Good evening, everyone. My name is Ted Tenthoff. I'm a senior biotech analyst at Piper Sandler, and before I begin, I'm required to point out certain disclosures regarding the relationship between Piper and our next presenting company, Kymera, which are posted both at the back of the room and also at the registration desk. So Kymera is the leading developer of protein degraders to treat autoimmune disease. The company recently was getting ready to present phase I-B broadened data on STAT6 degrader, KT-621, and the company's already initiated phase II-B studies in atopic derm and will soon in asthma. Additionally, the company is preparing to advance an IRF5 degrader, KT-579, into the clinic early next year, and the company has strong partnerships, including Sanofi, as well as a new deal with Gilead for CDK2. So here to talk about all this is my good friend, Founder, President, and CEO Nello Mainolfi.
Nello, always a pleasure.
Thanks, Ted. Actually, you just did my job. You went over all the things that I was supposed to talk about.
Relax. Perfect.
You can ask me questions now.
Thank you. Thanks for having me.
Always my pleasure.
STAT6 is a transcription factor for well-validated IL4, IL13 pathway, obviously a target of Dupixent. You guys are here looking at an oral program that could have similar efficacy. What should we expect from the upcoming phase I-B BroADen study? I know this is on, I think, maybe around 20 patients, atopic derm patients. And then tell us about sort of the plan to move into BroADen 2 and BREADTH for asthma.
OK. So lots of questions. So let me start with a bit of context. So a few years ago, we made the decision to focus our platform, which is based on targeted protein degradation, onto immunology. So the reason for that was because we know that many pathways have been validated with injectable biologics. And I would add injectable biologics have transformed the life of millions of patients. Think about dupilumab, think about Stelara, think about the TNF Humira, so drugs that have changed the life of patients all around the world.
But all these injectable biologics still suffer from many drawbacks, most of which, I think, have limited penetration into the broader patient populations, obviously challenges with being prescribed, being reimbursed, people that don't like to be injected with needles, challenges with accessing in many regions and countries in the world, cold storage, as well as sometimes challenges with immunogenicity. So all of those make the penetration of systemic biologics or injectable biologics limited. The beauty about protein degradation is that, thanks to the technology, we're able to catalytically remove protein and block pathways as effectively as saturating those of a biologic with a simple one-a-day oral drug. So with that as a background, we did a deep analysis of the most validated pathways with strong human genetics. And IL-4 and IL-13 was, I would say, close to the top of the list.
Targeting STAT6 with an oral degrader allows us to block IL-4 and IL-13 signaling. We've shown preclinically as well as dupilumab. In preclinical studies, we showed extensively that we can generate dupilumab-like effects in a series of cellular systems and in vivo models of disease. We've shown in preclinical safety studies that we had actually no adverse events in any studies that we run, going from two weeks all the way to four months. In healthy volunteer studies, we've shown that we can degrade the target fully and safely and block type 2 biomarkers, even in healthy volunteers, as robustly as upstream biologics. Now, going back to your question, we have run and completed recently a phase I-B study in roughly 20 patients of moderate to severe atopic dermatitis. We had four goals in these studies.
We wanted to translate the degradation from healthy volunteers into patients in blood and skin. We wanted to use the data from this translation to inform our phase II-B dose selection. We wanted to be able to demonstrate, as we've done in previous studies, that STAT6 degradation, but now for the first time in patients, leads to a biomarker impact in both blood and skin that we believe should be comparable to dupilumab, and also that we can affect clinical endpoints, we like to say in a way, in the ballpark of what these upstream biologics have shown after 28 days of dosing. So we say all that not because we believe we have to be like dupilumab, but because all the data that we've generated so far has pointed us in that direction. That's why we have that TPP. Now, as you said, we started a phase II-B study.
This is a four-arm study, three doses of KT-621 and one on placebo, roughly 200 patients, 16 weeks of dosing, 52-week open-label extension at the end of 16 weeks of treatment. The goal there is to really establish the relationship between level of degradation, safety, and efficacy of KT-621 in a placebo-controlled, randomized manner. This should allow us to select the phase 3 dose that we can take not only in AD, but we believe potentially in other skin indications, being able to go directly in phase III. The BREADTH study, which is phase II-B in asthma, we're on track to start in the first quarter of 2026. We haven't discussed the design yet, but it's going to be another 200-patient-plus in that case, phase II-B dose-ranging study, placebo-controlled.
That should enable us to select the phase III dose that we ideally can use not only in asthma, but also in other respiratory indications like COPD. So the opportunity here is to have an oral drug that can block the pathway as effectively as an upstream biologic. And for the first time in the history of immunology, you can combine the efficacy and safety of a biologic with the convenience of an oral drug. So you can imagine if you have a profile like that, which obviously we're in the early stages of hopefully demonstrating, I think the sky's the limit.
Yeah. I love too how you've gone after one skin and one lung to kind of look at different exposures in the different tissue sets. Are they the same doses between the two? Because you could see different individual dosing for maybe skin conditions versus respiratory or something like that. How are you thinking about that?
Yeah. So let me start with the easy answer. So the easy answer is that in both AD and asthma, we're using the same doses, the same three doses. So why are we doing that? For two reasons. One, because in all our preclinical studies, we've demonstrated that KT-621 both distributes and degrades equally in all tissues. The second, which is more of a kind of an empirically driven reason, is it doesn't actually matter if we degrade equally or differently in different tissues. Again, we believe we do. We're asking a very simple question in these dose-ranging studies. What is the relationship between degradation, safety, and efficacy?
So, even if by reasons that right now I can't even come up with, we have different degradation in blood and in skin and in lungs, we have the right range of doses that will be able to still ask the same question.
Yeah. Absolutely. And when can we get data from the BroADen and BREADTH trials? And I know this is still a long way out, but you guys have talked about very broad plans for phase III. Give us a sense for sort of what you would hope to do on positive data, II-B data.
Yeah. So first, I'll start by saying our phase II-B AD study, we started dosing recently. We actually had a press release last week talking about, I think Tuesday of last week, talking about our first dose, so we expect to be able to have data by middle of 2027 for that study. Again, we haven't talked about the design of the asthma study, so I'm not going to talk about the timing expectation, but we will do so early next year. At least that's our plan. You know we're very confident about this program, so confident that we're already investing in being phase III ready with this program, both in terms of manufacturing and obviously team and capabilities, and in the event of positive phase II-B data, we are prepared to initiate multiple phase III campaigns in parallel.
Yeah. Very exciting. Ultimately, is this a drug that you would hope to keep yourselves and take forward? I mean, I think there's probably a lot of investors who want you to, so.
I would say that there is no biotech in the history of the biotech industry that has ever developed a drug with this potential. Having said that, I think we are prepared, for sure, obviously, to take this program through phase II-B studies. And our base case is to continue to advance it on our own. I think that will be impacted by cost of capital, our ability to scale the company. But for sure, if you ask me, I'd love to keep this program wholly owned through commercialization.
I'll pause there and just see if there's any questions from the audience on 61 before transferring to 579. At ACR, you guys just presented new preclinical data on first-in-class oral IRF5 degrader. Tell us about the role this plays and when you'll get into the clinic.
You know, I'll start by saying a little bit like I did for STAT6. IRF5, another transcription factor, so the strategy of the company is very, in a way, it's very simple, yet ambitious. We go after pathways that have been validated, targets that have not been drugged, where we have access to large patient populations, where the technology is, we believe, protein degradation is the only way to drug these targets fully. IRF5 like STAT6 is another transcription factor. I would say technically extremely difficult to find a specific degrader for IRF5. IRF5 is, I believe, between nine and 11 different IRFs, as there are different IRFs, I think, between nine and 11. IRF5 is one of them of the family of IRF. And within IRF5, there are different splice variants. So you have to be specific for IRF5 and also degrade all the splice variants.
So it's technically extremely difficult. I think it's one of the most pursued targets by companies that work in immunology, or one of the, I should say, most pursued targets. But it's also one of the most difficult. So we're actually quite proud that I believe we're the first company by far that is going to take an IRF5 degrader or an IRF5 anything in the clinic. So we plan to be in the clinic early next year. We have completed IND enabling studies. Again, another program without any adverse events in the GLP tox campaign. And we expect to have data. We expect at this point in the second half of 2026 already.
You know the excitement around this target is that has really broad biology, has impact on cytokines, 5, 6, 12, 23, TNF, so pro-inflammatory cytokines, type 1 interferon, and autoantibodies, but very specific to particular cell types, dendritic cells, macrophages, monocytes, B cell, and also and only in particular context of stimuli, TLRs, kind of B cell activation. So broad biology, but specific to particular context. And what is the, let's say, the North Star in terms of where do we take this drug? We have strong human genetics. Like, again, for STAT6, like for IRAK4 and other programs, we believe the highest probability of success in drug development is correlation to strong human genetics. So IRF5 is one of the most elegant human genetics data showing disease association with lupus the strongest, IBD, and RA after that.
What we're doing internally is marrying these elegant human genetics data with robust preclinical data sets that will allow us to prioritize the indication. We've shown some compelling preclinical data in lupus. We're doing more work in both RA and IBD to then finalize our development path.
But this could be another one where you establish proof of concept and then move pretty rapidly into multiple indications.
Yeah. I think in this day and age, sequential development is challenging to do from a kind of regulatory and pricing perspective and reimbursement perspective, and so I think we're very keen to both kind of create early de-risking events for the program and then expanding in potentially multiple indications.
Yep. Very cool. Now, you guys are partnered with Sanofi for IRAK4. And I believe they discontinued KT-474 in favor of a next-gen more potent degrader. Tell us what went into this decision and what are their development plans to take KT-485 forward?
Yeah. Look, sometimes when you're very good at advancing degraders, you obviously create this tension. We've learned a lot in the past few years. The capabilities we have now are obviously not the capabilities we had seven years ago. So it's only natural that as we invest in a second-generation degrader, you should be able to come up with a superior molecule. So KT-485, in many ways, I like to call it a second-generation degrader of Kymera, like KT-621 and KT-579. They're all in the same kind of batch of next-generation degraders. And so we and Sanofi agreed, I believe, easily that KT-485 was superior to KT-474. I think they decided that if you have two molecules in the clinic, you should prioritize. And so they decided to discontinue KT-474 to favor a molecule that they believe was positioned to more both clinical and commercial success.
So I think there's probably other ways to have done that. But nonetheless, I think the decision to prioritize KT-485 was the right scientific decision. And we're excited about starting the phase I study. Actually, Sanofi will be starting the phase I study next year.
Will KT-485 ultimately compete with KT-621? And how are those conversations? You know, obviously, you keep it segmented, but in a way, you're creating a competitor to their program.
Well, I mean, as you know, Sanofi is also, from what they've publicly announced, also a big believer in the STAT6 mechanism. So I believe that the IRAK4 mechanism and the STAT6 mechanism are complementary. I don't believe they're actually competing for the same population. We have a KT-621, which is, I think, the perfect type 2 drug. And IRAK4 is more of a Th1, Th17 drug. And I believe that the indications will follow the complementarity and not much of the overlap.
Yep. Excellent. Very, very diplomatic answer. I like that.
Yeah. Very unlike me as well.
Scientifically correct, that's fair. I think it is complementary. Now, you guys just recently partnered with Gilead to develop a molecular glue degraders against CDK2. Maybe tell us about this target first. How do these MGDs differ from maybe some of your first degraders?
Yeah. No. So it's interesting because, as you know as well from the early days, we used to work in both oncology and immunology. A few years ago, we decided to focus almost only on immunology. And CDK2 was an effort that has been ongoing at Kymera for a while. And so eventually, with our investment in immunology, with teams and capabilities, while we're very excited about CDK2, we thought it was best to put it in the hands of an organization that is building a franchise in those diseases. With regards to molecular glue, our view is that you develop molecular glue degraders when you're solving a problem that heterobifunctional degraders cannot solve. So for us, heterobifunctional degraders are the best technology to go after targets where you can have a discrete binding event. And you can do it specifically.
We have found specific binders to IRAK4, to CDK2, to STAT3, to STAT6, to IRF5, to MDM2, and all the programs that we worked on over the past few years. And we believe when you have specific binders, you can make a highly specific and potent degrader with the heterobifunctional technology. When we use heterobifunctional, when we use molecular glues, they're in two contexts. One, we cannot find a binder. We need to use a protein-protein interaction technology to go after that target, or where the binder cannot have specificity. So we used to actually have, because we published on it, a heterobifunctional degrader with CDK2. The problem with all CDK2 programs, the ones in the clinic and most of the ones that are still preclinical, they all have some level of activity against CDK1, which has inhibited their ability to fully block CDK2 because they have dose-limiting toxicity.
We wanted to have an absolutely specific CDK2. You cannot do it with an active site binder, and so we identified this really elegant molecular glue. This is absolutely specific for CDK2. It does not touch any other CDK. It's brain-penetrant. It's highly orally bioavailable, and we believe it's a unique asset, and we're very excited about Gilead first agreeing with us for the opportunities, and hopefully, as we advance a bit more, they'll be able to take it into the clinic.
Yeah. What are their plans to take it into the clinic? And maybe you can remind me what you guys still own from the CDK2 program.
Yeah. So I think there are some things that I'm not allowed to say. But high level, there is, so right now, the program is still at Kymera in the preclinical stage. There is an option exercise that is still preclinical, but it's after having identified a molecule. And then the program will transition to Gilead. And we have, I believe, $750 million of milestones. And then there are royalties associated with it. So as you know, this is a big franchise that will be both single agent and combo. So we'll be hopefully watching and cheering it from the sidelines as they develop the drug.
And I know you guys never sit still, and there's a lot you're working on too. Can you give us a sense for sort of what else is sort of emerging or what else is maybe below the waterline right now?
Yeah. I mean, the case that I make to my team in research, we have a robust team in terms of numbers and an exceptionally gifted research team in terms of capabilities and strategy, that the only reason to keep that team going is if the next program are at least as exciting, if not more exciting, than our existing preclinical program. So obviously, the bar is extremely high. But I think we continue to meet that bar. I think we have, I don't know, 10+ programs at different stages of early discovery. But we have a couple of two or three programs that are in the stages where they're almost ready to be disclosed. And in fact, we have a goal next year to be disclosing one new program.
I mean, all I can say is that immunology programs in areas of targets that have never been drugged before, for sure not with small molecule oral drugs. I think if you think about IRF5, STAT6, in that kind of flavor of type of program.
Great. You guys ended the third quarter with cash of just below a billion, I think $979 million. I mean, really the strongest balance sheet you guys have had between financial raise and support from investors and also partnerships. How long does this fund the company? What does it really enable you to accomplish?
Yeah. Look, we're very fortunate that we have investor base that continues to believe in what we can do and what we've done. So that will allow us to get into the second half of 2028, which means the phase II-B studies for KT-621 in AD and asthma, initiation of some at least one phase III, for sure, startup activity and actual study, proof of concept study for IRF5, and taking at least one new program in the clinic. So we have lots of, obviously, the value creation opportunities between now and then, and also, obviously, new programs that will be continuing to be advanced in the preclinical stage.
What's the role of partnering for Kymera going forward?
I like to believe that Kymera is a company that wants to become a commercial stage global reality. And that's what we've been doing for the past 10 years. You don't get to suddenly become that. And we work in an ecosystem. So you have to be able to create efficiencies in the ecosystem. There are programs that we care a lot about that we want to take all the way. There are programs where I think it might have been beneficial to partner, like we did with CDK2. I think for programs that are part of our core strategy, immunology, I think it's extremely unlikely that we will do partnership before clinical proof of concept studies. And beyond that, we would only partner if it makes sense for the growth and the value creation of the company.
I think if we're successful in every program that we run, it's impossible that we will be able to develop all of them on our own. So I think partnering will continue to be an opportunity of value creation, but we will not be something that we rely on to develop and commercialize our drug.
Fair enough. Well, always a pleasure, Ted.
Always a pleasure, Ted. Thank you.
Looking forward to more progress in 2026.
Likewise.
Thanks, everybody.