Michael Schmidt, Senior Biotechnology Analyst with Guggenheim, and I'd like to welcome Nello Mainolfi, the Founder, President, and CEO of Kymera, to this next fireside chat. Nello, welcome, and thanks for joining us.
Thanks, Michael, for having us today in this snowy day, I guess.
So why don't we start out with just a high-level overview? So last year, you sort of outlined your strategic priorities, and again, earlier this year, as it pertains to this year, where obviously focus will be on advancing and expanding your autoimmune disease target portfolio. So just remind us of, if you give us a quick overview of your broader immunology strategy and how it fits into your well-established TPD platform at this point.
Great, thanks. So I just want to remind everybody, so Kymera is focused on using this transformative modality of targeted protein degradation to advance a whole new generation of medicines. And our strategy in immunology, which obviously has been years in the making, which I would say we unveiled more specifically early last year in 2024, the strategy is really what we have both learned from our own preclinical and clinical experience, and also by analyzing, observing, and understanding the opportunity, both clinical and commercial, is rooted into a relatively simple idea. If you are able to marry, again, the power of targeted protein degradation with the right target, you can generate profiles that have never been generated in this industry. And the profile that we are focused on is to have oral drugs with biologics-like efficacy.
As you know, that has been attempted by small molecule inhibitors for the past 10, 15 years after a lot of these pathways in immunology have been validated. But more times than not, or I would say almost always, small molecule inhibitors are not able to deliver biologics-like pathway inhibition. Because degraders have this catalytic mechanism that is able to decouple PK from PD, we're able to generate these really unique profiles. And so our strategies in immunology are focused on pathways that have been validated by other agents, usually by biologics, upstream biologics, going after targets that have been undrugged or poorly drugged, where we can have access and we can benefit millions of patients around the world. And so what we've generated is a series of programs, starting with IRAK4, which is now in phase IIb in HS and AD with Sanofi.
STAT6, we have our first STAT6 agent in the clinic for probably, I would say, one of the most exciting targets in this industry. This is now in phase I in healthy volunteers with multiple data sets this year. We have a TYK2 degrader entering the clinic soon with data also before the end of the year. And we're about to unveil another program. We've said we're going to unveil in the first half of the year. This is a program that is on track to be in the clinic in early 2026. And maybe if I can close with just a simple but very powerful concept, what is the problem we're trying to solve? So I think we have a lot of effective medicines in immunology.
If you think about the advances we've made in the past 10, 15 years with especially biologics, if you think about anti-IL-17, anti-IL-23, anti-IL-4 and 13, we basically drugged some of the most fundamental pathways. But if you look at the 10 most common immune inflammatory diseases, there are about 160 million patients. Only 5 million, 3%, have access to advanced systemic therapy. So Kymera is here to change that paradigm. And so the opportunity is to actually have patients access this advanced systemic therapy as oral drugs. And this is millions of patients that we're talking about and potentially hundreds of billions of dollars of value.
Great, thanks, Nello. So question KT-621, your STAT6 degrader, which obviously has generated a lot of excitement in industry and given its broad potential as a therapy for Th2-driven inflammation. So maybe first question is, how confident can we be that STAT6 knockdown or degradation can actually replicate the mechanism and biology of IL-4/13 antibodies like dupilumab?
Yeah, so the thesis, when we started this program several years ago, I wouldn't say exactly when, what we saw was a unique opportunity. It's very rare in human biology, and especially in immunology, to have a one-to-one relationship between a receptor and a transcription factor. And this is one of the few cases where actually targeting IL-4 receptor alpha, which dupilumab does, and we believe targeting STAT6 will lead to the same biology. And the answer is quite simple. If you activate IL-4 receptor alpha, STAT6 is recruited to the receptor. So STAT6 is a necessary step for IL-4 and IL-13 signaling to take place. So we've shown extensively, and so there are publications out there that point to this, and we've shown extensively that by targeting STAT6 and degrading STAT6, at least 90%, leads to a dupi-like effect, in some cases even superior.
KT-621 is actually intrinsically more potent than dupilumab. We have IC50 in the low picomolar range in human cell systems versus triple digit or even more for dupilumab. So we have a drug that works as well as a biologics that block in the pathway, but is also a conveniently dosed oral drug. The other thing I will say, which might be missed, there is strong human genetics on STAT6 that actually speaks to how coherently this target behaves versus the validated upstream biologics. If you have a gain-of-function of STAT6, if you have a human gain-of-function of STAT6, the phenotype is severe allergic diseases, which is totally, again, correlating with both the genetics and what we learn about for receptor alpha blockade.
Recently, there has been a first report of heterozygous loss of function of STAT6, which is both healthy, so it speaks to the safety of targeting STAT6, but also, as is shown in that publication, from a few subjects that were protected from severe Th2 asthma so we have a plethora of data that speaks to how well these two targets speak to each other and we've shown, again, as I've said extensively preclinically, that targeting STAT6 can give a dupi-like effect and so we ended up calling this program, dupilumab in a pill.
Great. So obviously, again, a super exciting target. Not surprisingly, you guys are upfront, I believe, but there's a couple of other companies pursuing it now, also with traditional inhibitors. And so I guess you mentioned this 90% knockdown target knockdown level. So first question is, I guess, how much confidence do you have that this preclinical knockdown data translates into the clinic? And then maybe follow-up is, what gives you confidence that your degrader approach could be best in class, perhaps, relative to traditional?
Yeah. So first, yeah, thank you. So we're the first company that actually, we are the only company that has released a comprehensive data set preclinical on KT-621 or STAT6 degraders. So I think we're probably the only company that can claim that we actually have a STAT6 agent that has been characterized preclinically. So first, I would say, answering your first question about translation into the clinic, this is the fifth molecule, the fifth assets across different both pathways, target classes, and indications that we have put into the clinic. In all the other programs, we've been able to reach the targeted degradation. In all cases, actually, we're able to reach more than 90% in a dose-responsive manner. So we have the utmost confidence in our platform and our capability, ability to design well-behaved degraders. So our confidence stems from that. The second part is the confidence of degraders.
So I take it down to biology because otherwise we'll kind of get tangled up in technology discussion about degraders versus inhibitors and the nuances thereof. I like to just focus on the biology. So what we've shown, and again, if others have similar data, we'd love to see them. We've shown that if you degrade STAT6 at 90% or more, but clearly 90% in this mouse model, our phenotype, and we're not talking about just an individual endpoint. If you look at the house dust mite model that we've run, which we use the humanized mice in which you can actually dose dupilumab, this is a model that actually Regeneron developed back in the day. We have shown that across a plethora of biomarkers and endpoints, 90% is at least as good, if not better, than dupilumab.
We believe that the only way to achieve this profile in a once-a-day oral drug manner is through a protein degrader. We have extensive experience with other modalities to target STAT6, including small molecule inhibitors like Kymera. In our hands, we've never been able to show that a small molecule inhibitor can lead to the same pathway blockade as a degrader with a reasonable dose with a once-a-day oral pill.
Right. And as we look perhaps at your IRAK4 program as an example of how well this works, what do we know about the resynthesis rate of STAT6, perhaps relative to STAT4, I'm sure you've looked at that in humans?
Yeah, so I like not to disclose many of these details. What I can say is that the half-life of KT-621 and the protein resynthesis of STAT6 work well together for us to have a drug that can be dosed once a day orally.
Okay, great. And then obviously, you are in your healthy volunteer study. I think there's a lot of excitement around the upcoming first-in-human data around this. And so in addition to the, obviously, knockdown or target degradation level, you've also talked about looking at some preliminary PD markers. So just remind us, what are some of those data and how should they inform investors about the potential of this?
Yeah. Yeah, so I'm going to get there, but I want to just talk a bit about our development strategy. So our development strategy stems from our commitment to actually file an NDA for this drug as soon as possible. Obviously, we've got to go through the stages of development. So what is on critical path for us is going from a healthy volunteer study into a dose-ranging phase II studies. And as you know, we're starting two phase IIb studies towards year-end early next in AD and asthma, which we believe will be sufficient to inform all the other indications. And so that is where we will establish, hopefully, in a robust manner versus placebo in a large study, the safety and efficacy of KT-621.
So now going back to where we are, what we've decided to do this year to say we're going to run a healthy volunteer study where our focus is really safety and degradation. This is the first time this target has ever been drugged. We have amazing safety preclinically, but obviously, we want to see that in humans, and degradation, as we said, it's something we have extreme confidence in, but it's never been done before for STAT6, so we want to be able to show that, so scientifically, robustly, the most important data is PK degradation in blood and skin, reaching this 90% that we need, and safety.
Now, we've decided to also include in our development plan a phase 1b in atopic derm patients because there, if you look at dupilumab studies, in 28 days, you actually can develop a very well-characterized biomarker signature in blood and skin that some would say it's a dupi signature. And so our goal for the phase 1b study is to actually power that study so that we can show a robust biomarker signature in blood and skin. We'll also look at some efficacy because it's a 28-day study, but really, it's around biomarkers in blood and skin, so why have I said all that? And I apologize for taking a very long time. It's because that is where we really want to establish a biomarker profile.
Now, in healthy volunteers, many of us will have detectable levels of TARC and detectable levels of IgE, mostly based on how much Th2 tone you have as an individual, meaning how much reactive you might be to allergens in the environment around you. But there is obviously no Th2 inflammation. So what you've seen with dupi is that you have a very non-dose-responsive qualitative reduction of these biomarkers that are already at baseline. Like IgE, I think at two weeks was like 7%, 8%. And TARC within the first two weeks, you can reach about 30%, 35%. So obviously, we'll collect the data because others have done it. And I mean, to be honest, I expect that it's going to look in the same ballpark as dupilumab.
What I was trying to say is where it's scientifically robust is in a patient population in a phase 1b study and clearly not in healthy where we're trying to look at whether we are decreasing something that is already close to the lower limit of detection.
Right. And then help us understand how you think about dose selection based on the healthy volunteer study and then perhaps dovetailing with your planned AD study?
Yeah. I mean, the transformative nature of TPD actually goes to the power of the technology all the way through how impactful is the technology and its help for you to develop these drugs, and I just give the example of if you run a SAD and MAD study with either a biologics or a small molecule, just to use simple examples, it's really hard for you to know exactly what's going on, how much target engagement you have, how much pathway suppression you have. Yes, you have some downstream biomarkers, but the noise of the biology, especially in healthy volunteer, doesn't give you an opportunity to know exactly what you're doing. So you do this dose selection that are often broad and that are based on some assumptions about PK and PD. With protein degraders, you know exactly what's going on.
So we know a dose that gives us, let's say, 90% degradation. We know a dose, or hopefully, we'll know a dose that gives us 80% degradation. We know a dose that gives us hopefully more than 90% degradation. So we like to think about using the healthy volunteer study to establish PK degradation and safety, and use this. At least on paper, we might be able to have more than 100 subjects on study. So we'll have a plethora of information to then decide what are the two or three doses that we're going to take into our phase IIb studies. Yes, the phase Ib will be helpful, but I think it's really the healthy volunteer that gives us a great starting point for the dose selection.
Right. And then obviously, safety is a big factor in autoimmune disease, especially atopic dermatitis, some of those indications. Is the KT-474 experience a good example of how safety could look like? Are there any particular side effects that you're especially looking out for?
Yeah. I mean, as I mentioned earlier, the human genetics for STAT6 is very strong. Our preclinical data, I would say it's even more convincing. Obviously, we just shared qualitatively what it was, but I repeat, we didn't see any adverse events in any of the studies that we've run at any concentration, even at 40-fold above the efficacious concentration, so we feel very good about safety, and we also appreciate that in order to develop a drug that can be as impactful as some of these biologics we're discussing, safety needs to be pristine, and we have a bar really high for that, and we hope that we'll meet it.
Right, and then maybe just to wrap this discussion up, so you did commit to this, as we just said, this AD phase 1b study. How do you, in the midterm, I suppose, plan on mapping out the development strategy beyond AD? Are additional studies gated by the AD data that you'll generate later on this year and next? Do you plan on pursuing multiple parallel development opportunities? How should we think about that?
Yeah. Yeah, so I would start by saying that we're benefiting from multiple studies that have been run by multiple companies that have gone after this pathway. And so we've seen that, again, using an IL-4 receptor alpha monoclonal antibody like dupilumab as an example, this drug has been shown positive phase III data in at least eight indications, if I can remember. It's been approved, I believe, at least six. And so we have a plethora of indications that are totally de-risked. Our approach is that we want to be ready as an organization to being able to run parallel phase III studies in all those indications. I'm not saying we will do so, but we want to be able to do so. The development plan is using this parallel AD and asthma phase II dose-ranging studies paradigm.
So we basically want to establish what is the phase III dose that we want to take into AD, expecting that that might be the same dose that we will take in all the other derm indications. And then we're going to use the phase III dose that will come out from the phase IIB study in asthma, not only for asthma, but also for the other respiratory indications, for example, COPD or chronic rhinosinusitis. So that's the development plan. These two, let's call it sentinel dose ranging, will potentially enable us to then run multiple parallel phase III studies across all the indications that have been de-risked by other drugs.
Right. And will you initially focus on dupilumab-approved indications and then branch out to additional opportunities, or will you take on some of these perhaps higher-risk opportunities earlier in the development?
Yeah. I mean, I think it will be silly if we didn't go after the indications that have already been de-risked. So I would say we'll start there. We are actually doing quite a bit of work internally to look even beyond these indications in which dupilumab has been approved and some being really large opportunities. But none of them will happen before we establish safety and efficacy in larger populations in indications like AD and asthma.
Right, and then how do you think about partnering this asset with the idea to enhance the development scope, perhaps early? Is that something that you're thinking about?
Yeah. I mean, the short answer, I don't think about it, but maybe I'm trying to be funny. So I think we're well capitalized as a company. As you know, we have $850 million as of December, which will allow us to fund the company through middle of 2027, which means that we're going to be running multiple phase IIb studies across our whole pipeline, not just direct for STAT6. So we have plenty of opportunities to continue to scale the company appropriately. And I think what's imperative for us is to be able to advance these programs through phase II studies to establish, again, safety, efficacy, and to be honest, the real opportunities and value. At that point, I think it will make sense for us to look at our portfolio programs, which is growing, as you know, and then decide how to maximize value.
I don't think partnering now will maximize anything, including value, or will maximize opportunities or timelines. I think we're best positioned to do what we're doing now. I think at that time, again, as we're embarking onto phase III studies across multiple programs, it is possible that we will have to make portfolio decisions about partnering because, as you know, these are big phase III studies across many indications, across many programs, and even a large company, much larger than Kymera, might not be able to prosecute everything in parallel independently on their own.
Right. And then maybe just the last couple of minutes, quick question on KT-474. Obviously, your most advanced autoimmune disease degrader, which is now essentially developed by Sanofi, your partner. And the drug's important for them based on what they're saying. And so just remind us of the status of the program and sort of the next development step for that.
Yeah. Yeah. The drug is important for both, which is great to be in a partnership where both parties feel that KT-474 is an important asset in their portfolio. As you know, in the first half of last year, there was a shift in strategy that was informed by an interim analysis of the data that allowed Sanofi to invest more into these assets and changing the existing phase II proof of concept study into dose-ranging phase IIb studies. Sanofi, as many of you know, is running those studies operationally and financially responsible for it. We're still on track to generate data as we both know, both companies have publicly said in 2026. This will be exciting. It will be the first phase IIb data with a degrader in immunology, or I would say in any indications.
And so on track and excited to see that.
Right. Any views on opportunities beyond the two initial indications in HS and AD?
Yeah. I mean, I think both companies believe that the opportunities are vast beyond HS and AD. As I've said in the past, there is a list of potential additional opportunities that have been prioritized, and obviously, we're looking to Sanofi to see when they will be willing to disclose and what the plans would be.
All right. And then I just want to add one more on KT-295, your TYK2 inhibitor, which obviously, as you mentioned, has an IND approaching here in the near term. And just remind us of the initial phase I study. How does that compare perhaps to the STAT6 program?
Yeah, so the 295, the TYK2 degrader. The phase I is, I would say, just high level, very similar to what we've done with IRAK4 and what we're doing with STAT6, really demonstrating degradation, safety, and pathway impact, and I think I project that this will be the first time in which we'll see that TYK2 is fully drugged by a small molecule.
Right. Great. Well, with that, I think it's time to wrap up now. I really appreciate the time.
Thank you.
Too much to discuss, but we're really excited to have future updates here this year.
Thanks, Michael.