OnKure Therapeutics, Inc. Class A Common Stock 0 Earnings Call

Reminder, this call is being recorded and a replay will be made available on the OnKure website following the conclusion of the event. I'd now like to turn the call over to Nick Saccomano, President and Chief Executive Officer at OnKure Therapeutics. Please go ahead, Nick. Thank you, Tara.

Indeed, this is an OnKure Therapeutics broadcast. The topic of today's discourse is Selectivity Matters and pan-mutant Allosteric Inhibition Delivers. We'll discuss selectivity and allosteric inhibition from a deeply scientific point of view, to give all of you a sense of how we designed and advanced our molecules. Today's presentation and discussion will be enabled by two of our KOLs, as well as a number of slides. Be warned, I suppose that there are forward-looking statements during this presentation, and we ask all to note that accordingly. I'll start off with some brief introductory remarks about where we are at OnKure in our portfolio, and then the conversation will be extended by Professor Ben Cravatt and Dr. Robert Abraham, and then I'll close.

By way of introduction of these two individuals, if you don't already know them, which I suppose you do, Ben Cravatt is a professor at Scripps Research. He is the inventor of several chemical technologies that have enabled a deeper look into chemical biology, and that work in total not only has advanced our understanding, but also led to the instigation of some important biotech companies. Benjamin, thank you. Ben, thank you for joining us today. Bob Abraham, say no more than 11 FDA-approved oncology drugs, as well as he was there at the beginning of the field of scientific inquiry that looked deeply into PI3Kα as an important signaling mechanism, both in health as well as disease. Welcome, Bob. We believe that we're developing a differentiated portfolio. We have pan-mutant selective inhibitors that we've developed and are now moving into development.

We have two distinct candidates that have been individually designed to meet the needs of patients that are afflicted with vascular anomalies, as well as a molecule which will uniquely move into cancer clinical trials. We have an experienced research team here, and a sort of an Array 2.0 company. We fully intend to advance our portfolios both in cancer as well as vascular anomalies. The two main molecules go by the numbers OKI-355, moving into vascular anomalies, and OKI-345. These molecules were selected specifically for these indications. We believe they have best-in-class drug properties. We have guided towards INDs in the first half of 2027. We are looking more closely at additional therapeutic opportunities that will help treat the conditions and progression of vascular anomalies. Those are embedded in our discovery programs. A conversation for a subsequent day.

The PI3K pathway is pleiotropic in every sense. It serves important roles both in normal biology as well as in disease signaling and progression. In wild type activities, certainly it helps with the survival, proliferation, stabilization, glucose homeostasis. It is there at many physiological and biological crossroads. If mutated into an activated state, it provides the cells within which it's mutated a survival advantage, a proliferation advantage, as well as a metabolic advantage. In the context of genomically stable cells that are seen in vascular anomalies, it leads to over cell proliferation, which eventually lead to vascular anomalies. OKI-355 will meet the challenge that those patients face. In cancer, as you imagine, in a genetically unstable background, it leads to cell proliferation, metastasis, as well as resistance. Again, our molecule, OKI-345, will move forward into that space.

Bob Abraham, who's spent a lot of his time thinking about this, will have additional comments. Simply, a simple portfolio at this point, but we believe differentiated. OKI-355 moving forward into vascular anomalies, a distinct molecule, OKI-345, moving forward in breast cancer as well as other cancers. As I mentioned earlier, that we are building a discovery portfolio with some depth, which will meet some of the additional therapeutic challenges seen with vascular anomalies. On the right-hand side, as I've indicated, the guidance thus far, INDs for both of these molecules in the first half of 2027. A brief and very high-level snapshot of where these molecules are and how they perform is given here. In the table on the right-hand side are given the selectivities of our molecules at inhibiting the important hotspot mutations, 1047, 545, and 542.

Given here for 345 and 355, the numbers as indicated, 58, 18, 10, 106, 24. In in-house studies in studying important molecules considered competition, you can see the selectivity marks that we believe these molecules have. Selectivity is critical in the sense that you want to smother signaling, which is instigated by the mutant protein, while sparing, if not entirely laying off any inhibition of wild type. Again, wild type PI3K alpha is found in every cell and controls a number of important processes. Interruption of those leads to significant and predictable side effects. In addition to selectivity, I'm on the left-hand side now, efficacy in preclinical models, safety as predicted by preclinical assays, target coverage. Combinability is going to be very important in any therapeutic area, given that these drugs will be combined with other standard of care, as well as compounds right now in development.

Paying attention to mutation resistance is something that we're studying as well. Comments at that on a later date. We have a great IP estate, that all flows into two candidates that we view as best-in-class entries into this very competitive area. I'm going to hand it off to Ben Cravatt now, who's going to teach us and talk to us about the importance of allosteric inhibition in the context of biology as well as pharmaceutics. Ben? Thanks, Nick. It's a pleasure to be here with you today.

Just a little bit of background on what our lab does. We develop large-scale chemical proteomic methods that allow us to look at how small molecules bind proteins in cells. Through those efforts, we've begun to appreciate the broad opportunity for what one would call cryptic small molecule binding pocket discovery in the proteome. Small molecule binding pockets that are not maybe represented in the classical crystal structure of a protein, but are revealed through protein motions that small molecules can bind to regulate proteins allosterically or non-orthosterically. This slide is intended to convey the potential value of such allosteric small molecule binding events on proteins. I think we all like to look at protein structures. It's a fun way to understand biochemistry.

I think over the years, we've also come to appreciate that many proteins operate through dynamics and conformational state interchanges. From a druggability perspective, every one of those distinct conformations that a protein goes through as part of its function may present unique pockets for small molecule binding. You might even argue by extension, and I think our lab's proteomic data to some degree support this, that the more conformationally dynamic a protein is, the more druggable it can be, because every conformational state it enters into is a new opportunity for finding a cryptic druggable pocket. Now, we'd like those pockets, if they're druggable, to confer a functional outcome. As described on the desirable properties part of this slide, that functional outcome can come from a couple different mechanisms.

The small molecule can bind a cryptic pocket, induce a structural change in the protein to confer inhibition or activation, that's referred to as sort of a classical induced fit model, or it can trap a protein in one of its many conformational states, leading to a stabilization of a protein in an inactive or activated form. My sense, and I think the community sense over the years is the latter model is probably the more frequent by which allostery operates. In other words, a protein has multiple dynamic states, and you conformationally select one of those out with a small molecule. Those states oftentimes are not visible in the traditional orthosteric state of the protein.

The outcomes that we'd like to have here, described on the right are, the protein should in principle access that cryptic state that provides visibility or accessibility to the pocket with some frequency in the cell. Your ligand can bind. It can actually be pretty infrequent. It can be kinetically accessed rather infrequently. If the small molecule binds well enough, you can trap the protein and sink it into that rarer form. What's really interesting is that some of these cryptic pockets are themselves highly druggable. You could ask, "Well, if they're so druggable, why weren't they found so often in the past?" I think in many of those instances, it's because the non-orthosteric or allosteric pockets, while they may bind a small molecule, the functional outcome of that binding can vary tremendously.

We're aware of many examples of allosteric pockets where small changes to the chemistry can convert a ligand from one that activates to inactivates to even is silent. There's another layer of medicinal chemistry that I think OnKure has done a great job of on PI3 kinase to confer not only binding to these cryptic pockets, but also the desired functional outcomes. As we'll touch on in the next couple slides as well, most of these allosteric or non-orthosteric pockets tend to have a greater potential to be unique to a protein relative to an orthosteric active site, especially for proteins from large families such as the kinases. The kinases have been a particularly fruitful area for allosteric ligand or drug discovery for a few reasons.

One, the family itself is so large, several hundred members, that conventional active site inhibitor discovery is generally challenged with trying to create high selectivity inhibitors. It takes a tremendous amount of medicinal chemistry, and I would say in almost all cases, there are still typically off-target activities that one needs to grapple with. When these allosteric pockets emerge on kinases, they tend to be much more unique to that specific kinase and therefore confer greater selectivity potential. I think something that may not be as well appreciated is that anytime you target the active site of an enzyme, you have the potential to have to compete with the endogenous ligands that also bind that site. For kinases, this can be ATP, which is at a very high concentration in the cell. Any orthosteric or active site ligand will have to outcompete ATP at that binding pocket.

Most allosteric sites are able to circumvent this. They are not directly competing with an endogenous ligand, and that gives them high potency potential. A couple other advantages we see of allosteric pockets is the likelihood that they'll provide what we would call orthogonal resistance mechanisms is especially important for cancer. If you have an active site-directed inhibitor of a given kinase, and one can then discover a novel allosteric pocket on the protein, you have the opportunity and principle to drug the protein simultaneously, even at two different sites that each would confer its own resistance mechanisms, presenting a factorial challenge to the cancer to overcome that combination drug treatment.

Finally, I think it's fair to say that the pharmaceutical industry over the last 40 years has gotten incredibly good at drugging active sites of enzymes like kinases, and therefore that is a heavily mined area of science. I think looking at allosteric drug pockets across the proteome is in its early stages. There's a tremendous opportunity here for expanding the druggable proteome, if you will, through targeting allosteric sites. The key value drivers on the right, I think I've already covered. You can imagine that if you have orthogonal resistance mechanisms and drugs that can bind allosteric sites with greater selectivity, you have a great opportunity for best-in-class therapeutics. We wouldn't be talking about allostery today if PI3 kinase didn't present its own opportunities in this area. First in class, PI3 kinase inhibitors like alpelisib target the ATP binding pocket.

Again, this is a pocket that is conserved across all kinases. It has to compete with ATP. There are challenges with selectivity, not to mention the fact that it also targets the wild-type PI3 kinase. The cryptic allosteric pockets that OnKure is targeting not only give an opportunity to achieve greater selectivity across the kinome, but also within the various states of PI3 kinase itself, wild-type versus mutant. As Nick covered earlier, that is a major goal of OnKure, to essentially wipe out the mutant PI3 kinases, which may actually adopt these allosteric states to a greater frequency due to their intrinsic activation than the wild-type protein, giving a greater potential for allostery to selectively perturb the mutant kinases over the wild-type form. This is not all theoretical any longer, as many of you will know.

The development of asciminib is a great example of an allosteric kinase inhibitor targeting BCR-ABL for Philadelphia chromosome-related CML. I had the privilege of watching this drug from its infancy, because the mechanism was initially discovered at GNF across the street from me at Scripps by Nathanael Gray and others through a phenotypic screen. Then Novartis went forward to develop drugs against this myristoylation pocket on BCR-ABL, which is removed from the ATP binding pocket. Watching this drug perform in the clinic has been really exciting for several reasons. We are starting to see the greater selectivity that this myristoylation pocket can provide, as well as the lack of direct competition with ATP translate into profound efficacy in patients.

I think there is even more recent data suggesting that these allosteric myristoylation pocket inhibitors can even outperform orthosteric inhibitors of BCR-ABL in the clinic, perhaps due to some combination of a greater safety profile with efficacy emerging from being able to hit the kinase harder due to greater selectivity. I think this is going to be one of many allosteric kinase inhibitors that will emerge over the next couple of decades to provide compelling alternative treatments for patients. Finally, this last slide, just communicating that something I have learned over the years from seeing the kinase inhibitor field evolve in oncology is that the first drug that emerges is not always, and rarely actually, the best drug. Over time, as pointed out on the bottom of this slide, tremendous value for patients and for companies can be achieved by continuing to innovate against validated targets.

Some of this is iteratively improving the potency and selectivity of active site-directed inhibitors. ALK is a great example of that, as is EGFR, and including treating resistance mutants through that mechanism. I think this emergence of allosteric inhibitors as a complementary approach for next-generation kinase inhibitors with superior activity is very exciting. We saw that, as I mentioned, already play out for BCR-ABL, and now OnKure and other companies are trying to do the same thing for PI3 kinase. Now I am going to hand the baton off to Bob, who is one of the world's experts in PI3 kinase biochemistry and signaling, to give his perspective on this pathway and its potential. Bob? Thank you, Ben. Thank you for the opportunity to speak today.

By way of background, I've been involved directly or indirectly with this field since the late 1980s. We were interested in lipid kinases in the lab. That interest eventually drove us to be one of the groups that co-discovered a very important downstream component of the PI3 kinase pathway that we called mTOR. I'm sure most of you have heard of mTOR. In terms of the PI3 kinase pathway, Nick covered this in some detail, so I'll be very brief. A key note in the pathway is the enzyme AKT, which is attracted to the inner leaflet of the cell membrane by the accumulation of PIP3, I'll use that abbreviation for the day, which is the product of the PI3 kinase.

AKT, in turn, activates a number of downstream kinases, including mTOR, which drive cell proliferation, survival, stress resistance at the appropriate level of activity, stabilize the vasculature, and very importantly, mediate a number of aspects of cell metabolism, particularly anabolic metabolism, which is required for cells to convert metabolic building blocks into macromolecules that are needed to drive doubling in cell size, DNA replication, et cetera, that are needed during cell proliferation. Importantly, this pathway plays a really pivotal role in the regulation of glucose concentrations in the blood within a very narrow range. As Nick mentioned, this pathway is mutated in both cancer and syndromes that involve vascular anomalies. In the case of vascular anomalies in the middle panel, these mutations are called mosaic. That is, they occur in only a subset of the cells. The target cells for this syndrome are the endothelial cells.

This causes vascular overgrowth, resulting in these malformations. On the other hand, in cancer, the same mutations drive high-level proliferation or dysregulated proliferation, and also stress resistance, particularly resistance to other therapies. What I'm going to do next is provide you a brief timeline which describes a path to today, which is the interest in generating these pan-mutant PI3K inhibitors. As I mentioned, we got involved in this field relatively early, due mainly to studies in other labs that were looking at a viral oncogene called polyomavirus middle T antigen. What was really interesting about this oncogenic protein was that the virus had evolved a protein that was essentially mimicking the signal transduction complex that was activated when receptor tyrosine kinases were bound by ligands.

It turned out that in one subset of these studies from our lab and others, we found that immunoprecipitates of the middle T antigen contained a lipid kinase activity which phosphorylated, at that time, phosphatidylinositol. We had really no idea what that meant, until Lou Cantley and Tom Roberts went on to identify in more detail this lipid kinase activity and found that it, in fact, specifically phosphorylated phosphatidylinositol 4,5-bisphosphate at the 3-prime hydroxyl of the inositol ring, generating what I'll call PIP3 and spawning the name that we use today, which is PI3 kinase.

Very importantly, it turned out when that binding site for that PI3 kinase was mapped and a mutation was inserted to prevent binding of the PI3 kinase, we found, and others found, that you abrogated the oncogenic signaling activity, that kinase, indicating for the first time that the function of PI3Kα was part of the transforming activity of the middle T antigen. As we moved into the genomic era, certainly this finding was buttressed by the observation that first in mutations in a tumor suppressor protein called PTEN, which actually dephosphorylates that 3-prime phosphate and eliminates or removes the kinase, removes the signaling activity of PIP3, that was mutated and inactivated in a number of tumors. More direct relevance to the current conversation, mutations in PI3Kα itself were also discovered, further indicating that this pathway played a key role in cellular transformation.

I should mention, very importantly, the subtitle at the top, that subsequent studies have now found that in cancer, mutations in the PI3 kinase pathway have been observed now in about 15% of all cancers. Just to put that in perspective, we all know that one of the most commonly mutated genes, or gene families actually, in cancer are the RAS genes. Those three RAS genes, collectively, mutations have been observed in 20% of all cancers. These PI3Kα mutations are approaching the numbers that we see with the collective mutations in the RAS proteins. Subsequent findings actually showed as well, as I mentioned, that the very same mutations that were oncogenic, in fact, were also found in these vascular anomalies. These biological findings spawned a lot of interest in the development of molecular probes and, in turn, drugs that were able to inhibit this pathway.

Early inhibitors, which I and many others worked with, proved to be valuable tools. wortmannin, being a natural product, the Lilly molecule LY294002, were used in a wide number of labs to further understanding the functions of this PI3Kα isoform. These compounds were nonspecific for PI3Kα, and development efforts really shifted towards isoform-selective inhibition. In 2019, a milestone in the development of PI3 kinase inhibitors was achieved when alpelisib was approved, specifically for PIK3CAα mutant ER-positive HER2- breast cancer. I should mention that the mutations in PI3Kα are rampant in breast cancer. About 40% of all ER-positive HER2- breast cancers bear these mutations. alpelisib also came with some limitations, and those limitations were mainly around the therapeutic window and the side effects.

A phase III study reported about 25% of patients were forced to discontinue the drug completely due to side effects, and considerably more patients underwent dose reductions in order to tolerate the drug. Those dose reductions almost certainly lead to reduced therapeutic activity. In 2012, another milestone was achieved with the discovery that a syndrome that included vascular anomalies called CLOVES was mediated by mutations in PI3Kα. In 2022, alpelisib then was also approved as a therapy for patients who had CLOVES and other PI3 kinase α related overgrowth syndromes, also called PROS. The drug was effective, again, but also limited by side effects.

We come to today, we are now realized, through advances in chemistry that Ben described, for example, in a position where we can take advantage of the fact that these driver mutations in PI3Kα can be specifically targeted while sparing the wild type PI3Kα in normal tissues and improving the therapeutic index. Also, as I'll mention, allow a deeper inhibition of PI3Kα itself, which could yield a greater therapeutic activity. My last slide. I think Ben has covered pretty well the chemistry, but I think it's pretty obvious at this point that the development of a pan-mutant inhibitor that acts in an ATP competitive fashion would present an extremely challenging chemistry challenge. We call this an orthosteric inhibitor, as Ben mentioned. We also know at this point that we need to be selective against the wild type PI3K.

We've designated greater than 10x selectivity as being desirable in order to circumvent the unavoidable side effects that occur when one inhibits the wild type form of PI3K. Those side effects are predominantly hyperglycemia, skin rash, and diarrhea. The clinical challenge here with the existing drugs like alpelisib is that it all comes down to tolerability. Chronic dosing will demand an improved therapeutic window to avoid those dose discontinuations and reductions that I mentioned. We know that the PI3Kα pathway plays an enormously important role in glucose homeostasis, and these other toxicities are also unavoidable. It's important to mention the fact that with regard to hyperglycemia, which is a very common side effect, you require about 90% inhibition, or greater than 90% inhibition of PI3Kα activity in the liver in order to get hyperglycemia.

It seems highly likely that a similar level of inhibition of PI3Kα in tumor tissues is required for therapeutic activity. It's almost an inescapable side effect of a drug that inhibits both the mutant form and the wild type form, that you're going to see some of these metabolic side effects that I mentioned. The path forward, a mutant-selective molecule should address these therapeutic index issues. We think we might see an increased probability of single agent cytotoxicity due to the fact that we can push the level of inhibition to higher levels, more dose-intensive therapy. Sparing of the wild type PI3K should improve the therapeutic window, reduce the need for dose reductions and discontinuations. Certainly, when you start to do drug combinations, which is clearly the case in ER-positive HER2- breast cancer, combination therapies can bring combinatorial toxicities as well.

It's highly desirable to have a single agent mutant PI3Kα inhibitor that has minimal side effects that have to be dealt with. That's my last slide. I'll pass the baton now back to Nick.

Thanks, Bob. Thanks, Ben. One doesn't get to this point, speaking for OnKure, in a position to make important medicines without the contributions of others. I really have to thank, as you can see from their presentations, that Ben and Bob really have added to our fundamental understanding of PI3Kα and ways to drug it to meet the high credentials that are needed to be an important medicine. Bob and Ben, thanks for your presentations, as well as the work that you've done that has helped us and others get to this point. What is this point? A clear view of what ideal performance is, and you need to smother, I would say, the target. Great target coverage, again, because PI3Kα is really a driver, and it's a menace in diseased tissue, and it needs to be stopped.

Better safety in that the diseases that you're treating, and more and more, there's a higher and higher bar for molecules that are very safe and perfectly tolerated in the context of chronic care. Greater combination potential, which is something you can engineer into a molecule, needs to be front of mind as you're selecting molecules to move forward, which indeed, the top three lead to better patient adherence because there's many instances where history has taught us that dose intensity is proportion to efficacy and overall clinical benefit. Our programs, and I think it's clear by now, we aim to minimize wild-type PI3Kα inhibition, maximize mutant inhibition.

To do that, we're going to exploit, I would say, an allosteric site, one not found by ours, but one that I believe we've mapped as deeply as is needed to be able to move forward with molecules that have the kind of selectivity I showed you. With that selectivity, you're going to see substantially or predict to see substantially reduced systemic toxicity, which will comport with great tolerability, safety, patient compliance, and would hopefully allow us to establish our molecules as best-in-class backbone medicines to which other new medicines of standard care are added too. In every presentation, you should show a ribbon diagram, and this is a map of PI3Kα. Very familiar to us, maybe some of you are seeing this for the first time. In our minds, there's four pharmacologically relevant binding sites.

Pharmacologically relevant in the sense that if you bind a particular molecule to it, you will abrogate the activity of the enzyme, whether it's in the wild type or in the mutant form. Again, selectivity is something that needs to be dealt with. Sorry if anybody's colorblind. The red site is the ATP site, to which we would call the orthosteric site, the active site, to which molecules like inavolisib, alpelisib express their activity. There's the purple site, which is a non-mutant allosteric site. It's the one where the Scorpion and Relay molecules have their effect. I won't be saying much about this today. The allosteric site, which is the subject of most of our work, is the H1047 allosteric mutant site, which is noted there in green. Again, 345 and 355 express their activity by binding this to this particular site.

A conversation we can have much deeper regarding the biophysics. OnKure is also happy to note that it has identified another allosteric site we right now call E mutant site. More details about that, but again, our view is that the way to control PI3Kα is through allostery, that is to say, non-orthosteric sites, where the green site is the one to which we've applied our trade mostly over the last two years, and a blue site may be something to deal with in the future. You've seen this slide before, but I just want to stress the points. It's not just about selectivity. That's the ante. It's necessary but not sufficient.

If you don't add to that efficacy in translatable preclinical models, safety, tolerability, lack of increases in insulin and glucose, as Bob had pointed out, great target coverage at the mutant as opposed to any activity at wild type, combinability, as predicted either by lack of DDIs or by non-overlapping toxicity. Mutation resistance, again, something we are studying and that we hope to talk to you about in the future. That is to say, what are the on-target drug resistance mechanisms, and how do our molecules perform in the face of it? A great IP estate and two molecules to move forward into the clinic. I just want to present one real data slide.

On the left-hand side are the selectivity metrics that I showed you previously, and the data on the right-hand side is a TGI, which was carried out for OKI-345, again, with the selectivity at the 545 mutant here shown, and that mutation is found in MCF7 cells. On the right-hand side, in the graph shown, at maximally tolerated doses in this model, that is to say, the doses that you can keep the animals on, and effectively finish the study, are used here, 100 MPK for STX-478, and you can see the doses that we use for 345. Any doses higher than this lead to substantial discontinuations and sort of an inability to understand actually what happened in the study. However, you can see that a maximally tolerant dose of 478 leads to a modest tumor volume reduction, but increase in doses of 345 as monotherapy.

As monotherapy in the more difficult-to-control mutant, that is to say, 545 You can see that 345 at 60 MPK can substantially regress if not eradicate the tumor. We find this to be a unique property of our molecules. We haven't seen any others that are able to have this type of monotherapy effect in an MCF7 cell that has to say E545, and with this kind of performance by comparison. Again, in very translatable models, very predictive of target inhibition in the clinic, 345 has greater selectivity, leads to superior target coverage, and again, that comports well with the type of regression you're shown here. Can we look forward and think about what kind of target coverage we might expect to get in the clinic?

Of course, we've done a lot of work with 345 as well as 355 to understand the kind of dose flexibility, the kind of therapeutic window that we have to explore doses that would be maximally efficacious. On this slide are shown four graphs where we've plotted clinical PK concentration, and it's divided by the EC80 for MCF7s, which is the E545 mutant. An EC80 is generally recognized as a hurdle that one needs to get over and surpass to be able to have effective, and if not, optimized target inhibition in the tumor. You can imagine that this here is. If I am above the EC80, then I'm above the blue line. What one would also plot here is the EC50 for wild type.

If you are above the EC50 for wild type, predictably in the clinic, you see that there is increases in insulin, increases in glucose. The pink area, which is above the EC50 wild type for these particular drugs shown, enzalutamide, palbociclib, relacorilant and Scorpion, that's all in pink. If you move into that pink, you can expect hyperglycemia or dose-reducing increases in insulin. What we've plotted is, these are clinical results from these representative molecules, and you can see that as they are dosing up to cover the blue line, which is the EC80 for this particular mutant, you can see that they've already penetrated the pink space, which is increases in insulin. This is what we've seen in the clinic, that these molecules, upon chronic dosing, predictably produce increases in insulin in their patients, which continues to be a problem in clinical care.

Our molecules here, when we model the blue line, again, for 345, is the projected clinical concentration divided by our EC80 for MCF7s, and the red line is the wild-type EC50. You can see nearly an order of magnitude difference between those two numbers in our favor. That white space above the blue line and below the red line, is greater separation, and as we believe, will be reflective, if not fully predictive of our therapeutic window. Better selectivity, better target engagement, better tolerability and safety allows for this type of dose regimen that we would expect to be able to use as we move. Coming full circle, this is a slide you've already seen. We're developing PI3Kα pan-mutant selectives, 1E for vascular anomalies and cancer.

The research team is very excited to move these molecules forward, Obviously, these are some of the most interesting molecules and most high-performing molecules I've had a chance to move into the clinic. 345, 355, pan-mutant selective inhibitors, 10x minimum selectivity, best-in-class drug properties, INDs in the first half of 2027. With that, I'll hand back over to Tara, We would be more than happy to entertain questions.

Great. Thank you, Nick. At this time, we'll be conducting a question and answer session with our speakers. To our analysts joining us live, please use the raise hand feature under the reactions button on your Zoom to indicate you have a question. To the remainder of the audience on the webcast, please use the written Q&A text box underneath the webcast player. Please hold for a brief moment while we pull for questions. Great. Our first question comes from Sam Slutsky at LifeSci Capital. Please go ahead, Sam. Hey, thanks for taking the questions, and thanks for the great presentation as well.

Just on the biology for breast cancer, I guess, what do we know about the degree that non-kinase PI3Kα mutations are disease-driving relative to kinase mutations? Do you think it's possible to see similar efficacy between kinase and non-kinase mutants assuming a sufficiently selective molecule? Would also just a quick follow-up on the degree of PI3K mutations you see in vascular malformations and just the expectations for your drug there.

Right. Yes, the helical domain mutations are every bit a driver as we come to understand the E545, E542, and the others that are found in that domain. We do recognize that it has a different activation mechanism. The protein only gets to dance in a certain number of ways. The helical mutations, they are perfectly competent to become drivers, and we see this in the clinic, as well as pre-clinic. The question is as to whether you can, as effectively inhibit both kinase as well as helical domain is one that you could state, well, from first principles of pre-clinically, you could see that they tend to be more recalcitrant no matter what site you're binding to.

You would say, "Well, can I get to the kind of tolerated target coverage needed to show optimal efficacy or combinable efficacy in the clinic?" We would say yes. We do draw a very hard line at maintaining a selectivity that allows you to be above the EC80 or EC90 for the mutant, and below the EC50, and ideally the EC30, for wild type. We've seen time and time again, molecules with modest or good, but not exquisite selectivity be able to handle the H1047 or the kinase domain even more readily than the helical domain. It seems as though it's an emerging need in the area to be able to address these mutants. All these helical mutant, those are different mutant protein.

Given sort of the consolidated activity that we can derive out from binding to the allosteric site, we think we have found a solution that allows for that selectivity. With respect to vascular anomalies, a substantial portion of the patient populations that have these are PI3Kα positive, and the vast majority of those are PI3Kα mutant H1047, E542 and E545. Of course, the numbers continue to evolve as we sequence more people. There are some minor mutants that can also drive disease. We're very interested in those because we believe our molecule might be able to cover those. There is some leftover genetic drivers aside from PI3Kα, which may represent a third up to a half. Again, that's something that we will study as part of our deepening portfolio over the next period of time. I hope that answered your question.

Great. Thanks for the question, Sam. Our next question comes from Yuanyuan He at Evercore. Please go ahead. Thanks for the great presentation, taking my question.

This is Yuanyuan He from Jump. Just a few questions. First, have you performed any preclinical studies that show improved ability for the new molecules to overcome resistant mechanism in maybe different tumor models? Is it fair to say, this is less relevant for the molecule OKI-355 in the vascular anomaly settings? My second question is, what are the clinical features of VA that requires more selectivity potentially than in oncology setting in general?

Yeah. Okay. Those are terrific questions, thank you for listening today. We are doing some work, both internally and in collaboration with other academic KOLs to understand how these tumors progress on either standard of care or experimental drugs. We are mapping our molecule with respect to where we lose activity and where we maintain activity. Of course, what is known is that in the face of orthosteric site inhibition, there are mutations there that alleviate the pharmacology of molecules like alpelisib and inavolisib. Resistance that occurs with treatment with the Relay Scorpion binding site and our site is something of current interest of ours and we'll be reporting it sometime. We do have that as part of an embedded portion of our research program. I would have to say we like where we are.

As Bennett said, there are oftentimes allosteric sites do not necessarily pick up the resistance mutations or, perhaps even those are orthogonal. We're going to understand this. Worst case scenarios, we know what patients we should down-select, and we'll know how to run clinical trials to optimize effect. In vascular anomalies, yes, on a genetically stable background, you don't expect these proteins to change. Although, obviously we won't fall asleep at the wheel on that. The increased selectivity, all these molecules need to be selective, but if there is a premium for selectivity in either of these indications, it's going to be in vascular anomalies for a number of reasons. Patients are going to be staying on drug long. Tolerability issues associated with PI3Kα inhibition seem to grow with time. In addition to that, a real medical need exists in younger and younger patients.

Having the best-tolerated drug with the best safety, which doesn't have any side effects that would be peculiar in a developing human or even prenatally, is really very important, not only from first principles, but from science. We will make sure that sort of the metric of high selectivity is one that's met for vascular anomalies. Thanks for those questions. Yeah.

Thanks so much. Great. Thank you for the questions.

Our next question comes from Leland Gershell at Oppenheimer. Please go ahead, Leland. Great.

Terrific. Thank you. Thanks for this presentation and taking our questions. Just a couple. In terms of the safety differential, wondering if you'll be able to show us work from animal studies that you may be doing as part of your pre-IND work that could help add comfort to improved safety and an attractive safety profile as you get into the clinic. Related to that, just wondering how you're thinking about metabolic monitoring as you enter phase I, given hyperglycemia associated with the class. Also just have a follow-up. Thank you. Sure. I'll answer the first question and let Sam Agresta, our CMO at OnKure.

The preclinical model for increases in glucose. The most striking and most dose reduced, but dose limiting toxicity is increases in glucose and then sort of associated increases in insulin. It turns out the mouse is a perfectly good model for that. We, in fact, with time, will be able to show SAR, where increasing selectivity leads to decreasing risk of hypoglycemia and increases in insulin. We won't show that for our own compound, we'll show that for everyone. It's a very well-characterized, translatable endpoint. I guess that we haven't evolved so far from mice, that we don't use the same metabolic processes regarding insulin and glucose.

While there are different conversations regarding the problem associated with increased insulin glucose in the clinic, we still feel that it's one which has to be taken very, very seriously. Sam, would you like to comment?

Sure. Yep. Ideally, we all know that hyperglycemia, hyperinsulinemia is a significant safety concern with the PI3K inhibitors that are approved. These drugs have non-trivial grade 3 and grade 4 events that can be managed, but do require dietary counseling, medications, metformin, insulin, et cetera. Probably most problematic are dose interruptions to what Bob has been stressing around dose intensity and hitting the target. What we'll do in the clinic, given the selectivity that we've shown, is we'll do the typical insulin glucose C-peptide monitoring throughout treatment, and we'll really hope to see very low rates of anything beyond grade 1 and 2 hyperglycemia, if any, or ketoacidosis. We'll also look at if there are patients who were on prophylactic or chronic antihyperglycemics, can we get them off those?

Clearly look at dose interruptions, discontinuations, reductions, with a goal of maintaining high dose intensity, and target inhibition. Ideally, we can use 345 and 355 in patients who are obese, or pre-diabetic, or have controlled diabetes, that'll all be a part of our clinical development planning for 345 and 355. I would say that it's probably, as Nick has said, even more important in the vascular malformations, where these patients will be on this at a very young age and for a very long time, you can't trade the benefits of decreasing their issues with their vascular malformations for metabolic toxicities that are chronic. The selectivity will be even more important there. Bob, I don't know if you have anything else to add with regards to your thoughts.

I think you've summarized it well, Sam. Thanks. Yep. The only thing to add on the back end of that is that the studies have shown that upon chronic administration of its non-selected molecules, the incidence of hyperglycemia goes up over time.

If your idea is that you're going to be treating chronically, whether it's in cancer or a rare disease, it's not like this issue goes away. It only becomes more manifest. You're keeping a patient in a pre-diabetic state, this is not going to go anywhere good. Being fastidious about this in clinical practice as well as in developing the molecule is important. Leland, you had a follow-up.

Oh, yes. Thanks. I just wanted to ask you, since we just did see yesterday the FDA approval of gedatolisib, which is both a pan PI3K and also mTOR inhibitor for certain forms of breast cancer. Just wondering, how that development program, any learnings from that may inform your forward view on OKI345? Thanks. Sure. We know a lot about the molecule, both pre-clinically as well as clinically.

I think the Celcuity group has taken the courageous stance of asking and answering an important question with respect to inhibiting this pathway that Bob detailed at two points. In what context does that provide a real advantage over other medications? With respect to that drug, it's great for patients. They will have to figure out how to deal with the tolerability. We will have to wait for it to see how they work in the mutant setting. It's going to be an important medicine, I think, in the second, third line. Our intention is with our molecules, great combinability, but great safety, that our molecule is going to more appropriately be used in earlier lines of therapy.

To the question of two-point inhibition in the pathway, it's something that we would study, and it's certainly something that we could contemplate for the forward development of our molecules as well. Hope that answered your question.

That's great. Thanks very much.

Thanks for the questions, Leland. Our next question comes from Boris Peaker at JonesTrading. Please go ahead, Boris. Great.

Thanks for taking my question. I guess my first question is that you showed significantly increased affinity of your molecules to specific three PI3K mutations. I'm just curious, is there any way to select patients, whether it's in vascular anomalies or oncology, where this increased affinity for these specific mutations will be most valuable, and therefore easiest to show with a relatively small data set? I guess the second question maybe ties into that is, in vascular anomalies particularly, we know that there's a lot of heterogeneity in PI3K-driven diseases, from CLOVES to vascular malformation and so forth. What patients do you anticipate to enroll in your upcoming phase I study next year?

Right. I can take it all. With respect to the genetics. Again, the vast majority of patients have three mutations, and there's some other ones. Pre-clinically, we will study to understand if we maintain the kind of potency at these sort of minor, very rare mutations, which do pop up here and there, but for the most part, they tend to be in the background. The genetic testing for PI3Kα, whether it's from tissue or in the cases of cancer, you could do NGS and a plasma, which would give us a very precise sense of the exact mutations that were evidenced. With respect to optimizing a response, that likely is more dependent on sort of the stage of the disease, as well as prior lines of therapy.

I think that that's something that we're looking at right now, both with respect to cancer, and how we move forward. In vascular anomalies, it's an evolving field right now as to which patients to select to get a clean homogeneous population. What type of endpoints, and this is a discussion which is going on between us KOLs and the agency, in fact. As foundational, certainly there'll be imaging to see lesion reduction size, but one cannot underestimate, whether it's the opinion of the regulators or the KOLs, that pain, inflammation, disfigurement, dysfunction are important endpoints as well. We'll be looking to sort of hone our studies to be able to see those type of endpoints.

Again, vascular anomalies, given that patients can be biopsied, certainly genetic precision in selecting patients won't be an issue, and we'll be mindful to make sure that we prove our pan-mut selectivity has therapeutic reach by making sure that our trials adequately represent the important mutations that present themselves in these diseases. I hope that answers your question, Boris.

Yeah, I just want to clarify. You're not going to be selecting and making sure that all patients have all three mutations. You're just going to be taking all comers and just assuming the majority of them will have it.

No, we will sequence patients. We will know- the 1047.

We will know what, because 1047 can mutate to three additional amino acids, R, Y, and L. We will know genetically who we're working on. We'll look more broadly than PI3K to see if there's any other aberrations we need to be mindful of. In the context of PI3, with this targeted precision approach, and we'll collect the data, and certainly we'll analyze in the context of the mutation that the patient presents.

Great. Thank you very much for answering my questions.

You bet. Great. Thanks for the questions, Boris.

I think we have some time for a few questions from the webcast, I'll turn it over to Dan Ferry from LifeSci Advisors to read those.

Thanks, Tara. Nick, we just have one here, one question from the audience. If and when you put out preclinical data for 345 and 355, what would a great molecule look like to you?

Well, the preclinical data that would be most telling is going to be the predictive work that allows us to understand achievable, tolerated plasma concentrations. A perfect molecule, I think we laid that out in slide 24, is that we should, as I said, smother the mutant and spare, if not lay off entirely, the wild-type protein. In addition, that looking at the molecule in the context of many combinations in helical as well as kinase domain, and showing that at very well-tolerated doses, one could substantially regress if not eradicate the tumors is what I would be looking for in a molecule, and certainly what we look for in moving our molecule forward. Things like predicted DDI, a great molecule, you would be able to talk about that. With regard to brain penetration, you should be able to talk about that as well.

These are the types of data that we and I have historically collected when we move molecules into development. If and when we show these data, which of course we would love to, one will get a bird's eye view of those attributes.

Excellent. Thanks, Nick. Tara, that concludes the written questions from the audience.

Great. Thanks, Dan. I think we can turn it over to Nick for some closing remarks.

Thanks everybody for joining today. Thanks everybody for engaging in questions. We feel that, again, science first, you know your target, know your molecules, and then go forward with your eyes open. I believe we've done that, and I believe we do have best-in-class molecules that will prove themselves as we move 345, 355 into the clinic for cancer and vascular anomalies respectively. Thanks again for joining us today, and we look forward to talking to you more in the future.