Thank you. Good afternoon, 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 Kymera that are posted at the back of the room and also at the registration desk. Kymera has announced its focus is on developing protein degraders to treat autoimmune diseases. The company recently initiated dosing in the phase I study of STAT6 degrader, KT621, and plans to file an IND on TYK2 degrader, KT294, in the first half of next year, and we'll get data from some of those programs next year. Partner Sanofi is also accelerating development of KT474, which is an IRAK4 degrader in atopic dermatitis and hidradenitis suppurativa, or HS, and they're accelerating towards registrational studies, which has been a big driver for the company this year.
Here with us is Kymera's founder, president, and CEO, Nello Mainolfi. Nello, I always butcher your last name. I apologize.
You're not the only one, so.
Mainolfi. Better or no?
Close, close.
Tell me.
Mainolfi.
Mainolfi.
Yeah.
Okay. Yeah. I wasn't close enough.
At least we did this live.
Yeah.
Usually, I do it after when I complain.
All right. So, Nello, let's talk about 474, partnered with Sanofi. Why is IRAK4 such a good target for autoimmune disease? And walk us through the safety and efficacy data you've reported to date.
Yeah. So first, thanks for having us, Ted. It's always great to be in the city this time of year. So starting with IRAK4, so our strategy in immunology has been actually consistent over the years, identifying these pathways that have been validated, usually by upstream biologics, where intracellular nodes have not been drugged or drugged well, where you have opportunities to really impact large patient populations across multiple diseases. And so IRAK4 and the IL-1/TLR pathway is one of those, those pathways. This was our first program at Kymera and actually the first heterobifunctional degrader to be in healthy volunteers, then in patients with other inflammatory diseases. So it's been an important program for us, both for the actual value that it has, but also for what it meant for the rest of the pipeline built in immunology.
So we know that the IL-1/TLR pathway is central to many disease states, especially diseases where there is both local and systemic inflammation. And you know, HS is a typical example of TLR local activation, systemic IL-1 activation. We've seen validation from upstream biologics with I think at this point, the most recent compelling data that I would like to cite is the IL-1 alpha/beta antibody from AbbVie that showed really robust data in Humira refractory HS patients. So showing that an upstream biologics can have an impact in an extremely complex disease like HS. And then how do we target again a pathway like this intracellularly?
If you go back 15 years, probably every pharma company had an IRAK4 kinase inhibitor program, most of which actually never made it to the clinic, a couple of which made it to the clinic, and I would say generally without success. The reason has been that first, targeting the kinase domain is extremely difficult to do selectively. I think where people actually, this is a bit of a nuanced insight that I never talk about, but just remember now, I think people were trying to figure out why they weren't getting the biology of this pathway with kinase inhibitors. Only after 10, 15 years, we learned that the reason for that was that the kinase function of IRAK4 was insufficient to drive pathway blockade. Some molecules were better, and they showed that in some contexts, you were able to block the pathway to some extent.
Us and others, actually, even independent labs in academia show that there is a well-characterized scaffolding function of IRAK4, which really means that IRAK4 is involved not only in phosphorylating through the kinase function pathway proteins, but also in allowing the MyD88 complex from, with functioning and propagating the upstream signals. We characterized that, and we showed in a plethora of preclinical models why degrader is really the only way to block IL-1/TLR signaling. That's why, sorry, long answer.
No, this is great.
A good question why IRAK4 is a good target. What we've shown as, you know, the first company in the space, and I'm actually glad that now we have several that are following our steps with IRAK4. I think it's always a good read on the quality of the work that we've done. We've shown first that by degrading, we could degrade fully IRAK4 in healthy volunteers. That led to impact on biomarkers ex vivo. We went into a small HS and AD study. We call it phase I part C. You can see it as a phase Ib study where we showed that after 28 days of dosing, we're able to degrade the target, have impact on both circulating biomarkers in circulation and in the skin.
This led to objective clinical responses in both signs and symptoms of HS and AD measured through EASI pruritus in AD and HiSCR , as well as pain in HS. So this was an uncontrolled small study, but the data were compelling enough that Sanofi decided to invest in two parallel phase II programs. Then that early this year have been. We've announced that have been, let's call it upgraded to phase IIb studies with multiple doses and roughly 200 patients each, that will read out in 2026.
So tell us a little bit what you can about that decision from Sanofi.
Yeah.
Obviously, it was data-driven, and we were originally supposed to get smaller data sets, I guess, this year or early next year. I can't remember.
First half of 2025.
First half of next year.
Yeah.
But tell us about, in a little more detail, what went into that decision, what the studies look like, and when we could get data from these enlarged studies.
Yeah. So, you know, the studies were designed. I would, you know, I've characterized them as proof of concept studies. If you look at the initial study, the HS was one dose, one placebo group, which obviously required, in order for us to go into phase III, to do dose-ranging studies. So the earlier design, you would imagine, required a, you know, let's call it phase IIA proof of concept study, then a phase IIb, and then a phase III. What, you know, Sanofi and we, you know, decided to do and saw the opportunity in potentially expanding the existing study into, let's call it a seamless phase IIa- phase IIb so that the next de novo study will be a phase III. So that was the opportunity to accelerate the overall development timelines.
Sanofi elected to do an IA looking at safety and efficacy to make a data-driven decision. Unfortunately, I can't go into the details of what data were seen and what questions were asked the IDMC, but you know, rest assured that in order to, I guess, doubling the size of the studies, obviously the data was supportive of such an investment for the collaboration. It's an exciting time, as we now, you know, we'll have dosed these molecules to close to 400 patients by the time we read out the studies. As we said, the projected completion date will be between first half and mid of 2026 for both studies.
Great. Excellent. And what are Sanofi's broader development plans for 474? And remind us what your retained economics are?
Yeah. So that, unfortunately, I'm not in the position to share much more than maybe a high-level statement that maybe speaks to the commitment to and the excitement towards this mechanism and the commitment to doing two parallel phase II studies. I think they've said, we've said, and they've said publicly that, you know, there is obviously interest to broaden the franchise in the face of early success, and you know, I will let Sanofi share more about the late development plans. With regards to the deal, this was a $1.4 billion deal of milestones between clinical, regulatory, and commercial. You know, the milestones we've had so far were, you know, a small fraction of it. So there's still a lot of milestones to be realized.
We also have an opportunity after phase II, before the first phase III study, to opt in to a co-development, co-commercialization with Sanofi splitting the U.S. market. Again, development costs and profits 50/50.
That's great.
So that's a decision that we're fortunate to be able to make with a robust data set now.
Yeah. Absolutely. So it would be on this data that you would make that decision. Is that correct?
Assuming that, yes, that the next study's a phase III study, yes. If the next study's another phase II, for example.
Then you take it.
Then we don't have to make that decision yet.
You'll take, obviously, as long as you have to.
Yeah.
A for cost, but B for data. So that makes sense.
Exactly.
All right. Cool. So I'm gonna switch over to your wholly owned pipeline, and KT621, STAT6 degraders. You wrote a really nice blog recently, which I read.
You're the only one that's done that.
No, that's not the one.
One of them.
I read it on STAT6 Biology. Tell us about this target, and maybe you can share with us some of the preclinical data you guys just presented at EADV.
Yeah. So thanks for mentioning the blog. I actually thought we did a good job telling a bit of also the story behind the program and not just the program. And so it's on our website if people wanna go and read it. So I, as I said, actually, in that blog, we always felt that STAT6 was the perfect target for a company like Kymera because it really exemplifies everything that we look for in a target. It's in a pathway that has been validated. You know, Dupixent is going to be the largest drug, for sure, in immunology, in the next two to three years. It's already a $12 billion drug, I believe, today. So highly validated drug, intracellular node, undrugged, transcription factor difficult to drug.
The additional kind of perfection about STAT6 is the way we understand and have shown the biology. This is one of the few highly selective transcription factor, meaning that it really only works downstream of the IL-4 receptor. So we have a one-to-one relationship between a highly validated target and an undrugged target. That happens very rarely in drug development. So validated pathway, undrugged node, both genetics and pharmacological validation of the pathway, genetics on the target, and then large, you know, commercial opportunities, clinical opportunities. And actually, our commercial plans are actually, I would say, quite sophisticated and how we think we can create a lot of value in this market. So it kind of has all the right, the right prerequisites. I think what was difficult when we started the program was are we gonna be able to do this?
What the team has done and had a little to do with it identified is this beautiful molecule, exceptionally potent, exceptionally selective, picomolar potent. I've never seen a novel drug being more potent than a biologic, or at least in the cellular system. We've shown, and referring to the data, we've shown that we're able to block the pathway fully, just like a, a saturating dose of dupilumab. In these asthma models, which we believe are the most translatable Th2 models out there, we're able to block both, downstream chemokines and cytokines and biomarkers of Th2 inflammation. We're, we're able to block cellular infiltrates into the lungs of these, of these mice, as well as we're able to impact disease as it is.
We've shown, and on top of that, we've shown that in all of our preclinical safety studies, really, we did not see any adverse events. We have a drug that really looks like a novel drug with biologics-like activity.
Yeah.
And I think that is so rare. We're used in talking about commercial opportunities. We're used in immunology to, you know, going to the doctor and being told, like, you know, you can get these injectable drugs that, you know, probably clears your lesions or your, you know, psoriasis lesions, for example, or AD lesions.
Yeah.
but, you know, you gotta inject yourself every two weeks.
Yeah.
Every few weeks or whatever. Or we have this oral drug that doesn't work as well, but you can just leave it on your medicine cabinet. You can take it once a day, and you don't have to worry about fridge and syringes and stuff. But you have to compromise. I think what we have the opportunity to do at Kymera, across our pipeline, and STAT6 being a perfect example of it, is to say you don't have to compromise. You can take an oral pill with the same level of activity. So we have to show that. Right now, we have preclinical data supporting this thesis, and that's the excitement about STAT6.
Yeah.
It's,
Now, it's.
Take changing the treatment paradigms in Th2 diseases. This is not so much about, you know, competing with biologics for the million patients. It's about the 100 million patients that have no therapy.
Yeah. And oral, which is so nice. So you guys have begun dosing healthy volunteers in phase I. When can we get data, and how do you envision developing 621?
So yes, we started with dose at first healthy subject on October 22nd, I believe, and we said that we're gonna share data in the first half of 2025. What we're gonna do, probably at J.P. Morgan, once we're deeper into the study, sorry to sponsor a competing conference here.
It's okay.
I'm sure you're okay with it.
I'll be there. Not in the meeting, but I'll be in the room.
All right. We got too used to that. Early next year, we're gonna talk about, with more precision, when we're gonna disclose the data. We're still on track in first half. We're just gonna say exactly a bit with more precision when in the first half. I think it's important to think about what is the important data readout.
Yeah.
For the phase I study, and then I'll get about the.
Yeah.
Late development plan. So again, this is the validated pathway, understood biology, but we're first targeting STAT6. So being able to demonstrate that degradation of STAT6, as we've seen preclinically, is, has good safety and good tolerability, to me, that's all I need to know.
Yeah.
The biology is understood.
All right.
We've shown comprehensively that basically you can block the pathway like an upstream biologic. So it's really demonstrated and the target is prosecutable in humans. And then, as you're saying, it's off to the races. We, as I've said in our R&D day early in the year, we stand on the shoulders of giants, right? People that have developed Dupixent and now other members of the Th2 biologics family have showed us, you know, seven, actually soon probably to be eight indications.
Mm-hmm.
That the drug has been approved and has changed, you know, people's lives, kids' lives.
Yeah.
Adults' lives. And so we know exactly what we need to do. What I will say, and then I'll share, maybe we'll share a bit more early next year, is obviously we're, we're gonna start with the larger indication.
Yeah. Yeah. Yeah.
I think at this day and age, that has to be the responsible way to develop drugs that can serve, you know, potentially millions of patients.
You know, obviously, atopic derm, asthma, COPD, a bunch of these. How important are early clinical readouts to for that? Or is really just market size the primary choice for the next step?
Obviously the skin.
You mean for indications.
Yeah.
Yeah. 'Cause I'm thinking like skin can read out pretty fast. Asthma can too, actually. So.
So AD, so for sure, AD, asthma, COPD are clearly the larger indications. I would say that, we're not probably going to disclose it. There should be a very smart way to develop this drug that will allow you to use data to inform late development of even on other indications.
Cool.
You shouldn't have to run phase II studies for all the indications that you're gonna develop. Dupixent has done that if you think about what they did in COPD. We know that there should be a smart way to do it, a capital-efficient way to do it. But obviously we need to generate robust, you know, phase II data in skin, in respiratory indications, potentially GI. We'll see where we're able to establish the relationship between the level of degradation, the level of clinical endpoints, and safety. I think once we have that, then we have our phase III doses, and then we can go really broad.
Transitioning, TYK2 fits almost as well as the target. And obviously well known with, so TYK2, you see the commercials on CNN or CNBC or whoever you're watching. So tell us why degrading TYK2 can be more efficacious than the inhibitors. And what are your development plans here?
Yeah. So, I think, you know, it's interesting. I don't think today there is a lot of appreciation. I feel like you can correct me if I'm wrong, about the opportunity with the TYK2 degrader. There's obviously a lot of focus on STAT6 from what we can tell in the investment community, rightly so. But I think the chapter on TYK2 hasn't even started to be written. We have an early drug that, you know, is an effective drug. It's a well-tolerated drug, that, you know, has been approved, and has been a key milestone for the TYK2 space. This is a target with beautiful human genetics data.
But we have to recognize that either that drug or, to be honest, all the other TYK2 inhibitors are not able to block that pathway fully, both in terms of target engagement and stoichiometry of PKPD with occupancy-based small molecule inhibitors, but also because TYK2 is another scaffolding kinase. Which is, you know, kind of the worst kept secret. It's never talked about, because for some reason. But if you look at human genetics of loss of function versus human genetics of kinase-dead, totally different phenotypes.
Yeah.
So we have an opportunity to have two angles for superiority. It's obviously the decoupling of PKPD with all degraders I have. You can hit 95% steady state. And the fact that we can block also the scaffolding function. And I truly believe, and hopefully I'm not wrong, that we're gonna be able to have a drug that looks like those upstream, like an IL-23 biologic. And you see the opportunities there. Yeah, you know, even the recent J&J Protagonist data with the IL-23 peptide, which is a beautiful drug. I love the concept about that drug. I think it's still falling short from what I can tell, on the biologics efficacy. So I think that game is still yet to be played.
Yeah. Very cool. And it is. It's a perfect example of why degraders can be superior.
And where the degraders need to be deployed.
Yeah. Yeah. I think it's smart. Now, sort of to this point, you guys have deprioritized KT333, STAT3, also KT253, MDM2. We're gonna get data from both at ASH, but what is the plan to partner these? What went into this decision?
Yeah. So first, STAT3 will have data at ASH.
Yep.
Only STAT3. Actually, this weekend, I believe.
Yeah.
You're going there, right?
Yes.
Yes. So let's start with why the decision was made to not advance beyond phase I. Actually, we're still completing those studies. I think that we have a bar as a company. That bar has been, I would say, refined over the years as the external environment has changed. The bar is we need to be able to have single-agent activity in large addressable markets with a clear path to having best-in-class pathway or best-in-class drugs for those individual diseases. Again, addressing hundreds of thousands, if not millions of patients. We will work also outside of immunology, you know, at some point. Right now, really focusing on immunology, but it'll have to meet that bar.
Those programs, I think, are best positioned in the hands of companies that already have built the capabilities so you can actually synergize and build much more value than having to build late development and commercial capabilities in areas where, you know, you really need to synergize with existing agents that you can combine as well as you know, oncology is.
Yeah.
It's really only about, at the end of the day, it's about combination, so that's why the decision.
Yeah.
Was made. I love, you know, those programs. I think you'll like our ASH poster. I'm sure you've read the abstract. I think it's impressive data. And yes, we're in, you know, obviously, I can't commit to this program.
Yeah.
We'll be partnered 'cause I don't get met, that they'll make that decision on my own. But yes, we would love for our oncology pipeline to continue to create value for patients, help patients, and create value for us and our shareholders.
Yep. Absolutely. So you guys have successfully raised over $500 million this year and I think ended the third quarter with nine, over $900 million.
Yeah.
How long does this fund the company? And maybe even more importantly, as you talked about 621 and 294, what does it enable you to accomplish?
Yeah. So the cash $911 million, I believe, is the number. Am I right? Bruce confirms from the first row. It will allow us to get into the mid of 2027, middle of 2027. And more importantly, as you said, I can't say exactly what, but we'll share more early next year. I would say multiple phase II readouts across our pipeline, including, but not limited to, obviously, the IRAK4, which, you know, as we said, happens in 2026. We'll have multiple data readouts across our pipeline. We have several robust clinical data readouts and inflection points between now and our cash run-out date.
That's all I've got. Any questions from the audience? We're excited for a really, really busy 2025.
Definitely. Thanks.
Thanks for being with us.
Thank you.
Thanks.