Good afternoon, everyone. Welcome to day two of the Leerink Partners Healthcare Conference. I'm Andy Berens, Senior Biotech Analyst at Leaning Partners. We're very excited to have Nick Saccomano from OnKure. Thank you, Nick, for joining us.
Happy to be here. Thank you for inviting us to speak today.
Great. Why don't we start with an overview about the company for those who may not be familiar with OnKure?
Briefly, OnKure was started over a decade ago based on the premise of another therapeutic that we've since deprioritized and are looking to license. About three years back, the science in the PI3K alpha area, as well as the clinical experience, suggested that there was a real opportunity to make a class of compounds that would be significantly differentiated and very valuable by comparison to those that were approved during development. Like I said, about three years ago, OnKure shifted its focus to be exclusively a PI3K alpha mutant selective drug discovery organization. Over the period of time, we've put a molecule in the clinic and are creating others for clinical development in the near term.
OK. The company's legacy is there are a number of employees, including yourself, from Array.
Right. The company was founded by Tony Piscopio, who was a founder of ARRAY. In fact, as ARRAY was increasing in size and decreasing in size, a number of very, very talented scientists were coerced into moving over to OnKure and sort of set up one of the many ARRAY 2.0. We maintained a lot of the rigor, a lot of the culture, and certainly the drug discovery productivity. I stepped in as President and CEO about 18 months ago and inherited a group of people, ostensibly, who I'd worked with earlier. It was really, for me, it was a very nice fit. The group had proven capabilities as well as productivity.
OK. There's another former ARRAY company located in Colorado.
Several.
Yeah, several.
I mean, there's several.
Cogent, who we also cover. They have a PI3K alpha program. I guess, was there any, is that a coincidence, or was there some sort of Manhattan project in ARRAY at the time that they were bought?
Yeah, there was no previous experience working on PI3K alpha at ARRAY for all the time I was there and then some time after. Boulder, Colorado, is fortunate in the sense that ARRAY was founded by another important person, Kevin Koch, who spoke here earlier today. There is sort of an overweight of talent in the medicinal chemistry space there. It was natural that as ARRAY was evolving and eventually turned over and retired by Pfizer, these very talented people found their way into biotechs. Cogent, one of them. There was no collaboration and so forth. This was a moment where the science and the evidence suggested that there could be a really interesting drug discovery program. Not just Cogent, but several other organizations picked it up as well.
Synnovation, Recursion, Black Diamond, others just saw the fact pattern in the literature as well as in the science community and said, now's the moment to work on this because we have all the information we need to make an important therapeutic. That was not previously the case. The talented medicinal chemistry groups picked up the challenge. We find ourselves competing with what are still very good friends and colleagues of ours.
OK. Maybe we start broadly and talk about PI3K alpha. Why is it relevant? Which mutations is it relevant in? What have been the limitations of current efforts and drugs to target the pathway therapeutically?
PI3K has gone through several generations of discovery. Originally, inhibit PI3K, then inhibit just a subtype of PI3K, and then inhibit the mutants that are most important in the context of several cancers. There were sort of three generations of molecules which came along until people recognized that a mutant selective approach, or at least a modestly selective approach, is what was going to be necessary to inhibit the cancer-relevant functionality of that protein without bringing along a lot of the side effects, which would be occasioned by inhibiting the wild type.
As you move forward, what turns out to be decades now, an increasingly sharper understanding of the protein and its role in the context of cancer and healthy tissue, it now sets us down a path to say that there are a set of activating mutations in PI3K alpha that we understand and that we can treat with pharmacological agents that will have a real and meaningful impact in a clinical sense. Again, like I said, the history has sort of created a molecule, and now it's not tolerated. Now we're on the doorstep of, and we're seeing a set of interesting molecules being developed in patients. We will talk about it. We have a slightly differentiated or a different point of view of exactly what's needed in a molecule.
That sets us apart from the molecules that have been approved and some of our competitors who are now in the clinic.
What have been some of the limitations historically for this class?
PI3K alpha is found in every cell in the body. It's found in healthy tissue. It senses and integrates a lot of inputs. It has a very important role in metabolic stasis. When you inhibit the wild type protein, there's a predictable set of side effects which happen quickly, happen predictably, and have an impact on lead to reductions in the dose of the molecule which would inhibit that simply because of tolerability. The most notable and predictable tolerability issue is hyperglycemia, increases in insulin and the like. This is something which sets in reasonably quickly. The work's probably pioneered by Novartis and then certainly a lot of others, suggested that you really need to inhibit the mutant protein 80%-90%, and not inhibit the wild type protein up to 20%-30%. There's like a split.
If you start titrating into the wild type, even if you're really slamming the mutant protein, then this leads to side effects. In a clinical sense, that's going to lead to dose reductions and discontinuations. It is really just about, in this case, the story starts and almost ends with selectivity. What is the appropriate amount of selectivity you need to be able to stay away from wild type and to cover the mutant target in a specific way that has efficacy with no tolerability issues?
OK. Which tumor types besides, obviously, breast cancer is where we've seen a lot of the development efforts?
It's interesting that PI3K alpha is mutated in a lot of solid tumors. It's almost kind of like across the board. I mean, it's hard to find a tumor where PI3K alpha isn't mutated. It is most prevalent in breast cancer. Of course, breast cancer is a large population. The absolute size of the treatable population for any of the mutations that one classically sees in PI3K alpha, that represents a rather significant market. The development of multiple lines of therapy in breast cancer makes it also a good time to bring a PI3K alpha inhibitor and add it to combinations which are represented in multiple lines of therapy across breast cancer. In the front line, we're seeing that we could talk more about, we're seeing the combinations that these naturally fit in.
This is where a lot of the excitement is right now, not only because the science has developed, the market opportunity, the clinical opportunity is really unprecedented. There are other important cancers where the usual driver is occasioned with a coexisting PI3K alpha mutation, which drives aggressiveness of the cancer as well as resistance. There is head and neck, colon, lung, pancreas, endometrial, cervical. There is a lot of other places one could go besides breast cancer. The real immediate opportunity is to move PI3K into combinations in multiple lines in hormone receptor positive breast cancer and very likely HER2 positive as well as triple negative breast cancer.
OK. Just a few more landscape setting questions before we dive into what you guys have been doing. In terms of blocking PI3K alpha, would you expect to see apoptosis? You said it's a metabolic pathway. Is it more of a static as a monotherapy process that you would see when you hit the pathway?
Clinically and preclinically, you do see cell death. You see restraint on proliferation. You can see clearing of tumor. Of course, PI3K alpha is usually occasioned with other mutations which could drive the cancer. PI3K alpha mutations and activation can make the cancer more virulent and more difficult to treat.
OK. In humans or in organisms, you generally see stasis as a monotherapy?
In animals, we could see frank regressions in tumor eradication. In humans, it's difficult to do the experiment as monotherapy because the patient population you're usually treating in that sense is either last line or it's a phase one study. Really, the value of PI3K alpha as monotherapy is as yet not fully developed. It's not clear that the most important place to develop the drug is as monotherapy. When you place it into multiple lines in various cancer types, it's going to be put on top of standard of care with a patient that has a coexisting PI3K alpha mutation.
OK. And then just the last question, I guess, the interplay of PTEN, AKT, PI3K alpha in the hormone pathway, estrogen pathway. How do those different mutations play a role in that pathway?
Both of those mutations are down. PTEN is upstream and AKT is downstream. In essence, a PI3K alpha inhibitor would not be useful in the context of those cancers because the way that you would slow that down would be inhibition of wild type. Now, if you did have heterozygous loss of PTEN and a PI3K alpha mutation, the drug could find utility there. If you have an AKT mutation or amplification, inhibiting the pathway upstream would only be in the context of inhibiting wild type, which again would reflect back on tolerability issues.
OK. Why don't you tell us about 219? What's that molecule's profile? What have you shown so far? Where are you in the dose escalation?
Just to set the stage a little bit, we really looked at our scientific charter to have an exhaustive portfolio or an exhaustive answer to the way PI3K alpha mutated proteins present themselves. 219 is our first molecule. It was designed to be highly selective for the H1047R mutation, which is well known to be a driver and well known to be important in the context of breast cancer as well as other cancers. We designed our molecule certainly based on drug discovery principles and information from the literature to be as selective as possible for that one mutation. We are over 80-fold, nearly 100-fold selective for that mutation over the wild type protein as measured in any number of preclinical models. We felt that that is a significant market opportunity.
This is a place to go with the most selective molecule, which will absolutely blanket the target but have no tolerability issues. Just again, just to back up for a second, there are two families of mutations which are predominant in PI3K alpha. One is called the kinase domain mutations. That is the one which is relegated to the 1047 site, the amino acid 1047. There are the helical domain mutations. Those are more commonly seen in positions 542 and 545. Both of those are equally activating. The former represents about 60% of the PI3K alpha mutated population. The latter, 40%. Our first molecule deals with the 60%. When we go into our studies, we are going to be selecting for patients that are 1047 alpha mutant positive. Of course, we have other inclusion and exclusion criteria.
We'll talk about some of the other programs that we're moving on which answer the problem associated with the other mutations. Two nineteen goes into the clinic. Preclinically, it showed an extraordinarily safe, predicted to be well tolerated profile. That allowed us to go into the 1A study dose escalation at a high level. By the second dose level, we were approaching plasma concentrations predicted to be consistent with efficacy. We went in at 300 milligrams b.i.d., 600 milligrams b.i.d., 900 milligrams b.i.d., and saw good target coverage as well as nearly perfect tolerability. We're very happy about that. We could slam the mutant target. We don't have any of the on-target tox that is seen by any of the approved products, alpelisib and inavolisib, or that we have seen with some of our competitors' molecules.
We could check the box on that. We continue to dose optimize as monotherapy. We're going up in dose. We're looking at different drug presentations to optimize the exposure. The important point is that at the doses we've looked at, we are seeing adequate, if not optimal, target coverage that would comport with certainly combination activity, if not single agent activity. We're going to optimize now because we want to find the very best dosing regimen and drug presentation that we will use in the context of phase two expansions. Now, as far as moving forward, the monotherapy study will complete the dose escalation shortly, 3, 6, 9, 12, and 1500 milligrams b.i.d. We have started the first combination study in combination with fulvestrant, which we all know is more of a classical SERD molecule.
We are going to prioritize that doublet study, OKI-219, with fulvestrant because that really is the first test of a clinically relevant program, a clinically relevant population. Monotherapy is interesting. Certainly, it is a test of a compound's directional activity. An important clinical population is the hormone receptor-positive breast cancer. Drugs in that setting will undoubtedly be looked at in combination. The first study that we are running is in combination with fulvestrant.
OK. Your preclinical model suggested levels above 200 would be optimum or adequate coverage. What are you looking for by going above 1200 at this point? Are you trying to find a DLT? What is the rationale for keep escalating?
Yeah. I mean, I think you want to see if there's a DLT. You want to know what kind of dose flexibility you have in moving up, certainly. If we need that kind of dose flexibility as we look at other combinations or outside of breast cancer, it's good to know what kind of exposure we get and what kind of tolerability profile we have in that we may expand our combination portfolio. In the absence of those data, certainly the regulators as well as the clinicians are going to say, is this a tolerated dose? Can you go forward? While we're at the helm of pushing forward the monotherapy study, we really want to understand dose, exposure, and tolerability so that we can set ourselves up to move more fluently into combination studies, combination studies down the road. How much optimization will we do? It's hard to say.
We really want to prioritize moving into these combination studies, especially in hormone receptor-positive patients.
What would you expect the DLT to be based on the animal models and the physiology?
Yeah. We've seen, interestingly enough, in exposures nearly 10x above where we are or expect to get with humans. In preclinical animal studies, we saw very, very few side effects. We've not seen hyperglycemia or increases in insulin. We're looking for more like pruritus, nausea, things like that. Thus far, the leading indicator is we had some grade 1 diarrhea or some grade 1 rash. The tolerability profile isn't really lending itself to say we've got a dose limiting DLT, which is good. It's good news.
The activity that you've seen, the efficacy?
Those data are very early. If you look at the swimmer plot that we presented at San Antonio, you do see at the lower doses, stable disease. What is going to be important is to be looking at the patients who are recruited in monotherapy into the 900 and 1200 milligram cohorts because that will sort of represent a saturation of the target in our mind. Again, the vagaries and the difficulties associated with monotherapy activity in the context of a single arm phase one study, it's difficult. We will understand PK tolerability. We will look for efficacy. Again, we'll very quickly move on to the fulvestrant study and then the triplet studies, which I think you'll want to ask me about.
Right. OK. What did you see in the PK profile as you escalated? What's the?
You can take a look at our poster. We saw after a single, what we've disclosed thus far is some data points at 36 and 900. After a single dose, we saw good dose proportional exposure with very acceptable variability. Fifteen-day steady state also looked reasonably dose proportional. However, there's some variances in the actual exposure profiles on a very few number of patients. We need to add additional, like everything else, there's variability in every biological measurement. We need to add some patients to each of the existing levels as well as to go to 12 and 1500 to get a really good sense of how this molecule is performing as a drug.
OK. I recall the PK curves. I thought that 900 did not go much higher than 600. I think you had indicated that you were already dosing at 1200 so that you had not bumped into a maximum level. Is that correct?
Yeah. We do not think we have bumped into a maximum level. The graph is on a log scale. There is an increase in AUC at steady state. For studies like this, you really need to add some patients to understand quantitatively what kind of pharmaceutical performance that you are having. The other answer, the other dialogue is that it does not really matter. Because again, if you look at our data and you look at the threshold that we believe we need to meet with respect to target coverage, we are getting up above that for a large preponderance of the dosing intervals. That is good. We have to optimize. We have to go from a capsule to a pill. We have to do pharmaceutical science. Even in a sort of a primitive presentation, we are getting the kind of exposure we need to progress the molecule.
OK. You showed also some ctDNA sampling, right?
We will measure ctDNA in all patients in all studies, of course. We only showed two patients in that. The first one, this was at 300, positive for two negative breast cancer. The ctDNA just dropped, was eradicated from a high level to no level at all. Second patient on study was a male breast cancer patient presented with very low ctDNA levels. Of course, perhaps PI3K wasn't a driver at that point. So that patient progressed. The first patient who saw decreases of ctDNA, she's been moved up from 300 to 600 and remains on study to this date. All very early data, but sort of an encouraging indication that the drug is headed in the right direction.
OK. One of the things I've heard from investors is their concern that you haven't seen enough activity yet, hence the dose escalation. What would you say to those concerns?
I would say that we have to keep in mind the experience that most of the communities had in phase I studies. As you're titrating up and you're getting to the right target coverage, the lower doses are unlikely to be active. They just are not. These are heavily pretreated patients that have progressed on other therapies. We had a very open enrollment. We did not restrict or have exclusion criteria, which would help us find single agent activity. What is important to look at is, again, tolerability. Are you covering the target? Where is the ctDNA going? At the higher dose level expansions, are you beginning to see monotherapy activity which comports with what we are seeing historically, not aberrations. If you look at molecules in this class, generally, it is low single digit, maybe mid-teens. Some of our competition saw some better responses.
It really depends on what types of patients you're recruiting into these studies.
OK. All these patients were enriched for 1047R?
Every patient was 1047R positive coming into the study. Is that a fresh sample or is that a legacy sample? All patients had to be 1047R positive. We allowed for even patients which had HbA1c levels up to 8, which is nearly prediabetic, as well as patients on our study could have seen prior PI3K alpha therapy. We had a very open study. We wanted to go as quickly as possible, again, to understand the pharmaceutics of our molecule and very rapidly transition to the more important combination studies.
OK. When are we going to get the next readout and what can we expect?
The catalyst, as they're laid out in the second half of this year, we will provide a more quantitative assessment of monotherapy activity, some additional PK at higher levels, and additional patients in the existing levels. We will progress towards an interim read on the fulvestrant doublet study. The numbers of patients and so forth that will be in each of these cohorts will provide guidance to those as time goes by. It's our intent. The kinetics of the study right now certainly suggest to us that we'll be able to make those important disclosures in the second half of this year.
OK. The combination data would be?
The fulvestrant data, we'll have interim data second half of this year. Again, certainly, we'll wait till we have enough patients, enough patients on study to have a significant number of serial scans and the like to make sure that we're guiding on the activity of our molecule as a doublet in a very accurate way.
OK. There are some patients, triple positive patients you're testing in there too, right, with Herceptin?
We have a guidance to start a HER2 positive setting. Excuse me, just a HER2 positive setting. There is significant preclinical data and clinical data suggesting the importance of PI3K alpha mutations in the context of HER2 positive disease. We have disclosed that we have plans to run a combination study of OKI-219 with Trazimera, which is Pfizer's biosimilar for trastuzumab. We are thinking of other molecules to combine with in the HER2 space. Certainly, HER2 ADCs or small molecule HER2 inhibitors are something of interest to us, as well as interest coming in from the clinicians that we are working with.
OK. Do you expect to see, at least in some of these settings, triplet therapy?
The most important triplet therapy, which actually has already been an important study has been run by Roche with inavolisib, would be a PI3K alpha inhibitor of some sort, a CDK inhibitor of some sort, and then an estrogen receptor targeted agent of some type. We certainly are very interested in combining OKI-219 with a CDK inhibitor, whether it's a marketed 4/6 or whether it's a late stage development selective CDK4 with fulvestrant or letrozole. This is really going to, in our view and many people's view, this could constitute what would be first line therapy in the hormone receptor-positive space. We are going to move as quickly as we can to those. Certainly, the interest on the part of investors and doctors and strategic pharma are that's the place to head towards. The INAVO120 study run by Roche is an important landmark.
We can create better regimens than that, certainly. That is certainly OnKure's intent.
OK. I think one of the things that's probably impacted investor perception is the former Lilly program. They had a drug from LOXO-783. It was also focused on 1047R. That drug had some data also, I think, at San Antonio that showed it had some toxicity issues, but they didn't get a lot of activity. They had a backup compound. They also decided to buy Scorpion, which is not as selective an agent as.
There's a lot to unpack there, right?
Yeah.
They analyzed this molecule from Petra, sight unseen, and put it into the clinic with great hopes because it was more of an 80-fold selective molecule. As they were dosing up, they never really were able to get to plasma concentrations that were going to be relevant in the context of treating cancer. They saw preemptive GI irritability issues. What came with that was diarrhea. That sort of puts that molecule on the sideline for them because eventually, they want to combine that with abemaciclib, which has its own diarrhea problem. Obviously, they're very excited about getting a PI3K alpha mutant inhibitor into their portfolio because the possibility to combine it with abemaciclib in imlunestrant chemotherapy really was quite attractive to the LOXO Lilly guys. It just so happened that the Petra molecule just did not have the goods.
They must have immediately started a backup program because they did bring forward another molecule that they did report out on SABCS. We saw some interesting ESMO data on the Scorpion molecule. It's two years ahead of their internal program. They did the right thing. It's an interesting molecule. It's going to have its, like any molecule, it's going to have its challenges in developing. The needs of their portfolio, the quality of that molecule made that a good purchase. I'm not going to quit. It's an interesting molecule. It's worth developing.
Are they going to continue? Do you know whether they're going to continue the 1047 program?
Yeah. They're smart. I mean, we worked with a lot of these people when I was at ARRAY, great scientists. I would hope they would. If I was there—oh, excuse me—if I was there, that's exactly what I would do. Because you don't know. I mean, molecules come and go. And they die. And they run into problems. And they have some sporadic off-target tolerability issues with that. If they're interested in winning in this space or at least having an entrant that they can combine with the molecules already that they've committed to in their portfolio, they'll keep their total program going or they'll turn around and buy somebody else. The molecule that they had coming forward sort of had the selectivity profile more similar to Scorpion and unlike our next generation molecule, which I don't know if we'll get the chance to talk about today.
I'm assuming they still have an active discovery program. All bets are on Scorpion STX-478 right now.
OK. Yeah, why don't we talk? I know we're running out of time. The pan-mutant PI3K drug that's going to enter the clinic.
If one looks back at our portfolio, we sort of had the intent to move from the 1047 site to the helical domain site. As we were doing that, we recognized that we did not have to just switch the selectivity, that we could just add to the selectivity. I mean, the science, the medicinal chemistry, the data led us to the conclusion that we could have a single molecule that could cover all these, not unlike Scorpion. We set a higher bar in that we reasoned that a minimum selectivity of 10x was going to be required to inhibit the target in a pharmacologically relevant way without the side effect profile.
We set as a goal for ourselves to create a next generation molecule which had at least 10x selectivity across all the mutants, which would make it superior to Relay and Scorpion given their selectivity measurements. In fact, we've gotten to molecules that we are becoming increasingly comfortable with. We've guided towards a clinical candidate nomination in the second quarter of this year.
OK. How will that fit in? You're looking beyond breast cancer, correct?
We're looking for that molecule in breast cancer and certainly beyond breast cancer as well. Listen, the attrition rate of molecules in the clinic, especially in oncology, is high. At 219, we love it dearly. We're going to take it forward with prejudice. In a sense of solving the entire oncogenic protein problem and doing so in a way that is good for patients and for our portfolio, we're going to move the next gen forward as well. We're going to develop both of these molecules, as they say, push them till they break. If neither of them breaks, then we'll figure that out. We should be so lucky a few years from now to be able to say, you know, this one has--but drug discovery requires us to understand the risk and understand the challenge.
Both of these molecules are going to go forward with haste.
OK. Any questions from the audience before we wrap it up?
Thank you.
Thank you, Nick. Thank you, everyone, for joining us. We look forward to seeing the progress continue.
Thank you.