Morning, everyone. Thank you for joining us today. I'm Brian Sullivan, CEO and co-founder of Celcuity. We're excited to have the opportunity today to discuss our plan to develop gedatolisib to unlock the potential of treating cancers involving PI3K/mTOR signaling. Joining me today from Celcuity are Lance Laing, our CSO, and my fellow Co-Founder, and Igor Gorbatchevsky, our Chief Medical Officer. I'm also especially pleased to introduce you to Dr. Sara Hurvitz and Dr. Karim Fizazi. Dr. Hurvitz is Professor of Medicine, Head of the Division of Hematology and Oncology, and Senior Vice President of University of Washington Fred Hutchinson Cancer Center. Her practice specialty is breast cancer, and she's served in leadership capacities for many of the major breast cancer studies conducted over the past decade. Dr.
Fizazi is Professor of Medicine and head of the Genitourinary Group at Institut Gustave Roussy at the University of Paris-Saclay. He also serves as president of the Urogenital Study Group, France's national clinical research cooperative for urological and prostate cancers. His practice specialty is prostate cancer, and he served in leadership capacities for many of the major prostate cancer studies conducted over the past decade. So now I'd like to turn to the agenda and review our plan for the day. I'll kick off the session with an overview of the untapped potential for a PAM inhibitor like gedatolisib. Lance will provide an overview of the PI3K/mTOR pathway, and by the way, we'll refer to this throughout the morning as the PAM pathway.
He will present data from a range of non-clinical studies, including ones that compare gedatolisib to other PAM inhibitors and ones that further characterize gedatolisib's mechanism of action. Igor will then provide a brief overview of the PK and safety profile of gedatolisib as a single agent. We'll then turn our focus to prostate cancer. We recently announced our plans to begin developing gedatolisib for patients with metastatic castration-resistant prostate cancer. Dr. Fizazi will provide an overview of current standard of care in prostate cancer and PAM pathway's role. Igor will follow then with a brief summary of our current development plan and second-line metastatic castration-resistant prostate cancer. Dr. Hurvitz will then give us an overview of the standard of care in HR-positive, HER2-negative advanced breast cancer and what the future landscape looks like.
Then Igor will follow with a brief review of our safety and efficacy data for second- and first-line advanced breast cancer. Our current focus at Celcuity is to develop treatments for patients who have cancers with PI3K/mTOR signaling, PAM signaling. And the PAM pathway is one of the most important oncogenic pathways. It regulates key metabolic functions, cross-regulates other pathways, and affects the tumor microenvironment, which can directly affect how a patient's immune system responds to a tumor. It's also the most highly mutated, by a significant margin, of all signaling pathways. 38% of all solid tumors have a PAM-related mutation or alteration, and mutations obviously serve as potential targets, but the overall proportion of pathway mutations in a tumor highly correlates to its overall role as a cancer driver.
Finally, despite its importance as a cancer driver, the number of patients treated today with a PAM inhibitor is trivial compared to the number who could potentially benefit from them. This is why we think the PAM pathway represents the largest drug development opportunity in solid tumors. In breast and prostate cancer alone, two tumor types known to involve the PAM pathway, over 500,000 patients in the U.S., Japan, and EU receive treatment each year. We estimate less than 1% of them receive treatment with a PAM inhibitor today. Primary reason why PAM inhibitors have not become standard of care drugs, despite the importance of the PAM pathway, is because it's very difficult to safely and efficaciously inhibit this pathway. Unlike most pathways, where inhibition of a single kinase may induce the desired activity, the PAM pathway involves multiple nodes.
Each of them must be targeted because of the complex interaction that takes place between them. Otherwise, uninhibited nodes will be activated, and compensatory resistance will be induced, and efficacy will be compromised. Further complicating the challenge of drugging this pathway is the narrow therapeutic window that exists. There is a graveyard of oral PAM-PI3K and PAM-PI3K/mTOR drugs that were not efficacious, too toxic, or both. The failures of these earlier generation PAM inhibitors led drug developers to develop single-node inhibitors as a strategy to avoid toxicity. However, you know, by compromising on the biological imperative that requires comprehensive blockade of the pathway, the resulting drugs have offered only middling results. To address this significant unmet need, we're developing gedatolisib, a PAM-PI3K/mTOR inhibitor. We think Geda represents one of the best opportunities to improve standard of care in tumor types that involve the PAM pathway.
Our optimism about gedatolisib is based on its highly differentiated mechanism of action, the compelling preliminary efficacy data we've reported to date in HR-positive/HER2-negative advanced breast cancer, and the favorable safety data from nearly 500 patients treated. Lance and Igor will review these attributes in more detail in a few minutes. And finally, the combination of compelling efficacy and tolerability enables us to potentially impact a significant number of patients, more than 200,000 alone in the second-line setting in breast and prostate cancer. In breast cancer, we're enrolling a phase III registrational study evaluating patients with HR-positive/HER2-negative advanced breast cancer who progressed on their prior CDK4/6 therapy.
We expect to get the top-line data for patients whose tumors lack PIK3CA mutations in the second half of 2024, and top-line data for patients whose tumors have PIK3CA mutations in the first half of 2025. In prostate cancer, we'll be enrolling patients with metastatic castration-resistant prostate cancer who progressed on their prior androgen receptor inhibitor. We expect to enroll the first patient in the first quarter of 2024 and report initial data in the first half of 2025. Lance will review non-clinical results from breast and prostate cancer models that provide a compelling demonstration of the superior cytotoxicity that results with a PAM inhibitor like gedatolisib, that has an optimal mechanism of action and is 25-200 times more potent compared to approved or late-stage single-node PAM inhibitors.
So unlike earlier generations of PAM inhibitors, gedatolisib has a favorable safety profile, and this is a function of its optimal pharmacokinetic properties and its IV route of administration. And this results in optimal liver and GI exposure, which in turn enables gedatolisib to induce minimal hyperglycemia and GI-related toxicity, the two adverse reactions most associated with this drug class. Igor will review the safety data for Geda and several single-node PAM inhibitors that illustrates this point. Ultimately, the impact a drug has on patients and the financial opportunity for a drug developer is directly linked to the relevance and prevalence of the pathway targeted. On the basis of the prevalence of pathway alterations alone, it would be reasonable to conclude that the PAM pathway is one of the most important oncogenic pathways, without even taking into account the critical metabolic functions PAM regulates.
38% of solid tumors have PAM mutations, alterations, compared to only 8% of tumors with a HER2 mutation, 5% with an EGFR mutation, or 4% with an ALK mutation. So on the basis of the relevance and prevalence of the PAM pathways to, as an onco driver, one would expect PAM pathway inhibitors to have revenues that dwarf revenues from these other drug classes. But just the opposite is the case. When you compare the drug revenues associated with these pathways, $10 billion for HER2 drugs, $5.5 billion for EGFR drugs, $2.5 billion for ALK-targeted therapies, to the $400 million of revenue for PAM inhibitors, you see a tremendous mismatch. And that's why we think the PAM pathway is the most underdeveloped target in solid tumors.
To validate the revenue opportunity for gedatolisib in breast and prostate cancer, I think it's helpful to review the revenues from drugs targeting two critical pathways in these tumor types: CDK4/6 in breast cancer and the androgen receptor in prostate cancer. Last year, CDK4/6 inhibitors generated $8.8 billion of revenues globally, with indications solely focused on breast cancer. Androgen receptor inhibitors generated over $10 billion of revenues from indications solely focused on prostate cancer. Unlike these two classes of drugs, gedatolisib's pathway target is involved in both tumor types, and this has potential to treat both breast and prostate cancer patients. And that's why we think it would be reasonable to conclude that the potential revenue opportunity for an effective PAM inhibitor is at least comparable to CDK4/6 or AR inhibitors. So with Geda, we're addressing sizable patient populations.
There are more than 200,000 potentially eligible patients in just the two indications we've under active development. Over time, if our programs are successful, we would hope to develop gedatolisib in indications addressing an additional 300,000 patients who have earlier stages of breast and prostate cancer. Each of our programs focusing on second-line patients has the potential to be a blockbuster indication. We estimate the addressable market opportunity to be over $5 billion for each. In breast cancer, favorable efficacy data we have in first-line HR-positive, HER2-negative advanced breast cancer compares very favorably to data for current standard of care regimens. Thus, we think we already have scientific rationale to justify development of gedatolisib for this $10 billion potential market opportunity in the first-line setting.
I'll wrap up this portion of the day here and summarize the key themes of today's meeting. Gedatolisib is a unique drug that solves the riddle of comprehensively inhibiting the PAM pathway without inducing unacceptable levels of toxicity. This uniquely positions gedatolisib to potentially improve outcomes for hundreds of thousands of cancer patients whose tumors involve the PAM pathway. Thankfully, with our current capital, we expect to be able to fund operations through the data readouts in both breast and prostate cancer. I'd like to now turn it to Lance, who will review the importance of the PAM pathway as a cancer driver.
Thank you, Brian. Good morning, folks, and welcome. We're gonna dive right into a description of the PAM pathway. As Brian said, that's our shorthand for the PI3 kinase AKT-mTOR pathway. As Brian alluded to, PAM is a command and control center for a number of critical cellular processes, outlined here simply in this little diagram. The processes include things like metabolism and survival, and ultimately, tumor cell proliferation. PAM is important in controlling all of those functions. Next slide, please. On this slide, we're looking at how PAM controls glucose consumption, as the tumor cells require hundreds of times more glucose than normal cells. This high glucose consumption rate causes excess cellular lactate, pH, and low oxygen, thereby creating a tumor microenvironment that promotes tumor cell proliferation and makes a hostile environment for normal immune cell function.
PAM pathway regulates this glucose consumption, which makes it a fundamental tumor driver in all tumor types. The therapeutic target exists regardless of whether or not a mutation exists then. Next slide, please. This slide, which we're not gonna perseverate on, is really just to highlight some of the key nodes of this pathway that have been either targeted or are known to cause redundancy in the pathway. This redundancy ensures that the tumor maintains this high rate of metabolic dysfunction and enables it to be resilient, sometimes even to treatment types. To overcome this sort of redundancy, it's important that you target multiple nodes of the pathway in order to get control of these underlying functions highlighted at the bottom of the image to the right there. Next slide.
In order to understand a little bit more about this redundancy and look at some of the work that's been done in targeting single nodes, you can see, by the image at the right there, that, for instance, if you were to target just PI3 kinase alpha, you would have a response or an adaptation to that, where PTEN tumor suppression is reduced, and then PI3 kinase beta becomes activated. Partial or imbalanced inhibition of these different nodes leads to a strong compensatory resistance and highlights the need for targeting multiple pathway components in order to get control of this pathway. The next slide is just reminding ourselves the different nodes that gedatolisib targets.
There are six different places where there's equipotent activity, and this equipotent activity across these different nodes really helps to limit the cross-activation that occurs with single drug or single target-specific drugs. This mechanism of action of gedatolisib creates the potential to not only control this tumor activity, but also is an important way of controlling, regardless of whether or not PI3 kinase or PTEN are altered in some way. Looking at 28 breast cancer cell lines, the heat map that you see off to the right of the image there is looking at a growth rate metric, whereby a blue color indicates maybe some reduction in proliferation. But what you really want to focus on is where the red color is, because that's the greater cytotoxic effect.
As you can see, gedatolisib exhibits strong cytotoxic effect all the way down to low nanomolar values, and indicated at the very left-hand side of that heat map structure, are the indication of the different, genotypes, clinically relevant, depending on whether or not it's a PI3 kinase mutation or a PTEN alteration. As you can see, up and down the rows, gedatolisib is effective against all of these different breast cancer genotypes. This slide just summarizes those effects with a focus on looking at the mutation status. And what you can see is that gedatolisib is two times higher in in vitro efficacy than the other single-node inhibitors, and that this leads to really a much stronger, cytotoxic effect, about 300 times more potent than alpelisib or capivasertib or everolimus.
So the other important takeaway from this slide is that regardless of the, this genotype, gedatolisib has this low nanomolar potency, which ends up meaning that you need less drug to get a very strong effect. So moving from the in vitro data to the in vivo data, the next slide highlights some information or data that we collected looking at patient-derived xenograft models. And what you can see here is that gedatolisib, shown in blue in the two images to the right, has significant tumor growth inhibition, either 61% in the wild type or 85% tumor growth inhibition in the mutant model, and it's really the only agent that's effective in both types. And as you can see, even in the wild type, there is not strong efficacy in the single-node models.
Moving from breast cancer into prostate cancer, as Brian alluded to there, we've got a clinical trial that we're getting ready to field patients for, and I'm providing some background information on cell lines. These are popular cell lines that are listed here in the heat map off to the right, similar to the breast cancer heat map. Red is hot, red means cytotoxicity, and as you can see, gedatolisib has good cytotoxicity across these different clinically relevant cell types, whereas the single drug, single-node inhibitors have less effect, a cytotoxic effect in this type of assay. By having this comprehensive effect, we have a more-- we avoid these confounding effects of the pathway reactivation.
So on this next slide, we're just summarizing those results again and highlighting that gedatolisib is more cytotoxic than the other PAM pathway inhibitors, that it's more potent by 65 times than alpelisib, and 25 times more potent than capivasertib, with the same potency and efficacy regardless of these PTEN subtypes. Moving from the in vitro data to the animal data. We're looking at three clinically relevant cell lines by virtue of the fact that they, some have PTEN wild type, as shown in the left-hand panel, or PTEN loss all the way over on the right panel. What you can see is that as a single agent, gedatolisib has robust sensitivity, regardless of enzalutamide or PTEN status. Looking a little bit further into, well, how do we get this effect?
You want to see that the drug is present in the tumor tissue, and that it's durable during the dosing window. What you can see by the panel on the left is that gedatolisib stays above the cytotoxic threshold for two of these cell lines that were shown in the previous slide for 96 hours. The 96 hours represents a four-day dosing schedule in the mice, and that's comparable to once per week in humans. The drug's present. The two panels to the right show you that while it's present, it's also very active. For EBP1, total protein is a good indicator of the reduction of translation, so less of this protein is made. That's a good anti-tumor effect. The panel to the far right, showing phospho-RPS6, shows that you've got active translation product suppression.
Both very good indications that the drug is doing what you expect it to do during the dosing window. So we started this introduction off by looking at how PAM dysregulation alters this tumor microenvironment, and that in that process, a number of things can happen that reduce the anti-tumor response. So in the upper panel to the left, part of high glucose consumption is known to lead to high lactate production, which reduces the pH in the tumor microenvironment. These tumors, while they're consuming huge amounts of glucose, also reduce the oxygen availability through their higher oxygen consumption, and then by virtue of their ramped-up translation, they make a lot of cytokines, which actually help drive the tumor.
So, this ultimately leads to what's known as a cold tumor, and that, we'll show you here in the next panels, next slides, that inhibition of the PAM pathway can improve the tumor microenvironment, moving it from a hostile situation to something that's more hospitable for an anti-tumor immune response. So the data shown on this slide here highlight two effects of gedatolisib on these two important functional metrics. One is that as gedatolisib concentration is increased on this primary breast cancer cell line, oxygen consumption is greatly reduced. That's the cause. The effect is that locally, oxygen concentration will rise.
And then in the bottom row, we're looking at how gedatolisib increasing concentration on the same breast cancer cells from patients are reducing the relative glucose consumption, which leads to the effect on the right-hand side for reduction of relative lactate production. So this demonstrates that gedatolisib can improve the tumor microenvironment factors that can affect anti-tumor immune function. The next slide looks at, well, did we do that? And this data, we're looking at a mouse model, where we really want to know what's going on inside the tumor. And what the table on the left shows is that CD45s, which is a marker of immune cells, are becoming higher proportionally dense within the tumor, moving from roughly below 5% to above 10%, so there's a doubling there within the first 10 days.
The panel to the right shows that these CD45s that are infiltrating into the tumor are coming from the blood supply, which is a good indication. When we look further and we ask, "Well, what types of immune cells are infiltrating?" the lower rows of the table on the left indicate that we see good infiltration by CD8s, which we know are tumor killer cells, as well as CD4s, which also have a strong anti-tumor response. In the bottom right-hand side of this panel, we're looking at, are the cells that are there, are they activated actually against the tumor? We use a CD69 marker to demonstrate that.
As you can see, there's good increase in not only the infiltration of the tumor cells, of the immune cells that can affect the tumor, but they're activated, and that's as we would expect based on what we know about how gedatolisib can change the tumor microenvironment. So in summary, on the next slide, the key takeaways are that the PAM pathway is complex, and that it's an important metabolic driver of underlying tumor cell function, and that really, through multi-node inhibition, you can get control of this pathway and thereby affect the underlying function. Gedatolisib does that by equipotently antagonizing these major PAM signaling nodes and reduces tumor, glucose and oxygen consumption and lactate production, which changes the tumor from a hostile environment to one that's more hospitable to immune cells that can actually begin to reduce the tumor.
Gedatolisib has a superior potency and cytotoxicity in vitro and in vivo compared to other single-node inhibitors... and, and that, in the end, all of this adds up to a reduced immunosuppression and a more hospitable environment for the immune cells to be able to infiltrate and become activated as an anti-tumor response. With that, I'll hand it back to Brian, who will introduce our next speaker.
Great. Thank you, Lance. I'd like to turn it over now to Igor Gorbatchevsky. Igor is our Chief Medical Officer, and, Igor, fire away.
Thank you, Brian. Good morning, everyone. In the next few minutes, I'll provide a very brief summary of PK metabolic profile and general safety summary for single agent gedatolisib data that has been developed to date. As Brian mentioned, the product characteristic is very important, that at the end of the day, chemical structure of the products will drive PK metabolic profile, which in the end, will also be providing differentiated safety profile for those products. We know that gedatolisib is a very stable product that has stable chemical structure, and a number of non-clinical and clinical studies has been proven. In a short summary of PK characteristics, we know that terminal half-time life for the product, it's approximately 37 hours.
At the same time, as you can see on the graph to the right, after infusion, which is quite short, 30-minute intravenous infusion, not requiring any pre-medication, concentrations of the product remained in plasma at a high enough level to inhibit PAM pathway efficiently up until next dosing on the day eight, when it's appearing. The PK profile in general in humans is pretty linear, dose proportional. There's no accumulation occurred, tested in a number of clinical studies after multiple doses, and there's a very limited, if no, variability in the PK profile between patients.
When we look into metabolism of this compound, because of the stable chemical structure, we also find that there's a very, low to no metabolic turnover, meaning there is no, metabolites have been identified, and product being excreted, virtually unchanged, predominantly through the feces, over 80%, and about 10% through the urine in humans. It also leads in a number of, non-clinical studies that have been performed to the, in data suggesting that, and proving gedatolisib having no impact on, CYP enzymes and, very likely having, no or very little impact on the potential, CYP, enzymes-mediated drug-drug interactions. So this is very positive information and makes gedatolisib potentially easily combinable with other therapies. So next slide.
To further summarize the differences of gedatolisib compared to other compounds in class, here we presented a summary in comparison to other PI3K inhibitors. As you can see here, we have three oral PI3K inhibitors targeting specific isoforms of class one, as well as a pan-PI3K inhibitor copanlisib. What differentiates gedatolisib, based on that unique stable chemical structure, is that it has very low exposure in liver, and which means so very little involvement with glycolysis in liver. Coupled together with very low volume of distribution, meaning the compound doesn't stay for a long time in a tissue or in a cell, it leads to improved safety profile.
So when we look on the on-target side effect related with alpha isoform , isoform inhibition, Grade 3 for hyperglycemia, when we use gedatolisib as a single agent, had been very minimal compared to alpelisib or gedatolisib. When we look at other side effects on target, GI toxicities, liver toxicity, or infections, we see the similar situation where, therapy with gedatolisib has been much more tolerable compared to other agents. Very few patients experience serious adverse reactions or adverse reactions leading to treatment discontinuation. And the next slide, in a couple of next slides, I will be showing a summary of, single agent, safety profile, as well as comparison it to single agent data from other PAM inhibitors.
But there was a quite large study, first in human, where 77 patients treated at a high, variety of different doses, ranging from 10 mg to 318 mg. And here's a summary, in 42 patients at 154 mg, which is MTD level dose, and it's very close to the dose that we use in our ongoing phase III study. As you can see, the most common adverse reaction associated with therapy was stomatitis, mucosal inflammation. And, unfortunately, a prior developer of the product, did not, use prophylactic therapy. We know, and it's been published widely, that this type of side effect can be easily mediated by a water-based oral mouthwash, steroid-based mouthwash when it's used, it significantly reduces severity and incidence.
Severity can be reduced anywhere from 90% to 100% in patients as well as incidence. Going forward in every single study with gedatolisib, we mandate use of this prophylaxis. It's happening in our phase III study and will happen in other studies. Comparing to other side effects, sorry, Brian, just go back a second. When you look, there's not a single patient with Grade four or five toxicity. Another important part to mention, I wanted specifically here, not a single patient experiencing neutropenia with a single agent for gedatolisib. The rest of side effects are really on target with very low number of events, and mainly of Grade 1 and 2 . The next slide is presenting a comparison. We selected number of adverse events that are quite relevant and associated with the PAM inhibitors.
As you can see, where gedatolisib is in a blue color, alpelisib orange color, everolimus green, and capivasertib in purple. Very visually, quite a big difference. When we look at the GI toxicity, for example, diarrhea, gedatolisib has only about 14% of Grade 1, 2 toxicity, not a single person experiencing Grade 3 and 4, which compares favorably to alpelisib, almost 35%, and for capivasertib, it's almost 80%, with 17% of patients having Grade 3, 4. When we go down the line, vomiting, fatigue, also experiencing at low level in, studies with gedatolisib. When we look at the hyperglycemia, important side effects associated with alpha isoform, inhibition. Compared to other PAM inhibitors, only about 26% patient and only 2% of those had Grade 3, 4 hyperglycemia.
When we look at alpelisib and capivasertib, we can see approximately 40% of patients for both products had hyperglycemia, with half of those patients having Grade 3 and 4. Again, the same situation happening with skin toxicities. As I previously presented, stomatitis is on-target side effect that had been associated in a situation where no prophylactic therapy used. Important message, very few patients experienced Grade 3, 4. There was no Grade four at all, and with the prophylactic therapy, we believe that both incidence and severity, severity will be reduced significantly. So I think, it's finished with my presentation, and I'm happy to give it back to Brian.
Great. Thank you, Igor. Now I'm pleased to introduce Dr. Fizazi, and who will walk us through the landscape in prostate cancer.
Thank you so much, Brian, and good morning, everybody. This is already afternoon here in Paris. So, I was asked to really set the scene for prostate cancer, and especially, treatment. But I'll show first a slide about the biology of prostate cancer, which is really unique. We actually have one either king or queen, depending on what you think is more powerful. So one king or queen protein, which is called the androgen receptor, in this disease, driving most of the issues, patients are suffering from. And I'm saying that because the androgen receptor is expressed in approximately 95% of patients with prostate cancer.
It's driving the progression of the cancer cells, and this is true at the beginning, but this is also true at the end when the patients have exhausted all the hormonal therapy that we are using in this disease, including some very potent one, indicating that the cancer cells prefer fixing their main engine, the androgen receptor biology, rather than inventing something totally new to survive. So this is key. And, the second key thing in the biology is actually what Brian explained about the PAM pathway, which is the phosphatidylinositol, AKT, and mTOR pathway. This is due in part to the fact that approximately 25% of patients have PTEN loss, loss of the protein, PTEN, making this axis very active in parallel to the androgen receptor machinery.
Next slide, please. Now, when it comes to the clinic and what was achieved in the last years, you'll see here in just a glimpse that we've changed completely the way we are treating patients with prostate cancer. Let's start first with the left-hand side, which is localized disease. It's true that in Western countries, the large majority of men who are diagnosed with prostate cancer do not have evidence of metastatic deposits at diagnosis, so they have localized disease. I'm saying this about Western countries because this is not necessarily true in other countries, such as China or India, for example, where it's actually the opposite. 60%-70% of men who are diagnosed with prostate cancer in these countries actually have metastasis at diagnosis. But anyway, for those with localized disease-...
The outcome, at least in the middle term, is usually excellent, with a five-year survival rate of 99% plus, thanks to local treatments. Now, having said that, still, approximately, a third of these men will experience a relapse, mostly a biochemical relapse based on a PSA, which is rising. But this is not necessarily associated with clinical consequences and, for sure, not necessarily associated with death. For these men, we also have a standard of care, and then a minority of them will move to metastatic disease, which will progressively becomes resistant to hormonal treatments, what we call castration-resistant prostate cancer, which actually is the lethal phenotype of the disease with really bad outcomes. Still now, approximately, one-third of patients, survive by five-year time.
Now, as I said, about 10% of men are diagnosed with evidence of metastasis from scratch. For these men, obviously the outcome was worse, clearly, and remains worse, although we have made very important progresses in the last years or so. We have developed, let's say, two big families of agents in this disease. Second-generation hormonal agents, such as abiraterone and enzalutamide, darolutamide, or apalutamide, which is one family, very potent. I'll come back to that in a second. A second family with a taxane, docetaxel and cabazitaxel. In the last, say, five years or so, two new families have joined, which is great. PSMA targeting with lutetium two years ago, and PARP inhibitors, at least for the subgroup of men with BRCA alterations, speaking mostly about 7% of the total, so not the majority.
Also, there is debate as to whether we should also use these agents in patients without those alterations. So you see, we now have at least four families of agent, just to make it easy, for you, that appeared in the last decade or so, that was not really existing or not really prior to that. Actually, the big, big, big progress we've made has simply been to use these same agents earlier in the course of the disease. And for example, we have recent data indicating that using abiraterone in the localized setting might actually make it cura-- make the treatment curative when combined with radiation therapy and androgen deprivation therapy, at least in many men. It, it's really big, big benefit that we're seeing then.
Also, using these same agents, abiraterone and enzalutamide, apalutamide, darolutamide, in patients with de novo metastatic disease, is associated with years of overall survival benefit, not only progression-free survival. Next slide, please. When the disease has became resistant to hormonal therapy, it's a totally different story, and most agent actually have limited benefit in this space. They do have some, but it's unfortunately limited. For patients who were naive of any second-generation hormonal agents, and when we were starting with enzalutamide or abiraterone, the progression-free survival and duration as a median was approximately 20 months, which was not bad at all, of course. Docetaxel, more six months or so.
Now, if you're using the same agents in a man who has already exhausted another one from the same family, say, abiraterone after enzalutamide or enzalutamide after abiraterone, actually, they typically not work, and this is one of the bad news we had. Typically, the cancer progresses after three, four, five months or so, no more than that. The good news remains, about taxane, which are still active in, in, in this scenario, but obviously, this is clearly very imperfect, and it's an unmet need. Next slide, please. Now, as I said before, I think combining what Brian and Igor called PAM, which is really PI3K inhibitors, AKT, and mTOR inhibition, together with AR inhibition, makes a lot of sense in this disease.
I'm saying that, first, for and very obviously, for the, say, 25% of men in whom PTEN is lost in their cancers. In these patients, the system is actually activated permanently in parallel to the androgen receptor machinery. So you really need to, at least theoretically, target the two axes together. But even in the other patients without PTEN loss, there is a crosstalk between the two axes. So in other words, if you're targeting one axis, you're activating the other one, and actually vice versa. Which again means that we should target the two axes as best as we can, and perhaps not targeting just AKT, for example. Next slide, please.
In the last five years, PAM inhibitors have mostly focused on targeting AKT, mostly because, again, in 25% of men, approximately, PTEN is lost and AKT is activated. Ipatasertib was the first drug to be tested in the clinic. In a randomized phase two, there was quite elegant demonstration that the lab is telling us the truth, meaning that if you're targeting both the AR pathway and AKT with abiraterone and ipatasertib in men with PTEN loss, it actually works better than abiraterone alone, with no real efficacy in patients without PTEN loss. Unfortunately, when a phase three was designed, the benefit was not as good as announced in the randomized phase two for diverse reason.
1, simply being the toxicity of a drug, and it's, you know, every day toxicity that patients really hate, and they typically stop swallowing their pills. So that was one issue. The second issue was about biomarker identification. NGS is better, but it's more expensive and more complex to use in a phase III scenario. So immunohistochemistry was used in this particular trial, and it failed to demonstrate really meaningful benefit. Although the trial is technically positive, the p-value is less than 0.05, and overall survival is not impacted. So those are the limitations. But again, besides the 25% of men with PTEN loss, the rest also have alterations of the PAM pathway, and we until now, we don't really know how to, you know, efficiently target this.
So it's great to have a drug that can target different nodules of this pathway. Next slide, please. So what do we have, and what did we have, and what do we have currently? A drug called samotolisib, the names are getting crazy, I'm sorry for that, was randomly tested in a randomized phase II fashion, together with enzalutamide. So enzalutamide with or without drug. And again, it appears to be working, not only for PTEN loss patients, better for patients with PTEN loss, but also in other patients. So again, we have a demonstration that targeting this pathway makes a lot of sense, and this drug is not currently under active development, so not really a competitor. The Celcuity drug is actually much more potent.
Ipatasertib, I just explained, what happened with the development and, why it's not on the market right now, because the phase III actually was positive but was not sufficiently positive, simply. Next slide, please. So key takeaways. First, I think the big triumph that we had in prostate cancer in the last year has really been moving the active drugs from very resistant settings to much earlier setting, where the benefit is honestly tremendous. So that's great. But this means that for patients with resistant disease, we are desperately looking for new options. So that's an unmet need, and nothing works perfectly. I'm mentioning here the taxanes AR inhibitors, but this is also true for other treatments such as PARP inhibitors or PSA, PSMA targeting, for example, which do have advantages, but they are not curative for sure in this setting.
Second, together with androgen receptor biology, the PI3 kinase mTOR pathway is a key pathway for progression in this disease. The lab rationale is a very serious one. The AKT inhibitors, until now, have not been able to make it to the market. We have another drug currently in phase III assessment called capivasertib. We don't really know what it's gonna do, but again, this drug is different. I think this is a very important program, and I'm very happy to be part of it. Thank you so much for your attention.
Thank you, Dr. Fizazi. That was great, and I hope helpful to all of our listeners. So Igor will come back on stage and provide a brief review of the program we're initiating in the second-line setting for castration-resistant prostate cancer.
Thank you, Brian. In my short presentation, I'll summarize the rationale for development of gedatolisib in prostate cancer, and then review our planned phase I-B/II study that we will initiate pretty soon. To summarize the background, as you've heard from Professor Fizazi and from Lance, this pathway is heavily implicated in prostate cancer as well. Proof of concept and rationale already exists there, with a number of products targeting this pathway being researched. If you heard from Professor Fizazi, unfortunately, not all of them resulted in a very positive larger phase III study.
In terms of other next steps to review our available data, we have presented before, and we know that there is a certain correlation as links, it's now believed, between breast cancer and prostate cancer, and association with between PI3K and mTOR pathway, as well as the hormonal-driven pathway, and both tumors has high connection with both of those. Non-clinical data in breast cancer have been now proven in clinical study settings that we've shared before, and I will talk about it later, has a high correlations. So these positive connections, we believe, will be also seen in prostate cancer, as you saw from last presentation, non-clinical results show that gedatolisib is very potent and active in multiple tumor models in prostate cancer, and is also active regardless of PTEN or AR status. So next slide.
All of this information led us to decide to discuss with the key opinion leaders, such as Professor Fizazi and others, the plans for initial study in prostate cancer. You've heard about the current high unmet need to find effective and well-tolerated therapy, especially in the setting of metastatic castration-resistant study. The G21 phase I-B/II study has been discussed with regulators, and as we earlier presented, we received positive feedback from the FDA, and we'll proceed with the study initiation. This is a pretty straightforward two-part study. In phase I-B, we'll be determining recommended phase II dose utilizing utility scores based on BOIN design, where we will be looking not only at safety but also efficacy parameters.
A good number of patients, 18 in each arm, at two different dose levels will be studied. Once we select the recommended phase II dose, additional patients will be enrolled in part two of the study. Primary efficacy endpoint in this study is radiographic progression-free survival, which is commonly accepted in this setting. For the primary endpoint, it will be at six months, and then additional efficacy and safety endpoints will be as main secondary endpoints, with the progression-free survival at nine and 12 months, median progression-free survival, response rate, overall survival, safety parameters, PK analysis. We plan to initiate this study early next year in first quarter, with the initial results available in the first half of 2025.
So the next slide, you can see here is a summary of countries and sites that will be involved in this study. We'll be enrolling approximately 50 patients and about 12 sites from three countries in Europe, France, U.K., and Spain, and in U.S. And a number of esteemed experts will be leading physicians. The study design was worked on with the heavy involvement of Professor Fizazi from Gustave Roussy, who you just spoke with, Professor de Bono from Royal Marsden, and also Dr. Elisabeth Heath from Karmanos in the U.S. So why did we select darolutamide as a combination? And the next slide shows you part of this rationale.
Darolutamide is a novel agent targeting these pathways and has been reported to have a good efficacy in a number of indications, but also quite differentiated safety profile compared to other products in this field. As you can see from this table, both severity and incidence of various adverse events are significantly lower compared to other products. As you already saw from my earlier presentation, safety profile for gedatolisib single agent also differentiated from other PAM inhibitors, and we believe that when we combine two active product with a good safety profile, we hopefully can make a difference for patients with metastatic castrate-resistant disease. That's the end of my presentation on that part, and I will give back it to Brian.
Great. Thank you, Igor. Now we'll turn our focus to breast cancer, and we will hear from Sara Hurvitz. Dr. Hurvitz from Fred Hutchinson. Sara?
Hi there.
Great.
Good morning. Thank you so much. Let's go on to the next slide. We're gonna talk about hormone receptor-positive, HER2-negative breast cancer. Been a lot of changes in the last decade or so, so we'll go through these. You already saw this very nice graphic earlier that Brian shared with you. Now just focusing on how the estrogen receptor pathway interfaces with the PI3 kinase pathway. We know that the activation of PI3 kinase and the mTOR pathway induces activation or estrogen-independent, estrogen receptor transcriptional activity by mTOR. The ER is able to act on those estrogen response elements, and the estrogen receptor is actually turning on those estrogen response elements, independent of estrogen itself due to activation of the PI3 kinase pathway.
We know that ER target gene expression activates upstream effectors of the PI3 kinase mTOR pathway, and ER activates the PI3 kinase mTOR pathway just by directly binding to PI3 kinase alpha. We know that inhibiting PI3 kinase and mTOR increases estrogen receptor activity, thus increasing sensitivity to endocrine therapy. For these reasons, it makes a lot of sense to target both the estrogen receptor or estrogen and the PI3 kinase pathway to obliterate this seesaw pattern of feedback and things being turned on. On the right side, you can see how the cyclin-dependent kinase pathway interfaces with the estrogen receptor, which has now been very well described. We know that estrogen promotes cyclin D1 transcription. Cyclin D1 can cause estrogen-independent transcription, and so there is strong rationale to target both ER and CDK4 and 6.
When you inhibit CDK4 and 6, there's incomplete cell cycle arrest, and if you add a PI3 kinase mTOR inhibitor, this enables more, complete arrest. Now, the problem with hitting both, the CDK4/6, pathway and PI3 kinase pathway, in a patient is the additive toxicity. So we're gonna go through some data now. Next slide. Here is a timeline giving you an idea of the advances that have been made since the mid-1970s. Of course, the very first indicator that the hormone pathway was important in breast cancer came in 1896, when, Sir, when a Scottish surgeon, discovered that removing, ovaries from a patient with recalcitrant breast cancer induced a response, and that was the first understanding that there was a link between ovaries and breast cancer.
This predated even defining what the hormone estrogen was or the estrogen receptor. But ultimately, this observation led to the development of the first SERM, tamoxifen, then the aromatase inhibitors, and then the first estrogen receptor degraders , fulvestrant, in 2002. It wasn't until just over a decade ago that we had the first approval of a PI3 kinase pathway inhibitor, the mTORC1 inhibitor, everolimus. And then in 2019, 77 years later, the PI3 kinase alpha inhibitor alpelisib. Among or during this time period, of course, came the explosion of data relating to the benefits of CDK4/6 inhibitors, and now we are in an era where we are seeing a number of oral estrogen receptor degraders in development. So let's go through some of these data.
On the left side, you can see the current management for patients with curable breast cancer, the majority of which is hormone receptor-positive. There are over 200,000 cases diagnosed annually. We stratify them based on risk of recurrence, and that helps us gauge how much, how aggressive our therapy should be in the curative setting. Those patients at higher risk of recurrence, may receive chemotherapy, and they may also receive a CDK4/6 inhibitor now that we have that available to us. And, in the metastatic setting, which is an incurable disease, we have a number of therapies available. The gold standard is a CDK4/6 inhibitor combined with endocrine therapy. And then in the second-line setting, you see a variety of options, including PI3 kinase pathway inhibition combined with endocrine therapy and more recently, an oral SERD, which is available.
After exhausting all those endocrine therapy options, the standard is to move on to chemotherapy-based treatment, which may include the use of an antibody drug conjugate. So let's go through what data shows for these various treatments. On the left side, you can see the stunning improvements in outcomes for our patients in the frontline setting with hormone receptor-positive, HER2-negative metastatic breast cancer. With the introduction of a CDK4/6 inhibitor when added to endocrine therapy, the median progression-free survival is consistently over two years now, with some studies with ribociclib indicating a median PFS of around three years in the treatment-naive setting. So this truly represents a major change in how patients' outcomes are due to these therapies, and we're also seeing very high objective response rates of over 50%, which is better than what, what we see even with chemotherapy.
So our gold standard really is a CDK4/6 inhibitor in the frontline setting. A recent study called Right Choice indicated this therapy with ribociclib is actually better than multi-agent chemotherapy. But then when we get to the second-line and third-line setting, look at how those progression-free survival data just plummet. You can see with the alpelisib/fulvestrant data from SOLAR-1, which was exclusively in that in the primary analysis, patients with PIK3CA mutations, the median PFS is now 7.3 months, so less than a year. And as you see more modern studies, including the capivasertib data, and data relating to SERDs, the median PFS is even worse, and those objective response rates are well below 25%, representing an area of unmet need. Next slide. So here are the unmet needs.
Certainly in that second-line setting and beyond, our patients need better outcomes. We really need to move the curve in terms of improving a median progression-free survival after the use of a CDK4/6 inhibitor. We know that for patients who have a wild-type tumor for PIK3CA, their median PFS is around 5.5 months, and for those with mutations, around six-seven months. And so we really need therapies that are well-tolerated and will help meaningfully improve on those outcomes. And so questions are: What role can the PI3 kinase, mTOR AKT inhibitors play in moving the needle, forward for patients? And, a number of investigators have begun to question whether or not patients can be sequenced, have, use a CDK4/6 inhibitor with endocrine therapy after progression of disease on one of them.
This is a natural question because in HER2-positive disease, we always keep the brakes on HER2 because the HER2 is driving the disease throughout the disease course. Is this really true in the setting of a CDK4/6 pathway in ER-positive disease? That still remains to be seen. We'll go through some data. What role will the new SERDs play, and what role will ADCs play? Next slide. This is a summary of initial development of PI3K/AKT/mTOR drugs, focused on the PI3K mTOR inhibitors. You can see on the left side, a number of agents that had their programs halted at phase I or II, because of toxicity.
In the middle, you have drugs like buparlisib, which did meet its primary endpoint but had such bad toxicity, mental health toxicity as well, that that was halted. In third generation, as you move from a more broad inhibitor to a more specific single-node inhibitor, you're now seeing that the therapeutic index was sufficient to meet the requirements for regulatory approval, first with everolimus, and second with alpelisib. However, some would argue there's no overall survival benefit by adding these agents to endocrine therapy, and the PFS benefits are on the order of a handful of months. So it's important to take into consideration toxicity, and these drugs do have on-target toxicities, including hyperglycemia, as well as diarrhea and rash, among other things. We've seen some promising data with the AKT inhibitor, capivasertib, that we'll go over in a little bit.
But again, although the toxicity profile does appear to be better than with alpelisib, there is on-target toxicity still, namely, hyperglycemia, diarrhea, et cetera. And then, gedatolisib, you've heard a lot about today. This is IV administered, which does distinguish it from most of the others, but the preliminary progression-free survival data and tolerability are quite promising, due to its likely excellent PK properties. Next slide. This slide here is summarizing the clinical trial results of PI3 kinase pathway inhibitors after progression on a CDK4/6 inhibitor. I think it's really important to be aware of these data. Let's omit or ignore for one moment, the gedatolisib data on the very top, and just focus on the outcomes one can expect with the use of everolimus, alpelisib, capivasertib, or everolimus with fulvestrant in the post-CDK4/6 inhibitor setting.
These are smaller studies, but as you can see, the objective response rate is very low, and the median progression-free survival is less than 12 months for all of these various agents. In contrast, we saw in a small 27-patient study that included patients with wild-type and mutated PIK3CA, the use of gedatolisib and palbociclib with fulvestrant yielded an objective response rate of 63% and a median PFS of close to 13 months. So this is actually really intriguing. I found these data to be quite compelling and certainly warrant further evaluation in a larger validation setting. Next slide. So one of the questions that's come up, as I mentioned earlier, is whether a patient whose disease has progressed on a CDK4/6 inhibitor would benefit from going on to another CDK4/6 inhibitor and swapping out the endocrine partner or swapping out the CDK4/6 inhibitor.
The first promising results from a clinical experiment to test this hypothesis come from MAINTAIN. This was a phase II clinical trial. The majority of patients in this study had received prior palbociclib, 103 out of the 117 had had prior palbo, and they switched to ribociclib and also switched to endocrine therapy. And it was interesting to see that the PFS was better in those patients who received ribociclib with endocrine therapy compared to endocrine therapy alone, with a hazard ratio that was statistically significant. There didn't appear to be benefit, however, of going from ribo to ribo and compared to doing endocrine therapy alone.
Some have questioned whether or not this is unique to palbociclib, probably, perhaps being the least potent of the CDK4/6 inhibitors and having properties that may make it a little bit less efficacious for patients. This is not yet standard of care, but certainly was intriguing and deserves phase three investigation to see whether or not this should become standard of care. In contrast, the PACE study looked at patients receiving palbociclib previously, primarily, who were going on to palbo with fulvestrant or fulvestrant alone. Switching the endocrine therapy, testing whether continuing the CDK4/6 inhibitor benefits patients, and the result was flat negative. There was no benefit to continuing the same CDK4/6 inhibitor.
What we don't know is whether switching from palbo or ribo to abemaciclib, which is, the least specific inhibitor and the most potent, would benefit patients. There is a study ongoing called PostMONARCH, which is interrogating this question. But in summary, at this point, the standard of care is not to use a CDK4/6 inhibitor after progression on one, until we have clearer evidence that that's truly benefiting patients. And from a cost perspective and a toxicity perspective, I think it's very important to underscore that that is not the standard at this point. Next slide. So what about the role that oral SERDs should play? We have a number of oral estrogen receptor degraders in development, and the first FDA approval of one, elacestrant, based on the EMERALD clinical trial. What do the data suggest regarding efficacy in the post-CDK4/6 inhibitor setting?
It's interesting to note, in EMERALD, all patients had received a prior CDK4/6 inhibitor, 30% had received fulvestrant, and the median PFS in the ESR1-mutated tumors was 3.8 months. That's really unimpressive, in my opinion. The FDA did approve this agent for patients with ESR1 mutations, but I think I represent the feeling among oncologists that 3.8 months is not a home run and that we do need to do better. There are other data from studies like SERENA, indicating promising benefit for a different oral SERD, camizestrant. But again, if you look at the median PFS, around four months, not a home run. And then two negative studies, the ACCELERA study and AMEERA-3, of other oral SERDs, both negative studies. Amcenestrant will not be going forward in development.
Giredestrant is going forward in development, but the data at this point is as yet unknown, and so we only have an oral SERD available for patients with ESR1 mutated breast cancer in the metastatic setting. Next slide. So when do we move on and call the disease endocrine resistant and switch over to cytotoxic chemotherapy? And, you know, there's a variety of indicators for when disease has become endocrine resistant. Generally, a short duration of benefit from an endocrine-based therapy can be used to give us an idea of when it may be time to turn to cytotoxic chemo.
But now we have two agents that are directed chemotherapies or antibody-directed conjugates, trastuzumab deruxtecan for HER2-low metastatic breast cancer, which is about two-thirds of ER positive, HER2 non-amplified breast cancer, and sacituzumab govitecan, which is the Trop-2 targeted ADC, for hormone receptor-positive, HER2-negative metastatic breast cancer, regardless of HER2 expression level. You can see the summary data from the two phase III clinical trials for these agents. These agents were tested in different disease settings. T-DXd was in patients who are less heavily pretreated, one-two prior lines of chemo, and only 70% had had a prior CDK4/6 inhibitor. Sacituzumab govitecan was tested in patients with two-four prior lines of chemo in the metastatic setting.
Both studies showed not only an improved median PFS, but a median improved overall survival, and both are available for our patients. But it's important to recognize that although these drugs have better outcomes compared to single-agent chemotherapy, they were not tested against PI3 kinase inhibitors in the second-line setting. They should be reserved for the later line setting after endocrine therapy has been exhausted, owing to their relatively significant side effect profile. Sacituzumab has complete alopecia, has a higher risk of febrile neutropenia and significant neutropenia. Trastuzumab deruxtecan has a risk of nausea, which over 70% of patients will experience and can be very difficult to treat, and also a risk of interstitial lung disease.
So these agents aren't used in the first or second-line setting, in the setting of hormone receptor-positive disease, and although their benefits are notable, their use should be restricted after exhausting endocrine-based options. Next slide. So here is a slide of our key takeaways, and a more effective PAM inhibitor may offer our best opportunity to improve outcomes for patients, especially in those whose disease has progressed after a CDK4/6 inhibitor. We have good validation that targeting PAM is effective, that tells us that that pathway is very important in ER-positive disease. And although we have two approved PAM therapies, there's limited efficacy, especially after CDK4/6 inhibitors, and the safety profile due to its on-target effects on the PI3 kinase pathway has been a problem in terms of widespread use of these agents.
While the oral SERDs are allowing better convenience, I would argue that they are not leading to really great improvements in our patients' outcomes, no survival benefit. We only have one approved, and it's only for the 30%-40% of patients who have an ESR1 mutation. I think these agents are probably going to be better utilized in combination with other inhibitors like CDK4/6 inhibitors or PAM inhibitors, or in the early-stage setting. Developing an effective and well-tolerated PAM inhibitor is a very important research strategy.
The results with gedatolisib from that smaller study were certainly very exciting, and if replicated in the VIKTORIA-1 clinical trial, this regimen could become a new standard of care, and that would be my hope, that patients would have a new standard that is effective and well-tolerated, giving them a better chance at a long-term outcome. With that, I'll pause. Thank you so much.
Great. Well, thank you, Sara. That was very, very helpful, and I appreciate it. We'll now turn to Igor Gorbatchevsky, our CMO. Igor will review the data that we've previously presented, but we thought it'd be helpful to provide a recap for people who might be newer to the story. Igor?
Thank you, Brian. It was a very great presentation from Dr. Hurvitz, and in my presentation, I will summarize results of phase I-B study. That is the basis for our ongoing VIKTORIA-1 study. We presented, as Brian mentioned, results in different group of patients in the last three years in San Antonio Breast Cancer Symposium as well as ESMO Breast this year. We'll focus on the summary in two specific groups of patients, in second plus line, those who've been pretreated previously with cell cycle inhibitors, and also a summary of results in treatment-naive patients with advanced breast cancer who did not receive previously initial therapy for their advanced disease. As you heard from Dr.
However, the number of different oncogenic pathways that drives tumorigenesis in hormone-positive, HER2-negative disease is quite complex, and they all are pretty tightly interconnecting. PAM pathways potentially plays important role in multiple ways by acting as effective therapy in itself, but also enhancing activity of hormonal therapy and CDK therapy, as well as potentially preventing development of resistance to those therapy. Therefore, addition of PAM inhibitors that is effective but well-tolerated to those treatment can have a positive effect in multiple settings. I will, with the next slide, just summarize early non-clinical work proving this point.
When you look at this figure, you can see that when gedatolisib was added to fulvestrant and palbociclib in xenograft mouse breast cancer tumor models, the efficacy was most significant with all the tumor cells stopping development and actually also inducing cytotoxic effect. So this is one of the initial proof of hypothesis tested in non-clinical study, and then it all was replicated in clinical work. So the next slide will and few slides forward will present a summary of both efficacy and safety data from clinical research. So next slide.
The B2151009 studies, which was originally conducted by prior sponsor, Pfizer, was one of the largest phase I-B study, almost 140 patients, and it included two study arms and dose escalation part, and then four study arms and dose expansion. There's a number of patients with hormone positive, HER2 negative disease were enrolled. They were treated in this combination with either letrozole or fulvestrant, depending on patient characteristic and prior therapy. In all the therapy arms outside of arm D, treatment was used in a weekly dosing schedule, and then we'll share safety profile for intermediate dosing schedule as well as efficacy for all groups.
If we go forward and review based on characteristics of patients in dose expansion, all four arms, there is a few important factors I want you to take away from this presentation. Even though we already shared this data before, in this study, we have a patient who not only have, in some instances, heavily pretreated disease, in a cell cycle-pretreated population, but overall, pretty high tumor burden. Every single patient had a stage four, with many patients having multiple visceral metastases and not a single patient having only bone-only disease, which really tells us that these patients groups have a poor prognosis compared to some of other studies that have been conducted in this setting. There is the two arms that include a patient who previously received cell cycle inhibitor.
It's arm C and arm D. Arm C had a weekly dosing schedule, arm D, intermittent dosing schedule. Few patient characteristics that differed between them that potentially explain difference in efficacy results, as we'll show later. As you can see, more than twice as many patients in arm C, almost 47%, or exactly 47, almost 50, received prior chemotherapy for their disease compared to arm D, as well as there was quite many more patients in arm C with multiple sites of metastasis. So the next slide will summarize some of the part of safety assessment that we do in this study. As expected in this heavily patient with a heavy tumor burden and some of them heavily pretreated, the main cause of treatment discontinuation is disease progression.
But when we look into adverse events and how they impact treatment, you can see overall, as we already presented, in all 138 patients, less than 10% of patients discontinued therapy due to adverse events. And then when we look into arm D, where the intermittent schedule was used, exactly only one patient discontinued the treatment and treatment due to adverse events, and it was not treatment-related adverse event, by the way. So you can see that it's quite differentiated from other compounds targeting this class. Here is a summary of efficacy. And important part to notice, I want you to see that efficacy has been observed in all treatment arms, whether patients receive prior therapy with cell cycle or not.
Efficacy quite high compared, of course, to published data with other products, both on progression-free survival level as well as response. Another important factor here is that efficacy observed in all patients, regardless of PI3K mutation status of their disease. As you've heard from Dr. Hurvitz's presentation, some of those PAM inhibitors proven to be active only in a specific group of patients. In arm D, where intermittent schedule was presented, without repeating Dr. Hurvitz's presentation, we have very promising results. All of this was the basis for our VIKTORIA-1 study design. The next slide will talk, in the summary of both safety and the study design in our second-line patient population.
So when we look into safety summary in arm D, where intermittent schedule was used, you can see that, again, stomatitis is one of the uncommon most common on-target side effect. Same story. Unfortunately, prophylactic therapy was not used by prior sponsor, but in our ongoing phase III study, it's mandatory, and we believe that it will significantly reduce both severity and incidence. Very few patients discontinued treatment; you saw only one patient due to adverse event. Very few patients had Grade 3-4 events. Many patients did not have a Grade 4 event. There was not a single Grade 5 adverse events observed. When we look into hyperglycemia, it was only 7% of patients with Grade 3-4, and not a single patient here discontinued treatment due to hyperglycemia.
When we look at the data presented in, multiple manuscripts, as well as the package insert for alpelisib, that is quite different story, with almost a third of patients discontinuing therapy due to adverse events, including hyperglycemia. The rest of adverse events targeting GI tract, skin toxicity, also predominantly within Grade 1 toxicity. Neutropenia that have been observed in this study is due to, palbociclib. As you saw from my earlier presentation, gedatolisib, single agent has not been associated with myelosuppression, no patient experiencing neutropenia, and the numbers really exactly what presented in package inserts for palbociclib. When we look into results in this group of patients between arm C and D, the main difference was, from the start, is the dosing schedule, and we wanted to find out how we can explain the difference in the results as you saw.
I already started building this story and presented to you difference in baseline characteristics of the patient. As you can see, I mentioned previously, a higher number of patients in arm C received chemotherapy, making disease more advanced and pretreated. Median number of prior therapy was higher, two in arm C compared to only one prior therapy in arm D. Duration of immediate prior therapy also was quite different, almost three times shorter, meaning the disease is a bit more aggressive in arm C compared to arm D. Similarly, number of patients who had three or more sites of metastatic disease was higher in arm C compared to arm D, making patients in group C with a poor prognosis compared to arm D.
But both of those are patients who previously received cell cycle inhibitor for their advanced disease. So we wanted to further dive in into finding explanations and, look at one of the parameter. And the parameter is the duration of immediate prior treatment, which has a very direct correlation to potential on the results in your, novel therapy or next line of treatment. When we group patients by duration of their prior therapy, less than six months or, less than 12 months between arm C and D, equaling that parameter between those two groups, we can see that regardless of the fact that in the same treatment arms, let's say we focused on, first column, where duration of prior therapy was less than six months, we had the equality in this parameter between arms, but efficacy was significantly different.
Objective response rate was 0% in arm C compared to 70% in arm D. This mean that not only that patient characteristic baseline can explain why there's such a difference in efficacy. So we went further, and we look into additional analysis, look at the logistic regression models. Additionally, we tested eight different factors that directly correlates with objective response rate. Out of those eight factors, we identified three factors that had a strong statistical significance, and that factors are duration of immediate prior therapy, presence of prior chemotherapy, medical history, and number of those therapies.
So when we control in this analysis for those factors, we come to the, the same, assessment that's, delivered in a prior slide, that treatment schedule, meaning intermittent dosing, has the strongest and most robust, correlations with objective response rate in between arm C and D when we control for all the factors making those equal. Providing further evidence, which by the way, have been supported by other publications and other researchers, where intermittent schedule with PI3K inhibitors has been associated with the improved efficacy compared to continued inhibition of the pathway. And this all, together, the results from phase I-B study, are better understanding, of the evidence that intermittent schedule, plays important role in improving efficacy, led us to design of VIKTORIA-1 study. And my next few slides, it's a short summary again, about this study.
Here, before I get into VIKTORIA-1 design, it's another way to look at the efficacy in arm D. As you already heard, progression-free survival is almost 13 months. Important part on the right, you see that outside of one patient, every single patient had stable disease or better, resulting in 63% response rate. You can see four patients had 100% reduction in target lesions, with the non-target lesion being stable, making this unconfirmed CR, so confirmed partial responses. The comparison, as Dr. Hurvitz already done, as you saw, the data presented for other PAM inhibitors used in this group of patients, is that, first of all, efficacy for some of those products are limited to a small group of patients, for example, those with PIK3CA mutated disease.
Overall, those therapies have been associated to second-line setting with suboptimal clinical benefits, with the progression-free survival less than 12 months and minimal objective responses rate. When we compare it to our results from 1009 study, that's... you can see there a big difference here. It's another very important basis for the rationale to initiate phase III study. VIKTORIA-1, which is being designed in collaboration with multiple experts, and Dr. Hurvitz, one of the primary principal investigators for this study, had a few major points in the basis for the study design.
We looked in the second-line setting, and as you already heard, the standard of care in this setting for hormone positive, HER2-negative disease is based on patient PIK3CA mutation status for their disease. Therefore, we had to figure out study design and selection of control, knowing that gedatolisib works in both groups of patients. We know approximately 35% of patients would have positive status for mutations. We also know, and based on our communications with regulators, that progression-free survival is accepted endpoint for this group of patients, and number of these factors were put in place before we publicly released the study design initiated it last year. So VIKTORIA-1, it's a quite large study, where initially we'll be testing PIK3CA mutation status of patient's disease using FDA-approved methods.
Then, patients manually will be assigned to one of the groups in our Study 1, where patients with wild-type disease will be randomized into 2 treatment arms. Two of them study arms, arm A B, studying triplet or doublet, gedatolisib palbociclib fulvestrant versus gedatolisib and fulvestrant there, and arm C is a control arm with fulvestrant. And then in a patient with confirmed positive mutation status for PIK3CA, patient will receive in a study arm gedatolisib palbociclib fulvestrant similarly, and then standard of care or palbociclib fulvestrant in a control. Primary endpoint in both parts progression-free survival. In Study 1, there is in a hierarchical order, we'll be looking into efficacy, comparing arm A, triplet versus control, arm C, and then followed by comparison of arm B to arm C.
Then, similarly, we'll have one primary endpoint for efficacy in Study 2, comparing triplet gedatolisib fulvestrant to standard of care palbociclib fulvestrant. In terms of other parameters, studies, actually, compared to other either finished or ongoing phase III studies in this setting have a very straightforward and easy parameter for enrollment. Eligibility criteria makes this study easy to enroll. The main factors I already mentioned, all patients, regardless of PIK3CA mutation status, are open to be enrolled. The main criteria to be included is the prior therapy with cell cycle inhibitor, any kind of cell cycle inhibitor in combination with non-steroidal aromatase inhibitor, any menopausal status, males and females can be enrolled. The main inclusion criteria will be prior chemotherapy for advanced disease. Chemotherapy used in adjuvant/neoadjuvant setting is allowed.
We do have a number of primary and secondary endpoints, and some of those I already mentioned. In both studies, we include doublet gedatolisib with fulvestrant to help provide information about isolation of effect of gedatolisib in this therapy. The stratification factors are pretty standard and straightforward as well, based on the geographic region, durations of prior response and immediate prior therapy, as well as the presence or absence of visceral metastasis. The study will be conducted, and it's ongoing in about 20 countries in over 200 sites, covering North, Central, South America, Europe, and Asia-Pacific region.
To summarize this presentation about VIKTORIA-1, we have here the summary in this specific group of patient, when we compare results from arm D in a phase Ib study to available standard of care. You already saw this presentation from Dr. Hurvitz, and it's just from another point of visual representation. You can see that progression-free survival has been confirmed in a limited number of patients, and the results are suboptimal, confirming that there is a quite high clinical and medical need to improve treatment results in this group of patients. So we go to the next slide, and now, as I promised, we'll focus on the earlier lines of treatment in our results in patients who had not received prior therapy for their advanced disease.
If you remember, out of six arms, there were two arms that received therapy with gedatolisib, palbociclib, and letrozole in patients who did not receive prior therapy. When we combine this group, we have 41 patients. More details were presented at ESMO Breast. Some of you may have heard or saw this. Baseline characteristics, very similar to the whole study in general. All patients had stage 4, every single one, even in this setting. Many patients had multiple visceral metastasis. You have here, half of patients having both liver and lung metastasis, and only one patient had bone-only disease. The next slide similarly presents a very similar message as you saw from the whole study.
The main treatment discontinuation cause is the disease progression, and out of 41 patients, only four patients discontinued treatment due to adverse events. Again, it compares quite favorable to data published with other PAM inhibitors. Efficacy. When we look at the combination of both arms, we can see that efficacy is very promising. In 41 patients, median progression-free survival almost 50 months. And response rate is quite high and getting to 80%... with some patient achieving complete response. We'll show the data later. And what's more important, again, to repeat, reiterate, this result was seen in patients regardless of PIK3CA mutation status for their disease. Another way to represent efficacy, again, as I already mentioned, a very promising median progression-free survival. Similar story as with the pre-treated patient, only one did not have response.
All other patient has stable disease, so better. Six patients had 100% reduction in their target lesions, one confirmed CR, others having very durable and stable, partial responses. When we compare this result from the 41 patients to publish data for palbociclib and letrozole or letrozole in this setting, you can see that, as Dr. Hurvitz presented, there is a very strong and interesting opportunity and potential for improve, not only results in second-line for hormone positive HER2 negative disease, but also in patients in frontline. As we discussed, part of the rationale and mechanism of action here would be to improve efficacy of the combination and prevent potentially developing of resistance to both hormonal therapy or cell cycle inhibitor.
Here I wanted to finish my presentation with a short stories from two patients who were treated in 1009 study. One patient receives combination in a frontline setting and another patient in a third-line setting. A patient, 62 years old, female, who was initially diagnosed with breast cancer in 2008, had a recurrence in 2018, 10 years later, with a stage 4 disease and metastasis to the lung. She previously received care, surgery, as well as adjuvant hormonal therapy, started on gedatolisib, palbociclib and letrozole in 2018. As of today, I have confirmed information from the team as of September as well. Patient still maintain on treatment with intravenous infusions of gedatolisib, was very stable and long-lasting partial response.
As of August, patient completed 67 cycles, so making treatment duration over five years. Again, stage 4 disease, visceral metastasis, patient. When we look in the third line patient, it was a 61-year-old female who initially was diagnosed early in 2000, had a radical mastectomy, went through adjuvant chemotherapy, hormonal therapy. Her disease recurred in 2016 with multiple metastasis in visceral organs. She received chemotherapy as the initial treatment for her advanced disease, which then followed by a combination of palbociclib and fulvestrant. She was on treatment for three years, and then again, disease returned as a stage 4 with metastasis to the lung in 2019.
So she was randomized, enrolled, not randomized, into gedatolisib-palbociclib-fulvestrant arm, and initially, it was weekly dosing patients, now on intermittent dosing, continuing therapy, and as of August, passing 57 cycles, was very stable and very long-lasting partial response. So here we have a third-line patient with stage 4 disease being on treatment for over four years. So to summarize overall, my representation, giving it back to Brian, as a clinician, I want to say that the results that we see with gedatolisib shows a strong differentiation of this compound compared to other PAM inhibitor. As we discovered that chemical structure does impact strongly PK/PD profile of the product and metabolic profile, which in return can impact safety and tolerability of this therapy.
So what we see here, the agent that, even though used intravenously, we know that this convenience is important for everyone, but in the end of the day, when you have a therapy that allows you to keep the disease at bay, it's very important compared to convenience of oral treatment. As clinicians, and I'm sure if any patients or their family member will highly appreciate the opportunity to have such an extended disease-free survival, progression-free survival for these patients. So chemical structure, PK profile, metabolic profile do matter, and this why we believe that gedatolisib may be first in class dual pan-PI3K inhibitor that both effective as well as well-tolerated.
To summarize, this been proven by overall research and development, where we have over 500 patients and healthy volunteers treated with gedatolisib as a single agent or in various combination. Our phase III study in breast cancer is ongoing, and as you heard, we will be starting a phase I/II study in patients with prostate cancer. Thank you.
Thank you, Igor. That was great. So I'd like to wrap up and just kind of summarize what I think we tried to convey.
The PAM pathway has confounded drug developers for nearly 20 years, and some of you have probably invested in those companies or followed this category closely. And the end result is that it's led many drug developers and investors to blame the pathway for this lack of success. We think that sentiment's misguided. We blame the drugs. The failures or limited efficacy and lack of tolerability of other PAM inhibitors reflect limitations of the drugs, not irrelevance of the pathway. Mechanism of action of a single-node PAM inhibitor simply has limited potential to achieve the potency or cytotoxicity necessary to optimize efficacy, and this limitation is further compounded by the challenges the oral route of administration presents.
We're excited about the opportunity to potentially offer breast and prostate cancer patients effective treatment for their PAM pathway-involved tumors. It's a significant unmet need, as you heard from Dr. Hurvitz and Dr. Fizazi, that we think Geda is uniquely positioned to address, and we look forward to updating you on our progress over the next coming years. That ends our formal presentation. We'd like to now turn to Q&A. You can submit a question through the Q&A feature on the event page. Lance and Igor and I will be available to answer those questions. And so I think we've received some questions in the meantime, and I will be the moderator here to track those down. The...
I think a general question came up about what we think is responsible for the superior tolerability of Geda relative to these other drugs, particularly, you know, do we relate it to the PK/PD profile of the drugs. And so, maybe, Igor, you wanna take that question, and then, Lance, if you have some thoughts, too.
Thank you, Brian. As we discussed and hopefully made it clear, at the end of the day, how PK profile and metabolic profile is defined as the impact on the safety as well. So there was some belief that Cmax directly associated with maybe safety. It's not always the case, and when we compare specifically PI3K inhibitors, we have here oral versus IV product. We also have other parameters that we discussed, how product is distributed and how long it stays in tissue or liver. So all of those factors plays role and then impact safety profile.
With this IV formulation, especially for gedatolisib, when we have very low tumor volume, you're able to inhibit your major tumor-driving pathway, but at the same time, you limit exposure of your healthy tissues to either directly drugs, in our case, when there is no metabolites identified to any metabolite. And when you use oral therapies, you have to maintain certain concentration, and with the higher tumor volume, even with the IV formulation like capivasertib and its higher presence in liver, having huge impact on glycolysis in liver, you're gonna increase hyperglycemia and other side effects. So that stable structures that leads to improved PK and metabolic profile of gedatolisib, in our belief, is the answer why the product is both effective but also well tolerated.
You know, I think the overall backdrop, it relates again to the information Lance provided, which is that Geda is very potent, and so you-
Exactly.
don't need a lot of drug to induce a treatment effect. And when you deliver it through an IV route of administration, you're avoiding the two organs most responsible for inducing adverse reactions. And the end result is you get the best of all worlds. You have a very potent drug that hits the proper pathway most effectively and is able to be effective at a low concentration, and then you're avoiding the effects in these other organs. And so I think some just because of the nature of the disease have focused on it as a purely an on-target effect. Well, it's really a combination of an on-target effect taking place at the relevant organ where that target is active.
In this case, in the case of PI3K alpha, you know, the liver is, is the primary organ that regulates the glycolytic cycle . And if you have a lot of drug, which will occur when an oral drug is administered, getting into the liver, you will induce a lot of hypoglycemia, and the data is very clear on that. You know, Geda is more potent against PI3K alpha than the single agent or the single node alpha inhibitors that presented data. So it's not a question of on-target effect. It's really a question of, you know, the location of where the drug goes.
And that's, we think, the key to being able to avoid this toxicity, while also having PK properties like volume of distribution that allow the tumor, rather allow the drug to, you know, remain balanced and optimized to our concentration.
Right. And I just echo what Brian and Igor have said, that in fact we're exploiting this therapeutic window, that these cancer cells have this high requirement for glucose that normal cells simply don't have. And if you have an inhibitor that has low nanomolar potency across the broad range of targets required to get control of this pathway, you effectively can leverage that therapeutic window better.
Okay, I'm scrolling through. We've got a bunch of questions here. We received a question about the, you know, the immune system effect, and, you know, what other markers might we think of, or what other data would be helpful to look at to get a sense of the effect of get on, on, you know, A, the tumor microenvironment, and B, you know, how that may in turn improve, uh, anti-immune, you know, immune cell function, in the TME.
Right. We started with just the basics, and that's what we had, have presented this morning. Of course, we're starting with those basics and demonstrating the key factors we think are the important ones, then looking further in future studies where there is more complexity, if you will, because as soon as you get away from these basic functions, there are a lot more cell types involved in the tumor response. We're highlighting this morning the key cells that are involved in getting an anti-tumor response and demonstrating that gedatolisib actually improves that environment from a hostile anti-immune system response to something much more hospitable by demonstrating that the key cells infiltrate and that they're active when they get there.
Right. Okay, and so, we have some question on VIKTORIA-1. I think, one of the questions was related to dose reduction. You know, what do we allow in the course of that study? And, you know, how might that relate to what we've seen previously? Igor, that would be a question for you, I think.
So, dose reduction criteria in VIKTORIA-1 is the same as was in phase I-B study. There's the two steps. In our phase I study, dose intensity was quite high. About 90% patients remain at the dose intensity from the starting dose, 180 milligram. We believe that the introduction of mandatory prophylaxis for stomatitis will significantly reduce number of patients with a Grade 3 toxicity that will limit need to have a dose reductions for that toxicity. So we don't see really any reasons to think that there will be different results in phase III study with improvement in relationship to stomatitis.
Great. So then we also got a bunch of questions on prostate cancer, and, and, I will go through that. One question related to whether tumors that have PTEN loss, you would still expect inhibition of PAM pathway to induce resensiti- resensitization of the androgen receptor pathway. Maybe, Lance, you would address that.
The answer is yes. That, as long as the androgen receptor is still being expressed in those patients, they should be resensitized. That's what the non-clinical evidence that we have to date supports, and that's also in line with literature.
Right. We had another question that relates to a study done with capivasertib. Capivasertib is an AKT inhibitor. It was studied in combination with docetaxel several years ago. The early readout of the data was not favorable. Essentially, showed no treatment, no benefit in PFS, median PFS, compared to docetaxel. However, a longer follow-up showed that there was a survival benefit, which is encouraging for drugs, you know, in our case, we think that that augurs well for us. You know, the question is, does that impact, or how do we think about that in the context of AR study and B, you know, potential phase three?
We've already had interactions with the FDA and engaged in conversations about appropriate endpoints for the setting that we're focused on, which is, you know, patients who've progressed after an AR inhibitor. The agency indicated, at least to date in our early interactions, that the primary endpoint of median progression-free survival would be appropriate for that setting. Obviously, OS will be an important endpoint, but given the data for AKT inhibitor, if it's providing or reducing favorable OS, we think that could be associated with a class effect for these drugs. But more to come. Obviously, we have to determine that. We have to report out data.
One other question on the study design of prostate cancer relates to exclusion of patients who had prior docetaxel. We wanted this study to have essentially a clean read for patients who were just progressing on their AR inhibitors. And it's similar to breast cancer. If doctors can postpone treatment of their patients with chemotherapy, they would like to do that. There aren't really good alternatives now in that post-AR inhibitor environment. But we wanted to isolate that patient group since that's the patient group, if our data result favorably, that we would want to study in a registration study, if the data warrants that.
So again, you know, our intention is to be a post-AR drug and wanna have a clean read on that data. The, just scrolling through my, the list of-- Oh, okay, I'm getting more questions here. I'm not keeping up. The, let me think. A question on PSA readouts. You know, PSA, we are monitoring. PSA is one of the secondary endpoints. We'll be reading that. I think there's general recognition that PSA may not be determinative, particularly in later-line studies, that the most definitive assessment of efficacy is, you know, radiological median progression-free survival. That's why we define that as our primary endpoint for the study, and we think that's the data that's most relevant.
As we report data, we wanna make sure we focus on that. And then, just one final question I think that we'll answer before time runs out. AR degraders, there are a couple that are in process. I think have been developed in combination, or they're being developed in combination with the current AR inhibitors. I think it's too early to say how that develops, but I think, you know, all of this gets at the question of what can be done to improve treatment in these patients.
You know, our general kind of thinking is that if you have an untreated disease mechanism that's contributing to the disease, in this case, the PAM pathway, you're likely, or at least certainly plausible to believe that inhibiting an untreated pathway could be more beneficial than improving the targeting of an important pathway. Certainly, you can get benefits, but I think we've seen in breast cancer with the new SERDs that you can induce a treatment effect in cases where there's a mutation, but that when those mutations are lacking, you don't see a treatment effect.
And that just may be that there's just a limit to the benefit you can get by inhibiting this a particular pathway when there are other pathways that are serving to drive that disease, that need to be inhibited. So we've run out of time. Thank you very much. If you've hung around this long, we appreciate your participation and appreciate the questions and look forward to continuing our updates. Thank you.
Bye-bye.
Thank you.
But that there's just a limit to the benefit you can get by inhibiting this, a particular pathway when there are other pathways that are serving to drive that disease, that need to be inhibited. So we've run out of time. Thank you very much. If you've hung around this long, we appreciate your participation and appreciate the questions and look forward to continuing our updates. Thank you.
Bye-bye.
Thank you.