All right. Good morning, everyone. Thanks for being here on day two of the Morgan Stanley 24th Annual Global Healthcare Conference. We are very excited to have the team from Kymera here for this session. Let me just get a quick disclosure out of the way. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. All right. With that, welcome, guys. Earlier this year, you celebrated your 10-year anniversary as a company. You are approaching another set of milestones now. Before we dive in, can we maybe give the audience a bit of an intro on the company and your degrader programs?
Yeah. First of all, thanks for having us. Yes, the idea when we started Kymera in May of 2016 was there is tons of biological data tying a disease-causing protein to diseases. We have really lacked the right technology to address many of them. While we make so much progress with oligo-based therapeutics and obviously injectable biologics and traditional small molecules, there was still a big gap, and I would argue there is still a big gap. Only, I think, 20%-25% of the proteome has been drugged. We saw this new small molecule-based modality called targeted protein degradation as a mean to expand the number of targets we can go after, and ideally, obviously, fulfill some of the key unmet needs that are still out there.
As people that might have heard about protein degradation, this is modality that uses the ubiquitin-proteasome system, which is the cellular machinery responsible for protein homeostasis and directs it against disease-causing proteins. We have focused in the past, over the course of the company, in different areas across initially oncology and immunology. In the past six years, focused really almost solely in immunology. The idea was, again, at the high level, quite simple. Lots of pathways have been validated in immunology. Lots of extremely successful drugs have changed lives of millions of patients around the world. These are almost only, if not mostly, injectable biologics.
We found these opportunities to go downstream of these biologics intracellularly with oral degrader molecules to provide what we believe is, for the first time, really specific-directed therapies that could deliver the best risk-reward profile for patients with immune-inflammatory diseases. Our wholly owned programs are a STAT6 degrader, which is downstream of IL-4 receptor alpha, the target of Dupixent, which is, I believe today, the number one prescribed drug in immunology. Another program that we are very excited about is IRF5 with KT-579, which is another undrugged transcription factor downstream of highly validated pathways in many immune-inflammatory diseases. We have many other preclinical programs that we have not disclosed yet, and we have a couple of partnership, one in immunology with Sanofi and one in oncology with Gilead.
Okay, great. I thought maybe we'd start in reverse order with that Sanofi partner program that's directed at IRAK4. That program goes back to the early years of Kymera, like you said, partnered with Sanofi. Can you talk about the discovery and preclinical efforts around that candidate? What were the specific issues you were looking to solve for?
Well, I haven't started IRAK4 since 2023, so that's a very interesting, exciting way to start. We started with the program with the idea of going after one of these key, again, undrugged nodes in immune inflammatory diseases. In this case, IL-1, IL-17 biology, a pathway that had actually upstream extensive validation. We had IL-1 biologics even more recently from AbbVie that had some exciting data in HS. We had initially back then IL-18 had some mixed data, but more recently we've seen some interesting data from IL-18 in AD. We have recently seen some really amazing data of IL-33 from AstraZeneca in COPD. Probably one of the most exciting data set of the year, I believe, in that area. Again, between then and now, we've seen these cytokines have impact across many diseases. IRAK4 is the central node downstream of those cytokines responsible for the signaling.
It was actually an obvious target that has been pursued by many in the industry going after the catalytic function. We demonstrated that there was a scaffolding function that required a degrader instead of a small molecule inhibitor. Obviously we advanced our first generation degrader, KT-474, through phase II, and then as a part of the collaboration with Sanofi, we decided to focus on the second generation degrader, which is a superior molecule that now entered recently phase I.
Okay, great. I guess maybe just given the experience with the IRAK4 program, what have been learnings that you've been able to leverage across the broader platform?
Yeah. I would say the biggest learning, and actually one of the reasons why we have decided to invest further and if not almost solely in immunology, was driven by the early translation of IRAK4 degradation in healthy volunteers. We saw that what we had studied preclinically, kinetics of degradation, safety, predictability of safety, predictability of degradation kinetics across different tissue types gave us the confidence that one can develop reliably degraders. In immunology, we were the first company to do so back then. That's, I think, a big learning, even the, let's call it, the platform translation and fidelity thereof. The second part was actually how important specificity is to successful drugs in this space, how important dose selection becomes, how important the distribution of the molecule and the impact of that distribution has on the profile of the drug.
This allowed us to develop this new generation of degraders. I would call KT-474 a first-generation degrader molecule with pros and cons and things that we learned from. This allowed us to invest and learn and optimize these degraders. I think KT-621, KT-579, and even KT-485, which is our second-generation IRAK4 degrader, have benefited from what we learned, and these are way better molecules than our first molecule.
Can we spend a minute maybe just on design of the phase I study for KT-485, what the objectives might be there, and how they could confirm further development?
Yeah. There's not a ton we can disclose g iven that this is a program run by Sanofi, but I think it's also, I believe, on ClinicalTrials.gov by now. It's actually a quite creative phase I study that has healthy volunteers and HS patients. The healthy volunteer portion is a more traditional SAD and MAD study with some interesting biomarkers. Again, we unfortunately can't go into it. Then there is an HS, let's say, proof of mechanism portion at the back of it that obviously we look forward to seeing the data when they are generated.
Okay, great. You touched on it, but I guess just given the interesting data we've seen in certain Type 2 indications, you talked about, but then non-TH2 targets in atopic derm like IL-18, I guess whether it's specifically for KT-485 or other potential shots on goal in the space, where do you see a product like this potentially fitting into standard of care for a disease like atopic derm?
To be honest, we're so focused on KT-621-.
Yeah.
That this occupies less than 5% of my mind, given that that's a wholly owned program. It's probably the best program in immunology today. I think what Sanofi, and we to some extent do with IRAK4, it's not center of our mind right now.
What I will say is there are opportunities. I would probably say AD is not probably the best place-.
Yeah.
For IRAK4, but I think HS is an interesting place. I think asthma, COPD are exceptionally interesting places. But again, because we don't control it, although we're trying to influence, and given where we are with our programs, we don't spend a lot of time on it.
Makes sense. All right, so switching to, like you said, the program that occupies, I think, most of your and investors' attention, obviously, KT-621, your oral STAT6 degrader, maybe just some numbers around the unmet need that you could solve for here. How big could the opportunity be?
Yeah, look, I think this is. Thanks for the question because this is probably the most underestimated aspect of the program. I think the mistake we all made, and we used to make it in the past, now we don't really have many excuses to still make it, but we always think about Dupixent. Dupixent is a $25 billion drug, and so we can take a fraction of that. That's actually the wrong way to think about the opportunity here. Actually, the opportunity here is that these diseases, and we can start with AD first, but asthma, COPD, EoE, chronic rhinosinusitis with nasal polyps, CSU, et cetera, I can come up with nine at least. These are diseases that actually have been put on the map in many, if not in most cases, by the work that Regeneron and Sanofi have done with Dupixent, meaning that they provided a solution to diseases that were not either well-characterized or well-treated.
As a result of that, these are still underserved patients, mostly because one drug, for as great as the drug can be, can never serve all patients, especially when it's an injectable drug. Let's use AD because it's easier, and let's use the U.S. market because we're here. There is about 6 million- 9 million patients with moderate to severe AD, depending on the publication you read. This is not our number. This is market research. Let's say for the sake of argument, I'm going to use eight. I like a full number. There is 8 million patients with moderate to severe atopic dermatitis. The patients that are today on advanced systemic therapy, which means Dupixent, Adbry, RINVOQ and a couple of others, are roughly 400,000 patients. There is about 5% penetration of this advanced systemic therapy onto the moderate to severe patient population. The question we asked when we did this market research is why is there such a low penetration? Other company will come up with different numbers, but these-.
Yeah.
Are actually unbiased numbers that are out there. The answer that we get from patients and prescribers is the feeling, the perception that they're not severe enough. Again, I'm not saying they're actually from an EASI score.
Yeah.
I'm saying from a perception, they're not severe enough to wanting to be on an injectable biologics or an oral drug with boxed warning box in the case of RINVOQ. That's the big barrier. Then we ask the next question is what type of drug would change that behavior, and the answer is a safe, effective oral. I think the opportunity for KT-621 is to build a market that is multiple of what these injectable biologics have built. I don't want to come up with numbers because it just doesn't make sense. You can come up with any numbers, but that 400,000-.
Right.
Patient number is a $25 billion market. Think about if we increase the penetration from 5%- 10% f rom 5%- 15%.
Right.
From 5%- 25%, and it's not just KT-621. I think we need more drugs to expand the number of patients, but we believe our drug is best positioned to be first in line, post-topical, to serve as many p atients as possible. That is probably.
Yeah.
in the realm of no other drug that is being developed today, either in immunology or outside of immunology, maybe besides obesity, which is a whole different world.
Right. And maybe just help us get up to speed on KT-621's clinical profile. Specifically, how did the preclinical work translate to the clinic? How is the drug's profile shaping up? Dupixent clearly is the right comparator, but within the context of Dupixent, how did that preclinical translate to clinical? And then, what is the drug's profile versus the key comparator?
Yeah, maybe I will start with the preclinical to clinical translation. I will let Terence comment on the, let's say, forward-looking drug profile. So I would say that scientifically, when we disclosed this program in January of 2024, it seems like 10 years ago, but it was only a couple of years ago. We have done work for more than a half a decade on this target. The fascination we had is what I was saying earlier, is that actually, there aren't many programs, or there haven't been in the past either, of a downstream transcription factor that has such a one-to-one direct relationship with a receptor. We felt the STAT6 beautifully could replicate IL-4 and 13 biology. We have done so much work, and some of it hopefully will be published soon, on mechanistic understanding of STAT6 degradation versus IL-4 receptor blockade. How does the biology play out? What we have seen preclinically and early clinically is this consistency of IL-4 and 13 blockade with a STAT6 degrader that is comparable to what we have seen with receptor or with dupilumab. Maybe Terence can comment more on the clinical profile, et cetera.
Yeah. A comprehensive preclinical package put together that showed that the asset completely and exclusively degrades STAT6, and of course, we've put together a nice biology package building on what's already there in the literature, that STAT6 completely and exclusively serves the signaling of IL-4, 13. Many transcription factors serve multiple masters. STAT6 is extremely focused. This provided a rationale to develop KT-621, which moved into clinic in healthy volunteers in the last couple of years, and at a range of doses ranging from a little over 1 mg a day up to 200 mg a day. We have a nice biomarker that allows us to directly measure degradation of the target STAT6, both in blood and in tissue.
We saw that the asset can produce near complete degradation of the target in blood and in tissue at most doses over one and a bit milligrams a day. This provided a rationale to complete a single and multiple dosing studies in healthy volunteers and bridge that into patients with disease. We conducted a phase Ib study called BROADEN1, where we took 22 patients with moderate to severely active atopic dermatitis and dosed them with either 100 mg or 200 mg once a day. Those data were shared at the American Academy of Dermatology earlier this year. The idea was to see if that degradation story, and particularly the relationship between dose and degradation in tissue, would replicate in disease where there's much more STAT6 activation.
What we saw was that it was, and each of those doses produced complete degradation in blood and in tissue. Of course, we then had the opportunity to look at downstream biomarkers, and even downstream of that disease activity in skin, and downstream of that disease activity or features of disease activity in people who also had related Type 2 diseases.
Right.
The whole thread lined up. Biomarkers like TARC and Eotaxin that are Type 2 related and downstream of degradation moved as you would expect for an advanced therapy asset blocking the Type 2 pathway. Disease activity improved in line with what you would also expect in skin. As we just presented at the European Respiratory Society in Barcelona a week or two ago, people with a proportion of people who had asthma saw movement in biomarkers and PROs.
People with allergic rhinitis also saw improvement. As Nello said, while the biology seems to tell us that there's a very reasonable reason to expect that this would produce efficacy exactly in line with the most efficacious advanced T2 biologics,-.
Yeah.
The market is telling us that that would be great, but it's not necessarily what the market needs for a successful offering for human health or indeed for a business case.
Okay, great. I think for a phase Ib data set, I think the handicapping on biomarker degradation and what would be viewed as good data for the phase Ib, you guys clearly surpassed the very high bars that were set. I guess in terms of what you saw in the phase Ib, and the potential for that to translate to a larger study in running BROADEN2 at this point, how confident are you in the translation, specifically in atopic derm from a smaller data set to a larger one?
This is a once in a lifetime program. I think you have a great molecule. Very well-behaved, highly specific, with pristine safety preclinically and through the end of phase Ib. Biology that is congruent with what we understand of this pathway. This is probably as confident of a translation that one can have going into this phase IIb data. There is not a lot of surprises here on how things have evolved to date. I do not know what the numbers will be, but again, we have seen consistently over the past few years that every time we ask the question, is that STAT6 degradation sufficient to block IL-4 and 13 in a disease-relevant manner, the answer has always been yes.
I think we are going into this phase IIb study expecting that we will see the type of efficacy that first we have seen in phase Ib and that we have seen also with dupilumab in the past. Again, you cannot really do cross-trial comparisons, especially if you are a decade later. I think that is why we keep saying we expect it to be in that ballpark. That is what the biology has been telling us for years- and- years- and- years. Again, we keep saying the market is telling us we do not need that is great, but we still expect to be in that ballpark.
Right. You said there haven't been surprises, maybe biologically. I think you guys certainly surprised the market with pace of enrollment into phase IIb. Maybe just describe what you've seen in terms of interest amongst patients and investigators relative to expectations when you were at trial initiation stage. We've talked about expanding the population of addressable patients to potentially include milder disease. Any early signals of that as you enroll patients?
Yeah. First, let me say, we're not expanding to milder patients. I want to be sure and repeat again that what I talked about earlier, about 5% penetration, is still in the moderate to severe population. The drug will be, if everything works out, obviously, we believe first line, post-topical drug for all moderate to severe patients. With regards to what was the excitement that we saw, I think there are maybe three, four main reasons. One, as I mentioned, even based on the market research that we've done, there is a huge amount of excitement, and we've seen this in both AD and asthma, actually for an oral drug by patients.
There is a level of understanding, comfort, and knowledge of investigators about this pathway. Obviously, Dupixent has been dosed to children as young as six months old. This is not the same target, but it is the same pathway. There is a level of comfort with this pathway, which obviously we will have to continue to earn with our own data. Then, I think we had exciting early data, both the phase Ib, the healthy volunteer, the preclinical data for the sciency-focused investigators on our study. Then, I think the team have done an amazing job being extremely high touch. We visited all countries and met almost every single investigators, and showed the passion and the rigor that we use to run our studies.
All of those things have come together to have basically hundreds of patients that wanted to enter a study. Obviously, we are limited by that protocol.
Right. Okay, great. You talked about kind of the ability to compare to older studies. I think, one area of concern amongst developers that comes up is high placebo rates that have been seen in atopic derm studies. I guess between the enrollment criteria and study execution, can you talk about how you are managing that risk in BROADEN2?
Yeah. Maybe Terence, you want to speak to that?
Yep. So I think since the early days of Dupixent, when the very first program emerged into atopic dermatitis in the advanced therapy space, it's not that dissimilar to other disease areas. You could pick rheumatology or gastroenterology. When the first therapies arrived, there was very little available, and therefore placebo response rates tended to be extremely low because patients and providers had low expectations of what might be possible.
Then time went by, expectations went up, patients were better treated, so the proportion of people with very severe disease who were available to enter programs went down. People had still moderate to severe disease, but perhaps less severe and more moderate as a proportion. You see this across multiple therapeutic areas as more treatments become available, and the field matures. Sure, in atopic dermatitis, placebo response rates in trials have generally crept up over the years. But in our view, and in my view, not in a catastrophic way. There have been multiple recent programs that have read out over the last year even this calendar year, with pretty respectable, non-problematic placebo response rates.
It is true that a couple of years ago, there had been a couple of programs that experienced very problematic placebo response rates, but perhaps there were specific reasons related to the design and execution of those programs. In our own study, we nonetheless remained paranoid about this problem and put in place a variety of measures related to the design and execution of the trial to try and control it. That ranged from selecting good and experienced sites.
Careful training of those sites. I would say high-touch oversight of the kinds of patients who were allowed into the program. We have not disclosed the specific measures, but we had some pretty interesting innovative measures to make sure people actually had atopic dermatitis and actually had moderate to severe atopic dermatitis. We made sure that a couple of the things that occasionally and typically trip you up with placebo response did not happen. Typical things would be making sure that medicines that they had been on beforehand, that they were allowed to be on, remained stable, or medicines that they had come off beforehand, that they were not allowed to be on, had come off at a reasonable interval before coming in.
The final thing I would say is that the team, both ourselves and our CRO partner, have a very high-touch approach as we are executing the study, maintaining oversight of things like rescue medications and other concomitant therapies. Again, things that influence response rates. The proof will be in the pudding very soon, before the end of this year. We look forward to the readout, but we think we have done everything reasonable, and we also think that generally in atopic dermatitis, while placebo response rates have crept up, it is still very possible to extract a nice signal from the noise.
Okay, great. I want to make sure we touch on safety. Safety has been extremely clean so far. It does seem like investors would not be surprised, given the mechanism and given prior experience with Dupixent of some conjunctivitis or eosinophilia cases propped up with longer term dosing. I guess how stringent is the safety bar in your mind?
I mean, for AD, we know that, as I said, what are patients looking for? Safe and effective oral.
Yeah.
Safety is key, and I think we've been fortunate and we've been good at I think selecting and making the right molecule with the right profile. Again, we look forward to seeing how that translates into longer duration and much bigger patient population. I've always said, I believe after these two big phase IIb studies, they both have open label extension.
We'll know almost fully the safety profile of this drug. I think this phase IIb are much more de-risking for the totality of the package. In some programs you might need phase III data for I think would be hugely de-risking-.
Right.
Because of the global setup, the over label extensions, the generally large end. We'll know soon as we continue to de-risk safety.
Okay. Speaking of, I guess you talked about potentially moving into phase III next year. I guess what questions could be answered from the BROADEN2 data that could inform phase III design potentially, whether it's dosing or-.
Yeah, dose for sure.
Yeah.
I mean, I love to take one dose only to phase III. It's cheaper and faster. I think, and then obviously you also learn about the profile of the drug, which are the endpoints that the drug might be doing better than others, and how you use them in your hierarchy for phase III. These are all kind of technical things that we'll solve along the way. I think the biggest, obviously, it's the efficacy and safety and then the dose selection for phase III.
Okay. Then maybe just lastly on BROADEN2, the efficacy measures potentially being kind of in that ballpark of Dupixent. We get the question, which endpoints matter? Do biomarkers still matter in this readout as much as maybe EASI and vIGA? How are you thinking about kind of the hierarchy of endpoints there?
Yeah, I mean, I think if in these type of studies, biomarkers are helpful to tell the story.
Yeah.
But I don't think they're going to be the story, right? I think this is about impact. We rely upon patients. We I think the endpoints in this day and age for atopic derm are the ones that are used for registration, so EASI-75, IGA 0/1. Obviously, our primary endpoint is still percent reduction in EASI, so we will definitely look at that. But I would say all, itch for us, I mean, I think not for us, but patients tell us that itch is the most important-.
Yeah.
Has the most important influence-.
Right.
On their quality of life, at least for most of them. That is going to be an important also endpoint that we want to disclose in the top line.
Okay, great. Maybe just thinking about other Type 2 indications beyond atopic derm, right? Clearly BROADEN2 can inform dosing for other dermatologic indications, but how much do the data for BROADEN2 de-risk other Type 2 indications? Is there a read-through from BROADEN2 to your Phase IIb BREADTH study or other indications here?
Thanks. I think, the question is how much they de-risk. I think the level of de-risking is profound. I think given what we know, given where the target sits in the pathway and what we know about the pathway, assets that drug the pathway, indications in which they work, and the doses required for optimal benefit risk in those indications, we can learn a ton from the first readout. If you think about Type 2 inflammation in maybe three disease area categories, derm, GI, and resp, obviously we are conducting robust Phase IIb studies in derm, in atopic dermatitis, and resp in moderate to severe asthma.
Strategically, the way we're thinking about it at the minute is that the first readout would potentially ungate and unlock, perhaps obviously atopic dermatitis and potentially other dermatology indications, and Nello named some of those in his opening remarks. Also we think we'd learn enough to make intelligent decisions around the design of a registration program in the key GI indication, which would be eosinophilic esophagitis. At that point, obviously we could make a lot of intelligent guesses about probability of success and dose in the respiratory indications too, but we'll have a readout coming from our phase IIb moderate to severe asthma study during 2027.
You can imagine that that would be an ungating event that all being well, would unleash the suite of respiratory indications, and Nello named some of those, too.
Okay, great. I want to make sure we touch on KT-579 oral IRF5 degrader. We're going to get some phase I healthy data in the fourth quarter, which I think will inform a lupus study after that. Can we maybe just talk about the opportunities in lupus and beyond for this asset?
Yeah. I want to go back. I know we have limited time.
Sure.
Why are we working on IRF5? Again, another key node that has not been drugged, another really difficult to drug transcription factor. The pathway that it influences are pathways that have been extensively validated in diseases like Type 1 interferon, like myeloid inflammatory cytokines, like IL-23, 12, TNF, and B cells, and all the impact that B cells produce, autoantibodies have. It is a very powerful mechanism, but what it has that is unique is that it is really only powerful when the pathway has been activated. So it is a disease-specific pathway activation. How do we know that? Because we know that people with this target mutation or activation develop diseases like lupus, like IBD, like RA, like Sjogren's disease. So it is actually a very unique target if you look at the landscape of other targets in immunology.
We have prioritized lupus as the first patient indication, given the strength of both genetics and preclinical data and the relevance of the biology. But we are well underway to potentially and hopefully add at least one other indication to execute some more in a parallel staggered fashion, because obviously, in this day and age, time is of essence, and the sequential paradigm is one of the past for any drug, especially small molecule drugs. More to be shared on this. I think a couple of other things I want to add. The data set on IRF5, KT-579 will be disclosed before the BROADEN2 data.
Okay.
We will have IRF5 data and then BROADEN2. Again, all of them now, I think we are in Q4 or soon, so it will be in Q4.
Okay.
For both of them. I think what we want to see from-.
Right.
The KT-579 data is the ability to safely degrade IRF5, and through some really sophisticated assays that the teams have built to measure, and all this biology that I talked about demonstrate that the biology replicate in humans.
Right. Okay. Excellent. In the last minute or so, we wanted to just tick off a few questions that we're asking all the management teams at the conference, specifically on China's rise in biotech innovation. How are you thinking about whether it's competition or potential for business development in terms of Chinese biotech?
I think it's both, obviously. I think competition is good for patients. We're all trying to improve human health. I'm a big believer that competition is fair if the playing field is level. Maybe I might have some questions about that, but maybe we don't have time to get into it. At the same time, yeah, we're a growing company that has big ambitions. We are looking at developing the next generation of therapies for patients, including combination. Yes, is it possible that we could look at some assets in China? I think our bar is very high, and not many companies. It's hard to obviously meet that bar depending on the work that people do. But I guess the short answer is both.
Okay. And impacts of AI on your business, whether it is helping or disrupting?
I think it is tremendous.
Yeah.
I would like Kymera to be a completely AI-powered company, and I know it sounds kind of silly to say, but it is actually the impact, the profound impact, and the efficiency that you can bring. This is not all the hype stuff. I will remove all of that out, but actually true impact on operating the company, on efficiencies, on the right patients, on the right processes. There is so much to gain from using it in the proper way that it is a train that we cannot miss, and we have to jump and actually drive and lead if we want to be a successful company in the next decade.
Okay. Excellent. Lastly, just on the regulatory side impacts from whether it's FDA, how you're thinking about pricing given MFN tariffs, anything on the regulatory side we should be thinking about?
Well, I mean, it's a lot that-.
Yeah.
You ask. I think the only thing I'm going to say is that we've had great relationship with the regulatory agencies. We are a data-driven, science-first company. We're a transparent company, and that has so far helped us to have really productive interactions. With regard to MFN pricing, we are actually deep in that work, but not ready to talk about it yet.
Okay. Excellent. All right. Well, thank you very much for being here. We appreciate it.
Thank you.
Thank you.
All right.