My name is Andy Chen. I'm the biotech analyst at Wolfe Research. And like Doug, today is also my first Wolfe Healthcare Conference. And today we have with us from Kymera Therapeutics, Jared Gollob, the Chief Medical Officer. And I guess what we have in the audience today is mostly healthcare investors, but some may not be familiar with Kymera. Can you maybe just briefly spend maybe two, three minutes and talk about the platform? What is Degrader? What is PROTAC? And why that may be revolutionary?
Sure. Thanks, Andy. Yeah, I mean, our focus at Kymera, we've been around for about eight years, and we're focused on targeted protein degradation. There are different ways you can accomplish protein degradation, traditionally with either heterobifunctional small molecules or molecular glues. The programs that we've moved into the clinic so far, we moved five of them, are all focusing on heterobifunctional small molecules. Just to give you a quick sort of one-on-one on the science there, these are small molecules that have three portions. There's one portion, which is a ligand that binds an E3 Ligase, another portion that binds the protein of interest that you want to degrade, and then there's a chemical linker that brings those together.
The aim is to essentially co-opt an E3 Ligase and then to bring it in proximity with the protein of interest so that that E3 Ligase can ubiquitinate that protein and tag it for degradation by the proteasome. The degrader system is very different from traditional small molecules. Small molecule inhibitors essentially are occupancy-based approaches that require continuous binding to a portion of the protein that allows for inhibition of function. With the degrader, it's different. There's essentially a binding event and a formation of a ternary complex, but there's no need to inhibit, and it doesn't need to be continuous. It just needs to be long enough to get that protein ubiquitinated and then degraded. It's a very different approach and allows us to go after targets that traditional small molecule inhibitors cannot reach: transcription factors, multifunctional proteins that have scaffolding function, for example.
And because of the catalytic nature of targeted protein degradation, one is able to achieve very selective, very potent, very deep continuous degradation of the target and pathway blockade continuously, even with oral degraders. And that's what you need if you're really going to block a pathway to the same extent, for example, as a biologic monoclonal antibody. That's something that's really not achievable with small molecule inhibitors, but it is achievable with degraders. That's one of the main reasons why, as a company, we've pivoted toward immunology, because there are high-value pathways and targets that have already been drugged with monoclonal antibodies with injectable biologics that have provided strong clinical validation. But now we have an opportunity with a degrader to drug that pathway as effectively as an injectable biologic, but now with an oral small molecule.
That has the potential to be transformative across multiple different indications in the autoimmunity inflammation space.
Yeah. And can you maybe also briefly talk about the capabilities at Kymera? So I think what we have noticed is that you're actually very fast at creating these new degrader molecules. Why are you uniquely able to do that? Or in other words, if I want to start a degrader company, can I easily do that? And what is a barrier to entry? Can I just do that and take over the world?
Sure. But no, it really isn't easy. And I've been at Kymera for over six years as Chief Medical Officer. We've been around for eight years, so I've really seen the evolution of our platform. And it's really been a remarkable evolution. The chemistry is proprietary. And to really do degrader as well, one needs, I believe, to focus 100% on creating degraders, because it's an iterative process. It requires understanding chemistry. It requires having the right expertise in-house. It requires having the right technology in-house. And if you're going to go after difficult-to-drug or undruggable targets, you have to really understand protein chemistry. You have to understand protein structure. You have to understand how to do hit finding.
You have to understand the changes in chemistry that you need to optimize these degraders to make actual drugs, to have PK properties that are desirable to turn these into drugs, especially into oral drugs. And so that requires an iterative process. I mean, we have probably synthesized tens of thousands of degraders over the last six, seven years. So there are a lot of learnings that go into doing that. And those learnings, I think, translate into our being able to develop degraders quicker and quicker. We've developed degraders that are highly, highly selective, that are extremely potent, single-digit picomolar, even subpicomolar potency, and with very well-behaved PK properties that allow us now, I think, to have an armamentarium of oral degraders in the immunology space. I mean, we really think that we're poised to have the best oral immunology drug pipeline in the industry with our degraders.
And speaking of oral immunology, maybe we can talk about the STAT6. We have compared it to Dupixent, or like an oral version of Dupixent, because mechanistically, it's sort of adjacent to Dupixent. And the first data is coming in the first half of 2025. And I think a lot of people are waiting for that. So given the mechanism, do you think there's room for it to be better than Dupixent, or are you just hoping for something that's similar in efficacy, or maybe even slightly worse? And maybe that would also be OK, right? What is the bar that you have set for yourself?
Yeah, that's an important question. I mean, there's been a lot of intense interest in STAT6 for, I'd say, a decade or so since Dupixent validated the IL-4, IL-13 pathway in Th2 allergic diseases. There's been a desire to find another target downstream that could be drugged potentially with an oral small molecule. STAT6 is the obligate transcription factor for IL-4, IL-13. It's highly selective for those two pathways. And we've now developed a degrader that is highly selective for STAT6 and highly potent. And it's very clear that STAT6 controls signaling through IL-4, IL-13. We've shown that when we fully degrade STAT6 across a variety of different cell types, we fully blockade IL-4, IL-13 signaling to the same extent as dupilumab, but actually more potently dupilumab. And that's almost unheard of to have a small molecule that's more potent than a monoclonal antibody.
And we've shown that our ability to shut down those pathways translates in vivo into efficacy that's comparable to, or even in some cases superior to, dupilumab. In a house dust mite asthma model, which is the gold standard sort of TH2 allergic disease model, where we go up against full dose, full clinical dose of DUPI, and in an AD model, we see those sorts of results. When we degrade STAT6 by 90% or more in those models, we have activity that's comparable or superior to DUPI. In terms of what our ultimate aspirations are, we sort of refer to 621 as DUPI in a pill. We think that our aspiration is to be comparable to DUPI in terms of efficacy, but importantly, also safety.
And if we have an oral small molecule with the convenience of oral dosing that is as effective and as safe, that's going to be an incredible drug, we believe, in this space. Right now, for example, DUPI is able to penetrate maybe 10% of the AD market, where there are tens of millions of patients. We think having an oral drug that's as effective, that doesn't compromise on efficacy, could penetrate a much larger segment there. Now, to your other point, what if it turned out that we weren't quite as efficacious as DUPI, but as safe? I think this would still be an incredibly successful, impactful drug, given the fact that it's an oral drug. If it's an oral drug with the same safety profile, even if there was some compromise on efficacy, I think it would be a major advance in the field.
But again, based on our preclinical data, we're expecting the drug to be comparable to DUPI in its efficacy.
Yeah, and I think Nello in the past has talked about skin distribution a few times, and I think he mentioned that the skin distribution data is very good, based on what we've seen, aside from humans, right, but obviously, dupilumab is approved in multiple indications: atopic derm, asthma, EOE, for example, right, so do you have more confidence that this is more of an atopic derm drug just because you seem to have emphasized skin distribution, or do you think that's just the priority indication for you?
Yeah, I think we're confident that this drug will be active everywhere DUPI has been active, whether it's derm indications, whether it's GI, whether it's respiratory. I think essentially we're blocking the same pathways. We're blocking IL4, IL13. We should be able to phenocopy the effect of DUPI in the clinic across all of these different indications. From a tissue distribution standpoint, this is a small molecule. It really gets everywhere. We get good PK in all tissues. In our preclinical tox studies, we get full greater than 95% knockdown of Stat6 in all tissues that we've measured: lung, GI, liver, blood, skin, et cetera. So we're not expecting any barriers to distribution or any limitations to being able to degrade, sort of regardless of the tissue type.
In terms of prioritization of indications for development, I think we are interested in prioritizing the larger indications first, so AD, asthma, and COPD, but then I think we're also very interested in going into all the other indications where DUPI has been shown to be effective and has been approved.
And with the first data coming out in the first half of 2025, I think we're going to see some biomarker data. And I think a lot of people will pay attention to that biomarker data, even though it may be difficult to interpret. So I think you're going to have some IgE data. You're going to have some target data. Can you maybe put things into perspective for people? Let's say, hypothetically, we see 15% reduction in healthy volunteers, or 20%-25%. What does that mean? What is good data, or should people just not pay attention to those percentages at all?
Yeah, I think that's a great question, Andy. I appreciate the question. I think going into the healthy volunteers SAD/MAD, so we dosed our first subjects last month. This is a traditional SAD/MAD. The multiple ascending dose portion has 14 daily doses, very comparable design to what we did with IRAK4, KT-474, and healthy volunteers. The main pharmacodynamic readouts are going to be STAT6 is really number one, right? It is being able to show that we can degrade STAT6 in blood and in skin. Taking skin punch biopsies in healthy volunteers is going to be essential, and what we want to show in skin and blood is that we can degrade by at least 90% or greater.
The reason for that threshold is that in our preclinical studies and these models, the asthma model and the AD model, where we have activity comparable to DUPI, it's 90% degradation that gets us to that same level of activity. So if we can show in the SAD, where we're looking at the blood, and in the MAD, where we're looking at blood and skin, that we get 90%, 95% degradation at doses that are safe and well tolerated, that in and of itself, we believe, is a huge de-risking for the program, because now we're able to achieve levels of STAT6 degradation that should almost certainly translate into clinical efficacy that we believe will be comparable to DUPI.
Now, in terms of the biomarkers, healthy volunteers give you an opportunity to look at several TH2 biomarkers, TARC and IgE, because there's some degree of TH2 tone in all of us, healthy individuals. But they're modest elevations. There's a lot of inter-subject variability in terms of what the baseline is. What Regeneron showed with DUPI with single doses is that you can see about 10%-35% reduction in TARC and IgE, with a lot of variability between subjects and not a very clear or strong dose response. So what it tells us is that in healthies, you can see some impact on those biomarkers. But the real testing ground for TH2 biomarkers will be in patients where those biomarkers and others are markedly elevated, and where you can see marked 80% reductions. And those reductions then correlate with clinical outcome.
But we are looking at it because we can. I think the number one focus on the phase one study should be STAT6. We do expect to see an impact on TARC and IgE that would probably be somewhat comparable to what DUPI was able to see. I think there is some signal out of the noise that we'll be able to see, just as DUPI was able to see that. But I think that the real emphasis should ultimately be on STAT6, because that is ultimately the biomarker that is really going to translate into efficacy.
Maybe transitioning to TYK2, that data is coming in the second half of 2025. Given that it's more or less of a de-risk target, so you're going to have phase 1 data, is that just a check-the-box kind of thing, or what kind of data would make you excited? Is it a cytokine panel? Are we going to have that, or is it something else?
Yeah, I think it's important to put the TYK2 degrader into perspective with all the TYK2 small molecule inhibitors. It's a very, very different sort of thesis here. We went after degraders because for us, the model is human TYK2 loss of function mutations. Humans who lack TYK2 are protected from autoimmune disease, and they have relatively low risk of infections. TYK2 has scaffolding and kinase functions. So in order to really get rid of all of the functions of TYK2, you've got to get rid of the protein itself. The problem with inhibitors is that they lack the depth and breadth of inhibition to match the human loss of function phenotype. And by depth, I mean small molecule inhibitors are not able to achieve 90%, 95% round-the-clock inhibition of TYK2, which is what you really need to fully block that pathway.
By breadth, what I mean is that TYK2 guides or controls IL-12, IL-23, Type I interferon signaling. The small molecule inhibitors are variable in terms of their ability to block those pathways completely and to also spare IL-10. The non-selective TYK2 inhibitors like Duecra hit IL-10, which is a real problem if you're trying to treat inflammatory bowel disease. I think the small molecule inhibitors are lagging or lacking in both of those areas, depth and breadth, whereas degraders, we've shown with our lead degrader, KT-295, which is going to the clinic in the first half of next year, that in animals, including in monkeys, we get 95% round-the-clock degradation. Even at trough, before the next dose with daily dosing, we're at 95% degradation, so almost complete degradation.
We also know that we're able to completely block IL-12, IL-23, and Type I interferon signaling in a manner superior to any of the small molecule inhibitors. Coming back to phase 1, in phase 1, even in healthies, we'll have a real opportunity to show that sort of pharmacology. By measuring TYK2 in blood and skin, we should be able to show that 95% round-the-clock degradation of the target. By doing ex vivo stimulation assays to interrogate the IL-12, IL-23, and Type I interferon pathways, we should be able to show blockade of that pathway also round-the-clock. That's the first step in phase 1: to show that sort of pharmacology. If we show that, we're already ahead of where any of the inhibitors are. The next step in that program is going to be to go into patients.
And in patients, we want to show in the first proof of concept placebo-controlled study that we have biologics-like activity. So if we were to go into a disease, for example, like psoriasis, we want to see biologics-like activity. For us to move that program forward sort of full speed ahead in patients, we need to show that we have biologics-like activity. We don't want to have a TYK2 small molecule that is incrementally maybe a little better than small molecule inhibitors, but not reaching biologics-like activity. And we really believe that this approach really has the potential to achieve that level of activity, just like Stat6. By degrading Stat6 the way we degrade Stat6, we believe is going to be able to achieve DUPI-like activity in the clinic.
We believe that our TYK2 degrader will stand out among all the TYK2 small molecule inhibitors and really be able to attain that level of activity. We need to show that, of course. Those are the steps we plan on taking first in healthies to demonstrate the pharmacology, and then in whatever that first proof of concept patient study is to show that we have biologics-like activity.
Can you maybe also speculate a bit on how much drug activity comes from removing that scaffolding function and how much of it comes from the non-scaffolding part? So in other words, let's say if deucravacitinib were a degrader, how much more efficacy would it have?
Yeah, it's really interesting. If you look at human TYK2 loss of expression, loss of function, and you look at experiments where people have used a kinase dead TYK2, so the kinase dead still has a scaffolding function. You just killed off the kinase activity. What you see is that in the TYK2 loss of function, loss of expression, you essentially obliterate 90%, 95% of signaling through the IL-12, the IL-23, and the type I interferon receptors. With the kinase dead TYK2, so the scaffolding function is still there, you do pretty well in blocking IL-23 function, but you leave a lot on the table in terms of IL-12 and type I interferon residual function. And so I think a drug like Duecra gets a little more bang for the buck because it's not a pure TYK2 inhibitor.
It also inhibits the JAKs, which is a problem because then you inhibit IL-10, which then is a problem if you're trying to go into inflammatory bowel disease. If you're trying to push the dose, you start getting more tox because now you're hitting not just TYK2, but you're also hitting the JAKs. The Takeda Nimbus allosteric inhibitor is more selective than Duecra. It only hits TYK2, but it doesn't get rid of that much of the scaffolding function. So you're leaving a lot on the table in terms of type I interferon response. So again, it comes back to really the only approach that can really give you the depth and breadth that you need on blockade of that pathway is going to be a degrader, essentially creating human knockouts using a protein degrader.
And hot off the press, yesterday, J&J had data with their oral IL-23. Have you seen the data? What's your reaction? I know it's a different mechanism, but it's an oral molecule in a relatively crowded space right now.
Yeah, we have seen the data. I think prior to this readout, it was looking as though that molecule was getting the closest to sclerosis-like activity and psoriasis as any TYK2 small molecule inhibitor. And that was very encouraging. It still was leaving something on the table, but it was getting closer than, say, Duecra and the Takeda Nimbus compound. I think the latest data might just be the result of larger numbers. We still need to see more details around baseline characteristics of patients who were selected for that study. But there could have been some characteristics of those patients that might have made them maybe a little less responsive. And therefore, the response rates might have been not quite as robust as what was seen with the phase two data.
But I do think overall, it still is clearly an active drug, but it's also clear that it's not reaching biologics-like activity. And so we think that that just further opens up the opportunity for a TYK2 degrader to sort of get there. And if we're able to sort of reach that level of activity, then our drug should be best in class in the TYK2 space.
During the last minute, the last few seconds, I guess a very quick question for you. JPMorgan. Morgan, are we going to see, well, in 2024, JPMorgan. Morgan, we saw STAT6, we saw TYK2. Are we going to see some new molecules next year?
I mean, next year is, I think, a big year for Kymera, right? We have, in the first half of next year, the readout from the Healthy Volunteers SAD/MAD. We're planning on reporting that for Stat6, the SADMAD data altogether in the first half of next year. TYK2 is going into the clinic in the first half of next year. There'll be data readout from the Healthy Volunteers study in the second half, and our hope is that we will report on a new program entering our pipeline next year. I can't guarantee whether that will be a JPMorgan. Morgan or not, but I think it will be an immunology program. We have a number of very interesting assets in our immunology discovery pipeline that are very exciting, as exciting as Stat6 and TYK2, we believe.
And so we'll be introducing those as they reach the stage of development candidate. But I think you should expect our being able to announce and talk about at least one new program next year.
Thank you, Jared. Thank you for being with us.
Thank you, Andy. Appreciate it.