Okay, great. Thanks, everyone, for continuing to join us at the Stifel Healthcare Conference. My name is Brad Canino, Senior Biotech Analyst here. Happy to share the stage for the next fireside with Kymera Therapeutics. We've got Jared Gollob, CMO. Jared, thank you so much for joining us
Yeah, thanks for the invite.
Maybe let's just kick off with an introduction to the company and walk us through some of the strategy changes and, I guess, reinforcements that we heard on the latest quarterly call.
Sure. Kymera, we've been around for eight years. We really see ourselves as the leader in the targeted protein degradation space, really by virtue of our innovation around selection of pathway and targets, difficult-to-drug targets, what we've done with our platform, evolving our platform so we can actually pursue these undruggable targets, including transcription factors and multifunctional proteins, and also really our clinical execution, moving now five programs into the clinic over the first four years. In terms of, from a strategic standpoint, earlier this year, we introduced STAT6 and TYK2. At that time, we announced our pivot of our pipeline more toward immunology because of our interest in these pathways and targets and very large commercial opportunities that we could really go after with our degraders. I think we've made a lot of progress, really, over the past year on that pipeline.
We've moved our STAT6 program, I think, with breakneck speed into the clinic. We've begun dosing our first subjects last month, and our plan is for there to be a readout of the SAD/MAD portion, the Healthy Volunteer Study, in the first half of next year. For TYK2, we recently announced our development candidate, KT-295, and are very excited about the ability of that drug to potentially reach biologics-like activity. And we're actively moving that into the clinic in the first half of next year with a data readout in the second half of next year. And on IRAK4, our Sanofi partnered program, we announced earlier that we had, with Sanofi, based on a blinded interim analysis of safety and efficacy, expanded the phase II studies into real dose range finding phase II-B studies, which now accelerate our timeline to phase III.
I think we've really made a lot of progress with that strategic pivot. On the oncology side, we did announce that on both of our oncology studies, we made the strategic decision to wind those studies down after completing dose escalation and enrollment. We're happy that we did actually demonstrate on-target pharmacology and clinical proof of concept across both studies. But now, with our prioritization of our immunology pipeline, what we do now with the oncology studies is really going to depend on whether we can find a partner to take those programs forward.
Yeah. And I think what you've done with the oncology programs, looking for a partner to bring them forward, makes sense in aspect of the difference in the commercial opportunities. But maybe can you drill in a bit more? What were the learnings from the oncology degraders, really, about the potential of Kymera's platform as we think about now starting to get a lot of data from STAT6 and TYK2 over time?
Yeah, I think that's a really, really important point, Brad. I mean, I alluded earlier to now having moved five programs into the clinic over four years. We have data on those first four programs, three of which are oncology programs. And really, what's really essential for us is that those programs show a high fidelity of translation of our preclinical PK, on-target PD, and also even clinical activity now into the clinic. On all those oncology studies, we've shown strong target knockdown. We've shown the expected safety profile. We've shown clinical proof of concept in those diseases where preclinically we expected to see responses.
And so we think there's an important read-through for those oncology programs as well as for the IRAK4 immunology program with that fidelity of translation, which now tells us, well, if we look at the amazing preclinical data package we have with STAT6 and with TYK2, we expect that to translate as well in the clinic in terms of what we expect in terms of target knockdown, in terms of safety, in terms of clinical efficacy. So I think those read-throughs from the oncology programs are very, very important learnings.
Okay. So for the STAT6 degrader, KT-621, you describe it to have the potential to provide dupilumab-like efficacy in a pill. Frame for us what supports that claim.
I think it's all about blockade of the IL-4, IL-13 pathways. The key to treating Th2 allergic diseases, as we've learned from drugs like DUPI through the clinical validation, is full blockade of those pathways can lead to amazing clinical results across multiple different Th2 indications. Our preclinical package with our STAT6 degrader, 621, is incredibly robust. We've shown that we can fully block the IL-4 and IL-13 pathways to the same extent as dupilumab, but with much greater potency compared to dupilumab. That's almost unheard of. You almost never see a small molecule that's more potent than a monoclonal antibody, so the fact that we can fully block IL-4 and IL-13 pathways to the same extent as dupilumab, first of all, we think tells us that we have a drug that could be a DUPI in a pill.
The other important part of our preclinical data package is what we see in disease models. So one of the gold standard TH2 disease models is the house dust mite asthma model. And we've gone up against DUPI, clinical dose and schedule of DUPI in that model. And we've shown that degradation of STAT6 by 90% or greater gives us activity that is either comparable or superior to dupilumab in that particular model. We've seen the same thing in an AD model. So it's really the combination of those two things, showing we can fully block the pathway as can DUPI, and that we have DUPI-like activity in these important preclinical models is what gives us the confidence that we think we have real potential for this drug being a DUPI in a pill.
Okay. And you've spoken about genetic evidence in the past as well. What do we know about gain of function or loss of function mutations in the STAT6 protein to support the therapeutic rationale for a degrader?
Yeah, I think that's another important question, both from an efficacy and from a safety standpoint. Starting maybe before the human, starting with the mouse, there's a STAT6 knockout mouse that these are fertile, viable animals, no phenotype whatsoever. So that's very reassuring. But turning to the human genetic data, which is arguably even more important, there are human gain of function mutations in STAT6 where the only thing those patients manifest are Th2 allergic diseases. So if STAT6 was mediating something other than signaling through IL4, IL13, you'd expect to see some manifestation other than Th2 allergic diseases from those gain of function mutations, and we don't. Importantly, there was actually a recent paper actually showing a small number of humans with heterozygous loss of STAT6. This is the first publication that we've seen with STAT6 loss. So they only have 50% of STAT6.
And what's interesting is those individuals are protected from severe type 2 asthma but have no infectious complications. And that's with 50% loss of STAT6. And then finally, I think it's looking at our preclinical data, our IND-enabling GLP tox, where in non-human primates and in rats, we pushed the doses where we're getting greater than 40-fold the exposures above the human efficacious doses that are giving us systemic complete knockdown of STAT6 without any safety findings whatsoever.
Okay. Anything else notable you would highlight from the IND package?
No, I think really the most notable thing is just how clean the GLP tox was in non-human primate and in rat, which really gives us a lot of confidence in being able to knock this target down hard chronically without there being safety consequences.
Okay. And now, when did you initiate dosing in healthy volunteers? And what degree of progress will you make before you report first clinical data in first half 2025?
We announced dosing first subjects in October. That SAD/MAD is underway. The MAD portion is going to be 14 daily doses. You can think of the SAD/MAD as being very similar in structure to what we did with the IRAK4, 474 Healthy Volunteer Study. Our plan here is to read out both the SAD and MAD at the same time in the first half of next year. Our primary objective of that study really is to show that we can fully degrade STAT6 90%, 95% at doses that are safe and well tolerated, given that 90% mark preclinically in those disease models for showing DUPI-like efficacy.
Okay. And now, how many dose levels do you predict you will need until you reach that 90% plus degradation target?
Yeah, that's harder to be precise about. I think we're expecting to see pharmacology even at the lowest doses, just as we did for 474. You could expect probably a somewhat similar number of dose levels to be prosecuted in SAD/MAD as we did in 474. It's hard to say where we'll see 90%, 95% knockdown, but we expect to see a robust knockdown at even low doses. And I should remind you that with IRAK4, we sort of overperformed in the clinic. The doses where we were expecting X amount of knockdown preclinically, we actually saw that with even lower doses in humans. So hopefully, we'll see a same sort of underprediction and even more robust activity than expected at certain exposures in the healthy volunteers.
Okay. And now, is it important to show that that degradation target has been reached in multiple different cell types? And which cell types will be the focus of the phase I study in healthy volunteers?
For the healthy volunteers in the SAD, we'll be looking at STAT6 knockdown in the blood, looking across human peripheral blood mononuclear cells as well as various subsets of those PBMC. In the MAD, we'll be looking in blood and also at skin using skin punch biopsies. I think for us, it will be very important to be able to show that robust 90% plus knockdown in both blood and skin, again, at doses that are safe and well tolerated.
Okay. And now, can you discuss the IL-4/13 pathway biomarkers that can be measured even in healthy volunteers? And how to think about that and compare it to the dupilumab healthy volunteer data?
So in healthy volunteers, you're alluding to the fact that you can measure or see some Th2 tone even in healthy individuals. And two biomarkers in particular, TARC and IgE, have been looked at in healthies. And you can see baseline elevations with a lot of intersubject variability. Regeneron and Sanofi published a paper giving single doses of dupilumab to healthy volunteers and looking at the impact on TARC and IgE. And they were able to show a modest 10% to 35% decrease in those biomarkers with a lot of intersubject variability and without a strong dose response. And so I think what that showed us is that in healthies, you can see some impact on those biomarkers, although it's not the strongest signal. The best signal you're going to see is in patients where those biomarkers are elevated to a much greater degree.
There are other biomarkers that are elevated as well besides TARC and IgE, and when there has been shown a correlation between impact on those biomarkers in patients and clinical endpoints, so I think we're including those in our phase I study because we think we will see some movement that probably will be sort of DUPI-like on those biomarkers. But honestly, our main focus from a biomarker standpoint is STAT6 because STAT6, we believe, is going to be the predictive biomarker. If we're able to knock it down by more than 96% in skin and blood, that should be predictive of success against clinical endpoints in patients down the road.
Okay. Now, given there is noise around the biomarkers, could you choose to just not disclose the biomarkers from the healthy volunteer portion as well?
I mean, I suppose we could, but I think because it has been looked at before and because we can look at it easily, I think that is a dataset that we will share. But I think it is important that we sort of manage expectations around what's been seen with DUPI. And again, really try to focus people's attention on STAT6 as the biomarker that really matters the most in healthy volunteers for predicting, we think, future success in patients.
Okay. Now, coming out of the healthy volunteer study then, what type of subsequent study do you run next? As I think about it, if you get safe 90% degradation of STAT6, that gives you the ability to then test in patients, are you getting DUPI-like activity? How do you get to that answer quickest to then accelerate mid-late stage development?
Yeah, again, another really important question. I think we've been a little bit careful about sharing information about our plans in patients right now because it is such a competitive space. We do have a fully formed clinical development plan, as you might imagine, for this program. I think our plan is to reveal sort of more of that probably next year once we're further along in the healthy volunteer study. I think what I can say is that our aim is to go seamlessly from the healthy volunteer study to the first patient study, and our aim is to adopt a development plan that's going to allow us to quickly and efficiently show clinical proof of concept in patients and enable dose selection for pivotal phase III studies. I think it's very important that we move aggressively and quickly with this program.
I think we'll be able to share more around the details of that plan next year.
Okay.
I'm sorry. One last thing I was going to mention, Brad, because we often do get this question, is among the different indications that we're thinking of, how are we thinking about prioritizing TH2 indications? We feel that all of the indications where DUPI has been successful are fair game, essentially, and we're very interested in all of those. I think we will be prioritizing the larger indications first. So when we think about the initial patient studies, the larger indications would be AD, COPD, and asthma, followed by other indications, which are important but will not be as large a priority initially as the larger ones.
Got it. I guess extending on the question I had, should we look at the Dupixent phase I-B studies in atopic dermatitis that they ran in the early 2010s as a good proxy for what you will need to do?
I think everything is on the table. I think, again, once we can sort of provide more details around the patient studies, then we can start diving into some of those specifics. I do think that in a very general sense, when you're talking about studies in patients, you have the opportunity to look at clinical endpoints as well as various biomarkers. There's established literature on that. As you're mentioning, Sanofi has sort of blazed the way in terms of what they've seen in their early phase studies. So I'm sure there are important learnings from those early studies that we'll be able to adopt and capitalize on.
Okay. And now you mentioned some of the priority indications, but I guess the advantage you have is, like you said, Sanofi not only trialed phase I-B, but they went with Regeneron and figured out everywhere in which this worked. How do you think about the aspect of running parallel development across all these potential indications that we now know DUPI is headed towards approval and already has approval in?
Yeah, I think it's important as we think about wanting to have a broad reach across multiple different indications where Sanofi has made an impact. We have to think about that carefully in terms of what's the best way to do that in the most sort of aggressive, accelerated manner, but to make sure that we do it well. And so I think we are thinking actively about ways to prosecute multiple indications at the same time because we think this drug can have such value for patients as an oral alternative to drugs like DUPI that we want to get drugs to patients. And we want to be able to do that across multiple different indications, and we want to do that efficiently.
And so I think we are giving very careful thought to how we do that, how we sort of multitask across multiple different indications potentially in parallel and do that in a way that's going to be efficient and effective. And part of that is also going to involve growing our development group and making sure we have, obviously, the people and the financial resources to deliver on that sort of an aggressive development plan.
Okay, and then if all of this plays out, how do you see Kymera as competitively positioned against the other emerging STAT6 targeting competitors?
Yeah, I mean, STAT6 is becoming a more competitive space. This is a target that people are interested in for a very good reason because it is the obligate transcription factor controlling signaling through IL-4 and IL-13. And if you can drug it with an oral drug, you can have an alternative to the injectable biologics. I think Kymera, I think we see ourselves as the leader in the STAT6 space. We've devoted a lot of resources over the past several years to this program, to developing what we believe is a first-in-class degrader. And so we are all in on this program from all different angles. When we look at what's out there, there is the Recludix STAT6 inhibitor, which they have claimed might be in the clinic sometime next year.
We haven't seen any real preclinical data with that compound in any disease models up against DUPI, for example. There could be some limitations to inhibitors. Any occupancy-based approach to being able to sort of fully and completely drug the IL-4, IL-13 pathway around the clock, which we know we can do with a degrader, that may not be possible. There may be more challenges doing that with an inhibitor and being able to match biologics-like activity. In terms of other degraders, we're not aware of any right now that are actually out there. We know that Nurix has partnered with Sanofi on trying to find a degrader, but we don't know what their timetable is. It might still be two years away from entering the clinic.
So we think we're well ahead in the clinic compared to either of these two programs, but we're very aware of the competitive landscape. And our aim here is to really win in the space because we really feel as though we have a drug that can be incredibly valuable to patients. And we're doing all that we can and really covering all angles of development with our STAT6 program.
Okay. And now, do you have an identified backup compound for STAT6?
I mean, with STAT6 KT-621, it's hard to imagine a compound better than KT-621 in terms of its selectivity and its potency. But it's very important that we do have a program for the reason I just gave. I think we're all in on STAT6. We're leaders in this space. We want to make sure we're covering all the angles. So we do have a backup program to make sure that we can remain leaders in this space.
Okay. I'm going to ask now a few questions on the IRAK4 degrader, KT-474. I guess just help frame and recap how Sanofi has recently changed the phase II studies that are being conducted in HS and AD.
So we think there was a very positive development this past summer. Sanofi, the phase II studies initially started off as more traditional phase II-A proof of concept studies. And then Sanofi expressed interest in trying to accelerate to phase III by converting these into seamless phase II-A, II-B studies with additional dose range finding, gating that on a successful blinded interim analysis. So that was done this past summer. And that took a blinded look at safety and efficacy and had for them a positive readout where they then decided to move forward with converting it to a seamless II-A, II-B, which meant the addition of a dose group to each of the studies, HS and AD studies. So now instead of having one active dose group for HS, there would be two plus placebo.
And for AD, instead of two active dose groups, now three plus placebo and expanding the number, roughly doubling the number of patients. I think while this moves the readout for phase II from mid-2025 to mid-2026, it actually significantly accelerates the overall path to phase III since now there will not be a need for another phase II. So we really see this as a very positive development for the program and sort of a vote of confidence on Sanofi's part after doing this blinded IA.
Okay. And maybe this is a question for your CFO, Bruce, but how does this change the potential opt-in strategy then, if at all?
I think it probably doesn't change the opt-in strategy. The way that is set up right now is after completion of these phase II studies, Kymera has the ability to opt in for 50/50 co-development, co-commercialization in the U.S. So I think that's still the case. I think one could look now and say now that opt-in will be based on an even richer dataset from a seamless two A, two B study rather than a two A study. So I think it's probably an advantage to have more data to look at now prior to opting in.
Okay. And then is there any recent evidence from IL-1 pathway drugs that have emerged that supports these ongoing studies for an IRAK4 degrader in either HS or AD?
Yeah, I think in HS, there had been some previous studies with some of the earlier IL-1 targeted agents showing activity in HS, although not always in a placebo-controlled manner. More recently, AbbVie showed with their drug that targets IL-1 alpha and IL-1 beta that against placebo control, they actually did see significant activity, including in patients who were refractory to anti-TNF approaches.
So I think that was very nice, strong clinical proof of concept or clinical validation for going after HS with an IRAK4-targeted drug, which is hitting all of the IL-1 family cytokine pathways. Interestingly, on the AD front, last year, GSK had a placebo-controlled anti-IL-18 study in AD, which was also positive, IL-18 also being one of the IL-1 family cytokines. Both of those, I think, are nice examples of clinical validation for hitting the IL-1 pathway, the IL-1 family pathway in both HS and AD.
Okay. Maybe we'll close out on some questions on the TYK2, which appears to have more of a similar degradation hypothesis to IRAK4, where it's got a scaffolding function. I think it remains to investors a controversial target because of the competitive intensity and what we're seeing out of the initial launches of the programs. I guess can you discuss those elements? What gets you excited at Kymera to be pursuing this as a target?
Yeah, yeah. I mean, TYK2 is a program that we're really very excited about because I think it's all about can a small molecule drug attain biologics-like activity? We've already been addressing that with programs like IRAK4 and STAT6. And I think the same question can be posed for TYK2. In order to really have biologics-like activity, for example, like an IL-23 Skyrizi-like drug in psoriasis, for example, that's where I was at the bar for biologics-like activity, you've got to phenocopy human TYK2 loss of function. That's the only way that you'll have the depth and breadth of inhibition of that pathway that will be able to match biologics. The small molecule inhibitors have shown that they're not able to have either the depth or the breadth. The depth in the sense of can they achieve 90%-95% round-the-clock inhibition of the pathway?
I think the answer has been no for almost all, if not all, of the TYK2 inhibitors that are currently out there in the clinic. Can they have the breadth, meaning that you block IL-12, IL-23, and Type I Interferon while sparing IL-10? None of these small molecule inhibitors have that breadth. We know that that only comes from complete loss of TYK2, and a degrader is the only mechanism that can achieve that. We've shown with our degrader KT-295, which is our development candidate being moved forward into the clinic, that we are able to get 95% round-the-clock degradation of that target in non-human primates with doses that are safe and well tolerated in our preclinical studies and our dose range finding studies. We've also shown preclinically that our degrader, by removing the protein, is able to shut off completely IL-12, IL-23, Type I Interferon, and spare IL-10.
Sparing IL-10 is very important for activity in inflammatory bowel disease, and so I think we have a compound here which should be able to phenocopy TYK2 loss of function and therefore provide biologics-like activity. I think it's going to be very important early in our clinical development, especially once we move into patients, to be able to show in that initial patient study proof of concept that we do have biologics-like activity.
That's where we're going to set the bar for wanting to move this program forward beyond the initial early studies in patients. If we don't have biologics-like activity and if we were just another incremental improvement over a small molecule inhibitor, we probably would not be excited about moving that program forward ourselves. We feel like this program has a real opportunity to actually achieve biologics-like activity and that we can show that in our first human patient proof of concept studies.
Okay. And now there are a range of biologics in psoriasis. So are you targeting Skyrizi, kind of the top end of where we're seeing activity in the biologic class?
Yes, yes. I think the J&J anti-IL-23 small molecule comes the closest probably to Skyrizi. But yes, I think we want to see Skyrizi-like activity. Just like for STAT6, right, we want to see DUPI-like activity with that program.
Okay. And then is this only a psoriasis play in your view, or are there opportunities for TYK2 that are being explored at early stages at some of the other companies or aren't even really being explored yet that you're interested in?
I think if we are able to show in the clinic that broad impact on IL-12, IL-23, type I interferon and show biologics-like activity in one sentinel indication, whether that's psoriasis or another, then I think it opens up multiple different indications for development, not just psoriasis, but also IBD, lupus, and others. So I think if we really were able to achieve biologics-like activity, that would be a potential green light for us to move ahead through in multiple indications where we think TYK2 targeting could be impactful.
Okay. Well, Jared, thank you so much. I think we'll leave it there. Thanks, everyone, for listening in.
Thank you.
Really appreciate it.