All right, everybody. Welcome. Good afternoon. Welcome back for lunch. Get psyched. Get the post-lunch sleepies out. We've got OnKure Therapeutics. Thank you, Nick, for joining us here this afternoon.
Thank you for inviting us.
Fabulous. I'll start just by giving you a minute or two. Tell us about where you're at, what you're looking forward to in 2026, and we'll get into some details.
So, good question. Our molecules in our portfolio and our platform are moving along such that 2026 should be a year full of data and progress, we believe. In the first quarter of 2026, we'll be reporting on clinical data, monotherapy, combination therapy, as well as a doublet and a triplet for OKI-219. We have other molecules moving into development shortly thereafter. You know, the area is evolving. You know, our platform is evolving, and we're going to have some very exciting data in the first quarter, and we think that will provide us momentum through the year.
Excellent. Let's talk about that data coming next quarter. So we were expecting initial data from PIKture-01 , from the phase 1 study, by the end of this year. You decided to push it out a little bit to Q1. So can you remind us what prompted the delay? I won't call it a delay. What prompted the change in strategy and what we should be expecting in Q1?
Yeah, the data or clinical trials make a lot more sense, and the data make more sense when they're more mature and you can put them into context and the appropriate context. So it was very clear to us that as enrollment, as well as time on therapy, both in monotherapy, as well as a doublet with fulvestrant, and more recently in a triplet with two triplets, one in HER2 positive, one in positive, that additional time on therapy, additional cycles would give us a better sense of the quality of our molecules. Going out with a partial story in a complicated area only leads to confusion.
And it was very clear to us that the trials were moving forward, the data were coming in, and we would be able to have the data sets to be able to compare ourselves in an absolute fashion to the kind of standard we want, as well as in a relative fashion with respect to the competition. That would have not been possible in this quarter right now, but it will be possible one quarter from now.
Yeah. So we know that, obviously, escalation dosing has completed. You had last patient dosed in September for the monotherapy, in July for the fulvestrant combo. When we get data next quarter, that seems like a reasonable amount of follow-up, potentially a pretty reasonable amount of follow-up for the setting. How much follow-up should we be expecting across the various arms? Will you have at least three scans plus for this combo?
Oh, we'll have greater than four months for everybody that's been on study and everybody that continues to be on study. And so, like I said, we'll be able to begin to even think about durability of response, but in a holistic fashion, we'll have a better sense of overall response in having patients on for that long. We did enroll these studies to have patient populations that would allow us to make comparisons to the competition as well as the molecules which are already marketed, and that's precisely what we wanted to do. So we need to follow these two cohorts, 34 and 36, for monotherapy and doublets, respectively, to be able to speak in a more definitive fashion about how good our molecule was.
Speaking about the comparative cohorts, can you talk a little bit about a number of prior lines, what the patient cohorts are going to look like in terms of the patient characteristics? What should we be paying attention to?
Yeah, that's really something that everybody should be paying attention to in that, you know, in these earlier studies, especially. It's very difficult to sort of harmonize with respect to the numbers of lines of therapy or the types of lines of therapy. So you're going to be looking at ours, and our patients are probably more heavily pretreated. We do understand what prior therapies they've had, but still, even within that, we should be able to call out a subset or the portion of the population which we can make a fair comparison to the competition, in particular, the Relay Scorpion studies, which has released data most recently.
Excellent. So to that end, the triplet arm with the CDK plus fulvestrant plus your PI3K, that feels like a really important regimen for moving into early lines. That's something that's going to be very important to directly comp versus the data sets that we've got. You'll have two cohorts, I understand, properly enrolled, starting to dose in the fall. So can you talk a little bit more about your expectations for the triplets?
Right, and so let me put that in context. So all along, when we put OKI-219 to the clinic, we wanted to move as quickly and as cost-efficiently as possible to move through monotherapy, doublet, and get to these important early line triplet studies. A molecule like ours, which has the selectivity and tolerability, is going to differentiate itself in earlier lines of therapy where those attributes are really most valued, and so the study was set up in such a way that we would be able to recruit and keep patients on long enough so that in the first quarter, we'd be able to say something about tolerability, combinability, and early efficacy.
Now, it's important to note that ribociclib was our choice for CDK4/6, and that's been a particularly effective drug in the clinic, but particularly problematic when you're trying to combine it with other drugs because of potential DDI, and so we figured we would go for the high bar. Ribociclib is an important drug in becoming ever more important, and demonstrating that we could combine with it in the context of a frontline triplet or near frontline triplet was really something very important and would be very value inflecting for us, so that's the study we chose to set up. The other triplet study we have going that we don't want to lose sight of is in the HER2 positive setting.
Don't worry. I've got questions about that one.
Okay, I'll just hold that. In going from first patient, first dose in March of 2024 to where we are right now, starting in triplet studies in the frontline, which can inform expansions, blinded studies as well as registrational studies, we feel that we've done a pretty good job moving from point A to point B and getting all the data we needed along the way to understand how to develop these medicines.
All right. Now, when we think about these triplet studies, there's a couple of things I think buried in your responses there. There are a couple of different ways that you could differentiate that are potentially interesting. And you mentioned tolerability as being a major factor there. Obviously, the mechanism of action for your drug being mutant specific versus just mutant selective, pan-mutant, is a potential driver there. But how much do you need to see on safety differentiation for that to be a meaningful driver in a clinical setting or a commercial setting?
I'd like to say perfect, right, that we don't want to have any in the course of clinical care or clinical trial that there be no dose reductions and no discontinuations whatsoever. And so we're going to leave that bar there. And again, I mean, everybody will recognize that keeping patients on therapy is a great way to improve your efficacy, and certainly, this is the way we're going to do it. So the bar is going to. We've already shown some safety data in 24 subjects, and there's no reason for us to ever reduce that high bar, like no grade threes, no dose discontinuations, no dose reductions.
On the efficacy side, in the triplet specifically, are you going to have enough on those first two cohorts to be in a position to make a case for efficacy differentiation at the time of the 1Q release?
You know, that's hard to say. I mean, when you look at these triplets that have been studied with other drugs in other settings, that with the number of patients and the amount of time, we should have a good sign of early efficacy, right? But it's not going to be a definitive hyper-quantitative sign. What it will provide us is with enough information to be able to decide on a go, no go to move to an expansion, right? We really designed how quickly can we get to a place where we understand tolerability, combinability, early efficacy in order to move on to expand that study, expose it to more patients, and to make a stronger investment into it. We think we'll have that.
But at the time of the 1Q release, we shouldn't be expecting full maturity on durability, for instance.
No. Well, durability you would hope is going to be out 10, 12 months, and so to get to a median thing, half your population needs to be out beyond that, so we won't be there. Durability is something that's going to have to be designed into the experiment for the expansion stage. You might take that from the INAVO study and from other triplet studies that have come forward. You may take that as an article of faith, but that, along with the data we would have, would be enough to make the additional investment to the expansions.
Makes sense. When we think about the totality of the triplet, doublet monotherapy data that will be able to comp to the relevant Relay and Scorpion data sets, saving the HER2.
Right, right.
The directly comparable data sets, what's most important? Obviously, the data will be most mature in monotherapy and fulvestrant combo, but you just said that the triplet is going to be the major driver for you, and you really want to get there as soon as possible. So where should we be paying the most attention?
Yeah, well, I think that most people would agree that we should be in the comp data that can be compared. Let's leave the triplet aside because that's going to be based on sort of the beginnings of the skeletal data that will allow us to go forward. But in the doublet study, clearly, you should be focusing on continued high bar safety. And in a comparable population, and you already mentioned it before, in a comparable population, do we have comparable efficacy? And so when we go and we look at the overlap between our studies and the other studies, prior lines, which prior lines, percentage of visceral mets, percent that is bone-only disease and the like, when we look at that, do we have comparable efficacy? And that's what we'll hope to be able to demonstrate.
Excellent.
Comparable, and this is sort of a simple message. Comparable efficacy, better tolerability. Whether we're talking about comparing ourselves to the Relay molecule in combination with fulvestrant in the second line, or we're comparing ourselves to inavolisib in the INAVO-1 study, it's about match the efficacy at a minimum and beat on tolerability.
Maintain dose intensity.
Because that's going to comport with better long-term efficacy and a real clinical outcome.
All right, great. Now let's talk about that HER2 triplet, which is very interesting, something that we haven't seen a ton of advancement in from the competitors who have been so focused on the HER2 negative population. What's driving you into that population and what should we expect?
Three things drove us into that. One was that there was a significant inbound interest to run this type of studies. There have been other studies run where people have looked at PI3K mutated disease in the context of HER2 positive. And so certainly, the KOLs were sort of, let's do that, let's do this study. The other is that there's some clinical validation of this. In fact, the inavolisib was put into a study when they're in the HER2 positive, PI3K positive population. They saw good responses. It worked pretty well. So we have clinical, we sort of have like the community is validating it, the literature is validating it, and our CMO has a long history in developing HER2 targeted agents. And it was really quite informed and quite excited to get this study up and running. And nobody else is doing it right now.
Frankly, it's a significant market. Maybe it's a third to a quarter of the size of the positive market, but it's still an enormous unmet opportunity. There also seems to be a lot of with respect to progression. There's crosstalk between positive and HER2 positive. And so having a drug that can be approved in either setting could certainly be an advantage if you had that in your portfolio to be combined with other drugs.
Yeah. It's an interesting combination with both the mAb and tucatinib in there, and it's interesting that we haven't seen other folks pursuing triplets there.
Yeah. And these drugs are available, people know how to use them. Tucatinib is a good drug. And in the context of intracranial disease, our drug with a high brain penetration, tucatinib as well, this could be a really remarkable.
So what should we be expecting from early data there? How far into the escalation will you have gotten?
Yeah. It's hard for us to say this is going to be a study that's going to take a little bit longer to recruit, and so while we're heavy with recruitment in the positive study, and staying on track is going to be pretty straightforward, we'll provide additional guidance on what the kinetics of that are going to be, but we are committed to that study given sort of the competitive advantage, the clinical validation, and sort of our uniqueness in that area.
What do you think about the potential for PI3K as a mechanism on top of HER2? Should we be expecting? I'm just thinking about relative effect size in a HER2 population on top of HER2 directed drugs versus in a HER2 negative population on top of fulvestrant?
Yeah. I mean, it may be the case that you're going into a setting where they have progressed. And so there isn't a lot of data to suggest how much better you're going to do in a set of patients that have progressed on, say, an HER2, and you keep them on that and move it forward. So it's interesting to think about. I think we'll get an early read on that, but I don't think we have the information right now to answer that question.
What are you hoping to see that would drive you into proper expansion cohorts?
I would want to see us to be able to match the type of efficacy that you saw for gedatolisib in that setting, in that triplet, with better tolerability or to improve upon HER2CLIMB-02 study with better tolerability.
Okay, makes sense. I want to take a moment to discuss some recent data we saw at ESMO that you and I discussed at the time of that conference. That's the Celcuity pan-PI3K/mTOR inhibitor. The field has moved away from those general inhibitors, but it seemed that their data was very strong, and safety, interestingly enough, remained pretty reasonable. So how do you interpret that data and how do you put it in context next to the mutant specific or mutant selective approaches?
I mean, let me answer the second question first. Time will tell when we see what their data look like in the mutant setting. It's a very interesting drug. And I think that all indication from the small study they ran in this setting earlier on, like 30 patients or so, and more recently, it could be an effective medicine. Now, with respect to thinking about the likelihood of success in the PI3K alpha positive population, one has to look at the true attributes of the drug as well as target coverage. And I think there's a good argument to be made that could be effective in that setting. But there's also some unknowns with respect to how strong a PI3K alpha inhibitor it is with respect to mTOR, what kind of target coverage they're getting, and the like. So the study needs to be run.
But still, I mean, with respect to a frontline mutant study or a frontline therapy, with respect to that regimen still has tolerability issues associated with it. And it's also a weekly infusion. Interesting drug, has to be developed, undoubtedly going to be important in the second line. Will it be an important frontline drug? It's hard to say right now.
Interesting. All right. The other program you alluded to earlier in your introductory remarks is a pan mutant program that you've been developing and really searching for some interesting chemical matter there. Can you talk to us a little bit about what your bar for picking an asset was relative to other mutant selective or pan mutant?
Right. A considerable amount of research that has been done by our group and others, I think, does more than suggest. It nearly proves that in the absence of a 10x therapeutic advantage, 10x selectivity, that you can't inhibit oncogenic signaling or you can't handle hyperstimulation of PI3K alpha without running into drug-related side effects. It's got to be 10x. It's simple clinical pharmacology. The difference between the wild type inhibition and mutant inhibition needs to be the difference between, say, EC30 and EC80. That's 10x, right? Any molecules you look at, whether in preclinical models or in humans, when you start titrating into wild type inhibition to any extent, you see these side effects. It's pretty clear. The numerics to us are very clear, 10x, okay, at least. We set the bar there. We recognize that.
Maybe can you remind us where the other mutant-selective, the pan-mutant selective inhibitors are on that bar?
Yeah. So if you just think of just the H1047R mutation, not the others for now, is the benchmark. Relay is 8.8, excuse me, Relay is around 5, Scorpion 8.8, and inavolisib 4, and alpelisib 1. And OKI-219 against that is 80, right? But now, importantly, you need to have that sort of high bar selectivity across all the mutants if you're going to be pan-mutant selective. So you might say that Scorpion certainly has the level of selectivity to be an important medicine in H1047R. The jury is out on the kinase domains, and so on and so forth. But if you could find molecules that a single molecule can control all of the mutants with 10x selectivity mutant over wild type, I think you have a really important drug, really important medicine. And so that's where we set the bar. And we have those molecules.
You have those molecules across both H1047R and the kinase.
So we have them, yeah. So we have them across the patch. So they maintain 10x or greater selectivity across all the important hotspot mutations. And of course, there's other mutations that we're looking at those. But the predominance of those we can cover with greater than 10x selectivity. And we think we're the only molecules that can do that right now. Maybe there are others that are moving into development. But again, important, that's the most important parameter. Everything else flows from that.
When can we see that molecule and start to see that head towards the clinic?
We will be detailing development candidates in the first quarter of 2026.
Excellent.
Right.
Fabulous. So when we see data next quarter for OKI-219, the lead across a couple of different cohorts, what should we think about next development steps? What are your priorities in terms of going to expansion cohorts? What are your priorities in combo space?
The highest priority has to be what is going to be the knife-edge decision for 219 in ER-positive breast cancer. And again, the performance in the triplets, which are ongoing, the triplet, which is ongoing right now, it will probably be the most important determinant of that. Of course, the monotherapy and the doublet work that we've done are all supportive. But the ability to flip that over and start expanding at a single dose in that frontline population is going to be probably the most important thing for us. But not so far behind is getting these pan-mutant selective molecules into patients as soon as we can. We feel that we can truncate the timeline in moving from first patient and moving those drugs into early-line triplet studies as well. We've learned a lot about how to develop these drugs. And so we would hope to get the IND, get that into the clinic, and move it as quickly as we can from first patient, first dose to first patient in a triplet.
Excellent. Go straight there. Would you run cohorts in a fulvestrant doublet as well? Are you parallel planning?
We have to think about that, right? When we're prioritizing patients, we're prioritizing sites and dollars. We don't want to skip a step, but we really want to move to the big show as quickly as possible.
Well, I think that does take us out of time, unfortunately. But thank you so much for joining us, Nick.
You bet.
Really looking forward to the data next quarter.
You too.