our data for our breast cancer and prostate cancer studies. We have a clinical collaboration with Pfizer for a supply of our palbociclib. We have a similar collaboration in place with Bayer, who are providing the darolutamide, the androgen receptor inhibitor for our prostate cancer study. And I think over time, it's typical, I guess, for companies at our scale to focus commercialization efforts on the U.S. market and then seek partners for rest of world activity. And those discussions, you can have those, but they really don't become meaningful until you have your phase III data. And so we would follow, I think you could expect us to follow a similar approach as other companies have taken.
Okay. Yeah. Well, I mean, we have a few minutes left. Is there any other topics you'd like to touch on or?
No. I mean, I think the question has been in this area consistently is, can you address this pathway safely? And we think the data to date suggests we can. And then the question is, is there a meaningful benefit when you inhibit the pathway comprehensively, or do you just need to inhibit, for instance, the activating mutation? I mean, we think our data suggests that this activating mutation plays potentially an additional role in driving disease. I mean, the response rates in patients who have activating mutations when you add an alpha inhibitor to fulvestrant, for instance, is about 20%. So basically a 10%-15% net objective response rate. And what to us that suggests is that if the activating mutation was playing a primary role, you would expect longer tumor control and greater objective response rates.
Certainly the data we've reported in the wild-type patients suggests the pathway is ubiquitously involved, intrinsically involved, independent of the activating mutation status.
Yeah. Well, it certainly looks impressive so far, and we'll be looking to those second-half results.
Great. Well, thank you. It's nice to be here.
Thanks, Brian.
Take care.