Welcome, everyone. Thanks for joining in for our last session of the day. I'm Gavin Clark-Gartner, one of the senior biotech analysts here at Evercore ISI, and really happy to be joined by Nello Mainolfi, who is the CEO of Kymera Therapeutics. Thanks for joining.
Thanks, Gavin. Thanks for having us.
Definitely. All right, why don't you just start off with a quick overview of the company, where things stand today, and then we'll run into more specific questions.
Sure, so Kymera, we founded Kymera about eight years ago with the mission of building a fully integrated biotech that will use protein degradation to go after a whole new family of targets that have not been drugged or drugged well before in areas of higher unmet need. And our goal has been, since the beginning, to work, at least initially, in pathways that would have application in both oncology and immunology. I would say three to four years ago, we started to invest much more heavily in immunology, especially since the early data we generated with IRAK4, and more recently announced that our focus, at least in the foreseeable future, is to be fully committed to immunology. The opportunity there is really unique, I think, and it's important to maybe spend a minute on it.
If you look at immunology, in the past 20 years, it's been transformed by innovative therapy. I would say mostly injectable biologics. They've both validated key pathways. Think about the IL-17, IL-23, IL-4, IL-13, and these have not only, again, validated the biology, but also helped, at this point, millions of patients, and traditional small molecule, oral small molecules, have tried to impact these pathways, but have kind of come short on the efficacy, I would say. I mean, mostly, when you talk about small molecule in immunology today, you're really saying you're going to compromise on the efficacy, sometimes even on the safety, for the convenience of an oral daily drug. What we want to bring forth, and the targeted protein degradation has a unique opportunity to do so, is to develop a whole new generation of drugs that have biologics-like efficacy with the convenience of an oral drug.
And we've shown with preclinical data and early clinical data across our pipeline that that can be done. And next year will be a big year of early readouts for our new program. So it's an exciting time for Kymera.
Awesome. So let's dive into STAT6 first, since I know there's a lot of investor focus on this indication. Maybe just kind of quickly frame why you're degrading Stat6. What's the validation for this target? Then we'll go into a little more specifics of the upcoming data.
Yeah, so one thing that has been unique about Kymera has been our philosophy about target selection, one of the things that are unique. The target selection has been driven by four key pillars. We want to try to degrade targets that have not been drugged or drugged fully in pathways that have been validated clinically, ideally where there is human genetics data against that target, where we have opportunities to have early differentiation and targeting large patient populations. I think when you think about STAT6, it fits perfectly into that Venn diagram. It's a transcription factor, difficult to drug, generally undrugged. In a pathway that has been validated, the IL-4/13 is right now the hottest pathway in immunology. Dupixent is the largest drug in immunology, close to $15 billion of sales per year.
Again, a pathway that has been validated, a target that has human genetics for both gain of function and loss of function, and a large target population. If you look at Th2 diseases, which is really what we're talking about, and then we'll talk about manifestation, which is AD for skin manifestation of Th2 disease, asthma for respiratory manifestation, COPD, and others. These are in the, actually, the largest seven markets. These are 150 million patients. So the opportunity is vast. The biologics are actually just the tip of the iceberg. Actually, what's on top there is actually most patients. 99% of patients don't have access to advanced therapy, and that's what we want to change with an oral degrader of STAT6.
Yeah, well said. All right, so turning over to the phase I healthy volunteer study. Maybe just lay out the design, including how many doses you're testing and where you think dosing could land.
Yeah, so maybe before I do that, just a bit of a background on the actual science. So what we've shown that by degrading STAT6 so remember, STAT6 is recruited to the IL-4 receptor when IL-4 receptor alpha is activated with IL-4 or IL-13. And so it's right downstream of, again, the Dupixent target. And so by targeting it with an oral degrader, we have shown preclinically that we're able to basically phenocopy the Dupilumab. We have shown in both cellular system and in vivo models that we can be at least as potent, if not more potent, than a monoclonal antibody. So the design and also safety has been exceptional in our preclinical species. So we have all the pieces in place for this to be a really amazing program.
So our phase I healthy volunteer study, which we started on October 22, when we dosed our first subject on the study, is, I would call it, let's call it traditional in terms of design, SAD and MAD study, where we're dosing patients in a single ascending dose of a single dose, and then we're giving the drugs for two weeks every day at ascending doses. So the key important outcome of the study is really to demonstrate that STAT6 degradation is safe and well tolerated.
Because we know the biology is so compelling, and there is so much parallel with the IL-4 receptor alpha blockade, that to be honest, our expectation is that upon demonstrating our ability to degrade the target safely, then we have eight indications which Dupixent has shown robust phase III, seven of which have been approved, that we have a blueprint of what that looks like, and we expect a similar level of efficacy. So this is a novel target. And so for us, is can we degrade it, degrade it well, 90% or more, and is that well tolerated? All the indications we have based on our preclinical data will be that the answers will be yes. But obviously, drug development is not done on paper, but it's done in the clinic. So we want to show that. And those are really the key outcomes.
We are measuring also some Th2 biomarkers that have been demonstrated can be measured also in healthy volunteers. Dupilumab has shown that you can reduce, even in healthy volunteers, by blocking the pathway completely. IgE in the, let's say, 10% to 20%, and TARC 30% to 35%, and so that's not really a meaningful outcome, and it's not really translatable to a disease context, but it's another measure of pathway engagement, so we'll measure those numbers, and we're confident they will look in the same ballpark, but the real test for, let's say, Dupilumab-like profile will be in patients, where you can look at blood, a plethora of Th2 biomarkers, as well as skin. You can look at the transcriptomic profile of Dupilumab, which is well characterized, and so we look forward, after the healthy volunteer study, to going to patients ASAP.
That makes sense. And sticking on the degradation side, are you also doing skin punch biopsies in addition to measuring in PBMCs?
Yes, we are. As we've shown also with IRAK4, we will look at degradation in blood as well as in skin using biopsies.
Yeah. So when you noted a 90% degradation target, is that referring to skin and the PBMCs?
Yeah. So what we've shown, at least preclinically, so we've shown two things that are both relevant, but differently. So in this, we actually not developed. We replicated a model that had been developed by Regeneron and Sanofi back in the day, where you use a humanized IL-4 receptor alpha mouse, where you can actually dose Dupixent. And in this house dust mite asthma model, exceptionally, I think, translational model of TH2 inflammation. So there we show that 90% degradation of STAT6, in this case, was in the central compartment, equated to a level of activity that was similar, some would argue even slightly better than Dupixent. Obviously, we didn't because this was an asthma model, we didn't look at skin degradation in mice. It's also actually quite complex.
But then we went into higher species and showed that the doses in which we saw 90% degradation in plasma, we would also see 90% degradation in skin, given that skin is a target tissue. Our goal, whether we must have it or not, I know we want to have it in blood. Obviously, in skin, we don't know if we really need to reach 90%. But I think we'd like to see 90% degradation in blood than skin to have really the best-case scenario. So yes, that's the bar.
Yeah, that makes sense. That makes sense. Going to the other biomarkers, CCL17/TARC, what should we expect for baseline levels in healthy volunteers? There's a fair amount of variability. And how do you think about the effect size, right? How do we account for that?
As I was saying earlier, it's hard to take a value that is within the limit of normal and reduce it, right? So the dynamic range of that window is small. And basically, you don't have the pathway activated. So how can you show impact on the pathway if the pathway is not activated besides the proximal biomarker, which is STAT6 in our case? But again, even if the levels of TARC are low, other drugs in this space, both the IL-4 receptor alpha, Dupilumab, as well as IL-13 biologics, have shown that you can reduce this level of TARC in the, again, 30%, 35%, even though the levels are not elevated. And again, given that our drug works in the same pathway, we are going to measure it because we expect to see the similar effect.
That makes sense. And is anything you laid out different for IgE other than the potential percent reduction?
I mean, IgE, to be honest, is even messier. If you look at the paper that Regeneron published on all these biomarkers, the IgE is the most confusing one because there isn't actually a clear dose response, and the levels of reduction are between 15% and 25%. In fact, I've noticed other companies in the space I don't even want to mention, but have not even reported IgE data. And I know I don't blame them. They're probably such a noisy assay that it's difficult to even interpret the data. But again, the data are out there. What we hope to guide here is to focus everybody on the key readout, which is degradation and safety, which is really what we need in order to continue development because the pathway blockade in healthy is measured by STAT6 degradation.
Hopefully, while we, again, we will share the Th2 biomarker data, understanding that those are not relevant to the disease, and they're very qualitative and not quantitative. Hopefully, everybody understands the science behind it. It's actually very easy to understand. Just the paper is available, and you just look at the numbers and the dynamic range of the window, and you'll take home the message that hopefully I'm trying to send here.
Yeah, I think that's clear. And you're not doing any ex vivo stimulation work, are you?
Yeah, we're not. I mean, it's actually probably not the best use of this pathway biology to do ex vivo. It's really maybe not very effective to do. And our focus will be everybody, us included, us first, I should say, wants to see what this drug does in patients. Because that's really the testing ground for any drug. So we're more focused on trying to move into patients ASAP than protracting a healthy volunteer study for questionable biomarker readouts.
Yeah, that's fair. I'll just squeeze in one last question on the safety side here, and we'll move on. Anything that's on target that could potentially turn up in a 14-day study we should be looking out for? Maybe just remind us what the small on-target effects with the pathway are.
Yeah, so what I mean, we haven't in our preclinical species, in the TARC studies, we haven't seen any adverse events in any dose or concentration, even going 4x above the efficacious concentration. Again, human genetics, gain of function, severe allergic diseases, loss of function. At least there was a recent publication, no phenotype. So we don't expect if you look at Dupilumab, safety is one of the best tolerated drugs. There is some conjunctivitis. I think that's the largest signal that is obviously treatable. To be honest, it's unclear whether in two weeks you can actually see that. But we don't have something to look for, which is obviously good. But obviously, we'll keep an eye out for anything.
Yeah, makes sense. All right, so let's turn to next steps. What have you said about after you get this data, dose selection, run through all the biomarkers, et cetera, what have you said about the next study or studies that you're thinking about running?
Nothing, actually. But we have actually not said a lot, mostly for, I would say, competitive reason. This is a space that while we're first, we know that there is lots of focus and lots of attention, and the competitive intensity will increase. But what we decided to do, given that we're still a pre-commercial company, we need investors to continue to be excited about the company and also understand where we're going to invest our capital. So early next year, we plan to share a bit of the high-level plan for the following, let's call it, 12 to 18 months. So that should give an idea about what happens after phase I Healthy and what is the mid to late-stage development plan.
Makes sense.
So slightly over a month more of wait.
Yeah, not long.
Not long.
All right, let's go over to TYK2. So just remind us, why degrader versus really potent inhibitor here? We'll go from there.
Yeah, so I go back to human genetics. There is TYK2 is probably the most compelling human genetic story in immunology of the past decade. And the loss of function TYK2 profile is very clear. You have inhibition of IL-23, type 1 interferon, and IL-12. And there is no small molecule that is able to replicate the loss of function profile for two reasons. One, which is a biological reason. TYK2 has both a kinase and a scaffolding function that even the allosteric inhibitors that have been developed are not able to turn off completely. Second, while I don't want to get into arguments with other companies, we don't believe there are molecules out there that can inhibit the target 24/7 completely, which is, again, the story of immunology of small molecules. We have shown now preclinically with 295, we're able to degrade the target completely.
You see, we have recent data on our website. We believe that profile will be highly differentiated. And our bar is both challenging and very simple, which means our bar is we want to reach the level of efficacy that has been seen with the biologics of those pathways, especially the IL-23 biologics. And we're happy to commit that if we don't see that efficacy, we are not committing more resources to that program.
Got it. Thinking about some of the safety events that we've seen with other TYK2 inhibitors, I know there were two that were an area of debate. One was the CPK increases. One was acneiform dermatitis. There was some debate as to whether those were TYK2 or JAK-related. Do you have any views on that? And similarly, what are you looking for in phase 1?
Yeah, so it's hard, I mean, my views will be speculations. So I usually leave that for non-FDA chat environment. I would say I look at human genetics. If you look, there are people that have loss of function of TYK2. And there is some susceptibility to a couple of infections, none of which are the ones or none of the ones that you mentioned that are easily treatable and treated and overcome. And I think everything aside from that, I believe, will be a molecule-specific event, at least in our case. So we have confidence that if you have a clean molecule and we know how to make exceptionally selective degraders, the safety profile should mirror the one that you see in humans without TYK2.
That makes sense. Thinking back to your comment around kind of the bar you're setting on efficacy in this, I may be jumping the gun here, but would you ever consider running head-to-head studies with, say, deucravacitinib?
I mean, I think Takeda is actually running their study in their phase III in psoriasis. I suspect that by the time we are close to market, so TYK2 will not be the best TYK2 molecule. But I don't think that will be needed because if we're moving into phase III, that means our phase II data shows that we're dramatically superior to the inhibitors. And maybe a question will be whether you run a head-to-head with the biologics, not with an inhibitor.
Got it. Quickly on IRAK4, we just kind of I think you've done a good job framing this. Maybe just remind us the changes that were made to the phase 2b.
Yeah, so the initial study was designed more of a proof of concept phase II-A study. If you look at HS single-dose placebo, we realized with Sanofi that there was an opportunity to accelerate and make these into a dose-ranging phase II-A/B study that will allow us to go into phase III. Sanofi elected to do an IA of safety and efficacy, an interim analysis, I should say, to make a data-driven decision. The analysis was supportive of the expansion. What we did, what they did, added one dose to each of the studies. HS is two doses, plus one placebo. It is three doses plus one placebo. This has almost doubled the studies for each. It's 170-200 patients now, each study. The readouts have been pushed to 2026 versus 2025.
That makes sense. On STAT3, would you ever consider advancing that in immunology?
We've debated this a lot in many of these FAIR chats too in the past. There is definitely a role for STAT3. There is definitely a role for STAT3 in immunology. Given the programs that we have in hand, where we have pristine safety and impeccable efficacy, STAT3 requires more of a walking a line between efficacy and safety. There is a place that we might go, but it's not high on our priority list today.
That makes sense. Awesome. Well, a little over time, so I'll cut it there, but really looking forward to 2025 and talking again soon.
Thanks, Gavin. Thanks for having us.