Awesome.
All right. We're going to go ahead and get started. So thanks so much for joining, everyone. Next up, we have Kymera Therapeutics. Really big year for you guys. Next year will be big, too. But maybe we can just start off with an overview of the company. So we have Bruce Jacobs, the CFO, Jared Gollob, who is the CMO. And over to you guys for an overview.
Yeah, thanks, Kevin. First off, appreciate you having us. It's always nice to be here. It's a great conference. We appreciate the invite. So it has been a big year for Kymera. So just for some context, we were founded almost 10 years ago. So we're celebrating the 10-year anniversary next May. The company was founded around the promise of taking this new, what at the time was somewhat new modality, targeted protein degradation, and taking that into some unique areas where we felt we could approach some large unmet needs where the targets had either been undrugged or inadequately drugged. And that was really the foundational promise of what we were trying to build as a company. And since that time, we've made, I would say, tremendous progress.
We have had a focus early on, and it really became the central focus on immunology markets, given the size and scale and scope and opportunity that's there. And largely because many of those are served, I would say, somewhat underserved by biologics, which obviously are highly effective, but leave something to be desired in terms of the penetration they're able to achieve for a variety of reasons. And we can talk about that later. So the company early on has been focused in part on that and now fully in that area. We've taken five programs into the clinic. Right now, much of the focus and attention is on our STAT6 program. I'm sure we'll get to that in about five seconds. And we're on the cusp of some data that we'll be sharing with everybody in a patient study and have already embarked on our phase II studies.
Beyond that, we're building a broad pipeline. We've got two partnered programs, one other wholly owned program, and some in the pipeline that we'll hopefully be in a position to talk about as soon as next year.
Perfect. All right. So let's dive right into the STAT6 program, since we'll have data later this month, actually. You started the phase 2 study. Phase 1b is ongoing right now. How much was the phase II study informed by what you're seeing for the phase 1b ?
You know, the phase 2 to be really the main study that informed dose selection was phase 1a, the healthy volunteer study, a large study. We learned a lot about PK/PD relationship and really used that as a framework for choosing the three doses that are now in the phase 2b study. We have always positioned the phase 1b as an opportunity for us to really see, hopefully, translation of PK and PD from healthy volunteers into AD patients, as well as an opportunity through that to really confirm those doses that we had already chosen based on the phase 1a.
We really see the phase 1b not being gating for the Phase 1b, but providing sort of confirmatory evidence on the translation side to sort of shore up our confidence in the doses that we chose for the Phase 2b, remembering that the Phase 2b is a dose range finding study. And I think we were able to accomplish that with the data that we were able to see in Phase 1b. at the time that we locked down those doses for Phase 2b. And as Bruce mentioned, we've already now kicked off and started the Phase 2b AD study, dosing our first patient. And we're going to be kicking off the Phase 2b asthma study in the first quarter of next year.
But clearly, there will be a lot to be learned from the study. We went into it with really four objectives. One was to show that we could, as Jared suggested, get translation of the level of degradation, also safety from healthy volunteers into patients. We were able to make the dose selection decision based also on the healthy volunteer, but also on some of the preliminary data from the 1b . And then obviously, I'm sure will be of great interest to everyone, will be the clinical outcomes that we see and also the biomarkers that will give us an indication of the degree to which the drug in patients looks like dupilumab, which it has in all of our preclinical testing. And we'll see how it looks in patients.
Obviously, it's a small study, 20-ish patients, only four weeks of treatment, but certainly there'll be a wealth of information we'll be sharing when we get to that point.
Awesome. That makes sense. How much was the starting up the Phase 2b and the dose selection informed by what you're seeing on the PK, PD, and efficacy side of things from the 1/B?
I think it's a combination of all those things. Again, I think the most important parameters that go into dose selection for Phase 2b are PK and PD, understanding what are our degradation targets for STAT6, understanding that we can completely degrade STAT6. We want to be able to test the spectrum of STAT6 degradation in Phase 2b in order to do adequate dose range finding to understand how these different dose levels correspond to both safety and efficacy.
With that being said, I think, yes, it's always very important, even in this small phase 1b, to be able to understand not just that translation, but also to be able to understand, are we able to impact key Th2 biomarkers, for example, in blood and in active AD skin lesions? Are we able to see any early signal of clinical activity across all the major endpoints in AD? And is there sort of internal consistency between degradation of the target, impact on biomarkers, and clinical endpoints? All of that certainly can provide potentially additional confidence in the doses that we're selecting above and beyond PK/PD for Phase 2b. And also, we think it's important, just from an enrollment standpoint, Phase 2b, we've talked about this study, three dose levels, placebo, 200 patient study, global multicenter study.
Data that come out of Phase 1b, showing potential impact on patients, can also go a long way in helping to increase enthusiasm for enrollment from investigators who are participating in that Phase 2b study.
Perfect. Have you disclosed anything from the phase I-B in terms of baseline characteristics? So baseline EASI, geography, prior treatments, anything like that?
We have not, so that will all come out in our disclosure this month.
Yeah, I think the only thing we've said is that the days of kind of EASI scores in the low 30s that dupi experienced with its first study, SOLO 1, SOLO 2, when there were not treatment options available to patients, like those days are clearly behind us. The industry is finding it more difficult to find that level of EASI patients. And so you've seen some of the recent studies have had EASI baselines more in the 25s. And we've sort of suggested that directionally, we would expect for both this trial and our future trials to probably be in that range as well. But beyond that, we'll save the rest for the data disclosure.
We do, I should say, because this gets asked a lot. We are allowing patients that have been on dupilumab onto both this study and our II/ B, but they can't have failed for lack of efficacy. They had come off for some other reason, tolerability, insurance stopped paying, got tired of injecting themselves, something like that.
Okay, that makes sense. And you haven't disclosed the percent of prior dupi patients in the study. I would assume it's kind of on the smaller side, directionally speaking.
Yeah, I mean, we haven't said one way or the other. As Bruce said, we certainly allow patients who are naive to prior biologics, but under the caveats that Bruce just gave, we do allow patients who have had prior biologics if they were responsive to them. But no, we haven't really indicated any cap or what the expected breakdown is going to be. Again, we'll share all that when the data come out.
Perfect. I think you're measuring out to 42 days in the study, 28 days being the primary endpoint. Are you planning to show any data beyond the 28-day primary?
We are. So it's 28 days of dosing, so once daily dosing, and then two weeks of additional follow-up. So we will be showing the full data set that will span that entire period, and that is with regard to safety as well as biomarkers and clinical endpoints.
Makes sense. What's the relative focus on mean EASI versus EASI responder cutoffs?
You know, I think both. I think with smaller studies, the continuous endpoints, so percent change in EASI over time is probably a more appropriate endpoint for a smaller N. With that being said, when you look at the categorical endpoints like EASI-50, EASI-75, when you have a small N of approximately 20, that can swing either way with one or two patients showing response, for example, or non-response. Our plan is to show all of that because people are interested in understanding what the EASI-50 and EASI-75 are in addition to the change in EASI over time. So we're going to be showing both the continuous endpoint and the categoricals. But just in general, in response to your question, I think the continuous endpoint is probably more appropriate for a smaller data set.
Yeah, that makes sense. What should our expectations be on speed of onset? Maybe you can just remind us what the Dupixent speed of onset was?
Dupixent, as an antibody and given with an induction regimen, so they start off with a dose that's higher than the dose that's used throughout the maintenance phase. So they give a single higher dose, and then they go on to their maintenance dose every two weeks. That allows them to saturate the IL-4 receptor alpha very quickly. So the onset of action is fairly rapid. Likewise, our degrader, although it's a very different mechanism, we've shown in our healthy volunteer study that we actually reach peak degradation as early as four to eight hours after the very first dose. So we also blockade the pathway very rapidly. So we expect between what we do through the degrader mechanism versus what Dupi does through the antibody mechanism, I think both modalities are blocking the path very quickly upfront.
What about on the safety tolerability side of things? I guess like on-target IL-4/13 going down to STAT6, what are the events we should be looking out for?
I think it's mostly what we see with dupi. We've, I think, shown from all of our preclinical data and understanding that STAT6 only serves signaling through the IL-4, IL-13 receptor. It's very specific for that receptor pair, and our drug is highly selective for STAT6. So the only pathway that we're affecting is IL-4/13, and we're blocking that pathway completely. Likewise, Dupi is only blocking that pathway, and so our expectation is that the safety profile that is seen with Dupi, we should be phenocopying that profile with our drug. So if you look at Dupi, a very, very well-tolerated drug, the sort of adverse events that people note are predominantly conjunctivitis, for example. And you can see that in up to 10%-15% of patients who get Dupixent. It rarely leads to discontinuations or dose reductions.
It's more of a nuisance adverse event than it is a dose-limiting adverse event. And so people are often asking us, well, do you think you'll see conjunctivitis like Dupi? And if so, do you think you'll see more or less? What we normally say is just based on the fact that we're both blocking the IL-4/13 pathway and also understanding that the mechanism by which Dupi leads to conjunctivitis, which happens mostly in AD patients, really isn't known. But nonetheless, we tend to sort of say, well, we expect to see a similar rate of conjunctivitis if you were to ask us before we even started the P hase 1b. But again, it's probably going to take a larger data set, larger patient numbers, longer treatment duration for us to really understand whether we do or do not see conjunctivitis.
Conjunctivitis in the first four weeks of D upi happens in maybe up to 5% of patients. And so again, our Phase 1b is a 28-day study. So whether we see something or don't see something, you have to take that with a grain of salt because of the size of the study and the limited duration of treatment.
But heading into this study, we've been, I think, couldn't be happier with the safety profile of the drug. We had really placebo-like safety in the Phase 1a , healthy volunteer. Everything we've done in all preclinical models, every species, every dose, up to 40x human efficacious doses, we've had literally no observations. So I think it speaks to the selectivity, potency of the molecule and what is known about the IL-4/13 pathway.
Perfect. And do you think STAT6 has any scaffolding function?
I wouldn't say scaffolding function per se. I mean, transcription factors in general are somewhat multifunctional proteins, right? They're interacting with receptors. They're interacting with other kinases. They're binding to DNA, interacting with other proteins that are involved in gene transcription. So they're complex in that manner. With a transcription factor in general, if you really want to abolish its function, you need to get rid of that transcription factor, which is why we think degradation is the preferred approach. What's also important here, because we do get asked the question, well, how is a degrader different from an inhibitor of STAT6? It's also about the pharmacology of what our drug does. Degraders use a catalytic mechanism, meaning that one molecule of degrader can degrade thousands of copies of the protein.
So even when the drug is cleared from the circulation after a dose, tiny amounts of drug in the cell are still mediating maximal degradation, which is why a single dose in healthies of our drug will give full degradation for three to four days before you see recovery. So that allows us to get round the clock, 24/7, full degradation of the target and full blockade of the pathway with once daily dosing. Inhibitors, small molecule inhibitors can achieve that pharmacology. Their impact on the target is very dependent on exposure. So as plasma exposure wanes after a dose, especially if you're giving a daily dose, so does the effect on the target. Very difficult to get full 24/7 suppression of a target like STAT6 with an inhibitor. Even if you were to give it two or three times a day, probably still difficult.
That starts becoming fraught probably with toxicity because of the doses and the frequency of dosing.
Perfect. And as we look ahead for the Phase 2b if you just started up, how quickly do you think you can move there?
Right now we've guided that for the Phase 2b AD study. As I mentioned, it's a 200-patient study, 16-week primary endpoint, which is mean percent change EASI from baseline. We've guided right now that we expect to share data by the middle of 2027.
Perfect. All right, let's actually move on to IRF5. I spent a little bit of time there. Maybe you can just kind of remind us of mechanism and why you chose this target.
Yeah, IRF-5 is a very exciting program for us. It's our other solely owned program in our immunology pipeline right now. Big pharma and biotech are very interested in this target for a decade or more. It's a transcription factor. There are multiple isoforms of the transcription factor, multiple different types of IRFs. So it's been very difficult to selectively drug IRF-5 only and hit all the isoforms. The reason there's been so much interest in it is that it sits at the crossroads of all of the Toll-like receptors and other innate immune receptors. And it's really essential in controlling type I interferon response, pro-inflammatory cytokines by myeloid cells, as well as antibody and autoantibody production by B cells. And there's very strong genetic associations between mutations in IRF-5 and lupus, rheumatoid arthritis, inflammatory bowel disease, and other type I interferonopathies.
So I think people can see what the value proposition is in those types of diseases if you could target IRF-5 just because of its key role across all those pathways. And also the fact that it's only selectively expressed in limited cell types and only activated in pathologic settings. So you can knock down IRF-5 hard and chronically and not have infectious complications. So for all those reasons, people have been very interested in the target. We have now developed a unique way of actually successfully drugging this target with a highly potent, highly selective oral degrader. We've shown very, very strong activity in mouse models of lupus, two different mouse models that we showed at ACR last October. We've also shown strong activity in RA. We're generating additional data across other interferonopathies and IBD.
We think this is a target that could really be a game changer for those particular diseases. We're excited to be moving this program into phase I healthy volunteers early next year. We'll have a data readout from that study early next year. Then we'll have our first patient study, which we haven't given details on yet, that will come on the heels of completing that phase I healthy volunteer trial.
All right, great. What's your target level of degradation for IRF-5? And to what extent is that formed by the preclinical data versus some of the human genetics also?
Yeah, it's a good question. Probably somewhere north of 90%. Our preclinical animal model data tell us that degradation in that range is giving us maximal activity. In these lupus models, we go up against all the approved drugs like Saphnelo and TLR7/8 antagonists, which are not approved but are active in lupus and multiple other drugs in lupus where we're superior to all of those when we're degrading IRF-5 at that level. And it seems to be well tolerated in the animals. So that'll be probably our target level of degradation. And we should be able to achieve that in our healthy volunteer study, just as we've done for STAT6 and IRAK4 before. We'll be looking at degradation in blood and in skin in order to make sure that we can get up to doses that are giving us that level of pharmacology.
That's also safe and well tolerated.
Are you doing a cytokine challenge in the phase I?
We haven't described the design of that phase I . I can say it's unlikely we'll be doing any sort of in vivo cytokine challenge, but in terms of biomarkers that we could look at to see how we're affecting the various pathways that IRF5 controls, that's still a work in progress in terms of what we're going to be incorporating into our phase I study. As we get closer to starting that study, we can reveal more about the sorts of biomarkers that we might be looking at within the study. I think certainly number one for us is going to be, can we degrade the target hard in blood and skin? And can we do that at doses that are safe and well tolerated?
Have you laid out the different PD markers you're looking at in phase I in healthies? And what do you think is going to be moving most clearly and with least variability?
I think the main PD markers for IRF5 in healthies, again, is going to be really IRF5 itself. Now, you can look at the activation of the pathway. You can stimulate cells even ex vivo with agonists of various Toll-like receptors like Toll-like receptor 7 and 8 and Toll-like receptor 9. These are important Toll-like receptors for myeloid and B cell activation. And there are ways that you can actually assess activation of those pathways and the effect of your drug on the activation of those pathways. We're in the midst of sort of looking at whether we want to use those sorts of assays and if so, which ones and how we would use those in the clinic. But it'd be very unlikely that we would do anything that would require in vivo challenge because you really don't need to do that.
You can do a lot of these things ex vivo, so you're not really putting any of your healthy volunteers at risk, but you're still getting that important information.
That makes sense. We're a little over time. So I think we'll wrap it up there. But thanks so much for joining.
Yeah, thanks for the questions.
Thanks, Kevin.
Appreciate it.
Thank you.