Thanks, everyone, for continuing to join us here at Stifel Healthcare Conference 2025. It is my pleasure to introduce Nick Saccomanno, CEO of OnKure. Thanks very much. Thanks to the organizers of the conference for inviting us here to speak about progress at OnKure. Thank you for all those who are joining by video link. I know some of the employees at OnKure are listening to this as well. I welcome them all to the conversation. Can we go to the next? Oh, I do that? Okay. At OnKure, for the last several years, we've been targeting PI3K alpha, immune PI3K alpha, in the context of cancers. More recently, there's an expanding set of opportunities for molecules for good medicines, good potential medicines, in this area. Let's point out that sort of uncontrolled PI3K signaling is at the heart of, we'd say, well, it's the most frequently mutated gene in cancer. It is the same proliferative behavior that is also found to drive disorders like vascular malformations. The existing PI3K inhibitors, certainly the ones that are marketed, suffer from lack of selectivity. That is to say, selectivity for a mutant protein over the wild-type protein is insufficient to be able to drive efficacy without tolerability issues. We are developing a portfolio of molecules that target selectively the mutations and do so with enough selectivity such that they would be able to drive optimal efficacy without driving unacceptable dose-limiting, therapy-limiting side effects. Our path forward really has been focused on breast cancers and also other PI3K-driven cancers. More recently, we recognize the expanding and very nascent opportunity in vascular malformations. Certainly, we could talk about those diseases at length, but suffice to say that selective molecules used in this type of non-life-threatening but chronic disorders could represent a real step forward clinically and a significant commercial opportunity. This is the group. I would point out that a lot of the individuals that are at OnKure right now followed us over there from the once Array BioPharma. And so this is a team of researchers that have discovered and developed two dozen kinase inhibitors and really do understand how to make good medicines here. So the portfolio at a high level currently right now is OKI-219. We'll talk a little bit more about that. That's an H1047R highly selective inhibitor that's moving forward in what we call the PIKture-01 study. Dose escalation has been completed and follow-up is ongoing for monotherapy as well as a doublet study in combination with fulvestrant. More recently, we have started triplet studies in the frontline or earlier lines in positive breast cancer as well as HER2-positive breast cancer. We recognize that H1047R is only a portion of the treatable patient population. We did recognize that our molecules, if engineered the right way, could be pan-mutant selective. We'll say a little bit more about that because, again, selectivity is probably the most important differentiating attribute for these molecules. A pan-mutant selective, that is to say, will block all of the hotspot mutations found in PI3K alpha, be that in cancer or be that in vascular malformations. Those molecules are nearing nomination right now. One would expect to see molecules move through and to the end of preclinical development in 2026. We also recognize that the other hotspot mutation, E542K, known more commonly as a helical domain mutation, also requires a highly selective drug. Certainly, in a balanced portfolio, we believe it does. OnKure has discovered, in fact, a new allosteric binding site more proximal to these mutations and is working in an early discovery program to drug that allosteric site as well. While this histogram to the right, while breast cancer does represent a significant portion of the PI3K alpha mutated cancer population with the relative distribution across hotspot mutations given color-coded here, I would also want to point out that there's a substantial population of other tumors that are the indication. While it is the focus of OnKure right now to move our molecules forward in the context of breast cancer, we also want to remind ourselves and others that there's a significant opportunity in other solid tumors, perhaps the most notably colon, lung, endometrial, cervical, ovarian, and others as well. Certainly, that may be a topic of development for us in the future. Currently, as I said, we are focused on the breast cancer opportunity. The ribbon diagram, certainly familiar to us, but it's noted here. On the left-hand side, we've marked what would be considered the four pharmacologically relevant binding sites. The green site, the PI3K alpha H1047R site, that's where our molecule OKI-219 has its effect as well as other molecules like the Synovation and Cogen molecule and also our pan-mutant selective molecules bind to that site and control the activity of PI3K alpha. The red site is the ATP binding site. Alpelisib and Avlisa bind there. The purple site, the colors are not relevant in the context of proteins. We're just using that as a formalism here. The purple site is the allosteric site that's marked by RLY-2608, Scorpion 478, and so forth. Then the blue site is, in fact, it sort of denotes the other allosteric binding site that we're currently working on. This is something just known to us. On the right hand, in the right-hand table, please note, again, these are very important numbers. We won't be exhaustive about them all. Just to note, if you look at selectivity of 1047R inhibition over wild-type, Alpelisib is non-selective. Scorpion, this is their own disclosure, 8.8. RLY-2608, 3.8. OKI-219, 80-fold and above, providing us a clear margin to be able to crush the mutant target without having any effect on wild-type. I do want to point out that these molecules, as they progress, certainly in breast cancer, are going to be used in the context of combinations. Combination therapy is going to define both certainly second and first-line therapies. The molecules to which you would be combining are well known to all of us, HER2-positive types of agents like ADCs and inhibitors, CDKs of various sorts, CDK4, 6, CDK4 selective molecules, as well as the CERMs and the SERDs and the aromatase inhibitors. All of these will represent components of what will very likely be doublets and triplets that will be used in the second and the first line, respectively, with time. This is really very important. As you pick molecules to develop, they not only need to be effective, but they need to combine in a non-disruptive way with other molecules which are found in that regimen. At the end of the day, it's going to be what's the winning regimen more so than what is the winning compound. The market size, just I want to point out the market size or the treatable patient population size for H1047R specific mutations in the context of breast cancer, this is a significant opportunity. In the adjuvant setting, these would be patients that have failed prior lines of CDK and aromatase inhibitor, 25,000 patients in the first line. What's approved there right now is Inavolisib, Palbociclib, and Fulvestrant as a combination, 9,000 patients. OKI-219 has the potential to move into both of these treatable patient populations. We are certainly prioritizing the development of 219 in this exact space. This just makes the point again. There are a number of development opportunities for OKI-219. More recently, in the last quarter, we have begun triplet studies that would put OKI-219 in positive breast cancer with ribociclib and fulvestrant, or in a HER2-positive setting with trastuzumab as well as tucatinib. Both of these studies are ongoing and enrolling. We would hope in the very near future we would have enough patient data to be able to assert combinability, tolerability, PK, lack of DDI, and early efficacy. We do believe that is the data set needed to provide the credentials for a regimen to become potentially an important frontline combination. I will go very briefly through this because I have shown these slides in the past. We at OnKure really do set a very high bar for the types of molecules we put into development. Certainly, any molecule which is moving forward in PI3K alpha needs to have the attributes going from left to right: selectivity, efficacy, brain penetration, safety, combinability, and also the opportunity to at least understand or, in fact, not understand, overcome resistance. On this slide, some interesting data, again, going clockwise, efficacy in translatable models. You could see that the dark purple line at the bottom is, in fact, OKI-219, and leads to eradication of tumors at very well-tolerated doses. The molecule is highly brain penetrant with a Kpu of 0.6. The safety profile, certainly with respect to any of the molecules, is very high on target toxicity that is seen as hyperglycemia, increases in insulin. Does not happen with 219, certainly with the competition. It does at efficacious doses. This is now the upper right-hand corner. Our drug is in preclinical models, highly combinable. In this particular, while we have a lot of data in this particular set, it's ribociclib plus fulvestrant. You can see that the bottom green line where there's near eradication of tumors is a combination of 219, fulvestrant, plus ribociclib. For the sake of time, I'll move on. The PIKture-01 trial design is shown here. We've completed enrolling monotherapy study at, of course, we went through 3, 6, 9, 1200, and 1500. Now we've backfilled, and we're just running that study out with follow-up. Again, as I said before, we'll be reporting out on data in the first quarter. The subsequent studies, the combination studies, which are all ongoing right now, is OKI-219 plus fulvestrant. We enrolled 36 patients in that study and currently have patients on that we're following forward. We will have a more mature and communicatable data set for that doublet study, again, in the first quarter of 2026. The two doublet studies in part C and E, as I have said before, OKI-219 in the HER2-positive setting plus trastuzumab and tucatinib, both received from Pfizer. That is moving forward and recruiting. A study that is recruiting rather well is OKI-219 plus ribociclib plus fulvestrant in positive breast cancer patients. In these particular studies, they are being recruited in such a way that it will provide a comparable data set, prior lines of therapy, similar inclusion criteria, exclusion criteria that allow us to get a good sense of the value of OKI-219 in these very important triplet settings, which again would define a second line and first line metastatic setting for HER2-positive and positive breast cancer, respectively. Again, data for these triplet studies that would read on to tolerability, combinability, lack of DDI, as well as early efficacy should be forthcoming in the first quarter of 2026. We've shown this PK slide before, and this is a year old now. I do want to point out that this profile is really quite beneficial. Certainly, EC80, we're above the EC80 mark, which tends to be a definition of the concentration needed for near optimal efficacy. We're over that for a predominance of the dosing interval. I do want to point out that we get above EC90 for a third to a half of the dosing interval. We hope to optimize further on the drug exposure profile, which tablets have been introduced into the triplet studies. Tablets not only can improve performance, reduce variability, but also are much more cost-effective and faster when moving a molecule into advanced registrational studies. Good dose proportionality, good exposure. On top of that, really, and we'll be reporting, of course, a lot more on the safety of this molecule, given that it is one of the distinguishing features. As you can see, nothing really notable, certainly from this data cut, this is nearly a year ago now, nothing more than grade 1 at any dose level. Again, we'll report out. One has to recognize that this is the distinguishing feature: good target coverage, great selectivity, great tolerability. The data that we'll be reporting on the first quarter will also provide a sense of combinability in important lines of therapy in positive as well as HER2-positive breast cancer. Again, a very early read. This is just the monotherapy study. Again, we'll be updating this with time, certainly in the first quarter. Again, we'll also be reporting out on a much more substantial data set looking at ctDNA as a measure of target engagement and activity. Just in a snapshot, the trial update, I think I've said most of this: 37 patients on monotherapy. Last patient was dosed in September. 34 patients in a doublet with fulvestrant. The last patient was dosed in July to provide a significant amount of follow-up as we report out in the first quarter of 2026. Last patient's dosed as given here. Again, we've initiated the triplet studies: 219 with ribociclib and fulvestrant in HR positive. Right now, we're focusing on 6 and 900. Certainly, we have some thinking to do about exactly what the expansion dose would be when we take this triplet into an expansion study in this population. Again, of course, the same thing holds for OKI-219 plus Tucatinib and Trastuzumab in the HER2-positive setting. This is a point that I just want to stress again. These molecules are going to help patients and make money in combination. Details matter. It is not just, "Oh, I can combine with that class." It is more specific. I can combine with this drug in this patient population. We often get asked, "What do pharma want to see from your drug?" Uniformly, it is the same thing. I want to know that you can combine with my regimen at my pre-established dose. Molecules are not really going to move that far in the PI3K space and spread that unless one can make an argument for or show that you are combinable with one or more of the CDKs, that you could be put in a regimen with the SERDs, or in the HER2-positive setting that you are combinable with the agent shown in the upper right-hand corner. This is something we factor into selection of candidates as well as how we factor it into the types of clinical trials we run. We want to prove that we can put our compound in combination with, in a well-tolerated manner, and add on to the efficacy of others. We see a lot of molecules right now having a hard time combining with Ribo or being put in combination with some of the novel SERDs. This is something that we want to avoid. We do research, and we do development to answer that question sooner rather than later and to design our studies and pick our molecules. That takes me to the end here. Currently, as of the 30th of September, $70 million cash and cash equivalents. The rest of the information is given here. I'd be happy to answer any questions about OKI-219, about our pan-immunoselective molecules coming forward. Something which I did not spend a lot of time talking about is the very interesting, compelling opportunity for these molecules, especially well-tolerated molecules like OnKure's, to move into vascular anomalies, whether it is vascular malformations, microcystic, lymphatic, or PROS. A really compelling opportunity. A lot of patients, even though it's given as a rare disease, and a terrific opportunity, especially for, like I said before, molecules with the type of selectivity and tolerability that we believe our molecules have and clearly we're proving it for 219. With that, I think I've said all of this. I'm happy to take any questions about OKI-219, NextGen, or the vascular malformation opportunity. Yeah. Thanks so much for that presentation. A few questions for me. You have pipeline assets that are selective for the H1047R mutation and E542K mutations and also pan-mutant approach that you have all emerging. Help us understand your thinking around having all these programs. What is the overarching strategy and vision and your foresight for future trial development? Given the amount of time that we spend in the industry, we recognize that molecules sometimes die and that approaches sometimes do not prove themselves. In a balanced, risk-adjusted manner, we see OKI-219 as a molecule that can go all the way, have a significant commercial opportunity. It does not seem to be any problems necessarily in front of us. With respect to obtaining a broader market, fighting off the competition, having a more optimal molecule, we also see a place for using capital to bring the pan-mutant selective forward. While I would love to say, "Oh, you know at this specific time, we are going to upselect this and downselect this," now is not the right time to do that. We are going to let data tell us, "Is 219, can 219 be an important medicine in breast cancer? If it can, it should go forward. Can it be an important medicine in the context of vascular malformations? We're going to let data speak for that. What is going to be the right way to sort of pile on the pan-mutant selectives across the patch? These data are going to be forthcoming in the next several quarters. They do not put an enormous burden on our balance sheet. We want to make the right decisions. We are going to do it based on we do not want to create a portfolio with a lot of redundant, sort of irrelevant molecules. We will be clear about what the criteria are for keeping molecules moving forward and how we make selections between them. It does appear that your trial development will allow prior exposure to PI3K inhibitors, if I remember correctly. Yep. How important is data generation in that particular population in the context of your competitive narrative and future competitive positioning? What should investors be looking for in the context of post-PI3K inhibitor activity from the OnKure molecule? I'm glad. I would glad. I would have asked myself that question in front of everybody. The number of prior lines, as well as the types of prior lines and what was the most proximal prior line, seems to be, especially in this area, and the data will prove itself, seems to be an important determinant of activity. The most important thing to do is to understand what population you're likely to have an effect and develop around that. Looking at other people's data and our own, we think we have a very good sense of exactly what the inclusion and exclusion criteria should be. We'll be talking about that as our data comes to a pass. Not only for making cross-trial comparisons, but also when thinking about your registrational study design, taking into account prior PI3K alpha, prior CDK, prior chemotherapy, prior ADC are all going to be very important determinants, we believe, of success in the clinic. Strategically, you still have to be thinking you also have to be thinking into the future about how are selective CDK4s going to be used? Are they going to be used with fulvestrant or aromatase inhibitor? And shouldn't that be the combination that you're focusing in on? The data are all coming out. The right studies are being run. If you pay attention, you should be able to find that map that takes you to include these patients, exclude these patients, focus on these markers. We think we understand that as it's emerging. Again, we'll fold that into our strategy. I hope that answered your question. It does. I see that on the selectivity window on HR mutations, you seem to have a wide therapeutic index potential. What should we be looking at in your first disclosure of clinical data to see early signals of clinical materiality of higher selectivity window translating over in clinical data? Yes. With the higher selectivity. When will we be able to assess that? Yeah. I mean, that's going to come more in the form of what kind of target coverage can I keep? What kind of engagement can I keep without leading to discontinuations and dose reductions? Because you do see that as sort of a chronic issue with any of these molecules coming forward. I would like to state that there is a selectivity bar that you need to be above in order to inhibit the target without side effects. I think people really have to focus on that, necessarily on that detail. If one goes back and just does the math, simple clinical pharmacology, Hill's Law of One, you can come to the conclusion very rapidly that in the absence of a 10x selectivity, you're not going to be able to translate your exposures into optimal efficacy because you're being hemmed in by dose reductions and tolerability issues. Now, when you look at the molecules that are out there, I'd say most of the competitors don't have that 10x threshold. And you've beaten it by a fold. I would say that, again, it's just textbook math. You just take it through and say, if I need to stay below 20%-30% inhibition of wild type, and I need to be above 80% inhibition of mutant, then that's going to be inhibition which comports well with what we understand for clinical compounds. If you don't exceed those thresholds, then you could expect to have to change the way you're dosing your molecule because of toxicity. It looks like we've had an initial look at your PK data from three doses, if I remember right. Will we be updating your PK curve? Yes. From IRMAP? Yes. Very much so. Our PK curve certainly will have additional calculations of how you do it, a lot more patients, a lot more time on therapy. We are excited, as well, about what a tablet introduction will do, more than just saving us a lot of money and time, what a tablet introduction will do to performance as well as variability. Do you expect to see a level of curve stacking with the tablet formulation for higher doses in a way that they're not kind of coming close together? Yeah, I could go back to that slide. You have to note that's a log scale, and those are 95% confidence intervals, which you know what that is. Undoubtedly, those begin. If you look at that from an AUC point of view, they remain reasonably dose proportional. AUC, steady state, you look at those lines, you look at the numbers, and they are dose proportional. Will we see a compression of exposure at 1,200 and 1,500? That's yet to be determined. That's yet to be disclosed. What I would say is, though, when you look at 900, and for a significant portion of the dosing interval, you're above EC90. Competitive agents do not really have the opportunity to go there without running into toxicity. I think we're happy with where our PK is, and we don't have to be hopeful. We do expect to be some kind of certainly improvement in efficiency in tablet introduction. What data do you plan to share at this readout in the first quarter for the single-arm and the full-fledged double-ed? We're just trying to understand how material this update is, what conclusions we can draw about its competitive dynamics versus. Yeah. Monotherapy, single-arm study, basket, do you engage the target? Can the patients tolerate it? That is what you can get from monotherapy. From a double-ed study, provided that you have a substantially overlapping population with competitors or agents, you could do cross-trial comparison. We would hope to be able to do that. If you look at the Relay data, Scorpion data, and Inavolisib, and so on and so forth, we will look for a subset analysis that will give us a clear sense of how we are doing in an absolute and relative sense with respect to the competition. That is what you want to see from there. You want to see, are you producing a similar effect in a similar population with better tolerability? That is what we would hope to show. For the triplets, again, I think I have already said it. Of course, the studies have just started. We would hope that we'd have a data set to be able to say something about tolerability, combinability, and early efficacy. Those three, again, the questions that Pharma asks about our drugs as they think about a place for them in the regimens they're going to be commercializing. That makes sense. If you wouldn't mind going back to some of those data slides very quickly, when you talk about cross-trial comparison for efficacy, that one, are we essentially just seeing an updated version of this slide? Oh, sure. Absolutely. I'm just trying to figure out what are the main endpoints you're going to read out. It sounds like this is going to be one of the updates. I mean, there'll be swimmers plots for monomer monotherapy as well as double-ed data. There'll be waterfall plots for monomer, PK plots for all these, as well as a robust safety update, both treatment emergent and treatment related for these studies. Again, you come out with a full data set, you could tell a full story. That's what we'll be doing. OK. Essentially, what this is trying to communicate is with more mild safety data, you would hopefully see more impressive monomer block spot data that then relates to a better stable disease progression on this drug. Yeah. I think I got what you said. I think that all lines up. Again, if we show similar efficacy in an analysis between our drugs and others, and we see an improved compliance, better tolerability, then one, if one just looks historically, that would predict a better outcome in a full blinded phase III study. Right? Yep. OK. If I could ask a follow-up. On the efficacy side of competitive benchmarking, will you be able to provide a Kaplan-Meier estimated median PFS? Or is that going to be something that investors will have to derive from your swim lane plot? Yeah. We'll give a sense of where we think median PFS is headed. Again, you have to look at the data. You have to look at how long the patient's been on. I mean, you have to see how many have been censored, where your analysis is. You have to be responsible about the kind of data. With respect to DCR as well as CBR, we should be getting close to giving a sense, is the progression free a month? Is it seven months? Certainly, we'll be able to hone in on that. We'll have enough follow-up on enough patients to be able to give people a sense of that. How would you like to set expectations around the numeric ORR? I wouldn't. But I did three times right here. What was it? I said was that there are benchmarks from a similar group in the Relay study, in the Scorpion study, in the Alpelisib studies to be able to say, in a cross-trial comparison, in a similar population, again, what's the prior lines, which prior lines, and the like, how are we performing with respect to them? That's what we've always hoped to get out of our trials. That's how we've designed our trials. That will give us the information to decide on how we're going to take the molecule forward. Does that get to it? Yeah. So I take it consistent with historical ORR benchmarks would be a positive, in your opinion, or would you be looking at? I think we could just at a very, very high level is that if you were to say, think about triplets in the front line, like in EVO-120. Think about some of the double-ed studies. If we could have similar or slightly better efficacy with a clearly better side effect profile and predictable combinability to move into other companies, then you've got a winning drug in our view, and I think in anybody's view. All right. Thank you so much. Just 26 seconds. Any questions from familiar faces in the back? No questions. OK. Thank you very much. All right. Have a nice day.