Good morning, everybody. Thanks for joining us here at the Leerink Partners Global Healthcare Conference. My name's Thomas Smith. I'm one of the senior biotech analysts here at Leerink, and really pleased to be welcoming our next company to the stage, Kymera Therapeutics. Happy to be joined by CEO, Nello Mainolfi. Nello, thanks so much for joining us.
Thanks, Tom. Thanks for inviting us.
Awesome. Nello, I'm sure in the audience there's quite high awareness. You guys with your STAT6 degrader, I think are potentially revolutionizing the way we treat some of these autoimmune diseases. Maybe you could just kind of kick us off with some introductory remarks, talk us through some of the transformative data you showed in 2025, and then what you're looking forward to most in 2026.
Yeah. I mean, if you don't mind, let me just give a brief history of how we got to where we are today, what are we trying to do going forward, and then, you know, I'll spend some time on KT-621. Just to remind everybody, when we founded Kymera, actually soon it's gonna be 10 years ago, the goal was to develop a new generation of medicines using targeted protein degradation to go after historically undrugged targets. We decided to do so by focusing on pathways that have strong validation, clinical and commercial validations, against targets within those pathways that have been undrugged, but targets that have strong human genetics validation, where the technology would allow us to really unlock the clinical and commercial opportunity.
About five, six years ago, probably even more, we decided to focus our efforts in immunology. The reason was, again, quite simple. There are many drugs that have transformed diseases. If you think about psoriasis, how it was treated 10 years ago versus today, it's night and day, right? If you look at AD, if you look at IBD, if you look at lupus even more recently. Most of these drugs that have transformed diseases have actually accomplished two things. Not only have they helped, you know, the human condition, but also they validated biology and pathways. Most of those drugs have ended up being injectable biologics. We know that if you either target a cytokine or a receptor, in most cases, you can have tremendous impact on disease.
What we haven't seen in the past 10 years are drugs that have targeted intracellular targets in those pathways with success, whether it was because we didn't have, you know, the right technology in most cases, sometimes it was not the right target. We saw this unique opportunity with a protein degrader, which as many know, is a catalytic entity that can be dosed orally and can degrade targets fully and block the pathway just as effectively as a biologics. You can deliver biologics-like activity in an oral format. That's been the premise for the past few years of our efforts, and I think there is no better target, I think to elucidate this strategy than STAT6.
KT-621 is a drug that we've been working now for more than half a decade, where we've shown pre-clinically that degrading STAT6 is able to replicate both IL-4 and IL-13 blockade at least as effectively as an IL-4 Rα blocker like dupilumab. We've shown that you can go into healthy volunteers, degrade the target safely, fully, and block Type 2 biomarkers as effectively as upstream biologics. We went into a phase I-B small study, four weeks, 22 patients. Even in such a short time with such a small number of patients, we were able to show impact on all biomarkers of Type 2 inflammation, not even limited to atopic derm. We looked at FeNO, for example, that is usually measured in respiratory indications like asthma.
In all of those, we're able to block them at least as effectively as upstream biologics. We looked at clinical endpoints and EASI and itch and SCORAD and sleeplessness and other PROs, where we show robust activity, at least numerically, at least as effective, if not better than what has been seen with upstream biologics after four weeks of dosing. We looked at comorbidities, which I don't think anybody has done before in a four-week study, and we saw that you can not only block FeNO, but you can actually have clinical impact even in four weeks when patients with AD have comorbid asthma. We're able to block FeNO in the 50%-60%, which is also pretty unprecedented after just a few days of dosing.
We also looked at allergic rhinitis, which obviously is not an indication that people go after given that it's treated with over-the-counter drugs, but speaks to us being able to block Type 2 allergic inflammation in the lower respiratory tract with FeNO and ACQ-5 in asthma and upper respiratory with PROs and clinical measures for allergic rhinitis. The other important thing is that we had two doses that we selected, 100 mg and 200 mg that looked very similar in healthy volunteers. We wanted to see whether they will look different in patients. It turned out they look also quite similar in patients, and both doses gave very consistent data in both biomarkers and clinical endpoints. Since then, actually even before we reported the data, we started a phase II-B study in AD.
We started dosing end of November. We started a phase II-B study in asthma. We started dosing in January. Both are global dose ranging studies, three doses of KT-621, one placebo arm. The AD study is a 200-patient, 16-week study with a 52-week OLE, open label extension. The asthma study is, again, three doses, one placebo, 12 weeks, FEV1 is the primary endpoint. It will allow us to select the right phase III dose to then initiate our late stage development, which will include several phase III studies beyond AD and asthma. Both of those studies will read out in 2027. AD by the first half, by middle we say, and then the asthma by the end of the year.
Awesome.
I don't know if I covered everything. I can leave now. No?
I think you covered everything. I think there's a mic that could be dropped somewhere. Let's come back to the phase I-B BroADen experience and headline number, four weeks. I think it's 63% median EASI reduction. Like clear signals of activity. Looks very competitive. I think some would argue, albeit in like a small number of patients, maybe a little bit optically better than dupilumab across some measures. You also saw like really impressive STAT6 degradation. I think the medians there were like 94 to 90.
Eight.
98%.
Yeah.
Just talk about the significance of those levels of degradation and what did you see in the follow-up period from the four-week?
Yeah. I think what we learned in preclinical studies is that if you degrade the target 90% plus, you're able to phenotypically block the IL-4 and IL-13 downstream signaling in the same ballpark as dupilumab. I think we had a very clear bar of wanting and needing to degrade the target at least at 90%. In reality, I think it's always a bit risky to using preclinical animal models as an absolute direction of what's needed clinically in humans. Often diseases are much more complex, are much more heterogeneous. We wanted to be able to degrade the target completely.
Being able in a dose ranging study, as we're doing now, being able to also go down in doses and in degradation and really being able to answer the question, what is that particular degradation profile does with regards to safety and efficacy? I would start by saying that we felt it was critical for us to being able to degrade the target fully. If you talk to people that have worked with that have developed dupilumab, they will, I think the general expectation is that the drug works well because it blocks IL-4 and IL-13 signaling almost completely for almost all the duration of dosing. We believe it is paramount to being able to access this deep degradation profile. The fact that in both healthy volunteers.
Actually, in healthy volunteers, we had to go to 1.5 mg once a day to see less than 90% degradation. All doses above 1.5 mg once a day, think about how small of a dose that is, gave more than 90% degradation, either equal or more than 90%. In patients, we went into the top end of that range, and we dosed 100 and 200. I think it's clear that we have plateaued the degradation because we saw the same. Although the 200 exposure was twice as high as the 100 exposure in terms of PK, the degradation was the same, which tells us that we've maximized degradation in blood and skin, as you say, 94%-98%.
When we get in the 94-95 range, our ability to measure the target obviously is dramatically reduced. Usually we think about 94-95 as maximal degradation that we can measure. Again, long answer to your question that it's important to be able to get there and then go back rather than being stuck at a degradation profile without being able to ask the clinical question completely.
Yeah. Clear obvious signal. When we think about safety tolerability, this is also like extremely clean four-week readout. When we think about degrading STAT6 to that level on a prolonged basis, is there some biologic rationale for thinking you could actually have a better safety profile relative to an injectable IL-4? Or also help us think through potential liabilities if there are any.
Yeah. You know, great question. I like to start what do we know about STAT6 as a target from a safety perspective. We always go back to human genetics. Again, I think there is plenty of reviews that show that since we started using human genetics to select targets, our actual productivity as an industry has increased dramatically. We, as a company that degrades protein, the best proxy is you know, what does the genetics of that target in humans look like. When you look at STAT6, you have gain-of-function mutation. They basically tell you what is the phenotype of a highly activated STAT6 as a target, and the phenotype of STAT6 gain-of-function mutation is severe allergic atopic diseases.
If STAT6 were involved in other biology, you would probably had seen different phenotypes on top of the allergy phenotype. That is a big important point. The other side of the human genetics is, you know, let's say the field has identified a few heterozygous loss-of-function mutant humans that are completely safe and normal. We have mouse genetics, which to be honest, I don't usually pay a lot of attention to, but it's important to know that knockouts STAT6 in mice are normal, fertile and normal development. The pathway obviously is one of the most validated pathways in immunology for sure. There are close to 2 million patients on IL-4 and 13 drugs. Patients as young as six months old.
If you believe that STAT6 is a necessary transcription factor in this pathway, so that speaks to the biology and the safety. On top of all of this, obviously, we've generated a complete safety preclinical package. We've recently completed 6-9-month chronic toxicity without any adverse findings, again, consistent with all the other studies. So far in the clinic, we've had, I would call it placebo-like safety. We obviously hope, believe, and have confidence that that will continue to be the case, but that's why we're running these bigger studies now.
Some reason for thinking you may actually.
Oh, it's better.
Yeah.
Yeah. I mean, it's hard. Sorry, I forgot that part. The other question was could it be differentiated on the positive side versus dupilumab. It's hard for us to have a rationale for it 'cause I just spent 20 minutes telling you that we believe we block IL-4 and IL-13. Now I couldn't be speaking from the other side of my mouth, but by the way, we're gonna be better. I think our base case expectation is to have a dupilumab-like safety, which, to be honest, would be a dream scenario for me, 'cause it's still a novel target, right?
I think, you know, in the early days, you know, we, you know, in the phase I-B, we have looked for the, let's call it AEs of interest of the IL-4 and 13 class of drugs, like conjunctivitis. We haven't seen it, but I think it's too short of a time and too small of a cohort to being able to answer that question. Again, we will know more in 2027.
Yep, to be defined. Okay. Your press release this morning, your late-breaking oral presentation at the American Academy of Dermatology Annual Meeting, AAD, later this month. Your.
I wanna say we're very excited about it. Actually, complete your question.
Well, your top line data presentation was one of the most robust presentations of a top-line data set, like the biomarker to translational clinical efficacy. I was hoping you could just orient us.
Yeah.
On the other data sets.
Yeah.
That we should be tuned into and additional details that would come out of this.
Yeah, I don't know that you can call it top line. This is a full line because I think we disclosed every data that was relevant and. Before I actually continue, I think it's important I wanna highlight both EADV and AAD. EADV, last year, we had a late-breaking oral presentation of our phase I healthy volunteer data. Now, AAD, which is, you know, one is European, one is the American Academy of Dermatology, now we're disclosing the phase I-B. I believe, I might be wrong, that I think it's very rare, if not unique case, that phase I data are given podium presentation at a late-breaking at these conferences.
This is not about Kymera per se, but I think it speaks to the level of interest that there is in the derm community about this target and the early data that we've generated. Now, going back to your actual question, I don't think, or actually I know there won't be any new information in that presentation, but it's a unique opportunity for us, given that, again, we shared everything there. It's a unique opportunity because you're actually never as a... When you do company-sponsored event, while you're able to access everybody, you know. As you know, the medical community tends to use these conferences as the place where new ideas are discussed, new data are reviewed and discussed.
At EADV was our first preview into this derm space, and I think this will be a huge boost for the already existing interest in the ongoing studies and engaging the derm community. We'll have more. We'll present at other conferences. We had a small healthy volunteer Japanese study, again, to allow us to go in Japan for a phase II without asking for waivers. We have a publication that we're writing on the clinical study. We have another publication we're writing on the preclinical work. Hopefully, this year will be rich of additional, again, either incremental information or kind of full stories in peer-reviewed avenues.
Yep, continuing to raise the profile of the target.
Yeah.
Compound.
Educate as well. Yeah.
Yep. On that driving investigator interest and maybe patient interest, I mean, you have the BROADEN2 study that's underway. Could you give us an update on what you're seeing from the early enrollment kinetics?
I'm not gonna provide updates on where we are because it. I don't think there is anything to gain from that. I can say two things. One, we're on track versus what we had initially guided, and if we veer away materially, we will obviously update. I think the data we generated, we disclose in December, has gone a long way to both educate, inform, and I think create lots of excitement about this program, about this mechanism, in the investing in the KOL community, investigator community, and I assume based on the interest we're seeing on the study also in the patient community.
Yep.
For both, actually. Both AD and asthma.
Yep.
I think the four comorbid asthma patients have gone a long way.
Yep. Well, on that, yeah, on that point, you did see a 56% FeNO reduction in those asthma patients. You're enriching in BREADTH for patients that have high FeNO and high eosinophils. I guess help us think about sort of bar for success in that study, how that 56% number stacks up versus your expectations from the larger phase II-B.
Yeah, I mean, I think it's important. I think the data in comorbid asthma, because FeNO is one thing. FeNO reduction on themselves is not gonna translate to clinical activity. We've seen drugs that reduce FeNO without changing the course of disease. We also had actually clinical measures in the four weeks. I think what the data tell us is that the drug gets to the lungs, it blocks the pathway fully in the lungs 'cause the level of FeNO reduction is, you know, I think kind of best in class for this pathway. That's, to me, the most important de-risking event of the phase I-Bb. Like, the drug is doing its job in the lungs. I wouldn't kind of read too much into the rest.
For the reason why we the inclusion/exclusion criteria for BREADTH are high Th2 patients is driven by the fact that we wanted to use a relatively small and short study to select a phase III dose. I don't think we're inventing this. If you skew your population to high Type 2 patients, high EOS, high FeNO, you are setting up, hopefully, for a bigger, for a deeper, for a bigger treatment effect, which will allow us to capture enough placebo-corrected treatment even at week 12, and potentially, ideally, and hopefully differentiate between doses. Obviously, we're not measuring in the study 'cause it's a 12-week study, the exacerbation rates. For this pathway, I think it's well understood that getting FEV1 impact should drive also impact on exacerbation given the, you know, again, the validation of the mechanism.
If I could come back to AD for a second, 'cause yeah, you also had a very interesting signal on IL-31 reduction, which we know is a key pruritogenic cytokine. Like, it hasn't really been measured so much. I guess, how do you think that could translate to a potential benefit on pruritus relative to the injectables?
Yeah, I mean, you know, we've shown actually impact on itch in the actual study when you look at Peak Pruritus NRS. We look to SCORAD at itch, we look at sleeplessness, which is really how many times you wake up at night scratching. In all of those, we had really robust effect or some would say quite competitive, let's say, with upstream biologics. I mean, we were able to do two things, measure IL-31 and then show that we impacted IL-31.
I think the challenge with many other drugs has been for companies that are science driven, obviously not everybody does what we do, because you have to be really curious about the science and not just doing, you know, development of a program at the barest minimum, because I think you learn things that will make you a better company. Sorry for that aside. For the few companies that I think have been looking for these things, I think the challenge has been IL-31 is so low expressed that sometimes, you know, technologies haven't been able to pick it up. I think we're now, as everything is improving, we can now measure a baseline. I will say in a dupilumab study, I think they did measure, and they didn't see a change.
I'm not sure today I wanna be claiming that our drug impacts the IL-31 unlike an upstream biologics. I don't think that would be credible. I think once we generate more data on it, I think we can maybe make different statements.
Yep, makes sense. When we think about the phase II-B AD study, one of the concerns over the last 18 months, I would argue from an investor standpoint, has been variability on placebo response. Maybe just talk a little bit about how you're managing that, mitigating that in your IIb?
Yeah. I'd actually say if you think back, there was a time in, like, the back end of 2024 where we saw a lot of bad placebo. I think in the past few studies, I think things have looked a bit better, right? Nonetheless, your point is still valid. Which is, you know, there is a fact, right? The fact is, AD is now extremely competitive. I think there's. I would argue way too many drugs that are not highly differentiated. Generally, there are a lot of mechanisms in AD that are being tested. The patient population that are enrolled in these studies have changed over the years. If you look at the early dupilumab studies, the baseline EASI of that population was in high twenties, early thirties.
Now we're talking about mid-20s% if you're doing a good job. You know, low 20s% if you're not doing a good job. With, let's call it, the less severe disease presentation, you have naturally more variability of disease. That is a component of the higher placebo rate. It does not explain many very high placebo rates that we've seen in studies. I think that those have to do with trial conduct, patient presentation, site engagement, site oversight. You know, I'm not gonna say that we'll deliver perfect, you know, extremely low placebo population to our study.
What I can say is that we believe we put all the measures in place that are humanly possible today, to ensure that we have, you know, as well managed the placebo rate as possible, including, you know, relying on a highly geographically diverse population that I think will help in that part as well.
Got it. I wanna switch gears and talk about KT-579 and your IRF5 program. Maybe just start with the target and how you think about the biologic applicability of degrading the target, and we're gonna have phase 1 data in the second half of this year, like help frame expectations around. I think you've laid out a target at 85% degradation of IRF5 would be a good number, but help us put that into context.
Yeah. You know, I think IRF5 is another one of those targets that is being pursued without success for the past, you know, five-seven years. I would say STAT6 and IRF5, at least obviously in our company, were the highest priority target. If you look at many immunology companies, these targets are high top of the list, probably number one or two, number two or three, whatever. Why is that? Let me start there. Why is that? Because, you know, we talked about STAT6, so we'll talk about IRF5. It's very rare that you have human genetics data that says that if you have an activating variant of IRF5, you are extremely likely to develop diseases, immune inflammatory diseases. In fact, 30% of patients with lupus have this activating mutation.
Going from there, IBD, RA, and a couple of other smaller diseases. If you have an activating, let's call it mutation on IRF5, you will have auto-inflammatory diseases, most likely are gonna be one of those three. Once you have that Type of human genetics, it's historically drugs against those targets have been successful. What we did pre-clinically, say, okay, let's find out what's this biology, because one thing is genetics and one thing is biology. The biology also turned out to be very compelling because if you activate IRF5, you have this activation of these three key pathways. One is the, let's call it more traditional immune inflammatory cytokines like TNF, IL-12, IL-23, IL-6. You have generation of Type I interferon, and you have generation of autoantibodies through B-cell activation.
If you block IRF5 through degradation, and only IRF5, you're able to block. In the context where this pathway is active, you're able to block all this biology. Each individual biology has been proven to be. If you think about lupus, B-cell, autoantibodies, check. Type I interferon, check. Pro-inflammatory cytokine, check. If you can get them all with a single mechanism, you have a really high probability of success. On top of it, from a safety perspective, the beauty of IRF5 is if you're able to target only IRF5, and that has been the challenge in the industry. It's not. The IRF5 is really somewhat redundant in normal people. There are other IRFs that can come into play if you're thinking about viral surveillance.
Our goal is in the second half of the year to demonstrate we can degrade the target, we can do it safely, and we can replicate this biology even in healthy volunteers, ex vivo, cytokines, Type I interferon, and autoantibodies. What is the level of degradation? I go back to STAT6. Yes, we've shown preclinically that if you degrade between 85%-90%, you drive maximal pharmacology. In fact, in this lupus model, we were the best, the most active drug compared to all the other drugs that either are approved or in development. I think it's always risky to say, "Okay, we're only gonna get to 85%-90%." Our goal is always to get to more than 90%, being able to show that you can do it safely, and then in a dose-ranging study, try and create a correlation between degradation level of safety and efficacy.
You just laid out the largest autoimmune markets, right? RA, IBD, lupus. How do you think about.
AD, asthma, COPD.
How do you like how do we think about indication selection within this, you know, cornucopia of opportunity?
Yeah. I mean, we try and triangulate three things, the genetics, the pre-clinical data, and the biology validation. When we do that, we've shared some RA data. We have not shared IBD data, but that's coming. When we triangulate these things, I think lupus continues to be a priority indication because there are no oral mechanisms that work well, and it doesn't matter what happens to these, you know, B-cell depleter mechanisms. You're still gonna need an oral drug for moderate to severe patients. I think for the other indications, we will do more, for sure. This is not gonna be a lupus-only drug.
I think when we're ready to talk about how we prioritize, but again, we think about genetics, pre-clinical data, and biology validation in the clinic of other mechanisms that kind of intercept this pathway, and that's how we're gonna add the other indications on top of lupus. Most likely, our first patient study will be in lupus.
Lupus. Lupus is a proof of concept. Thoughts around a potential basket study, maybe a rheumatology basket?
I think it's too early to tell.
Okay.
I think basket studies sound good on paper.
Yep.
Difficult to execute on.
Maybe last question. You got into nominating an additional program, like, just help us think through. I think you've alluded to maybe an autoantibody angle, but what should we be looking forward to?
Yeah. You know, just to be clear, it's not like we're trying to tease the world on this. We wanna talk about targets once we have a development candidate that has gone through non-GLP tox. This is a message to the team. Obviously, we need to get there soon. But as we are close, I think we feel confident that in the second half of the year, we should be able to talk at least about one of these programs. As I've said, we've been very interested in autoantibody-driven diseases for the past five years, and so we have a few programs in that area. We think there are areas in kind of Th1-t ype inflammation that have been not addressed by any existing therapy. Those are things that we're focused on. We'll see what delivers, what we're looking for.
Later this year. Awesome. Well, we're up against time, but thank you, Nello, for joining us and for the insights and a lot to look forward to in 2026.
Thank you, everybody.