Good morning, everyone, and welcome back to Oppenheimer's annual healthcare conference. I'm Jeff Jones, one of the analysts here on the biotech team. I'm delighted to welcome the management of Kymera Therapeutics with Bruce Jacobs, CFO, and Jared Gollob, Chief Medical Officer. Welcome, guys.
Good morning, everyone, and welcome back to Oppenheimer's annual healthcare conference. I'm Jeff Jones, an analyst here on the biotech team.
Operator.
All right, so trying a little of that again. We'll see if we don't hear myself again. Okay, so diving right in, Kymera's been really a leader in the targeted protein degradation space since your founding and have been shifting over and now completed a shift into I&I indications. Can you speak to what has driven Kymera to shift focus to I&I indications and why you feel this is the right approach for the targeted protein degradation platform?
Sure, yeah. Thanks for the question, Jeff. You know, I think, you know, one of our earliest programs, you know, started off, you know, in immunology, our IRAK4 program. And I think, you know, our success with that program in Phase I, and that program's now in multiple Phase II studies with Sanofi, I think, you know, encouraged us to want to, you know, go deeper in the immunology space, you know, especially as our platform, you know, evolved, you know, to allowing us to go after more and more targets of interest that are undruggable. And especially as our thinking around pathways evolved, where we really wanted to focus on pathways that were highly validated in the clinic or that also had genetic validation and that were driving, you know, diseases where there was high unmet need and large commercial opportunity.
So this is really what brought us, you know, into the inflammation space even deeper. You know, last year, early last year at our R&D day, when we announced the STAT6 and TYK2 program, you know, those were emblematic of our approach where we're going after, you know, pathways, whether it be IL-4, IL-13, you know, for STAT6, or the IL-12/ 23 interferon pathways for TYK2, highly validated in the clinic, high genetic validation, but also pathways where there are unique targets where only a degrader can actually provide the pharmacology that can fully engage and block those pathways and provide us with biologics-like activity with oral degraders.
I think that was really the driving principle around the pivot to immunology to be able to essentially transform, we think, the immunology space by being able to have these highly selective and potent oral degraders that don't compromise in either activity or safety when compared to biologics and that allow us to go after biologically de-risked pathways like IL-4/13 or IL-12/23 or IL-1R/ TLR, and really prosecute those pathways with this novel approach that can really open up incredible commercial opportunities for the company and also allow degraders to truly be transformative in that particular space.
Great. So let's talk about the benefits of degraders here in interrogating some of those pathways where obviously monoclonals do very well for some of those indications today, but they come with their own unique sets of challenges and how a degrader could potentially provide benefit there or differentiation.
Yeah, I mean, maybe I'll start and then Bruce can also add in there, but I think if we focus on STAT6 and the IL-4, IL-13 pathway, I mean, obviously given the validation of that pathway with a highly successful drug like dupilumab, there's been a lot of interest for years in trying to find alternate ways of drugging that pathway, especially if it can be done with an oral approach since I think access to these large patient populations with diseases like AD and asthma and COPD has been really limited by injectable biologics, and so I think our ability now to develop a degrader to STAT6 that allows us to fully degrade that target very selectively so that we would only impact STAT6, we already know that STAT6 is highly specific for IL-4 and IL-13.
So we know we can deeply degrade that target and only affect signaling through those two pathways that we now have the opportunity with a degrader to be able to pharmacologically block that pathway with an oral drug in a manner that just isn't possible with any other sort of small molecule inhibitor and allows us to be able to potentially match the activity of an injectable biologic by focusing on STAT6 and by specifically focusing on a degrader approach.
And as you look, obviously you've got a number of programs active in IRAK4, STAT6, TYK2, and others. But as you think about leveraging this platform across different targets, and you've spoken to it a little bit, but are there key characteristics, be they indications or targets that you look at that are specifically attractive for the degrader approach?
I think when there are targets that are either undruggable with traditional small molecules and transcription factors like STAT6, you know, fall into that category, or targets like TYK2 that are multifunctional proteins that have an important scaffolding function as well as a kinase function, then really only a degrader can address being able to go after those specific targets. I think for STAT6, you know, the unique pharmacology of degraders where a degrader, given the catalytic mechanism of action of protein degradation, can degrade STAT6 by 95-plus percent and keep it down at that level, you know, 24/7, that's the sort of blockade that you need of the IL-4/13 pathway to match the activity of injectable biologics, for example.
So I think that's a great example of being able to go after an undruggable transcription factor with the pharmacology of a small molecule degrader that's going to give you the degree of pathway suppression that you need to get biologics-like activity. Whereas TYK2, you know, is really the way that we can mimic or phenocopy the TYK2 loss of function phenotype that protects from Th17 diseases and type I interferonopathies. In order to really phenocopy that, you have to get rid of the scaffolding function and the kinase activity, and you have to be able to keep that target degraded by 95% or more 24/7. Small molecule inhibitors can only partially inhibit that target and don't have the same breadth of inhibition because it's not tackling the scaffolding function. So you're not getting across the board IL-12, IL-23 interferon suppression, and you're not getting that 95% 24/7 blockade.
But a degrader can actually achieve that. So, you know, getting the depth and breadth of inhibition of that particular target to maximally block these pathways in a manner that a biologic, you know, can attain is really the degrader advantage here over any small molecule inhibitor approaches.
Jeff, if maybe I could just add quickly, so we've been very clear and articulate. I would hope people agree on our target selection strategy from really from the beginning. It's been focused, as Jared mentioned, on targets that are either undrugged or inadequately drugged where there's a proven biology and then where there's a clear path to commercialization, ultimately large market opportunities. So that's really been the central tenet that has tenets that have guided our approach to target selection and how we think about new immunology targets. We, I think, disclosed it was on our JPM presentation recently that we'll be sharing our next target in the coming months. I think you'll see that it'll fit quite nicely with that set of target principles that we use to guide our research.
Yeah, and I think to add to that, just, you know, to further sort of, you know, punctuate our philosophy here, the aim is to take as little biological risk as possible when choosing validated, clinically validated, genetically validated pathways so that the risk we take is more of a technical risk. Can we develop a degrader against an undruggable target? And as our degrader platform has evolved, you know, we now almost at will can develop, you know, degraders against these difficult-to-drug targets and, you know, have drugs that have amazing drug-like properties, you know, highly selective and potent and can be given orally. So now we have this incredible optionality to develop these oral drugs that can really give us, we think, the sort of best in industry oral immunology pipeline.
Okay. Obviously, most of the investor focus right now is on the STAT6 program, a lot of attention on the upcoming healthy volunteer data readout in the second quarter, and a lot of folks trying, for better or worse, to benchmark against what Dupy has shown. So can you speak to the biomarkers you're going to look at in this study, STAT6, obviously, some of the others you've talked about, but also how you think about the bar for success in your view internally at Kymera, but also what investors should be keeping in mind here given this is a healthy volunteer population?
Yeah, I think those are great questions, and I think, you know, I think this Phase I healthy volunteer study, we've made a lot of progress since kicking off that study in October of last year. You know, this is a classic SAD/ MAD study where the MAD portion is 14 daily doses, and as you mentioned upfront, you know, the primary objective here is to show that we can fully degrade STAT6 in blood and skin at doses that are safe and well tolerated. You know, we've used, I think, very strong gold standard preclinical models of asthma and AD and put our drug up against Dupy in those models and have shown that if we can achieve at least 90% degradation of STAT6, we can achieve activity that's at least comparable, if not in some cases superior to Dupy in these preclinical models.
Our aim therefore in Phase I is to show that we can actually attain those levels of degradation, you know, 90 plus percent, you know, round the clock degradation of STAT6 in blood and skin. And if we can show that we can do that at doses that are safe and well tolerated, we feel that's an incredible de-risking event for this program given how well validated the IL-4/13 pathway is and the role of STAT6 in that pathway. I think we will have an opportunity in the study to look at several Th2 biomarkers. You know, we often get questions about those. Even healthy volunteers can have some elevation of Th2 biomarkers like TARC and IgE.
Dupy has shown in healthy volunteers that they can see some impact, whether it be in the 10%-30% reduction range, you know, on those particular Th2 biomarkers in a manner that's not really clearly dose responsive. So there is sort of noise in that system because when you're talking about a biomarker that's mostly at baseline or below in these healthy individuals, it becomes a little harder to sort of sort out signal from noise. But I think Dupy and their published reports have shown that you can clearly see some impact on those biomarkers. And we intend to show a similar impact on those biomarkers in addition to what we plan on showing against STAT6 in blood and skin.
But I think our real opportunity for showing a biomarker effect will come from our Phase I-B AD study where we'll be giving 28 days of dosing, bringing in our sort of top active dose from Phase I-A. That Phase I-B is due to kick off in Q2 and readout in Q4 of this year. And I think that's going to give us more abundant opportunities to measure multiple highly elevated Th2 biomarkers in blood and an active skin lesion and show that we have a Dupy-like effect on those biomarkers. So I think that will be the most powerful demonstration that's most clinically relevant of the impact we can have on those biomarkers that will come from the Phase I-B study.
Okay. And for the molecule in terms of the hurdle for success here, obviously it's a Phase I SAD/MAD study. Safety is your baseline, but look at the focus for the molecule is the STAT6 degradation rather than say the biomarker, the TARC and IgE.
Yeah, absolutely. I mean, I think, you know, if you've looked across our other programs that have moved into the clinic, be they IRAK4 or oncology programs, I mean, clearly what's most important to us is being able to show good translation of preclinical PK/PD, you know, into humans. And I think being able to show 90 plus percent degradation of this target in blood and skin at doses that are safe and well tolerated, given the strong, strong connection between STAT6 and the IL-4/13 pathway and our strong preclinical data, where, as I mentioned earlier, when we go up against Dupy, if we achieve those 90 plus percent levels of degradation, we have Dupy-like activity, I think that's going to be the greatest predictor of success once we get into patients.
So yes, I think our emphasis is much more on STAT6 than, say, TARC and IgE in healthy volunteers, although we will be looking at those. I think the biomarker data set will be much more robust once we're in that Phase I-B AD study where we can look at impact not just on STAT6 in active skin lesions and in the blood, but we can look at a variety of Th2 biomarkers in the blood and in the skin transcriptomics and where we can also then, you know, match that up against impact on clinical endpoints like EASI and on pruritus.
Yeah. Okay. And so that Phase I-B will, in addition to the biomarkers in an actual patient population instead of healthy volunteers, you'll be able to look at, albeit small numbers and short-term dosing, actual things like EASI scores and things like that.
Exactly. And then connect the dots between STAT6 degradation, impact on Th2 biomarkers, and impact on these clinical endpoints. I think it's a very powerful way to sort of show that we hopefully will be able to demonstrate a Dupy-like impact, you know, on those biomarkers and on those clinical endpoints even in a small Phase I-B study.
Okay. And looking, obviously, the most advanced program for you guys as we look beyond STAT6 is the IRAK4, obviously being driven by Sanofi at this point and the Phase II in AD and HS. I guess given what we just talked about, is there any conflict between Sanofi pursuing atopic dermatitis for IRAK4 in your own work? And so are you free and clear there as far as Sanofi and your relationship?
Yeah, we have, Jeff. I'll take that. We have a great working relationship with Sanofi. Obviously, they're running the Phase II studies for 474 now, both in HS and AD. Those are completely separate and distinct from any activities that, you know, where we advance STAT6. We have no restrictions whatsoever on where we market that product, where we take it into clinical development, and in fact, we've already said that, you know, we run in this Phase I- B in AD, and the first Phase II study will be in AD as well, so, you know, no restrictions there. It doesn't, you know, hasn't really impacted our partnership in any way.
Right. And then as far as IRAK4 is a target, obviously Sanofi is also moving forward with STAT6 with other parties. You know, they made some decisions earlier, well, sorry, later last year as far as the AD and HS programs. And I guess the question we get asked is around the level of confidence Sanofi has in the AD and HS programs there for IRAK4. Obviously, you can't speak for Sanofi, but how, you know, you guys think about it just in the context of the actions that Sanofi has been taking here.
Yeah, I mean, maybe I'll start and then Jared, you can jump in. I mean, yes, you said it. We can't speak for Sanofi, but they did undertake an interim assessment. We announced this, as you kind of alluded to it last year. Middle part of the year, they did interim safety and assessment. And on the strength of that, decided to expand the studies and to seamlessly transition from what was effectively a II-A type construct to a Phase II-A, II-B study, and ultimately with the goal of shortening the overall regulatory timelines. So again, not speaking for them. I think actions hopefully speak louder than words. And their increased investment in this program is something that was encouraging to us and hopefully to others as well.
Right. And then I think the timing there, you guys have been pretty clear. And I guess moving on to the TYK2 program, it's clearly a validated target, but one that's certainly seen some challenges in terms of small molecules beating deucra and, you know, really comparing, say, Takeda's molecule, Alumis's molecule versus the J&J program, albeit for potentially different indications. This program is a little bit different in that there are oral competitors here for you guys. Can you speak to a little bit more about how you think about the benefit of that scaffolding effect versus just the kinase inhibition and the benefit you see potentially there as you look forward into efficacy studies or initially, obviously, safety in your Phase I that's just kicking off?
Yeah, I think it's a really important question. You know, there are a lot of TYK2 inhibitors out there and a lot of different approaches, which in general have underwhelmed. But I think our reason for going after TYK2 with the degrader is because we really believe that we could really be an advance here against this target in a way that's more than just incremental. Our aim is really to achieve biologics-like activity with the TYK2 degrader. I think the holy grail in TYK2 has been to phenocopy the human TYK2 loss of function phenotype, where we know these humans who lack TYK2, they have profound, you know, a blockade of signaling through IL-12, IL-23, and type I interferon. Their IL-10 pathway is preserved, and these patients are protected from Th17 diseases and type I interferonopathy.
That's been, I think, the holy grail for anybody developing a targeted approach to TYK2. The problem, which you alluded to earlier, is that you have to have the proper depth and breadth of blockade of that target in order to achieve that sort of a phenotype. And it's just not possible with a small molecule inhibitor. Small molecule inhibitors have suffered from lacking the appropriate depth of inhibition. You know, they at best achieve 60%-70%, 75% inhibition of the pathway. They're not able to suppress the pathway 90 plus percent 24/7. I think that's a real problem regardless of the indication that you're going after. And they importantly lack the breadth. They don't have that breadth of blockade, especially of the type I interferon pathway when you're not completely addressing the scaffolding function.
And for some of these drugs like deucrava's, they also suffer from selectivity issues because they're blocking one of the JAKs. They're hitting IL-10. And that's a real problem if you're trying to treat inflammatory bowel disease. And so we think there are many clear explanations for why these different flavors of TYK2 inhibitors have underwhelmed in the clinic. We're very confident from our preclinical package that our TYK2 degrader can actually achieve that TYK2 loss of function phenotype. We've shown in higher species that we can degrade this target 95 plus percent 24/7 around the clock with daily dosing. We've shown that by doing that, we can block the IL-12, IL-23, and interferon pathways and spare IL-10.
We think we're going to have a great opportunity, you know, in the clinic now to show that sort of pharmacology in Phase I in healthies and then to be able to show in a proof of concept study in psoriasis that we have biologics, say, Skyrizi-like activity. Our Phase I healthy volunteer study is kicking off in Q2. That's going to be a great opportunity for us to demonstrate just that pharmacology I was describing with various pharmacodynamic assays that can show that depth and breadth of pathway blockade that is required and that we can do that safely. The aim is to then take a dose from that study, you know, the following year because that Phase I study will read out later this year.
And then our hope would be next year we could initiate a Phase II proof of concept study in a disease like psoriasis where we could go up against placebo and show biologics-like activity. And I think that's the bar we're setting for ourselves to be able to show biologics-like activity in a disease like psoriasis to then say that we're not just another TYK2 inhibitor. We're now a drug that has biologics-like activity, just like we think we can show for STAT6, and then now move that program forward on all cylinders potentially across multiple different indications that have been at least partially validated with the inhibitors like, you know, whether it be lupus or IBD or psoriasis.
Yeah, there are a lot of indications to go after with a TYK2 inhibitor and going after those pathways. And I guess similar to what we talked about with STAT6 and in the Phase I study, what are the particular signals one would look for in the TYK2 study in healthy volunteers to sort of validate you're getting the level of exposure, potency of inhibition, tissue penetration, and other factors that you want to see with this molecule?
Yeah. Well, I think using highly qualitative assays to assess TYK2 degradation, you know, be it mass spec or other approaches, to be able to show that as we dose escalate and once we get into the MAD where we're giving 14 daily doses, that we can suppress and degrade TYK2 by 95 plus percent around the clock. So that even in between doses, when you're looking at trough levels, even there, you're still keeping it down by 95%.
So to show that chronic deep suppression of TYK2, which is the depth of inhibition that I was speaking to, and then also using various ex vivo stimulation assays to show that we're profoundly blocking IL-12, IL-23, and type I interferon pathways and sparing IL-10 pathways, I think that's through the pharmacodynamic assays that we'll have in the study. I think we'll be able to show just that sort of pharmacology, which I think will be greatly de-risking for the program. And again, the next step after that would be then a proof of concept study to then show real biologics-like clinical activity in a disease like psoriasis, picking the dose that comes out of Phase I.
Got it. And I guess just in terms of a bit of detail, will you be looking at like exposure in the skin versus serum and things of that sort as, you know, as we look at some of these TYK2 inhibitors and where they've seen challenges in psoriasis, where they got good sort of serum exposure or inhibition of TYK2, maybe one of the issues that's been postulated is that perhaps there wasn't the level of tissue penetration you got or.
Yeah, I think we're feeling very good about our preclinical, you know, data that tissue penetration is going to be very robust. But yes, in Phase I, we will be looking at drug levels in skin and blood as well as target knockdown in skin and blood, really to be able to answer that sort of a question, to give people and ourselves, you know, the confidence that we're getting very good distribution to the relevant tissues and that that's leading to, you know, profound knockdown of the target there.
Got it. And I guess with your legacy oncology programs, are there? I know you've clearly moved away from those opportunities. Is there a plan to partner those or what are you thinking about there in terms of next steps with those assets?
Yeah, maybe I'll tackle that, Jeff. So, you know, we announced somewhat recently our plans to advance those programs only in partnership. Obviously, the flip side of increasing one's focus in immunology, as we've done, is that it has to come at the expense of something else. And we've just prioritized the programs that we have in immunology, given the size and scale of the opportunities and how encouraging the results have been. It's certainly at least the preclinical results for our, you know, programs that we've recently announced and obviously IRAK4 in the clinic. And so, you know, we'll continue to see if we can find the right home for those programs, but we've effectively completed the Phase I studies for both MDM2 and STAT3. And at this point, you know, we'll only advance those in partnership.
So that's something our BD team is working on, and we'll share news if, you know, if and when there is news to share.
Got it. No, makes sense. And talked about timing. So I guess, Bruce, just to continue on your theme, obviously you guys are in a robust cash position, but just remind us where you guys sit today or most recent disclosure in 3Q and then where that takes you through.
Yeah. So actually in January, when we did our beginning of the year goals, we did announce the cash position. It's $850 million as of December 31st. And the runway that that provides is out to the middle part of 2027. And I think most important there is that if you look at the catalysts we have upcoming over the next 12 to 18 to 24 months, they're all well, obviously encompassed by that cash runway. So this will be a big year for us, obviously. In the second quarter, we're going to have the 621 data. We'll have the start of the TYK2 trial. We'll have the announcement of the new program. As we move towards the latter part of the year, we expect to have the TYK2 Phase I data.
We'll have the Phase I-B data for 621, and we'll start the Phase II campaign, first in AD, followed shortly thereafter by asthma. And, you know, that's just in this year alone. And then everything else that we'll see in 2026, which should include that new program entering the clinic, the readouts from the Sanofi studies as well, all of that is encompassed within the, you know, well within the runway that we have out into the middle part of 2027.
Great. Yeah, it's an exciting year for you guys. I'm really looking forward to the multiple updates you guys are going to have. With that, operator, I think you can take us clear.
Thanks, Jeff.
Thanks, Jeff.
Thank you, guys. It's been a pleasure. Hope you have lots of good meetings today. I will catch my breath before the next one.