Hi 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 Brian Sullivan, the CEO of Celcuity. Thanks so much for joining us today, Brian.
You're welcome.
We're going to do fireside chat format. Maybe for those who are new to this story, if you can provide a one-minute intro to Celcuity.
Sure. So I started the company a number of years ago to develop a platform that could quantify signaling activity in a patient's live tumor cells. And one of the areas of interest to us was the PI3K/AKT/mTOR pathway because it presents a bit of a conundrum. It's probably one of the most important oncogenic pathways, yet has the least number of patients being treated with drugs that hit this pathway. And so we focused on this area, ended up bringing on a drug called gedatolisib. That's our lead asset. It's a pan-PI3K/mTOR inhibitor. We have three current programs that are active. First is in breast cancer, second-line setting, post-CDK treatment population. We'll go into more detail on that, I'm sure, later. The second program we're focused on is also in breast cancer. And this is in the front-line setting, patients who are HR-positive, HER2-negative, endocrine treatment resistant.
And then the third program that's ongoing is treating men who have metastatic castration-resistant prostate cancer who've progressed on their prior androgen receptor inhibitor.
Got it. Yeah, it's a great intro. And just setting the stage, let's talk about gedatolisib, which is a unique drug. Maybe provide a short background on how you came about the drug and in-licensing.
Sure. So as part of our work quantifying signaling activity in tumor cells, we do an evaluation as we're trying to deconvolute the pathway of all the drugs that we can get our hands on to evaluate. And that includes single node inhibitors like PI3K/alpha drugs, AKT drugs, mTORC1 inhibitors, and gedatolisib, as well as other pan-PI3K or other mTOR inhibitors. And we found clear superiority in our internal evaluation of gedatolisib. And we had a lot of interest in addressing and focusing on this pathway. And so based on that result, and we knew Pfizer owned the drug, we had a good relationship with Pfizer. We were doing some other work with them. We just called them up and said, "Hey, we have an interest in this drug and potentially partnering with you." And that's when we learned that they had made the decision to out-license it.
And so we basically made the decision to become a drug developer rather than a company that's partnering with drug companies to support their drug development, and went from there.
Got it. Makes sense. And then multiple PI3Ks targeting small molecules are currently approved in the HR-positive, HER2-negative BC setting. Can you elaborate on how gedatolisib's mechanism is differentiated from some of the other drugs out there?
This pathway, we kind of refer to it as a PAM pathway, is probably one of the most complex pathways to address in oncology. That's because, A, it's a critically important pathway. It affects and drives and controls key metabolic activities in your cells. Because of that importance, it's built in a number of redundancy mechanisms. Essentially it has six different components that interact that enable this pathway to retain function if one of them is insulted or disabled. As a result, to effectively address disease that involves a dysregulated PAM pathway, you need to comprehensively blockade it. That means inhibiting all four Class I isoforms, as well as mTORC1 and mTORC2. The drugs that are approved to date are what we refer to as single node inhibitors. They hit either PI3K/alpha, hit mTORC1, or hit AKT.
And those drugs were developed in response to toxicity concerns and the challenge of addressing this pathway without inducing unacceptable levels of toxicity. But they made a compromise in efficacy because they're not controlling this pathway as comprehensively as what we believe is necessary. And so Geda, by inhibiting all of these components at low nanomolar biochemical potency and then very low nanomolar biological potency, we've been able to show, and we've published data, significant superiority (be careful using the words) superior differentiation from these drugs. Just to give you one metric, Geda is 300-fold more potent than either of these, any of these approved single node inhibitors when you evaluate the impact on growth rate proliferation of tumor cells. It's the only one that's cytotoxic. So the mechanism matters, and it's key to maximizing the potential benefit you get from controlling this pathway.
Got it. And unlike the approved drugs, which are administered orally, gedatolisib's an IV injection, how do you think IV administration could help gedatolisib to differentiate versus competitors?
Sure. So with an IV-administered drug, essentially an in-office administered drug, there are a couple of benefits, actually. One is that because it's a medical benefit as opposed to a drug, it has a different approval process than, let's say, orally administered drugs. So it's less burdensome to get approval to treat with that type of drug. Doctors will also benefit. They'll essentially be able to recover costs. So essentially, it's friendly to the doctors when they have an in-office drug. And it's also friendly to patients because they're not at risk of a similar copay penalty that they are with an orally administered drug. And the other benefit, which is important and sometimes overlooked, payers like this, doctors like this, patients like this, is that you're ensuring that they're compliant, that they're taking their medication.
And with many therapies, obviously, depending on the toxicity profile, you could have patients not wanting to take the drug every day because it creates a level of toxicity that is not good for them. And so greater compliance, easier payer approval, benefits to the docs and patients financially, we think, motivate doctors. Rather, it creates not an incentive that they'll use a drug that isn't superior efficacy or safety, but it means that it's not a barrier to them wanting to use a drug that's in-office administered.
Got it. Makes sense. And are there differences there, whether it's the patient's front line or second line? I guess any perspective on that based on some of the feedback and market research you've done here?
No, actually. As we start to lay the groundwork commercially to understand attitudes to just this kind of question, we probe, we do it on a blinded basis so we aren't distorting and kind of kidding ourselves in what we're hearing, and if you're delivering superior efficacy and the drug is well tolerated, we anticipate really zero based on our research pushback on use of an IV-administered drug, except in the case where a patient has a geographic obstacle that may prevent them from consistently coming into the clinic, but outside of that, if it's just purely on a question of using this drug to treat a patient even with an in-office administration schedule, we don't anticipate that being a barrier at all and potentially has advantages.
Got it. Okay. And let's talk about some of the data that you've shown from your phase 1b. So there's discussion around arm D versus Arm C showing different efficacy results there. We've talked a lot about this in the past, but maybe if you could just kind of recap some of the key reasons for the different outcomes.
So both of those arms of our early phase study evaluated a woman who had prior CDK. But the Arm C patients had a greater number of lines of prior therapy. Two-thirds were receiving their third or fourth line, whereas in Arm D, only one-third were receiving their third or fourth line of therapy. The second difference is that 50% of the patients in Arm C had prior chemo, less than 20% in Arm D had prior chemo. And then the overall tumor burden in the patients with Arm C versus Arm D was greater. One way to sum up the difference in the clinical characteristics between these patient populations is looking at the median duration of their prior therapy. So Arm C patients were on their prior therapy for only five months, whereas the Arm D patients on their immediate prior therapy were on that for 13 months.
Both numbers happen to coincide with the median PFS we reported. You typically see a degradation in subsequent therapy relative to the prior therapy on duration of treatment. So we actually view that as favorable. Now, in the front lines, rather, in the VIKTORIA-1, our phase 3 study, because we're enrolling primarily a second-line population, we expect to enroll relatively few third-line patients, no patients with prior chemo. We would expect the median duration of treatment that the patients will have experienced of their immediate prior therapy would be closer to the median for CDK4/6s, which if you average it across the three different CDK4/6s, is about 20 months. We'll see. But overall, we would expect to be closer to 20 months than the 13 months. And again, net-net is probably a favorable factor.
Got it. Yeah, and for the phase 3 study that you're running, so there are some slight differences in those patients compared to ARMD from the phase 1b. Maybe highlight what some of those are and how that could influence PFS.
Right, so our goal in defining the patient population for VIKTORIA-1 was to get as clean a read as possible on the second-line patients, patients who are coming off a CDK4/6, because that's the dilemma that clinicians are facing: how do I best treat the patients in a second-line setting, and so to ensure we had a representative population, we excluded patients who had prior chemo. That tends to be beneficial in general because data has been pretty consistently shown that patients who receive chemo have a less favorable response to subsequent targeted therapy, so that's a typically good factor. The second factor that we think suggests we'll have a population that's more favorable prognosis is the fact that in the phase 3 study, we're allowing patients who have bone-only disease as long as they have a measurable lytic lesion or blastic lesion.
Whereas in our early phase study, we only enrolled patients who had measurable visceral disease, 80% of liver-lung mets, just as an example. And again, the greater the disease burden, typically the less favorable response to subsequent therapy. And there's clear data from a number of breast cancer studies that show significant delta between response of bone-only patients versus patients who had visceral disease, measurable disease. So those two factors we think are to the goods. There's always the unknown unknowns that can bite you in the tail between early phase and later phase studies. But it's nice at least that we have a couple of factors that are in our favor.
Got it. Yeah. And that's kind of the next question. It's a large study that you're running, a worldwide study, a lot of different sites and regions. I guess what are some of those unknowns that could impact PFS? You've mentioned before that you want to show a three-month delta between the.
I'd like to show more, but we think that's the endpoint. That's the minimum, right?
What are some variables that could influence the PFS and drive it one way or the other?
Well, so when you're doing a global study, you have two risks. One is just high deltas between the different regions that you're enrolling. And one of the variables that can impact you is how investigators assess progression. And so in studies that have investigator-assessed PFS, and depending on the other characteristics or other standard of care that's used, you can see pretty significant delta between regions. The second factor that can lead to variance or can impact results overall is patient compliance taking the therapy. So for self-administered therapies, depending on the toxicity profile, you can have patients not taking the drug. It's not visible to the doctors. We don't have that burden. So first, relating to the assessment, we're using a blinded independent central review to assess progression. And so we expect across the globe, we'll have a very consistent read on progression.
We'll eliminate that risk and just the randomness that can occur when you have investigator-assessed PFS. And then the other factor, because gedatolisib is administered in office, we know the patients are taking the drug. And so we eliminate the risk of lack of compliance that could potentially negatively impact your efficacy.
Got it. Okay. Yeah. That's helpful. And just based on your phase 1B experience, was there any difference in efficacy results between the ESR1 mutant versus non-mutant?
So we didn't have a lot of data on that front, so that's why we haven't broken it out and reported it, but I can say just with the limited data we saw, there was not any difference between those outcomes, and that's consistent with what was reported for PALOMA-3. PALOMA-3 evaluated palbociclib and fulvestrant, and they broke out the results for both patients with and without PIK3CA mutations and patients with or without ESR1 mutations, and the PFS was almost exactly the same for each of those subgroups, so it did not appear with the palbo-fulvestrant combo that the mutational status of those two pathways mattered and had an impact on outcomes.
Okay. And for your VIKTORIA-1 study, you're enrolling patients who have experience with CDK4/6 inhibitor in the front line setting. And so given the main triplet comparator arm in the study is testing Geda plus palbo plus fulvestrant, in parsing out contribution of components, how much benefit in terms of durability do you expect the addition of a CDK4/6 inhibitor could add?
Sure. So if you were just to add palbociclib to patients who've been pretreated with prior CDK and fulvestrant, we wouldn't expect to see any benefit. And we think the contribution of effect that you get when you add palbo to gedatolisib fulvestrant is a function of resensitization of these patients to CDK4/6 inhibitors. Non-clinical data has demonstrated that tumor cells that are refractory to CDK4/6 inhibition, they were initially sensitive, actually can become resensitized. You reactivate that pathway in the presence of a PAM inhibitor. And so essentially, then you can continue to get benefit from the CDK4/6 inhibitor. The difference that you've seen to date, which has been nominal, typically only occurs when you're switching from one CDK4/6 to another. But again, the results suggest it's a nominal benefit.
Our early phase data essentially only enrolled had nearly 100% of patients that had prior palbo, and then we retreated them in our study with palbo, so that's, in fact, a worst-case scenario. We would expect more patients just because of the shift that's occurred towards ribociclib in the front line setting to have had prior ribo, and net-net, that's certainly not all to the bad, and it might be somewhat to the good.
Got it. Okay. That's helpful. And in the past, we've talked too about the prophy mouth rinse that patients are using in the phase 3 study. Can you just clarify, well, maybe talk a little bit about that and clarify if the prophy starts in all patients at the start of randomization, or do you need to show early signs of stomatitis?
Sure, so the one adverse event that requires management with geda is stomatitis, even though we had high rates of stomatitis, what was interesting is that we didn't have high rates of discontinuation. In the patients that received our phase 3 dose, we only reported 4% discontinuation due to adverse events, but there was a lot of data that suggested, based on a study that Novartis ran for everolimus, that you could get a significant reduction in incidence and severity of stomatitis if you had patients use the dexamethasone mouth rinse, the steroidal mouth rinse, prophylactically, which means as soon as they begin treatment, and so in this study called the SWISH study, which compared everolimus with and without dexamethasone, they found that they reported a 90% reduction in incidence of grade 2 or greater stomatitis and actually 100% reduction of grade 3.
And so all of our patients will start off their therapy with use of dexamethasone for the first two cycles of treatment. Essentially, it's probably an immune response and that once patients adapt to the drug, they aren't as prone to get stomatitis. If they're going to get it, they'll typically get it in those first two cycles. So if you can get them through that period, they should be fine.
Could it lead to better outcomes in the study?
I think you'll certainly get better patient-reported outcomes, which is important. Just as an example, everolimus in their phase 3 study didn't use prophylaxis for stomatitis. They reported a 24% discontinuation rate, which is very high. I mentioned earlier, we reported 4% with our phase 3 dose. So we think the type of impact that stomatitis has on, A, the patient experience with the drug, as well as potential risk of interruptions or reductions of dose, is somewhat low. So I would certainly call it a to the good. The question is what the magnitude is, because on the margin, we didn't really see much diminution of the dose or interruption as a result. The dose density for Geda was 90%. So you might get a little higher, but it's hard to say that's going to have much of an impact.
Got it. Okay. And there's been a lot of debate around what we could see in the fulvestrant control arm in the phase 3 study. And so what are your latest thoughts on what a good assumption is to use for the fulvestrant?
Sure. Well, the good news for us is that fulvestrant is the standard control for most of these studies. And there have been four studies that have reported out results for fulvestrant as the control recently in a patient population that's very similar to ours, post-CDK, primarily second line, if not only second line. And three of these studies, EMERALD, VERONICA, SERENA-2, reported results of essentially two months. The fourth study was for CAPItello-291, reported 3.5 months. And if you do the average weighted or unweighted, it equates to three months. And so I think our view is that it's a three-month plus or minus half a month likely to expect for that population. We've been more conservative in our assumptions. I mean, essentially, whenever you're designing a study, you assume the control will do better than the data that's been reported.
You'll assume your drug will do worse, so you're not blindsided by underpowering your study.
Got it. Okay. Makes sense. And in your third quarter earnings, you mentioned that you're 100% enrolled with the PIK3CA wild type cohort and updated your readout timeline to late 1Q 2025 or second quarter 2025. Maybe just talk a little bit more about the timeline for the study and what the implications of moving the timeline a little bit mean and also where you're at with enrolling the mutant part of the study as well?
Sure. And so again, it's an event-driven study. We're blinded to the data. Because we have three arms, we have to connect the dots between the event threshold for the two primary analyses. So the two primary analyses are A versus C, B versus C. You have a specific event threshold for those two analyses. So we have to essentially say, okay, three arms event level will kind of equate to hitting the threshold for these two, but we don't see the data, so we don't know. So there's a certain uncertainty there. That's why we have to use a fairly wide band in projecting the timing of that. But the two factors that can affect you are the time that the median PFS of the control or your study drug.
I've indicated what I think the likelihood of being surprised on the control drug is, and beyond that, it's really not appropriate for me to comment more. People can draw their own conclusions.
Makes sense. And Arvinas, their VERITAC-2 phase 3 study, they just announced recently that they're delayed, too. They're using fulvestrant as a control arm. It'll be interesting to see what comes out of that. I don't know.
We'll see. I mean, again, I don't think there's any magic. I mean, at some point, there's certainly variability. There's certain randomness that can occur with results. But having four studies in the past three years report out very similar results, different sponsors, that suggests that the likelihood of having an outlier is low is how I would think about it. The one aspect of their data, though, that you have to pay attention to is that they're only enrolling patients who had at least six months of prior benefit on their prior endocrine-based therapy. And so those, obviously, they're selecting out patients who are potentially endocrine resistant, which will have the net effect of somewhat goosing their results for either the control or potentially their drug as well. In our VIKTORIA-1 study, one of the stratification factors was just that.
So, basically, plus or minus patients with less than or more than six months prior treatment. So, we would expect to report out those results so people can do a comparison, cross-trial comparison.
Got it. Yeah. And also wanted to ask about just with the multiple SERDs in this space, how you view that and how that could influence just the treatment paradigm?
Sure. So if you look ahead a little bit, ultimately, I think what is going to drive the eventual winner, the eventual standard of care in the setting is going to be based on the biology of the disease. You have three interconnected pathways that are driving this disease that have been validated: estrogen receptor pathway, CDK4/6, cyclin D1, and the PAM pathway. And so our hypothesis would be that the regimen that can effectively control those three pathways, whether it's in the second or first line, will be the winner. And that therapies or regimens that are controlling only two of those pathways or just a single pathway as a monotherapy would likely, just purely on a biological basis, report less favorable results. Obviously, we have to report our data.
But I think, in general, you tend to see greater improvement when you address and inhibit an untreated pathway than you will see when you're inhibiting or optimizing inhibition of an already treated pathway. So ultimately, I think a triplet will be the winner, first and second line, but we'll see.
Got it. And maybe talk about just status for the mutant study and just what your expectations are there. And currently, capivasertib is widely used as a second line option because it has better tolerability than alpelisib. What do you need to show in terms of safety and efficacy to differentiate versus capivasertib?
Sure. So we expect to report our mutant data second half, 2025. We're using alpelisib, fulvestrant as a control. Alpelisib has reported between 5.5 and 7.3 months. We're assuming better results than that in our control, as I indicated. We're conservative. Capivasertib reported 5.5 months. To be clinically meaningful, we would need to show, based on what we've heard from KOLs, regulators, as well as community docs, a three-month delta relative to alpelisib. Since the data to date suggests that alpelisib is at least as good or maybe better in delivering a PFS benefit, I think the transitivity principle will apply that if we can demonstrate superiority against alpelisib, it'll translate to superiority to capivasertib. Based on our early phase data, with a 4% discontinuation rate, we think we'll certainly not be at a disadvantage relative to capivasertib. We have some advantages.
They have a different profile of certain adverse events that create their own challenges. Certainly better than alpelisib, led to a big shift away from alpelisib towards capivasertib. But if our data is consistent with our early phase data, we'd be at least as comparable, if not better, safety, and we'll see, and efficacy.
Got it. And we need 20 more minutes to go into the rest of the questions I have. But maybe in closing, if you want to just briefly talk about the front line study and the prostate cancer study and cash and runway.
Okay. In 49 seconds. VIKTORIA-2 is a front-line study that we expect to begin enrollment in the second quarter. That'll be enrolling HR-positive, HER2-negative women who are endocrine treatment resistant. Okay? That's a subset of patients. These are women who progressed on their adjuvant endocrine therapy or quickly thereafter finishing it. So that'll be ongoing. That's a global study.
Prostate cancer.
Prostate cancer. So we started a study evaluating men with metastatic castration-resistant prostate cancer who progressed on AR. We expect to have that data Q2 this year. Strong biological rationale for that study. A lot of nonclinical work has demonstrated this linkage. And there's also compelling clinical data for drugs that have been discontinued, but very favorable clinical data. We reported at the end of Q3 that we had $264 million in cash that.