Brian Abrahams, senior biotech analyst at RBC Capital Markets. Really pleased to have our next featured company, Kymera Therapeutics, represented by their CMO and CFO, Jared Gollob and Bruce Jacobs. Thank you guys so much for being here.
Thanks.
Thanks for having us.
Thanks for having us, Brian.
I wanna start on STAT6, but I know there's a lot to cover, and the pipeline is continuing to expand. Maybe just starting with KT-621, you're now several months into enrollment for the phase IIb, atopic derm study. Can you talk a little bit more about really, I guess, bigger picture how that's all going, and, you know, you can touch on the pace and quality of enrollment at a high level, the overall enthusiasm you're seeing from the populations of interest, such as adolescents, and just, I guess, your sense as to, you know, any initial learnings, and takeaways as that's starting to proceed?
Sure. Brian, thanks for the question. Thanks again for having us here. We decided we're gonna try to stay away from blow-by-blow updates.
Of course.
on the trial. Suffice it to say that going into this study, one of our objectives was to do what we could to build awareness around the program and excitement around the potential. There's lots of ways to do that, one of which goes all the way back to the phase Ib study that we ran last year, and we shared the results in December.
Yeah.
That was an opportunity for us both to show ourselves in the investment community, obviously the potential of the molecule, but also to create a data set that we could use to build excitement amongst the clinician population, the investigators out there, and ultimately the patients. We do believe that it has served that purpose. Obviously, we shared the data in December, but we also had the opportunity at a late breaking trial at AAD to share it with a broader audience. I think that was really important.
Yeah. What was the feedback like from the AAD presentation?
Yeah, really very, you know, very positive, very enthusiastic. You know, even though we had presented data back in December, you know, this was an opportunity for all the, you know, major clinicians and KOLs in the space to really see it presented, and then to have an opportunity to interact with us at multiple different levels.
You know, we were there both, you know, our medical group, our operations group, our medical affairs group. I think the feedback has been really uniformly, you know, very positive. You know, the data that we showed across the two different dose levels, you know, the safety data, the fact that it appears to be sort of potentially phenocopying Dupixent.
I think as Bruce said, I think it really has been, you know, stimulating a lot of enthusiasm both on clinicians' part and investigators and patients to want to enroll onto this study, you know, with an oral drug.
I think one aspect that has always energized us as a company with respect to this opportunity is the large patient population that is right now underserved with existing therapies. If you look at the moderate to severe type II population, there's something on the order of 50 million patients, of which only 2 million are served by advanced systemic therapies.
That has always been exciting to us in terms of the scale of the opportunity that's in front of us. We felt both going into this trial and then obviously most importantly when it comes to commercialization, that the appeal of an oral molecule, if we're able to deliver the profile that we'd like, would be very, very high. I think that's been.
Yeah
something that has, as I said, excited us, and it will hopefully also be a contributing factor as we move through clinical development.
Maybe coming back to AAD, we were fortunate to have a late-breaking plenary session presentation. There were thousands of people in the room, and that just speaks to the keen interest, you know, in the program. There were a number of different KOLs when they had their own sessions that they were moderating, you know, including Kymera and what's in our pipeline, you know, in their presentations. I think it just shows that the word is really getting out there.
That's great. As the trial proceeds, what are gonna be some of the key things that you guys are going to be watching for overall to help guide any potential adjustments, including, I guess, you know, you probably will have some sense of what the open-label extension enrollment might look like. Could that also provide any clarity on or ability to detect any aberrations in 621's activity or safety profile? What are some of the things you're gonna be watching for overall as this trial goes?
I mean, I think the important point is that, you know, we don't take anything for granted on this study, so we're providing a lot of close oversight of both the CRO that's running the study as well as each of the sites. You know, we have very, I think, close relationships with the study teams and the investigators, you know, through both, again, our medical, our operations, and our medical affairs people.
I think what's important to us is that, you know, we're able to, as patients are being screened for the study, we're also able to see those screening data sort of in real time to make sure that when patients are eligible, they truly are eligible, and we're able to see what those baseline characteristics look like sort of in real time as patients are coming on.
That starts to give us confidence that we're bringing on the right patients onto the study. I think it's important, you know, to have a good cadence of site activation, you know, as well as enrollment. You know, we had metrics that we had built prior to the start of the study to see how we're tracking, and I think, you know, we've been very encouraged, you know, how we're tracking according to those metrics.
I think for us that that's been really important, is not taking anything for granted. Really understanding, you know, the cadence of enrollment, the types of patients that are coming on, and knowing that all the sites have been rigorously trained, and that we are very accessible to the sites if they have any questions or concerns.
Sounds like things are going according to plan.
Yes.
That's great.
What, you know, our publicly stated guidance has been that we would complete enrollment this year and share the data by mid 2027. As we've said recently, you know, we're very much tracking against those expectations.
Great. You guys have reported on degree of degradation, on biomarkers, on clinical effects. You know, thus far there haven't been any notable safety issues at all. I know you've generated a lot of preclinical data around safety to address any potential questions there might be about just any off-target small molecule effects or on-target degradation effects. Then can you talk a little bit more about the, you know, what your observations have been and just what your learnings are about the potential therapeutic window of KT-621 based on some of these preclinical studies?
Yeah. I think, you know, preclinically, I mean, I think it all starts with, you know, even the human genetics, you know, that gave us confidence in not just STAT6 being important in driving type II inflammation, but that it was safe to actually drug STAT6. Our preclinical data now includes six and nine-month tox data, nine-month in monkeys, six months in rats, where we pushed to high doses, high exposures that are giving a systemic complete degradation. We've seen no adverse findings whatsoever in any of our tox studies, you know, all along at this point. I think that's also been very encouraging.
I think in addition, when you just look at what we've seen or haven't seen, you know, in the phase I healthy volunteer study where we had over 120, 130 subjects in a placebo-controlled manner, safety was indistinguishable from placebo with 14 days of dosing in our phase Ib, where we had four weeks of dosing across the two higher dose levels, 120 milligrams, also no safety findings. I think all of that, I think is very encouraging.
Overall, our expectation is because we're hitting the IL-4, 13 pathway completely, and DUPY has done that, and there's a lot of precedents there. Our expectation is that our safety profile should be comparable, you know, to dupilumab, and we'll see how that plays out in the phase IIb and beyond.
You know, I should mention in the phase IIb, we also have an open-label extension study. After the first 16 weeks of placebo-controlled data, patients are then going to be able to roll over onto this 52-week open-label extension study. That will give us, I think, important further long-term safety, as well as efficacy information, but especially safety information, as we then, you know, move into, hopefully into our phase III campaign shortly after completing the phase IIb.
I get asked a couple of questions pretty frequently on just the overall safety profile, and obviously people are just thinking about theoretical risks because what you've seen has looked really clean so far. I guess are there any considerations around just the different relative biodistribution of a small molecule that targets the same pathway versus a biologic that targets IL-4 and/or IL-13, firstly? Is there any potential for a heterobifunctional degrader to have association with teratogenicity, or are there ways that you can kind of eliminate that theoretical risk concern?
I think from a biodistribution standpoint, yes, you're right. Small molecules will widely biodistribute, maybe even more widely than antibodies. We think that's an advantage actually, in terms of being able to get to all disease relevant tissues and cell types.
Yeah
especially when you're going after a target that we believe can be safely degraded fully systemically, for all the reasons that I gave before. I think what's also very important about KT-621 that contributes to its safety is its potency. You know, it's a picomolar degrader.
Yeah.
Highly potent, so allows us to use low doses in the clinic, and it's exquisitely selective, more so than your traditional small molecule. Having those features along with a drug that's only hitting, you know, STAT6, which only serves the IL-4, IL-13 pathway, I think all of that together, you know, makes us very confident, you know, in the safety profile of this drug or hopefully, you know, eliminating or at least, you know, reducing the possibility of there being sort of unknown safety events.
Yeah
down the road. You know, there's always that possibility. We're always keeping our eyes wide open, you know, throughout these studies, but all of those things are very reassuring.
Where do we stand with regards to asthma? I guess how's the phase IIb progressing so far? Have your thoughts on the next potential indications beyond AD and asthma evolved? How have those thoughts evolved?
Yeah, sure. As I think you're aware, the asthma study started a little later than the AD study. The AD study got going in the kind of winter of last year, late in the fourth quarter. Really just to sequence things, we started asthma later, so the first site and activated patients enrolled in the beginning of 2026, so just in January.
That study is ramping up. Its timeline is such that we have guided to completing enrollment next year and having data before the end of the year in 2027. On a, I guess a later timeline than AD, in part because it started later, in part because also it probably will take a little bit longer to enroll.
It's also a larger study, 260 some odd patients versus 200 for AD. You know, we'll obviously have more to share as we move through the enrollment, but probably wouldn't have much more to update you than that. We continue to be excited about both these indications. We kind of, you know, consider AD and asthma to be the almost like sentinel indications, if you will, for the program.
We are certainly looking much more broadly, and our development plan is predicated on a strategy that will have the phase II AD study effectively being the foundation for future dermatological indications that we might pursue, likewise asthma and other respiratory indications. We've talked about COPD.
Yep
as an area of focus. We've also talked about EOE.
Yep
which is particularly interesting, because of the fact that it, that it affects younger patients, and also the DUPIXENT dosing is twice that of that's required for AD and the other indications. I'd say those are the two that are front and center for Kymera. There's others, chronic rhinosinusitis with nasal polyps and a handful of others.
Obviously, in today's day and age, you know, with the IRA, one of the incentives are such that you want to pursue as many of these as early as you can, but also we're realistic and practical about what we can and can't do. Suffice to say we're building really broad development plans that, you know, we're well into that phase III planning today, given that phase II is underway all, you know, well underway already.
If I could also, I wanted to come back. I'm sorry I missed one part of your question before around teratogenicity, which is an important question. Maybe if I could just address that just for a quick moment.
Sure.
You know, for KT-621, you know, we've done embryo-fetal development studies in multiple species, including rabbit and monkey. No evidence for teratogenicity. You know, we haven't mentioned what the E3 ligase is for the STAT6 program, people do worry about cereblon and potential teratogenicity.
We harken back to our IRAK4 program, where we published a paper in December of last year showing the exhaustive set of work that we had done pre-clinically to show that there is no teratogenicity, to show that the binders that we have to cereblon are neutral. They have no IMiD activity whatsoever, they don't have any effect on IMiD neosubstrates that you see with classic IMiDs. We've also put, you know, drugs like KT-474 through embryo-fetal development studies, which have been negative.
We've also got no feedback whatsoever from FDA across any of our programs with regard to that concern. Finally, you know, Arvinas recently had, you know, their first oncology drug approved, which we know does use cereblon.
Yeah.
You know, it's an estrogen receptor degrader. Essentially, if you look at the label, the only thing in warning and precautions pertain to what you see classically with selective estrogen receptor degraders. There was nothing unique to, you know, heterobifunctionals, molecular degraders as a class with regard to teratogenicity. All of that I think is very reassuring to us.
Good. That's really helpful color. Maybe we could shift gears to 579. I know we're going to see some additional data this year. You guys have talked about your internal bar being 90% plus degradation of IRF5 in blood, 50%-80% inhibition of TLR signaling in the ex vivo assays. Can you help us understand, I guess, what shapes these goals, how those expectations fit in with the dose levels that you're going to be testing in the MAD portion? Are you looking for dose dependency in the ex vivo signaling inhibition?
Yeah. I think those are all good questions. I think for IRF5, you know, we do get the question, "Well, how much knockdown do you need really, do you think you need for clinical activity?" If we look pre-clinically, we know that mice with complete loss of IRF5 are protected from lupus in those particular models or from IBD or RA.
We know that mice, even with heterozygous loss, so only 50% loss, are also protected. In our own lupus models, where we see profound activity better than approved drugs or other active drugs in development, we see that activity in association even with 80%-85% knockdown of IRF5. I don't think we need complete knockdown of IRF5, you know, to see the activity.
With that being said, traditionally, you know, in our phase I programs, you know, we expect that our degraders should be able to achieve 90%+ degradation because we see that pre-clinically.
Yeah.
Coming back to the phase I healthy volunteer study, SAD MAD, that's why we've set the bar at at least 90% degradation, you know, in blood. You know, we do expect to be able to see a dose response, although in general with degraders, as you've seen from our other programs, it's a pretty steep dose response.
Yeah.
We do expect to be able to see one. Being able to get 90% plus degradation at doses that are safe and well-tolerated is one of the goals. The ex vivo stimulation assays you mentioned, you know, we don't have a circulating biomarker in healthies like we had for STAT6, where there's Th2 tone even in healthy individuals, and you can follow TARC or Eotaxin-3. You know, similar biomarkers don't really exist for IRF5 because IRF5 is controlling signaling through multiple Toll-like receptors as well as other innate immune receptors.
Rather than look for something in vivo in these healthy volunteers, we'll be doing ex vivo stimulation assays, focusing on stimulating Toll-like receptors seven, eight, and nine, which control Type I interferon response, pro-inflammatory cytokines like IL-6, IL-12, and IL-23, and B-cell activation and autoantibodies.
With those ex vivo stimulation, we can look at downstream cytokines and pro-inflammatory transcript. I think there we've said we'd like to see 50%-80% inhibition across all three of those Toll-like receptors to tell us that the degradation of IRF5 is sufficient to have a biological effect on those pathways. We think that that degree of inhibition should translate into activity in subsequent studies in patients.
Makes sense.
Earlier this year, obviously, we announced that we had commenced the healthy volunteer dosing. It follows a conventional SAD, MAD.
you know, approach. You know, we are into the MAD component of the study now, and when we have that data, we'll share. The expectation's that it would be in the second half of this year. At that time, we'll also share more, and I'm sure you'll probably ask this, about what our clinical development plans are beyond that. We've talked about an intention to move into patients as quickly thereafter as we can.
We had suggested our most likely initial indication would be lupus. We've also recently shared some interesting preclinical data in some IBD models, so that suggests some promise there, and I think, you know, fully flesh out what the development plans are and share those with the investor community as we're ready.
Will that be guided by something you observe in the data itself or more kind of broader strategic considerations or other scientific developments?
I mean, one of the attractive features of IRF5 is the strong genetic association of polymorphisms in IRF5 with diseases like lupus, IBD, RA. The strongest association is with lupus. That combined with the very strong activity we're seeing in several different lupus models, having lupus probably be the first proof of concept study. With that being said, there are also strong genetic associations with IBD, maybe not as strong as lupus, but they're clearly there.
You know, myeloid activation is, in particular in IBD, is important, and we know our drug can impact that, as we showed in the recent data that we showed at DDW. I think that, you know, these other indications, you know, also play off of having strong genetic data plus preclinical model data.
I think that we all factor into, you know, which of these indications we want to prosecute and how we prioritize. I think the lupus prioritization is being near the top is for the reason that we gave, that genetic association is especially strong. Our aim is not to get, you know, bogged down in a long, large lupus study to take three years and sort of roll the dice.
I think the aim is if we see the level of degradation and pathway inhibition that we think could translate well into patients in the phase Ia healthy volunteer study, you know, a lupus study, even though we haven't revealed details of that design yet, would be hopefully an efficient study that would use, for example, both biomarkers and clinical endpoints to be able to show proof of concept in a timely manner.
Others are developing IRF5 inhibitors instead of rather than degraders. I guess How do you think about the potential advantage of an IRF5 degrader versus an inhibitor? I guess how similar is the relative value proposition versus the advantage a STAT6 degrader might have over a STAT6 inhibitor?
Yeah, I mean, it's a great question. I mean, IRF5 has been a very attractive target for multiple different pharma companies and biotech companies for years, but it's a very difficult transcription factor to go after, in part because there are multiple IRF family members. Any drug that you're going to create, be it small molecule inhibitor or degrader, must be highly specific for IRF5.
There's the added complexity of the fact that there are multiple isoforms of IRF5 itself. If you're going to develop an inhibitor, you have to inhibit all the isoforms, or a degrader, you need to degrade all of the isoforms. We've been fortunate, you know, through a lot of hard work and time to develop a degrader that sort of meets all of those criteria. You know, it's highly specific for IRF5.
It degrades all of the isoforms of IRF5. It's potent, you know, it's orally bioavailable. All of those features I think are necessary to have a drug that's going to be successful in the space. There's also, again, the unique pharmacology of degraders versus inhibitors, which we often bring up with STAT6, which is that, you know, because of the catalytic mechanism of protein degraders, you can have an oral daily dose that will keep the target and the pathway blocked 24/7.
Whereas with inhibitors, the blockade or the inhibition of the target is very exposure dependent, and it's very hard to have an inhibitor if you're dosing 1 or even two a day to maintain constant exposure. You have waxing and waning of target inhibition, which can limit the efficacy of inhibitors against the pathway.
We think for all those reasons, degraders have a real advantage. The one inhibitor that we're aware of that's out there is the hotspot inhibitor that's still in preclinical development.
Maybe just before we wrap up on KT-485, can you maybe talk about the potential differentiation of your guys' IRAK4 degrader versus other degrader approaches? Were there any features that you sought to optimize there based on some of your prior learnings and based on what else was going on in the field that you think could confer a key advantage? How excited are you about that part?
Yeah. As I think most of you probably know, that program is now with Sanofi.
Yeah
our expectation-
Yeah
that they will start a phase I study this year, hopefully in the not too distant future, that would generate a milestone. Sanofi will then run obviously and manage that program from here on out. No financial or really operational responsibilities on Kymera's part. We always are looking to improve upon molecules, even good ones, to find better ones.
I think we've talked about 485, vis-à-vis 474, having being more potent, having broader tissue distribution, and then solving what was the one issue that we found, which was the modest QTc impact from 474. Sanofi was sufficiently excited about that molecule to decide to advance that one forward in lieu of 474.
We're excited to work with them to help make that happen, hopefully that will happen in the very near future here. We still have a large number of dollars of milestones potentially in front of us, royalties. In that program, as a reminder, we do have the right to opt into a 50/50 in the U.S. co-co. That's an exciting optionality that we retain as well.
Good. Then maybe just in the last minute before we wrap up, I guess, how are you guys thinking there's already a lot on your plate and a lot of programs and a lot of trials that you guys are prosecuting? As we think longer term, what are you guys most excited about in the earlier stage pipeline? Are there targets or disease areas or programs that we should be kind of keeping an eye on or have on our long-term radar?
Yeah, it's great. I mean, we've talked about our two lead wholly owned programs. We're very excited about both. I think the opportunities are significant. They both have the opportunity to be both best in class and first in class. We've had a very disciplined target selection approach from day one.
Under the covers, if you will, are a host of targets and programs that we think are equally exciting, that have as significant a potential and as unique of a competitive position as the two that we've already disclosed. We're looking forward to sharing more on the pipeline as we move through this year and beyond.
Good. Well, we'll look forward to seeing that and to a lot of the data coming up in the back half of this year and into next year. With that, I know we have to wrap up, but thank you again.
Thanks, Brian.
Yeah. Thanks a lot, Brian. Thanks for the questions.