Good afternoon, everyone, and thank you for joining us at the 4th day of the Needham Healthcare Conference. It is my pleasure to have with me today Brian Sullivan, the CEO of Celcuity. As a reminder, any viewers who are watching through our conference portal are able to submit questions via the Ask Question box below the video feed window. Brian, with that, I think we should start with a bit of an introduction.
Sure.
Just walk us through some of the basics, specifically what are the expected catalysts toward the end of this year and the beginning of next?
Sure. So we have two programs that are active today. One is in second-line positive breast cancer. We have a phase III study in process. The study has essentially two independent cohorts. We expect to report data from PIK3CA wild type cohort by the end of this year. And then to report the data for the PIK3CA mutant cohort in the first half of 2025. The second program we have is in patients who have metastatic castration-resistant prostate cancer. We started enrolling that study first quarter. We expect to get preliminary data and report out those findings sometime in the first half of 2025.
Excellent. So a good place to start is to speak of your main asset, gedatolisib, and PIK3CA. A key feature for gedatolisib is its ability to block several pathways at the same time, including PI3K, AKT, mTOR. There've been quite a few attempts to target PI3K, including commercial products, Piqray comes to mind, that have been challenged by safety issues. So just for the benefit of our audience here, how is gedatolisib different?
Well, gedatolisib is different both in its mechanism and its safety profile. When the role of the PAM pathway, PI3K, AKT, mTOR, role of the PAM pathway was discovered 20 years ago. Almost every major pharma company had a program to target this pathway, and pretty much every drug they were developing was a PAM PI3K mTOR inhibitor because the biological imperative to address disease involving this pathway required, in effect, inhibition of all of these. We call them nodes. Pathway essentially is built in redundancy mechanisms to enable to continue to function. Those drugs were all too toxic. They weren't very effective. Difficult to hit all these nodes at roughly equivalent potent IC50 levels. So the tendency, the trend, then was to focus on single nodes. Alpelisib hits PI3K alpha. Capivasertib, which was just approved, hits AKT.
Then everolimus, which was approved a while ago, hits mTORC1 . Those drugs, while they induce a treatment benefit, have provided only nominal improvement relative to endocrine treatment on its own. So there's clearly a need for better options. Gedatolisib is equally potently effective against all six of these different nodes, the various Class I isoforms, as well as mTOR C1 and mTORC2. We've shown non-clinically that gedatolisib is 300 times more potent than either of any of those three other inhibitors. So the mechanism is very important. But just as importantly, gedatolisib, because of its route of administration, it's IV administered. And its PK properties, it has a very balanced volume of distribution, is able to avoid the toxicity that has really been a challenge to overcome, which is hypoglycemia.
This pathway essentially is involved in regulating the gluconeogenic function, which primarily takes place in the liver. And in regulating, which induces excess production of glucose, resulting in hypoglycemia. And oral drugs obviously are on first pass, processed through the liver, highly concentrated exposure, and the result is consistently high levels of hypoglycemia. There's been a development. There was a drug that was approved since been discontinued. It was a pan-PI3K inhibitor, or IV administered. So essentially, they met the first requirement we think is needed to really optimize for hypoglycemia. But they had a very high volume of distribution, which essentially meant they had much greater distribution into tissue versus bloodstream, which essentially meant this drug got bound up in the liver, which is, again, is the last place you want PI3K drug.
And that drug, even though it was IV administered, reported similar levels of grade three, grade four, in the 30%-40% range as alpelisib. So essentially, IV administration is, we think, a necessary but not sufficient condition. And a balanced volume is that other condition required to essentially optimize the targeting of this pathway, induce, we think, over the dosing window, IC80 levels of pathway inhibition. But avoiding overexposure in the target organ, which in this case is the liver.
That's very helpful. And maybe related, then somewhat backwards looking. So gedatolisib was originally developed by Pfizer. Do you have any insights as to why that was discontinued at Pfizer?
Sure. I mean, obviously, Pfizer, unfortunately for it, has developed a bit of a reputation for giving up good drugs. We think this is another example of that. But I think that just reflects the complexity of managing a very large organization where you have a wide range of people. And in this particular case, if you look at the history of the development program, you'd see that it was initially focused on using gedatolisib or evaluating gedatolisib in combination with chemotherapy in colon cancer patients. I think the rationale for that was focused on significant unmet need in that population. These patients are getting only 2 months from their second line treatment. So there was a rationale for focusing on that, but not necessarily a biological one. And so those results weren't very favorable.
So fast forward to 2019, a strategic review, which Pfizer does every few years of their portfolio. They had really only generated data in what we would say are non-optimal indications. I mean, you can evaluate any drug in the wrong tumor type and not get favorable results. And I think that was the case here. They did introduce and start the trial whose data we took over and have reported for breast cancer. But that data wasn't mature. And so they made this decision, I think, primarily on the prior studies, which were not in necessarily the tumor types we would have focused development on. And then there's always circumstance. The two individuals who are responsible at an executive level as a sponsor had left. Actually, one died. And so they were no longer in a position to "defend" the drug.
So I think this drug became a bit of an orphan. Development history was very mixed. Didn't have the data we ultimately had to review. And so, again, it just got swept into the BD bin. And we were the beneficiaries of that. We came across the drug, actually, interestingly, because of the work we were doing on our platform. We were assessing PI3K activity in live tumor cells. Investigating activity across a range of different PI3K inhibitors. And found that gedatolisib was by far superior at shutting down tumor activity. We're able to turn on and off this pathway and see how effective it is. And so we approached Pfizer not knowing what its development status. It looked active if you just look at the studies on CT.gov. And we had a relationship with them and said, this looks like a great drug.
We'd love to collaborate with you on this." And that's when we learned that it was being outlicensed. So our focus on PI3K, because of its critical role as a cancer driver, and then subsequent evaluation of these drugs flagged this drug to us. And it was serendipitous that at the time we raised our hand and showed interest, it happened to be available for outlicense.
Yeah. Sometimes you get lucky.
Yeah. As they say, better be lucky. It's better to be lucky than good.
That's a good segue to start talking on the metastatic breast cancer. Again, from an outside view first. What is the unmet need here, and what are we trying to address with gedatolisib?
Sure. So you really have to break positive breast cancer in the second line setting into 2 populations. Patients without PIK3CA mutations, we consider them or call them wild type. And then patients who have mutated those mutations. For patients that are PIK3CA wild type, they're getting about 2-4 months of benefit, median PFS, from either SERDs, whether it's fulvestrant or elacestrant for ESR1 patients, patients who have ESR1 mutations. Or getting the combination of everolimus with fulvestrant or exemestane. And again, retrospective studies show these patients are getting about 4 months with that regimen. In the patients who have a PIK3CA mutation, they're getting between 5.5-7 months, based on the reported data for either capivasertib, the AKT inhibitor, or alpelisib PI3K alpha inhibitor.
So essentially, they're not getting much benefit relative to the benefit these patients get in the front line setting, where they're getting a couple of years of median PFS, 24, 25, 26 months. So the unmet need is significant, because, again, these patients aren't getting much benefit from the subsequent lines. And if we replicate the data that we reported in our early phase, we would have the opportunity to really reset standard of care and dramatically improve the second line paradigm for these patients.
Maybe going back to that data, there were some interesting differences between different dosing regimens as it relates to responses. Any thoughts on how to explain that?
Sure. I think one of the more interesting findings in our early phase study was that we found that patients who received gedatolisib on a three week on, one week off schedule showed a greater treatment effect than patients who received gedatolisib on a weekly basis, once a week IV. And we think there are two explanations for that. Which are hard to tease out the relative contribution of each, but we think both are probably important. One is that by going on a three week on, one week off schedule, we were synchronizing the dose schedule with palbociclib, palbociclib and ribociclib, another CDK4/6 inhibitor. Are each administered for 21 days daily. And then seven days off, essentially three weeks on, one week off.
When you have interdependent pathways that can cross activate each other when one is inhibited, we think it is important to inhibit these pathways simultaneously. Otherwise, for instance, if we're inhibiting the PAM pathway without coverage of CDK4/6 pathway, we could essentially reactivate that pathway and essentially offset the benefit you get from your PAM inhibitor. A second benefit, and this is a little bit more complex. But it's been well established that the PAM pathway plays a critical role, when it's dysregulated, in making hormonally driven tumors less immune responsive. Essentially, it somewhat masks the tumor microenvironment, or serves to, in fact, mask for CD45 anti-tumor immune cells from being able to gain access to the tumor. By inhibiting this pathway, you essentially bias the tumor in favor of anti-tumor immune cells.
During the holiday, you allow these anti-tumor immune cells to infiltrate the tumor and induce a treatment effect. We have non-clinical data that has shown that significant increase in the composition of the tumor that's comprised of anti-tumor immune cells 10 days, 17 days after a dose of gedatolisib. So we think it's likely that we bias the tumors to be more immune responsive. But again, in human, it's very hard to tease out those two factors. But we think each is relevant, and probably each are part of the explanation.
Okay. Moving forward, then looking at the pivotal study design, maybe it's a good juncture to remind everyone what that structure is.
Sure.
It's separated between mutant and wild type, and you have some different doses.
Right. So the two primary differences, or the two important features to think about, are the control arms, which are different between the mutant cohort and the wild type cohort. The wild type cohort, fulvestrant is the control. That's become pretty much the go-to control for almost every study that's been run in second line setting for years. We're comparing gedatolisib fulvestrant as a doublet to fulvestrant, and then comparing gedatolisib palbociclib fulvestrant to fulvestrant. The primary endpoints are comparing the triplet versus fulvestrant. That's the first primary endpoint. We test hierarchically if that result is positive. We test the doublet, gedatolisib fulvestrant, against fulvestrant. That gives us, we think, two shots on goal. An opportunity to potentially, if the data is favorable, to submit for both indications. In the mutated segment, alpelisib fulvestrant is the control.
That makes the study very interesting from a scientific standpoint, because there really hasn't been any comparative data in this setting. I think clinicians are very interested in seeing the relative benefit of a drug like gedatolisib, but also the benefit of combining with CDK4/6. The study that was done with capivasertib was not a head to head against alpelisib. And so again, it didn't really demonstrate any superiority as a result. And so it's an option in that case. We wanted to, hopefully, show that our regimen is superior to alpelisib. And ideally, if the results are what we hope, we would show that we can establish a new standard of care.
Kind of in a related sense, you mentioned earlier addition of novel SERD and novel AKT targeting agent. Does this change what the real control arm should be, or you don't think that matters very much?
Well, I mean, it certainly could matter. But I don't think it does matter. And that's because, for the most part, every drug that's being evaluated in the setting is using fulvestrant as the control. So you will have a common control. Obviously, you'll have cross-trial comparisons. But each drug is being evaluated relative to the same control. And so your hazard ratio can, I think, pretty reasonably be compared, because you're using the same control in pretty much all of these studies. And so I think the data will be interpretable by clinicians and to demonstrate, or rather to help them select the treatment that offers the best improvement available.
Another related question, now that we look at the ESR1 mutations and AKT mutations. Is there any retrospective analysis from data that you guys already have stratified by the different mutations?
So we have small samples of data. So it's not the kind of data you'd really publish because it's too small. But we didn't see anything, nonetheless, that was interesting, i.e., different and differentiated. And so we're going to be evaluating various panels of mutations or pathway markers. And we'll be in a position to assess any potential treatment difference outcomes in those patients. But the data to date doesn't suggest that we would expect to see a meaningful difference in those patient populations.
As to the enrollment of the VIKTORIA-1 study itself. Are patients with such mutation backgrounds, ESR1 and AKT, do they get enrolled into the study, or?
They do. Yeah. All these patients are eligible. There's no exclusion based on either of those mutations.
My question is more from a practical sense, meaning if a physician gets a patient with a mutation, wouldn't they prefer to put him on labeled drug?
Well, our drug will, in the wild type setting, our drug will have included patients that have ESR1 mutations and other mutations. And so the data will be applicable in that case.
Okay. That's fair. Okay. And typical question. If you can provide any details on how enrollment is going?
It's on track relative to what our internal expectations have been and consistent with the guidance we provided on when we think the data will be available. We did a filing that was related to a debt facility that we have. As part of that debt facility, there was a tranche that we were eligible to draw down that would be eligible to us, where we could draw it down upon achievement of 50% enrollment of the wild type subgroup. We satisfied that criteria in the first quarter. That's essentially the only guidance we've really given on our status of enrollment. But that's consistent with what our expectations were. That's why that milestone was identified in the debt agreement to start.
Okay. You've also shown some very interesting data in treatment naive patients as well. What would trigger additional clinical exploration in this larger market?
No, you're right. I mean, the data is very compelling. In this treatment naive patients, we reported 48 months median PFS. These patients had a 79% objective response rate. So compares very, very favorably to the reported results for, let's say, palbo, letrozole, or ribociclib letrozole. So clearly, very, very strong rationale for us to pursue an indication in the treatment naive population. We've got our hands full right now. But we would expect, without projecting per se, but we would expect to be in a position to explore first line opportunity once we've reported data for a wild type population.
Okay. I think at this point, maybe we can move forward and look at gedatolisib and prostate cancer. A lot of analogies here to the breast cancer space.
No, exactly.
You guys recently enrolled your first patient in phase I-b for mCRPC.
Metastatic castration-resistant prostate cancer. It's a mouthful.
Words are becoming hard. Can you remind us of the logic in patient selection for this preliminary study?
Sure. So the standard of care for men that have either hormone-sensitive prostate cancer or castration-resistant prostate cancer is to receive an androgen receptor signaling inhibitor, or next-generation hormonal therapy. Eventually, these men progress. The disease is not curable at that stage. There's been a lot of work done, both non-clinically as well as clinically, that have demonstrated the interdependence between the hormonal pathway, in this case, the androgen receptor pathway, and the PAM pathway. So there's a very strong biological rationale to evaluate the combination of a PAM inhibitor like gedatolisib and an AR inhibitor. So we'll be evaluating men who are either hormone-sensitive, castration-resistant, who've progressed on their prior AR inhibitor, who haven't had chemo in the castration-resistant setting. And then essentially, we'll be adding gedatolisib to their regimen. With the twofold potential benefit.
One, we're blocking comprehensively the PAM pathway. But two, by doing that, non-clinical data has shown that you resensitize or you reactivate the AR pathway, which in turn would resensitize patients to treatment with an AR inhibitor. So similar to breast cancer, where you get a kind of a double effect with gedatolisib. Benefit from inhibiting the PAM pathway. Benefit, in particular, resensitizing breast cancer to the CDK4/6 inhibitors. We'll be doing that. Well, at least we think the data is pretty compelling to suggest that'll occur in prostate cancer. And also what's interesting, I mean, one of the benefits we have of following the development of a lot of other drugs that have never made it to the clinic is that they, in some cases, generated pretty interesting data. So there was a study with an AKT inhibitor that Roche had that's been since discontinued.
Then there was a study with a pan-PI3K inhibitor that's also been discontinued in metastatic castration-resistant prostate cancer patients, combined with an AR inhibitor, and found very significant treatment benefit. So those drugs had issues, weren't able to continue development. But in our opinion, that serves as a very good proof of concept for the study that we're performing. So our underlying premise is that while our drug is more effective than those other two drugs and more tolerable, we think net net that we should see at least comparable data to what those drugs showed. Which if we do, it would be fantastic. It would be a very, very meaningful result. But there's certainly logic to support that we could do better than those drugs. But that's why we're running the trial. We'll see.
Speaking of the preclinical assessments here, is there any insights as to the underlying biology? Why would the tumor become resensitized to hormone receptor blockage?
Sure. Well, so in the case of prostate and breast cancer, the hormonal pathways are linked. Essentially, PI3K activates AR, and AR activates PI3K. They're essentially cross or interdependent. I mean, essentially, they are cross regulating critical activities intracellularly. And so when one is inhibited, let's say PAM pathway is inhibited, it in a sense sends a signal and the cells adapt to, in effect, increase the activation or the activity of either the or AR pathway. And so even though, at least in the case with AR drugs and CDK4/6, these patients become basically transiently resistant to—let's focus on prostate cancer—to the AR inhibitor. They don't become genetically transformed. Now, some do with an AR-V7 mutation. But actually, the data from one of these studies shows that these drugs can work independent of the status of AR-V7.
The end result is that when we apply gedatolisib, we're essentially sending a signal to the cells that they need to, in effect, rely more on AR. It gets that pathway going again. And so if you are blockading it, then essentially, you're inducing a treatment benefit. That pathway becomes relevant again for treatment. And so you're getting the benefit primarily from inhibiting the PAM pathway, but you're preventing diminution of the effect by maintaining control of the AR pathway.
Maybe the good analogy here is the infamous TKI whack-a-mole.
Yeah, somewhat.
As you block one side, right? The other side peaks. And in this case.
Exactly. Again, when you and we think of these pathways as essentially a circuit. You need to control the circuit and prevent the circuit from allowing escape and activity. In effect, people call them resistance mechanisms. I think they're really intrinsic.
They're compensatory mechanisms. Resistance is a little.
Adaptive. No, it's an adaptive response because the pathways are interdependent.
Yeah. And we spoke about this before, about dosing. But I didn't want to bring it up. Metronomic dosing. That's all part of the lore of how to manage TKI inhibition, right?
Right. Right. And again, with the PAM pathway, for instance, one, at least we find this interesting. If you look at the results for PD-L1 drugs, they've been consistently effective in every tumor type other than the two primary hormonal tumor types, prostate and breast, or at least positive breast. And each of these tumors have been found to be fairly dependent on the PAM pathway. As I mentioned earlier, the PAM pathway, when it's dysregulated, essentially reduces the immune sensitivity and affects the tumor microenvironment in a way that leads to immune suppression. And so essentially, those tumors, one way to think of them is being cold tumors. And that may be an explanation for why these PD-L1 drugs haven't found any treatment effect, found to have a treatment effect in those two tumor types.
We think with gedatolisib, with this intermittent dosing, again, we are creating a window for the immune system to become effective. Hopefully, or at least we think it's plausible to think that it's inducing an anti-tumor effect as a result.
Yeah. That makes sense. So going back to the study here, just to remind us what the endpoints are for this really quickly.
Sure. So the endpoint here is PFS, the percentage of patients who are progression-free at 6 months. So PFS rate at 6 months. That's relevant because if you look at the standard of care, and again, there's not a lot of studies in this setting. It hasn't been much work. But with an AR inhibitor or chemo, these patients are getting between 5-6 months. So if we can demonstrate a meaningful improvement relative to 6 months, greater than 50%, 45% PFS rate at 6 months, we think that would be very, very meaningful. And encourage us to continue to develop the program.
All right. Very helpful. And maybe moving to kind of the commercial side of things. You've recently brought in an expert to help you with this. What early activities have been done regarding commercialization?
Sure. So we brought on our Chief Commercial Officer. And one of the reasons why we brought Eldon, his name's Eldon Mayer. We brought him on. And it was a key factor in how we were considering candidates. Was their experience doing a first launch for a drug. When you are launching a drug for the first time, there's a very, very significant amount of work needed to essentially characterize the landscape, the payer landscape, physician landscape. You're needing to establish infrastructure that doesn't exist in the company. And so you lay the groundwork essentially month from month T-24 to T-12. You're laying a lot of groundwork, both intellectual groundwork, data, just analytical information. And then building out some infrastructure. And really developing by the end, by that T-12, a very, very robust go-to-market plan. Obviously, it's being formed by the data.
But along the way, you're able to get insights about positioning of the drug in the space, attitudes, etc. Understand if there are any obstacles to wide usage, etc. And factor those insights into your ultimate launch plan. So not a huge I mean, there's meaningful activity, a lot of paddling under the surface. Not huge expenditures. Obviously, the expenditures increase the closer you get to launch, especially as you get closer to hiring a sales force. But that type of expense is much closer to actual launch than we are now.
On the back of that, just to remind us, company capital position and runway.
We ended 2023 with about $181 million of cash, which we expect will take us into 2026 with our current operational profile.
All right. Excellent. We're a little early. But that's most of the questions I had. I think you're ahead of a very exciting time for the company with 2 major readouts. If there's anything you'd like to add, this is a good time.
No. I mean, we're obviously very excited. We think this pathway is probably the most intriguing pathway in solid tumors because of the critical role it plays, but the relatively small impact these drugs are having for the tumors of most interest, breast and prostate cancer. I mean, if you look at the volume of the revenue generated by drugs that hit HER2 with mutations, $10 billion or so. Only 8% of solid tumors have HER2 mutations. EGFR, only 5% of solid tumors have EGFR mutations, but generate nearly $6 billion of revenue. So PAM pathway, 38% of solid tumors have some form of PAM pathway related mutation. And yet, the revenue generated, which essentially is a way of expressing how many patients are benefiting from these drugs, is only $500 million.
That's very small.
It's very small. There's clearly a big opportunity to help a lot of patients who aren't getting benefit if the right drug that treats this pathway can be brought to market. That's what we're focused on.
All right. Thank you, Brian, for your time today.
Oh, you're welcome. It's my pleasure.