Good morning, everyone, and welcome to the Faeth Therapeutics virtual KOL event. At this time, all attendees are in a listen-only mode, and a question and answer session will follow the formal presentations. To our Analysts joining us live, please use the raise hand feature to be added to the queue, and we kindly ask that you limit your questions to one. As a reminder, this call is being recorded and a replay will be made available on the Faeth website following the conclusion of the event. I'd now like to turn the call over to Anand Parikh, Co-founder and Chief Executive Officer at Faeth Therapeutics. Please go ahead, Anand. Good morning, everyone, and thank you for joining our inaugural analyst and investor event. My name is Anand Parikh. I'm Co-founder and CEO of Faeth Therapeutics. Next slide. We will be making forward-looking statements in this presentation, so please refer to this slide for appropriate disclosures. Faeth was founded at the intersection of cancer biology and metabolism with the goal of broadly enabling multi-node inhibition of crucial cancer pathways. We began by attempting to solve the pi3k/AKT/mtor conundrum. That is how to effectively drug a pathway crucial to the livelihood of both cancerous and healthy tissue. Our work began in the lab of Lewis Cantley, discoverer of the PAM pathway. Research by Lewis and Dr. Marcus Goncalves, who you'll hear from later, paved the way for our multi-nodal approach, which we call PIKTOR. As the industry doubled down on novel ways to target PI3 kinase, most recently with mutant selective inhibitors, our resolve in multi-nodal inhibition never wavered. With the recent approval of Celcuity's REVTORPYK, we believe that multi-nodal PAM inhibition is now a validated pillar of cancer care. Our work here is just beginning. Ultimately, we would like to get PIKTOR into the hands of nearly half of all cancer patients who have a PAM pathway alteration, starting in endometrial and breast cancers. Next slide. Here is our agenda for this morning. I'll start with an introduction into Faeth's history and strategic direction. Marcus will then provide you with an overview of the company's scientific foundations, which include several Nature publications. Oliver, our Chief Scientific Officer, will then discuss preclinical and translational data that we believe supports selection of the dose that we've chosen for our phase II trial in endometrial cancer, PIK-201. Debbie, our Chief Medical Officer, will then walk through some of the clinical data that have gotten us to this point, preview PIK-201's data, and why we believe there's read-through from PIK-201 to our ongoing efforts in breast cancer. Brian, our Chief Financial Officer, will wrap up with the market opportunity for endometrial and breast cancer indications. Analyst Q&A will follow. By the end of the event, I hope to convince you that our approach is grounded in strong science and that multi-node inhibition of the PAM pathway is the solution to finally unlocking the true potential of PAM inhibition. We can completely disable PAM. Single-node inhibitors, no matter the dose, cannot. Next slide. Here's a pipeline overview. We are currently exploring PIKTOR in two clinical trials. PIK-201, which is in endometrial cancer, is currently in phase II. We look forward to that readout at the year-end this year. PIK-101 is a phase Ib trial exploring PIKTOR in breast cancer, which will read out at year-end next year. Next slide. Our Scientific Co-founders include some of the world's preeminent cancer biologists and endocrinologists, including Lewis Cantley, the discoverer of the PI3K pathway, Dr. Sid Mukherjee, Dr. Karen Vousden, and Dr. Scott Lowe. The provenance of the PIKTOR molecules comes directly from Kevan Shokat, one of the world's leading medicinal chemists. Next slide. The PI3 kinase/AKT/mtor pathway, or PAM, probably needs no introduction to this audience. It's altered in up to half of all solid tumors. PAM regulates cell growth and division. It also regulates glucose metabolism. That combination is not a coincidence. Cancer is a disease of growth. Growth takes energy. A tumor that alters PAM gets both at once, the signal to grow and the fuel to do it. Next slide. Here you can see how frequent PAM alterations are in cancer. In terms of sheer prevalence, endometrial tops the list at over 80% PAM altered, with breast cancer coming in a close second. Next slide. The prevalence made PAM a priority for drug development. It has also made it one of the harder pathways to drug multiple regulatory loops, and those loops are what defeat single node inhibition. Block one node, and the pathway compensates by upregulating another, like a game of Whac-A-Mole. This is exactly the case for hitting more than one node at once. Exactly what PIKTOR does. Next slide. This has been the crux for drug developers for decades. Single-node inhibitors, which now include alpha-selective PI3K inhibitors, mutant-selective PI3K inhibitors, AKT inhibitors, and single-node mTOR inhibitors, all fail to completely disable PAM. Increasing the dose of single-node inhibitors will dampen the pathway, but it's never completely shut. At those higher doses, on-target toxicities, such as hyperglycemia and stomatitis, quickly become untenable. Our approach is different. We combine inhibitors at three nodes, each at a lower pharmacologic dose. We get deeper pathway suppression than either agent achieves alone at exposures that are more tolerable than maximizing either one. As you'll see in Oliver's presentation, translational data that we have in-house shows complete shutdown of the PAM pathway at the doses being tested in PIK-201. Next slide. We call our multi-noded approach PIKTOR. It combines serabelisib, an alpha-selective PI3K inhibitor, with sapanisertib, an inhibitor of both mTORC1 and 2. Both agents are oral, taken with food each morning, Monday through Wednesday, then off for the rest of the week. That intermittent dosing is part of how we get suppression without the toxicity that comes with continuous exposure. Next slide. In terms of its reach, multi-node broadens the treatable landscape relative to single-node approaches. For example, in the graph below, you'll see that single-node inhibitors, such as PI3K alpha-selective inhibitors or even mutant-specific inhibitors, can only target the yellow space, a small fraction of the overall PAM alterations in solid tumors. We can target the yellow and green and potentially beyond, as REVTORPYK has demonstrated. As mentioned earlier, endometrial has the highest incidence of PAM alterations of any cancer. However, you can see here only a small percentage of the PAM alterations in endometrial cancer are purely PIK3-related, meaning that the majority of PAM alterations in endometrial cancer cannot be served by a single-node inhibitor. Next slide. PIKTOR is the culmination of decades of research into drugging the PAM pathway. Early work conducted by Lewis and then Marcus found that certain low-carbohydrate diets could blunt the impact of PI3K to the insulin feedback loop, improving the efficacy of early PI3K inhibitors. The company was founded on this trailblazing research, which was published in Nature in 2018. It also led us to seek out a PI3K inhibitor of our own, and in 2021, serabelisib was in-licensed from Petra Pharma via Takeda. We later found that combining serabelisib with an mTOR inhibitor could recapitulate much of that prior diet-based work. This was the birth of Faeth's multi-nodal strategy. Sapanisertib was subsequently in-licensed in 2023 from Calithera Biosciences, leading to PIKTOR as we know it today. Next slide. Sapanisertib and serabelisib were both initially developed by Kevan Shokat at UCSF and subsequently put into a company he co-founded called Intellikine. Intellikine was subsequently acquired by Takeda. Takeda mainly developed these two drugs as monotherapies and sometimes in combination with fulvestrant or paclitaxel. Takeda did do some subsequent work combining serabelisib and sapanisertib, testing different doses and different dosing schedules. That work gave us a strong foundation from which to build our ongoing programs in endometrial and breast cancers, which Oliver and Debbie will describe later. Next slide. This table summarizes much of what I've already talked about on the advantages of multi-node inhibition relative to single-node inhibitors that are currently in development. It also compares us to gedatolisib, which as I mentioned, was recently approved under the trade name REVTORPYK. Next slide. While we believe that multi-nodal PAM inhibition has been validated, there are several ways we believe that we can improve upon it. First, PIKTOR is orally available, adding the convenience of a daily pill versus a weekly infusion. Secondly, our safety profile thus far looks quite tolerable relative to other options, with a specific emphasis here on hyperglycemia and stomatitis. Stomatitis in particular, which we believe is more of a Cmax-driven event, we believe is derived from gedatolisib's IV formulation. We'll touch on PK in more detail on the next slide, but the bottom line is that PIKTOR spends around 2x to 3x more time above IC90 than gedatolisib in a given week. As many of you know, usually in cancer drug development, greater time above IC90 generally correlates to more efficacious drugs. Debbie will highlight some of those safety differentiations as well in detail later. Next slide. Here we outline our PK in more detail. The blue curve is gedatolisib. What I hope stands out for you is that relative to gedatolisib, we're relatively similar. We believe that gedatolisib has demonstrated that pulsatile dosing of the PAM pathway is feasible and delivers a clinical benefit relative to incomplete inhibition of PI3K or other nodes of the pathway on a daily basis, which we see with alpha and mutant selective PI3 kinase inhibitors. However, as an IV formulation, gedatolisib has a much higher Cmax, which we believe contributes to greater stomatitis. But overall, we both cross IC50 around the same time. Finally, note that PIKTOR spends around 2x to 3x more time above IC90 than gedatolisib in a given week. This is my last slide, beginning with our most advanced indication, endometrial cancer, and then translating to breast cancer and beyond. Oliver will explain to you why we believe that PK development has set us in good stead for PIKTOR's development in endometrial cancer. Debbie will then walk you through prior clinical data with an eye towards our first public readout, or our first readout as a public company later this year. She'll also tie in why PIK-201 should provide relevant read-through to our ongoing development in breast cancer. But first, I'll hand it over to Marcus, who'll walk you through more of the rationale behind multinodal inhibition of the PAM pathway. To introduce Marcus, who's not only my Co-founder, but he also directs the Holman Division of Endocrinology, Diabetes, and Metabolism at NYU. He did his postdoc in Lewis lab, which is where this work started, and he's one of the few people who is an expert both in endocrinology and in PAM pathway biology, and that combination makes him a unique voice to have with us today. Thank you, Marcus, and I'll hand it over to you. Thank you, Anand. I'll be reviewing the PAM overview and single-node inhibitor escape. The objectives of this part of the talk is to uncover the flaws in single-node PI3 kinase inhibition approaches, explain the origins of PI3 kinase inhibitor-induced hyperglycemia, and set the scene for multinode PAM inhibition. I'd like to start by showing the relationship between glucose and insulin. Here, we are seeing the changes in glucose in red following a glucose bolus after a period of fasting. This is similar to what you would see after eating something rich in sugar or starch. The digestion and absorption processes prompt a rise in blood glucose. The pancreas senses this increase and releases insulin into the circulation. Insulin mediates the clearance of glucose from the blood and resets the system. I'd like to note the relative scale of these changes. You can see that relatively small changes in glucose can lead to large rises in insulin, especially in people with obesity or other causes of insulin resistance. Most of the glucose cleared from the blood by insulin goes into the skeletal muscle. Estimates suggest about 90% of this glucose is cleared by muscle, with other organs like the liver and gut clearing the rest. Here are human data that led to these estimates, showing that roughly a quarter of glucose disposal goes into the leg, which is mostly comprised of skeletal muscle and bone. Tumors have a small mass but may contribute disproportionately to glucose clearance. Tumor cells use insulin signaling components to promote cell growth and survival. A key node in this pathway is PI3 kinase alpha, which Lewis Cantley discovered in the late 1980s. Mutations in PI3 kinase alpha are among the most common driver mutations in cancer, so researchers set out to develop selective inhibitors of this protein. These agents were somewhat effective, but they didn't have the dramatic effects that were anticipated with blocking such a critical node in this pathway. What we have since learned is that part of the problem with drug efficacy were that these drugs block the PI3 kinase pathway everywhere, including the skeletal muscle, which uses a simplified pathway, including PI3 kinase alpha and AKT, which drive glucose transporters to mediate glucose disposal. Note that mTOR is not as important in the skeletal muscle for glucose clearance. Therefore, blocking PI3 kinase in muscle, prevents glucose clearance from the blood and creates massive amounts of insulin, which can override the PI3-kinase inhibitors effects in the tumor. This is an animation of this process in action. Insulin binds to the insulin receptor in skeletal muscle, activating the pathway and driving glucose transporters to the surface of the cell, and clearing glucose from the blood by entering the muscle tissue. PI3 kinase inhibitors block this activation and don't allow the glucose transporters to go to the surface of the cell, and that leads to large rises in glucose in the blood, accumulating over time. The pancreas senses these rises in glucose and leads to insulin feedback. The beta cells generate more insulin, which can then bind to both insulin receptors in a tumor and muscle to reactivate the pathway. While skeletal muscle is the most important organ for glucose clearance in humans, other organs are involved. For example, the liver provides glucose for the body during periods of fasting, and insulin is responsible for turning off this process. Here are data from hyperinsulinemic-euglycemic clamp studies, which are the gold standard for measuring glucose flux in vivo. You could see that the liver's contribution to glucose flux is suppressed by insulin, whereas the muscle's disposal is increased. I'd like to highlight the relative changes in flux that occur with insulin. There is over twofold more disposal into muscle than suppression, which is what drives the clearance of blood sugar. Back in 2014, when I joined Lewis Cantley's lab, one of Faeth's other Co-founders, Ben Hopkins, was working on methods to suppress the high insulin levels induced by PI3-kinase inhibitors. He came up with the idea of removing carbohydrates from the diet using insulin-suppressing diets, and that that would lower glucose and therefore block the drive to produce high insulin levels. Here are some data from that study. Each graph is showing the growth of the same tumors over time. The green lines are the control tumor growth without any treatment. Panel 1 shows the modest growth suppression observed with PI3 kinase inhibition, which reflects the minimal efficacy of this class when given as monotherapy. Panel 2 shows the lack of a strong anti-tumor effect of an insulin-suppressing diet when given alone. Panel 3 now shows the combination of the inhibitor plus the diet, which now produces outstanding efficacy and tumor regression. Panel 4 is the key experiment, which shows that adding back insulin at the hyperinsulinemic levels now overrides the beneficial effects of the combination therapy. We then examine the activity of each signaling node in the tumor histology using immunohistochemistry. To orient you to these panels, we have tumor histology from each of the four treatment groups in the columns from left to right, and then immunohistochemistry for each key signaling node in the rows, including the insulin receptor, AKT, and S6, a marker of mTORC1 activity. The darker the brown color you see, the stronger the node is active. In the control setting, we saw that tumors had high PI3 kinase activity, as assessed by AKT and S6. The diet arm had reduced insulin receptor activity, as predicted by the suppression in systemic insulin levels, and a large reduction in mTORC1, but only modest effects on AKT. The PI3 kinase inhibitor had strong suppression of AKT and mTORC1 by higher circulating insulin levels. Finally, the combination of inhibitor and diet gave a strong suppression at all key nodes, including potent reduction in mTOR signaling that went over and above the other conditions. These data suggest three things. One, mTOR is a vital coordinator of pathway activity and reactivation in the setting of PI3 kinase activity. Two, that multinode inhibition is essential for complete pathway suppression. And three, PI3 kinase inhibitors may need to be paired with mTOR inhibitors in order to reproduce the regressions we saw with the diet drug combination. Here's a more detailed view on the intracellular signaling changes that occur following inhibition of each node. So far, we've discussed pathway reactivation by other organs like the pancreas, which can produce insulin. However, tumor cells have complex strategies to reactivate the pathway on their own. For example, it has been shown that tumors can adapt to inhibitors of different pathway nodes. PI3 kinase inhibitors lead to hyperinsulinemia and upstream tyrosine kinase activation, as well as selective pressure to form genetic alterations in other components like PTEN, which normally turn off PI3 kinase. mTORC1 inhibitors leave mTORC2 active, which can then activate AKT and downstream signaling. AKT inhibitors can result in upstream tyrosine kinase upregulation and activation, and the cell can leverage other AKT family members to activate mTOR downstream. Second-generation mTORC inhibitors, which also hit mTORC2, can lead to feedback activation of growth factor receptors promoting PI3 kinase signaling. Finally, full PAM pathway inhibition can be achieved with multi-node inhibition using both PI3 kinase and mTOR inhibitors like serabelisib and sapanisertib. With more complete pathway suppression, you may expect more hyperglycemia, but this does not occur, and there are several reasons for this. One, more complete pathway inhibition enables lower drug dosing. For example, Faeth Research has found that serabelisib can be dosed over 4-fold lower when given in the PIKTOR combination and achieve similar pathway suppression. This lower dose may better preserve muscle PI3 kinase signaling and glucose clearance. Two, adding mTOR inhibition does not worsen muscle's ability to clear glucose, since that process is regulated primarily by PI3 kinase and AKT. Therefore, the PIKTOR combination may better suppress tumor pathways while preserving the muscle pathway. And lastly, and most importantly in my opinion, the dual targeting approaches are dosed intermittently, which allows time for the muscle and the pancreas to recover between doses. Interestingly, Lewis, Ben, and others have been proposing this intermittent approach for decades. There has been some question as to whether the oral versus intravenous routes of administration are important for hyperglycemia development. Oral drugs are absorbed in the intestine and then concentrated in the portal vein, which directly feeds the liver before entering the circulation. Therefore, oral drugs may disproportionately affect the liver versus muscle. However, this explanation is unlikely to explain hyperglycemia in this setting. Muscle is the primary site of control of glucose clearance, and both oral and IV dosing hit the muscle. There is clinical data confirming this concept. The CHRONOS series of studies with copanlisib, an IV formulation, can be compared to SOLAR-1 results with alpelisib, an oral formulation. In these trials, the rates of any grade and advanced grade hyperglycemia were similar. PIKTOR, our multi-node PAM inhibitor, has shown low hyperglycemia with very permissive A1C and fasting glucose inclusion criteria in a high-risk population. In summary, multi-node inhibition may improve both efficacy and tolerability. By targeting several points in the pathway at once, we can prevent pathway reactivation and more completely suppress the signals that drive tumor growth and survival. Importantly, if we block multiple nodes, we do not have to inhibit any node as deeply. That allows us to use lower relative doses and less frequent dosing. Why does this matter? PI3 kinase alpha is also critical for normal insulin signaling in skeletal muscle. When we inhibit PI3 kinase alpha, muscle takes up less glucose and blood glucose rises, and the pancreas responds by producing more insulin. That high insulin can then reactivate PI3 kinase signaling in the tumor while also contributing to hyperglycemia. Intermittent dosing gives normal tissues time to recover between treatments and may therefore reduce this metabolic stress. Ultimately, the key question is not simply the route of administration, it is how deeply and for how long we suppress PI3 kinase and AKT signaling in normal tissues such as skeletal muscle. With that, I would like to introduce and turn the presentation over to Oliver Maddocks, who is Chief Scientific Officer and Co-founder of Faeth. He is an Honorary Professor of Cancer Biology and Metabolism at the University of Glasgow, and he will cover the preclinical and translational data that has been generated to date. Thank you, Marcus. Thanks, everyone else, for joining us today. My section will cover three topics. I will start with the mechanistic background for PIKTOR. I will go on to describe in vitro and in vivo preclinical data, and then switch over to a clinical study which featured PK/PD data which supports our dose selection. I will start off by picking up on some of the data that Marcus has already shared. I will emphasize this point about how more complete pathway inhibition, as we see in the lower part of the pathway at mTORC1 and mTORC2 and higher up in the pathway at PI3K and the insulin receptor, correlates with much more complete tumor growth inhibition in preclinical models. Based on all of the data that Marcus described, we believe that the optimal profile for targeting the PI3K pathway is to hit PI3K alpha and mTORC1 and mTORC2 using our PIKTOR combination. We believe to allow lower dosing and better tolerability. I want to take you through each of our drugs in a little more detail. I will start with sapanisertib. The first point I will make about sapanisertib is it's a rationally designed small molecule and contrasts quite significantly with the first-generation mTOR inhibitors, otherwise known as the rapalogs. Here we have a diagram of the everolimus structure. This is a natural compound derived from a type of bacteria from Easter Island, of all places. This is a very large, clumsy molecule, and it does not bind mTOR directly. In fact, the rapalogs bind a partner protein, FKBP12, and that drug protein complex then interferes with just the mTORC1 complex. That leaves the mTORC2 complex active, which actually allows pathway reactivation. In contrast, sapanisertib, designed by Kevan Shokat in his lab, targets the ATP site of mTOR, and that means that it inhibits both mTORC1 and mTORC2 signaling. It's highly potent, has 1 nM IC50 in vitro, and largely spares the PI3K isoforms. In similarity, serabelisib is also an ATP-competitive small molecule inhibitor. It targets very specifically PI3K alpha, and has excellent cell activity in that regard. You see that especially PI3K delta and gamma that are expressed in immune cells are much less inhibited by serabelisib, which is a nice contrast to the pan-PI3K inhibitors, and again, gedatolisib being a pan-PI3K inhibitor. We've talked a lot about pathway inhibition and more complete pathway inhibition. I'd like to delve into a little bit of detail as to what we mean by that. When we look at pathway activity, we can look at a number of readouts. Two of the most important are phospho S6 and phospho 4E-BP1. They have slightly different functions. S6 is tied more closely to cell size and 4E-BP1 to cell number, i.e., the ability of cells to proliferate and multiply. When we look at the effect of the single-node approved PI3K inhibitors like alpelisib, everolimus, capivasertib at clinically relevant exposures, what we see is that they all do an excellent job of inhibiting phospho S6, but are much less able to inhibit 4E-BP1. When we transition to multi-node inhibition, we see, especially as we progress to the PIKTOR combination, that we can now completely inhibit S6 and inhibit 4E-BP1. What I will also note, and we've said a lot that the combination, the multi-node combination, allows us to dose the agents at a lower level for better tolerability. What you can see here is an example of that. The Cmax exposure here of serabelisib at 20 micromolar achieves good S6 inhibition and reasonably good 4E-BP1 inhibition. Now when we take serabelisib and give alongside sapanisertib, a fourfold lower dose can achieve the same amount of pathway inhibition. Four times less drug, which will give better tolerability, but now have an equivalent pathway inhibition. Then, as you can see, as we progress that dose of PIKTOR, we can even more fully inhibit the pathway. Is it important indeed to inhibit 4E-BP1? Work we published last year indicates that, yes, this is the case. When you look at the correlation between drug potency as it pertains to cellular IC50, it is the case that ability to inhibit 4E-BP1, but not S6 necessarily, correlates more closely with cellular IC50. Ultimately, we believe you need to inhibit both concurrently, and that is what the data suggests. Briefly, I will not go into complete detail here, but we are also showing that the inhibition with PIKTOR works at the level of phospho-AKT as well. So now we are looking at AKT, S6, and 4E-BP1 phosphorylation. Again, these lower doses of PIKTOR are very effective in inhibiting all elements of the signaling here, and this contrasts with the mutant-specific inhibitors that are being developed and inavolisib, and this is the case across a range of endometrial cancer cell lines above and breast cancer cell lines here below. So that is the kind of signaling story. Does that in fact translate to cellular activity? So here we are looking at cellular dose response curves, and what you can see is that ability to more completely inhibit the pathway does indeed translate to greater potency at dose response curve level. So the first thing I will say is that the multi-node inhibitors, both PIKTOR and gedatolisib, have by far the best and lowest IC50s across the class of other PI3K pathway agents tested, and that extends both across these endometrial cancer cell lines and breast cancer cell lines, with PIKTOR having the lowest IC50s in the class. So that is at the cellular level. If we move to the in vivo tumor growth inhibition level, again in preclinical models. On the left-hand side, we have a breast cancer model, on the right-hand side, an endometrial cancer model. Both these models are mutated in the PAM pathway. What you can see is that PIKTOR alone has excellent monotherapy activity, especially in the breast cancer model here. Also good activity on the right-hand side in the endometrial cancer model. When you add paclitaxel, you get, especially in the endometrial model, a further boost to efficacy, whereby in both situations you have essentially complete tumor growth inhibition with the combination. A further thing I would add is, in contrast to the work Marcus presented where the dietary combination with just the PI3K inhibitor could create a big improvement in efficacy, really because the PI3K inhibitor alone is not completely inhibiting the pathway, and that the insulin suppression can really benefit to a great degree here in that context. Here, because we have excellent multi-node inhibition at the drug level, the effect the heavy lifting here, there is less delta that can be created with the diet, which reassures us that the multi-node approach and the drug combination is really working very well in this context. So that is the preclinical data. I will now move on to the PK/PD and dose selection. For this, I will be talking about a clinical trial conducted by Takeda, and this study was performed in heavily pretreated basket study of advanced solid tumors that had patients that had exhausted prior standard therapies. Over 60% of the patients had Stage 4 disease at entry, so again, in a very advanced and heavily pretreated population. This study used escalation arms with different regimens of escalation of serabelisib or sapanisertib, and different Monday, Wednesday, Friday versus Monday, Tuesday, Wednesday schedules. They settled on an expansion cohort of a 4 mg sapanisertib dose and 200 mg serabelisib Monday, Tuesday, Wednesday. This, of course, was monotherapy for PIKTOR without any additional agent. While we're going to focus today on the PK/PD data that helps support dose selection, I will briefly mention the efficacy signal that was seen here. This data hasn't been shown publicly before. In the escalation phase, there was a clinical benefit rate of 51% without any responses. But in the expansion phase, two partial responses were seen, both in endometrial cancer. Again, there was a notable clinical benefit rate. These data are very in keeping with PAM pathway inhibitors when given as monotherapy. Again, the PAM pathway is a pro-growth pathway. Inhibition of that pathway would be expected to be more cytostatic, and to get a cytotoxic effect to drive more responses, you have to partner with other agents, which is why all approvals for PAM agents have been done in partnership with other agents. Nevertheless, we think this is a nice and reasonable monotherapy efficacy signal. Moving on to the PK/PD data. Here we're looking at drug concentrations for sapanisertib on the left-hand side, serabelisib on the right-hand side. Again, we're looking at these key readouts for phosphorylated 4E-BP1 and phosphorylated 4 S6 kinase. Again, S6K, you're driving ribosome biogenesis related to cell size generally, and eBP1 translation. What you can see is that there are thresholds around about the 10 ng per mil mark for sapanisertib, 2,000 ng per mil mark from serabelisib, which give good pathway inhibition above which there are kind of diminishing returns in terms of pathway inhibition versus increasing dose. We took these thresholds through into comparative studies. If we convert those thresholds derived, again, I should mention, sorry, that these thresholds and stainings are done in skin biopsies taken from human patients. If we take those thresholds, convert them into AUC and compare that with exposures that we will see in patients with 2 mg, 3 mg, or 4 mg doses of sapanisertib, we can see that the 3 mg dose gets the majority of patients above that threshold without giving excessive exposures that might be expected to drive more AEs. On the right-hand side, it's a similar story for serabelisib, where the 200 mg dose sits most patients above that threshold without having to be excessively dosed above. It's interesting also that when a separate clinical phase II study was done, phase Ib, phase II study, that they found purely through that clinical exercise that the 3 mg and 200 mg dose was also judged to be the RP2D. This is a case where the PK/PD work was nicely concurrent with the clinical work. Finally, to bring some of this together with the other thresholds developed from preclinical work. If we look at sapanisertib PK over time, this is the first three days of dosing, and this is five days of exposure. We see that the human skin biopsy threshold there at 10 ng per mil is exceeded on each day of dosing, and that the tumor growth inhibition threshold and IC90 group very tightly with this, and again, that the PK shows exceeding those thresholds consistently through the week. We are above IC50 as well for about three and a half days. The numerical values for the time above those thresholds is on the right, and again, it amounts to a substantial period above thresholds. Of course, we are dosing every week out of four, so we are going above those thresholds every single week. It is a very similar story for serabelisib. Again, there is nice concordance between the human skin biopsy thresholds, the cellular IC90, and the tumor growth inhibition exposures. So the serabelisib's exposures and time above thresholds is very similar to sapanisertib. When you distill all this down, and this is a slide that Anand has already covered, you land on a slide that can show you when you plot the data on an IC90 ratio basis, and we can do this for serabelisib, sapanisertib, and gedatolisib all on the same chart. What we see is the similarities are that both approaches dose above IC90 at the beginning of the week and then allow a period where exposure dose is below IC90, which we think is important to help with tolerability. We also know because of our oral dosing, we are able to exceed our IC90 threshold on consecutive days, which gives us time above IC90 that does exceed gedatolisib. The other point I will make is what we know from clinical studies and the study I have already mentioned today is that once you start to see Cmaxes that exceed a kind of five-fold IC90 ratio, you do see more stomatitis, grade three stomatitis with sapanisertib, which is an on-target mTOR effect. So we think for sapanisertib and for PIKTOR in general, having our PK curves lie between the IC90 threshold and this four or five times IC90 threshold is really the place to be that is going to drive efficacy with tolerability. Of course, for gedatolisib, the IV dosing means a very extreme Cmax peak, which is always likely to exceed the level that is associated with stomatitis. So with that, it is my pleasure to hand it over to Debbie Chirnomas. It has been my pleasure to work with Debbie for the last three years. Debbie has a fantastic background in both academic and clinical medicine, including at Yale University and School of Medicine, and then switched to development at Pfizer, first of all, Gamida Cell, and then most recently, leading oncology clinical development at Arvinas. So, with that, I will hand it to Debbie for the clinical overview. Thank you, Oliver. Good morning, everyone. It is great to be here. Today, I am going to take you through Faeth's clinical story. We will talk about why we chose endometrial cancer, the data that gave us conviction, and how it reads through to our clinical development plan in breast cancer. Next slide. Anand showed this slide earlier describing how the PAM pathway alterations are frequent in many tumor types. I will draw your attention to the bar all the way on the left, where you can see that endometrial cancer has the highest rate of PAM mutations, making it an excellent candidate for targeted therapy. The other point I would note here is that only 8% of tumors can be addressed by mutant-selective agents, as opposed to the entire population that can be addressed by PIKTOR. Next slide. We will talk about endometrial cancer. This is the most common gynecologic cancer in the United States, with approximately 68,000 new cases a year. Over the last decade, incidence has increased by 26% and mortality is up 36%. For women with metastatic disease, the five-year survival rate is only about 20%, and there are no approved targeted therapies. Chemotherapy remains the backbone with very limited second-line options, which, taken with the rise in incidence and mortality, leads to an urgent unmet need. An important and specific feature of endometrial cancer, which may be one reason why it is on the rise, is the link to obesity and metabolic syndrome, known drivers of this disease. This makes targeting the insulin glucose pathway with PIKTOR even more biologically compelling. How did we get here? On the next slide, we will look at how the early data that supported the further development of PIKTOR in endometrial cancer came from a randomized phase II trial in patients with advanced recurrent disease. 241 patients were randomized to four arms, paclitaxel alone, paclitaxel plus sapanisertib alone, and sapanisertib plus serabelisib. The paclitaxel versus paclitaxel and sapanisertib arms enrolled the majority of patients, with 87 versus 86 patients, and showed a benefit with the addition of sapanisertib. Paclitaxel alone had a PFS of 3.7 months versus 5.6 months when the sapanisertib was added. In the patients with an endometrioid subtype, the PFS was 3.3 months in paclitaxel alone versus 5.7 months in the paclitaxel plus sapanisertib arm, with a hazard ratio of 0.66. Next slide. Here we can see that there are some further data from this study showing the read-through of these endpoints. The ORR was 24% versus 18%, and the clinical benefit rate is 80% in the treatment arm with sapanisertib, compared to 58% in the paclitaxel arm alone. It is worth noting that the ORR is not as noticeably different than the PFS and the clinical benefit rate. This is important because it indicates that the benefit to patients may best be reflected in duration of effect rather than the overall response rate. This is consistent with the endpoints that are used for FDA approval. While the combination arm of sapanisertib plus serabelisib did not show activity here, partial responses in endometrial cancer were seen previously in the combination phase Ib that Oliver just reviewed. On the next slide, I wanted to touch on why PIKTOR was partnered with paclitaxel and why that makes perfect sense. There are two main reasons. Number one, paclitaxel is an important established backbone therapy for endometrial cancer. Again, there are limited options. Second, the scientific rationale behind combining it stems from data that the PAM inhibition is a potential mechanism for taxane resensitization. On the left panel, you can see that the PAM pathway is activated in paclitaxel-resistant models, and that is shown by the green bars indicating the markers phospho-AKT S6 and 4E-BP1 are elevated in the resistant cell lines compared to Taxane sensitive. To the right, you can then see that despite that, when you give PIKTOR, the paclitaxel-resistant cells are still sensitive, just like the paclitaxel-sensitive cell lines. The clinical data that really took this story to the next place are that a phase Ib trial in patients with advanced solid tumors was done with serabelisib and sapanisertib combined, given three days a week at low dose with weekly paclitaxel across five dose escalation cohorts. These doses are three or 4.5 times lower than their monotherapy recommended phase II doses. That reflects the multinodal advantage you have heard about from Marcus and Oliver, that when you inhibit the pathway in more than one place, you can drug each drug lower. The results can be seen on this waterfall plot and show the efficacy of the combination. In the response evaluable patients, there was a 47% overall response rate and a 73% clinical benefit rate. In the endometrial patients, specifically, there was an 80% response rate, four of five patients with three complete responses and a median PFS of 11 months. The next slide shows the swimmer plot, which tells us about durability. As you can see, the patients had an average here of four prior lines of therapy, and they had ovarian, breast, or endometrial cancer. Three patients had complete responses, and one patient unfortunately died early due to COVID. Four patients had a partial response, and four others had stable disease for six months or longer. Patients with and without PIK3CA mutations had responses to this regimen. Taken together, these data represent an opportunity to provide benefit to patients with both wild-type and mutated tumors, not only those with pathway mutations. If you remember from the slide I started with, this may be a huge advantage compared to the mutant-selective drugs. On the next slide, we will look a little bit at safety. I will share data on two specific adverse events known in this class of drugs, hyperglycemia and stomatitis. In a data cut from our ongoing phase II study, we saw a 14% rate of hyperglycemia with 5% Grade 3. This was taken in 22 patients. This compares favorably, as you can see, to the other drugs in this space. As a reminder, our exclusion criteria included a hemoglobin A1C of eight or less and a fasting glucose of 160 or less. These are among the most flexible parameters in clinical trials, and this was intentional in order to enable treatment of a population that we know has a high incidence of diabetes and prediabetes. On the next slide, we can see the stomatitis rates. And in the same data cut from our ongoing phase II, we saw 14% with no Grade 3. We do not recommend prophylactic steroid mouthwash in our trial. Once again, this compares quite favorably compared to the other agents in the class. On the next slide, we can see that all of these pieces taken together, the strong mechanistic rationale combined with the efficacy signal in endometrial cancer, a disease with an urgent unmet need, have led us to PIK-201. PIKTOR plus paclitaxel in endometrioid endometrial cancer. This is currently enrolling and reading out top-line data later this year. Endometrial cancer represents multiple diseases. About 80% are endometrioid subtype. These are hormone-dependent, estrogen-driven, ER/PR positive, and heavily PI3K pathway altered. That's our target population. The other 20%, serous and clear cell, for the most part, tend to be not estrogen-driven, but rather P53 mutated. By focusing on endometrioid, we go exactly where the biology and our mechanism line up. You can see in the schema on the right that the ER/PR pathway, which we haven't touched on much in this talk today, have direct communication with the PI3K pathway, making it an excellent target. It is no surprise then that we are also studying ER- positive, HER2- negative breast cancer, which is also driven by the ER axis and with the same PI3K pathway crosstalk seen in endometrioid endometrial cancer. So promising results in an endometrioid-selected population are likely to be a positive harbinger of what we expect to see in breast cancer. On the next slide, you can see that this takes us to our PIK-101 study, which is a combination phase Ib/II umbrella study in HR- positive, HER2 negative advanced breast cancer. As you can see in the schema, we are studying a number of combinations, including fulvestrant alone, fulvestrant and palbociclib, as well as unnamed SERD partners with CDK4/6 as well. All of these are, of course, with PIKTOR. We are currently enrolling in cohorts A1, A2, as well as B1. Next slide. With that, I'm delighted to introduce our Chief Financial Officer, Brian Stephenson, to walk you through the market opportunity in both endometrial and breast cancer. Brian brings a rare mix of scientific depth and capital markets expertise. He previously served as CFO at BridgeBio Pharma and previously as a Director and Vice President at Leerink Partners. Brian, over to you. Thank you. Thank you, Debbie. I'll now walk you through the market opportunities for PIKTOR in endometrial cancer and breast cancer, as well as provide you with a few benchmarks as you think about analyzing the upcoming PIK-201 readout in second-line plus endometrial cancer. Starting with endometrial, I think a fact that much of the investment community misses is that endometrial cancer is now the deadliest of all gynecologic cancers, recently surpassing ovarian, and its incidence is expected to continue to grow with population aging. As Anand mentioned in his opening remarks, endometrial cancer has the most PAM alterations of any cancer, being altered in over 80% of patients. Therapeutically, we view PIKTOR as occupying a lane of its own. All of the other noteworthy therapies in the clinic are testing variations of Topo I-based ADCs. We believe there's value in offering physicians a targeted solution that they can reach for in lieu of an ADC. As in breast cancer, we don't expect that sequencing Topo I ADCs will be possible. Thus, we think it's likely that one or two ADCs will dominate market share, and we believe there's a real value proposition for PIKTOR as an alternative to ADC therapy. Of course, we have to be sentient of changes to the treatment paradigm, including the likely approval of sac-TMT in the second-line setting. For that reason, we are designing our phase III eligibility criteria to allow patients who have previously been treated with a Topo I-based ADC. That protocol is in development as we speak, and we hope to share more on the design of our planned registrational trial early next year. On the next slide, we show relevant benchmarks for second-line treatment in endometrial cancer. You'll note that patients lack a consensus second-line treatment option once surgery with curative intent is no longer an alternative. Most patients are offered rechallenge therapy with either paclitaxel or docetaxel. Usually, this consists of weekly taxane therapy instead of the once every three weeks schedule that's often given in earlier treatment lines. Rechallenge tends to yield around a 15% ORR with four-month median PFS, as recently demonstrated in the control arm of KEYNOTE-775. That study, as we'll dive into in the next slide, was a confirmatory study exploring the combination of lenvatinib and pembrolizumab after patients had failed at least one line of platinum therapy. Turning next to ADCs, most are still in early clinical development with small ends, and the average ORR is in the 30%-40% range with a couple of outliers. The higher ORRs have yet to translate to greater durability of response than we saw with Len/Pembro, and most of these trials haven't exclusively enrolled prior PD-1 failures. Finally, I'll just point out here that everolimus plus letrozole is on NCCN guidelines as a salvage option, although it's not officially approved. Oftentimes, doctors will prescribe it to patients that are considered hormone positive and that have low-grade disease. We often get asked what our internal bar for success is on the PIK-201 trial. Obviously, we want to convince ourselves that PIKTOR is active and contributing to the combination with paclitaxel. The best comp that we have right now is KEYNOTE-775, which was the largest trial in second-line endometrial cancer in recent memory. The control arm in that trial had a 15% ORR with a 95% confidence interval with an upper bound of 18%. Median PFS was 3.8 months. Importantly, there was no difference in outcomes between endometrioid and non-endometrioid histologies, with both showing similar benefits to treatment. On the next slide, I note an important caveat of KEYNOTE-775 is that it read out before the advent of IO therapy in the front line, and the combination of carboplatin with PD-1 is now standard of care for patients regardless of their mismatch repair status. Therefore, a more relevant comp for PIK-201 is Merck's TroFuse-005 trial, which will read out on October 26th at ESMO. This will be the first trial to actively test whether initial immunotherapy adversely impacts the activity of drugs in later-line settings. TroFuse-005 is comparing sac-TMT against salvage chemotherapy. Merck acquired the ADC from the Chinese biotech Kelun, which had run its own phase II trial in China that delivered around the 35% ORR at the highest dose. At the recommended phase II dose of 4 mg per kg, sac-TMT showed a 31% ORR with a six-month median PFS. Considering that the trial hit on its co-primary endpoint of overall survival at its first interim analysis, we believe the magnitude of benefit will likely be similar to or greater than that of the KEYNOTE-775 trial. The performance of the control arm will provide an updated view on how paclitaxel rechallenge performs in a contemporary patient population. Merck is pushing sac-TMT into earlier treatment settings with a trial called TroFuse- 033, and we would expect other big pharmas to follow suit. TroFuse- 033 is testing sac-TMT with pembrolizumab as a maintenance therapy after induction chemo IO. The following schema represents our best guess at how the future treatment paradigm for endometrial cancer will shake out. We believe that increased usage of Topo I-based ADCs in frontline settings would lessen their use in later lines, potentially enhancing the value proposition for PIKTOR in the second line. This follows the logic that Topo I-based ADCs cannot be sequenced one after another, given that their main mechanism of resistance is increased expression of efflux pumps. We believe the market opportunity in second-line plus endometrial cancer is sizable and largely underappreciated. Endometrioid histologies represent around less aggressive than uterine serous and clear cell histologies. Endometrioid still accounts for roughly 50% of all endometrial cancer deaths. We estimate that there are around 9,000 patients each year that fail induction with carboplatin and a PD-1 therapy. Based on available comps, including Jemperli and Lenvima, we estimate the second-line market at around a $1.5 billion annual opportunity. Moving on to breast, which is obviously the larger of the two markets, we believe that PIKTOR could be a solution for all patients, and not just the 40% that have an activating PI3K mutation. While the industry has focused the majority of its efforts on mutant-selected PI3K inhibitors, our multi-node approach targets a larger patient demographic and can be utilized agnostic to mutation status. On the next slide, we show a graphical visualization of what a mutant-agnostic therapy like PIKTOR might look like in clinical practice across both front-line and second-line settings. You can see no restrictions on PI3K or ESR1 status, the two most common mutations associated with HR-positive breast cancer. While the SERD that we are currently testing PIKTOR in combination with is fulvestrant, the goal is ultimately to combine with a novel SERD, and the PIK-101 trial has been designed with an additional cohort C to test that combination. Here's a graphic on the second-line opportunity. You'll note that treatment today is directed by mutational status. For example, oral SERDs are given to patients with an ESR1 mutation, while PI3K or AKT inhibitors are given to patients with PI3K mutations. You can see here in yellow that PIKTOR and geda are the only treatments that work agnostic to mutational status. We believe this could be important as we think to future combinations with novel SERDs. Big Pharma has spent a lot of time and money developing these drugs, but as you can see in the top row, they've only been approved in ESR1 mutant patients. We believe that PIKTOR has the potential to bring oral SERDs across the line to work in both ESR1 mutant and wild-type settings. As you can see in this table, roughly 30% of patients who don't have an ESR1 mutation do have a PI3K mutation. When you extend that to PAM alterations, that number approaches 50%. The bottom line is that endocrine resistance often runs through PAM, and we think that makes combinations with novel oral SERDs all the more compelling. We plan to have initial data from the PIK-101 trial next year that will help inform our future development strategy, including which choice of oral SERD to take forward. Finally, in terms of actual numbers, we believe the second-line breast market is potentially a $5 billion market opportunity, 60% of which is PI3K wild type patients, which currently available PI3K or AKT inhibitors do not serve. I'll now turn it over to Anand for closing remarks. Thank you again for joining us this morning. We are proud of where we've been and excited about where we are going. Let me close with the milestones. Top-line data from PIK-201, our phase II trial in endometrial cancer, reads out later this year. Initial data from PIK-101 in HR-positive breast cancer comes year-end 2027. Beyond those two, we are actively evaluating expansion into additional tumor types and potential rare disease opportunities. We also have earlier pipeline work that builds on the same foundational science. In sum, Faeth has near-term catalysts, a validated pathway, and a differentiated way of hitting it. We look forward to reading out milestones that create value for patients, shareholders, and physicians. With that, I will hand it over to the operator, in order to open it up for Q&A. Great. Thank you, Anand. At this time, we'll be conducting a question and answer session with our speakers. To our analysts joining live, just a friendly reminder that we kindly ask you to limit your questions to one. Please hold for a brief moment while we pull for questions. Our first question comes from Tara Bancroft at TD Cowen. Please go ahead, Tara. Hi, can you hear me? Yes. Yes. Okay, great. Hi, good morning. Thanks for this extremely comprehensive overview. It's really great to see. I guess my question is going to be on the PIK-201 readout. Maybe you could start by just telling us exactly what we can expect to see in that data set, like what types of metrics, and how much follow-up can we expect from these patients? Then if you reach the bar that Brian really thoroughly discussed, can you talk about the regulatory path forward, like whether you think accelerated approval is an option and phase III plans that I know you're going to disclose next year, but maybe some preliminary thoughts on that would be great. Thank you. Yeah. Thank you, Tara, for the question. We plan on presenting data from approximately 40 response evaluable patients. We'll provide swimmer plots, landmark analysis, a general sense of discontinuations of the tolerability profile. Brian talked about what we see as the bar, and we're looking to the analog of sac-TMT, where a 30% overall response rate in a China-only phase II with only one-third of the patients IO pretreated, but sufficient to translate into a global phase III that won't on the first interim OS slope. We know the likely comparator is probably going to be paclitaxel re-challenge, which as we discussed, gives a roughly 15% response rate in three to four months of PFS in an IO-naive population. We know that sac-TMT cleared it after a phase II with the data I described. In terms of more regulatory feedback than that, I don't think we have much at this point, but the decision to move to a registrational trial is going to rest on the totality of the data, response rate, durability, tolerability, and the competitive landscape at the time. That's how we're thinking about the go-forward development plan. Great. Thanks so much. Thank you. Thanks for the questions, Tara. Our next question comes from Li Watsek at Cantor Fitzgerald. Please go ahead, Li. Hey, great, guys. Great webinar. I just have one question. You have shown some pretty nice synergy between taxane and PIKTOR due to some resistant mechanism here. I am curious if you have looked at Topo I-based chemotherapy, its impact on the PAM pathway alterations, any preclinical combination studies that you have done here? Yeah, great question, Li. It is something that we think about quite carefully. We will hopefully have some preclinical work ongoing in the near future that will elucidate those mechanisms further. I will say that in the PIK-201 study, we have had some patients who were previously treated with an ADC. Those patients are not excluded, and we will report baseline characteristics, including prior therapies, with the data upcoming. Anything you want to add, Oliver? No, nothing to add. Great. Thanks for the questions, Li. Our next question comes from Hunter Hurley at Guggenheim. Please go ahead, Hunter. Hey, guys. Thanks again for that awesome history, I guess, start to finish to the company. It was really good to hear. I guess, you touched on a lot of different things mechanistically for intermittent dosing, multi-target, IC50, IC90, Cmax. I mean, when we look ahead at this catalyst that we are seeing at year-end in endometrial, how is that essentially going to validate a lot of that work? Then I guess kind of the read-through from that, you kind of touched on that you are hitting a similar pathway to geda, but maybe in a more differentiated fashion. How does that kind of read through to the comparison to geda in breast cancer moving forward? Thanks. Yeah. Thanks, Hunter. It's definitely a topic of a lot of conversation. When I think about our PK profile, I think we generally understand that greater target coverage and duration above IC90 generally translates to greater efficacy for cancer drugs. The comparison that we've presented is modeled from our own human PK and published geda data. It's not head-to-head, but we've also seen through some of the FDA materials relating to geda and our own experience with sapanisertib and serabelisib that Cmax generally has a negative impact on stomatitis in particular. That's somewhere where we definitely think there's going to be read-through to our work in breast cancer, we hope. We'll also see, hopefully, activity in endometrial cancer that then portends well for potential future activity in breast cancer. Thanks for the question, Hunter. Our next question comes from Geoff Meacham at Citi. Please go ahead, Geoff. Hey, guys. Thanks for doing this. Super helpful. Anand, I wanted to go on your last comment. You guys have done prior data has suggested activity for PIKTOR for a range of tumor types. Assuming you have positive endometrial data, can you maybe go into a little bit more granularity? What would give you optimism in breast? Have you done mechanism studies? Have you done sort of AI work? What is the extent of kind of the preclinical and clinical potential read-throughs as you look to that, because I have endometrial data. Thank you. Yeah. Thanks, Geoff. It's something you and I have obviously talked about previously, but I think that when you look at endometrial cancer, the mortality is greater than breast cancer. 85% mortality at five years compared to 50% for HR- positive, HER2- negative breast cancer. We look at our combination partner, paclitaxel in endometrial cancer, potentially CDK and oral SERD in breast cancer. We definitely think that's a more tolerable combo partner. From both the disease pathology and the combination partner, we believe breast is a really attractive opportunity for us. We've absolutely done preclinical work with PIKTOR and also have some clinical data with sapanisertib and serabelisib in breast cancer already evidencing some activity. We absolutely think that, at least from our perspective, that endometrial is a higher mortality, potentially tougher disease. We are really looking forward to the opportunity for PIKTOR to stretch its legs in breast cancer as well. Anything you want to add, Oliver or Debbie? Yeah. I would just add from the biological standpoint, endometrial frequently has multiple mutations in the pathway, so not uncommon to see two, three, or even four PAM pathway mutations concurrently in endometrial. That is less prevalent in breast cancer, so that drive in endometrial at the biological level is very high. You also see that the patient population tends to be less metabolically well, hyperglycemia, hyperinsulinemia in endometrial as well. Again, less prevalent, relatively in breast, too. Again, echoing what Anand is saying, but at the more biological and physiological level, too. Yeah, I would just echo the tolerability will also be really meaningful. So the tolerability we see in endometrial in a much sicker population should translate even, let us say, better to breast. So we are looking forward to working in that population. Thanks, guys. Thanks, Geoff. Thanks for the question, Geoff. Our next question comes from Jack Allen at Baird. Please go ahead, Jack. Great. Thanks for taking the questions and really thank you for the broad presentation here. It's great to get some more context around your thoughtful approach to developing the sapa sera combination for a number of solid tumors. I know a number of questions have already been asked by other analysts on the call, but I wanted to ask about your dose selection and if you could provide some more color on your decision to go forward with the 3 mg sapa and the 200 mg sera dose, and if that's under consideration at all for breast cancer, or are you locked into 3 200 dose paradigm moving forward? Great question, Jack, and it's definitely something that we get a lot of questions on. It's one of the reasons why we put out a presentation at the STOP Cancer conference, available on our website, that shows basically full pathway shutdown at those doses of 200 mg and 3 mg. We see pathway shutdown in terms of human skin punch biopsy. We see tumor growth in vivo efficacy, and we see significant time above IC90 at that dose with our three on, four off dosing regimen. I think the totality of evidence tells us that's a great dose for endometrial. When we look to breast cancer, I think that there is the possibility, potentially, for dose exploration, and it's something that Debbie in particular has voiced, given her experience with Project Optimus, making sure that we explore a broad range of doses. So we're doing that in breast cancer with the knowledge that those patients are also a little more robust, and we may have the possibility to dose even higher. It's something we're exploring, which is why we have a variety of dose cohorts, but it'll obviously be data dependent. Anything you want to add to that, Debbie? Yeah, I think the other exciting piece is that we have pharmacodynamic modeling that we've been able to build on and will continue to build on, and that will really inform where we go. Thank you. Yes. Thanks for the questions, Jack. Our next question comes from Sean McCutcheon at Raymond James. Please go ahead, Sean. Hi, guys. Thanks for the question. I'll echo everyone else in thanking you for the robust overview here. Touching on maybe a point that Oliver touched on briefly, but maybe contextualizing the hyperglycemia signal and what we'll see in the update later this year, can you speak to the metabolic disposition of specifically endometrioid endometrial cancer patients, the risk factors for metabolic dysfunction, and how this compares to other tumor types, particularly breast cancer? Are there meaningful differences between earlier stage endometrial cancer and advanced stage endometrial cancer to this end? Thanks. Thanks, Sean. Great question, and I think it's an important point that maybe people are not aware of, is that endometrial cancer, 90% of the patients are obese, pre-diabetic, or diabetic. These are the exact prognostic risk factors that typically lead to greater incidence and severity of hyperglycemia. A great paper published by Dr. Marcus and Komal Jhaveri a few years ago. I think that endometrial cancer and the patients we're enrolling in that study as a result of the prevalence of these diseases in endometrial cancer, really provide a very difficult set of test subjects, particularly as it relates to hyperglycemia. If we show tolerability within that population, particularly as it relates to hyperglycemia, I feel very confident in the translatability of the hyperglycemia data to breast. Anything you want to add to that, Debbie? I think you've said it well. I think that the question, Sean, you're asking about earlier grade or later grade, I think metastatic disease is basically a train without brakes running downhill. So at every progression, you see a worse picture. But again, I think we will get a lot of evidence from the heavily pretreated population we're testing, which will give us a lot of confidence to go forward in breast, where patients have a range and are a little bit less heavily treated. Understood. Thanks, guys. Thanks for the question, Sean. Our next question comes from Jay Olson at Oppenheimer. Please go ahead, Jay. Oh, hey. Thank you for providing this super educational event. Really appreciate all the details. After Topo I ADC treatment, is the PAM pathway further activated? Is that a resistance mechanism to Topo I ADCs? Would it make sense to combine an ADC with PIKTOR? Eventually, could the combination of a Topo I ADC with PIKTOR become the standard of care in first-line endometrial cancer? It's a great question, Jay, and something we're absolutely exploring. We do know that the PI3K pathway is upregulated in a variety of different treatment resistance contexts, including CDK4/6, paclitaxel. We've published on some of this. It remains to be seen with Topo I. That is work that's ongoing, and we're excited to talk about that when the time is right and the work is done. We think that if we are able to pair with paclitaxel, and assuming that we don't see any sort of negative interaction with an ADC, that in the future, a first-line regimen that pairs ADC plus PIKTOR would make a lot of logical sense across a variety of different gynecologic cancers. Oliver, anything you want to add on the resistance mechanisms? No, just to echo, as you've said, the PI3K pathway is engaged across a very broad set of different drug resistance mechanisms. Be it efflux, DNA damage, you name it. As Anand says, the work's ongoing, but as a general principle, PAM is really central to multiple mechanisms of drug resistance. Great. Super helpful. Thank you. Thanks, Jay. Yes, thanks for the questions, Jay. Our next question comes from Gil Blum at Needham. Please go ahead, Gil. Good morning, everyone. Can you hear me? Yes. I'd like to add my thanks for the comprehensive presentation. Maybe just looking back at one of the slides that was presented, showing comparison of the different PI3K inhibitors and how that relates to low-grade hyperglycemia. How meaningful is low-grade hyperglycemia when you think of a target product profile? Thank you. Yeah. Gil, thanks, and our comprehensiveness, I'm not going to take as code word for boring, but I appreciate it. Hyperglycemia generally is incredibly important, particularly as we think about the TPP for patients. I think what people fail to realize when you look at hyperglycemia as just a number on a page, you don't realize what it means for the 85% of patients that are receiving treatment in a community setting, particularly breast cancer as well. If you're seeing 40% hyperglycemia, regardless of grade, it's often going to mean that these patients have an additional visit to a doctor that is not their primary oncologist. It's another day at another doctor's office to manage that hyperglycemia and make sure there's a plan in place. If you can lower those rates of all grade hyperglycemia, it reduces a significant burden on the patient and the medical system more generally. I think those rates of hyperglycemia matter. The lower the grade, the better, right? That's just the reality for both patients, physicians, and the medical system writ large. Hopefully that's helpful, Gil. Yes. Thank you. Thank you. Thanks for the question, Gil. Our next question comes from Jeet Mukherjee at BTIG. Please go ahead, Jeet. Hey, good morning, everyone. Thanks for taking the question and thanks again for putting on this really great event. One question we continue to get is around the difference a pan PI3K-directed agent such as gedatolisib might have in terms of anti-tumor activity versus a PI3 alpha targeted approach with PIKTOR. Can you just remind us what data you have or that you may plan to show that addresses this point? Thank you. Yeah. Thanks, Jeet, for the question. This clinical race has been evaluated, right? The history of PI3K kinase inhibition has looked at both pan PI3K kinase inhibitors and alpha-selective inhibitors. At least in solid tumors, alpha-selective inhibitors were overwhelmingly seen to have the right mix of efficacy and tolerability. There are some biological edge cases where we see that PI3K beta may be upregulated, particularly within the context of PTEN loss. But given that we've shown data with complete responses in patients with PTEN loss, we feel like having the downstream inhibition of TORC1/2 inhibition really solves that conundrum that may have arisen if you're only looking at PI3K as the node you're targeting. Net, we feel like downstream inhibition of TORC1/2 really addresses any potential edge cases of wanting to inhibit PI3K beta, gamma, or delta. And we feel like there are more downsides associated with inhibiting those isoforms, given the expression of those in immune cells. Oliver, Marcus, anything I missed or you want to add? Nothing to add. Okay, great. Thanks again. Thank you. Thanks for the question, Jeet. Our next question comes from Silvan Turkcan at Citizens. Please go ahead, Silvan. Yeah, thank you. Thanks for this great event. Thanks for taking my question. I just have a question. Maybe will this first data cut in endometrial be enough for us to get an idea which mutation or patients with differential mutations, for example, PTEN, PIK3CA, mTOR, could have differential efficacy, and what would that mean for breast cancer? Thanks. Yeah, thanks, Silvan. Great question. Given that 85% of endometrial patients do have mutations in the PAM pathway, obviously, an overwhelming number of folks, in fact, all the folks in our study, will have mutations along this pathway. I think when we look to breast cancer, where there is a little more prevalence of plain vanilla PIK3CA mutations, we'll look at the various mutational subtypes across the PIK-201 study to evaluate any differential response. But we think that in many ways, as Oliver mentioned earlier, the molecular subtypes of endometrial cancer are a tougher patient population because of the multiple co-occurring mutations. So I think we'll see what we need to from this study in order to move forward into breast cancer with confidence that we can address the broad spectrum of mutations there. Thanks. Thanks. Thank you for the question, Silvan. Our next question comes from Boris Peaker at JonesTrading. Please go ahead, Boris. Boris, you might be on mute. Yeah, sorry about that. Thanks for the great overview. Just wanted a regulatory question. Have you discussed contribution of components in PIKTOR with the FDA? Just curious if the agency will want to see potentially efficacy of the individual component going into PIKTOR. Also kind of part of that is how can you be confident that your dose ranging is sufficient to satisfy Project Optimus, again, given the fact that you have a combination product? Yeah, it's a great question and something that we're absolutely discussing internally and will discuss with the FDA. I don't want to speculate until we've had those conversations. As we've mentioned historically, we will need to answer contribution of components, likely for serabelisib plus paclitaxel. The contours of what that will look like will be discussed with the FDA at an upcoming meeting, then we'll share more with you once we have clarity on that. Anything you want t o add, Debbie? No, just that we are having the right conversations and are thinking exactly about those key things. If you want to roll in regulatory, give us a call. Great. Thanks. Thanks, Boris. Thanks for the question, Boris. Our next question comes from Luis Santos at H.C. Wainwright. Please go ahead, Luis. Hi. Good morning. This is Luis in for Patrick. Thanks for this absolutely not boring presentation, Anand. This is a great overview. I think many questions have been asked about the PAM alterations and molecular subtype of the patients that you're targeting. Of course, we're optimistic that your new interval and treatment break approach and dose selection will treat most of the patient population. Is there anything from phase Ib that can tell you what proportion of patients is expected to achieve that pharmacologically active exposure and what evidence supports the antitumor activity through patients who already went through other treatments, checkpoint inhibitors, taxane-free intervals? Yeah, thanks, Luis. Great question. In terms of prior activity with patients who have received prior taxane or IO, in our phase Ib, we did have patients who were previously taxane exposed, particularly in the endometrial cohort, but also the ovarian cohort. Four out of five of the endometrial patients were previously taxane exposed, and two out of the five endometrial had prior IO exposure. We have seen some prior evidence of PIKTOR activity in the context of patients who have had exposure to both of those treatment regimens. In terms of dose selection, as we mentioned, PK/PD analysis that we've done from data that was generated by Takeda in human skin punch biopsies gives us confidence that the 200 mg, 3 mg dose is an active dose, and makes sense. In addition, that was the dose that was selected as a result of the dose finding in the phase Ib. Those two things kind of triangulate in this case. Yeah. Anything you want to add, Oliver or Debbie? No, nothing from me. Great. Thank you for the question, Luis. Our final question comes from Dev Prasad at Lucid Capital Markets. Please go ahead, Dev. Hi. Thanks for taking our question, and thanks for putting this event together. We see that PIKTOR stays above IC90 for roughly three and a half days, and then we have four days off. Are there any tumor or surrogate data showing what happened to pathway signaling during the off-days and whether this can affect duration of response or PFS in the ongoing PIK-201 trial? Thank you. Yeah, great question, Dev. I think that was a question for the field, so to speak, until the gedatolisib data. The gedatolisib data has demonstrated convincingly, in a context of a randomized phase III, that pulsatile dosing with an on/off fashion can indeed generate successful PFS in a registrational study. What we are saying is that within the context of that pulsatile dosing, that our greater exposure and durability should translate, hopefully, to solid efficacy as well. We've seen that not only within the context of gedatolisib with a multi-node dosing or a multi-node approach, but also capivasertib, which has a four on, three off approach. It's now well-validated within this pan pathway with two separate approvals. Anything else you want to add, Oliver, Debbie? No, I think that covers it. I think you would expect pathway inhibition to be less on those days off, of course. That's the whole point of the pulsatile dosing. The clinical data, it's really clear that you can maintain efficacy with that pulsatile system. Yeah, I would just add that actually all therapy is intermittent if you think about it. Healthy cells recover much faster than cancer cells because they're addicted to certain pathways, so they don't have the resilience that the healthy cells have. It usually works quite well, as we've seen with geda and capi, et cetera. Great. Thank you. Great. Thank you for the question, Dev Prasad. This concludes today's Q&A session and the overall event. We thank everyone for joining, and you may now disconnect.