Good morning, everyone. Welcome to day two of the Leerink Partners Global Biopharma Conference. Very pleased to have with us today Dr. Nello Mainolfi, CEO of Kymera Therapeutics. Nello, could you provide us a quick intro to the company and kind of frame what's ahead for 2025?
Yeah, thanks for the invite. Thanks for giving me the doctor. Nobody does that anymore, but I'll take it.
PhD will do it, yeah.
Yeah, yeah. You know, Kymera was founded almost nine years ago with the goal and the ambition to create a whole new generation of medicines using targeted protein degradation. Our strategy has been consistently focused on trying to marry the power of the technology, which, just to remind everybody, it's a small molecule that can give a phenotype that is as powerful as genetic knockdown. You remove a protein with a small molecule. Huge potential. The strategy has been marrying the power of TPD with the right target. For us, the right target has always been a target that has not been drugged or drugged fully before in pathways that have been validated clinically by other agents, usually upstream biologics, where the target has human genetics data, targeting ideally large patient populations.
Historically, once you build that Venn diagram, we found that where it's best suited in terms of target types is multifunctional proteins or scaffolding proteins like TYK2 or IRAK4, for example, or transcription factors that have been historically undrugged. We've seen with us working on STAT3, now STAT4. You'll hear about a new program soon in early May. I think with that strategy, we've been able to generate some unique profiles.
I think when we started our broader communication on immunology about a year, almost a half ago, our goal is really to build, for the first time in industry, oral drugs with biologics-like efficacy. That's only, I think, a profile that an oral degrader can give. The fact that we can block the pathway in a saturated manner with an oral degrader that can mimic upstream biologics.
That is how our pipeline has been refined, I would say, right? I think we learned along the way what are the best targets, what are the best pathways. And, you know, if we were the same company that we were nine years ago, we shouldn't be here, right? We continue to refine and learn. I think we have right now, I would argue, one of, if not the best oral immunology pipeline. If you look at, again, IRAK4, TYK2, STAT6, and again, the new program, it's a very exciting time. This year is a big year for many programs in our pipeline. I would say for STAT6 first, this is probably the best example of going after a target that is directly downstream of a highly validated receptor, IL-4 receptor alpha.
We've shown preclinically that by degrading STAT6, we can phenocopy the dupilumab in all contexts that we looked at. This year we'll have healthy volunteer data, we'll have patients' data, we'll start Phase 2b studies. It is going to be a great year for us. Hopefully, it will be a great year for us. For patients that soon will be able to have a completely different treatment option. We have a TYK2 data also in healthy volunteer this year. As I said, for the third time now, we'll also disclose a new program.
Great. Thank you for framing that for us. You know, I think a lot of the investor interest on your stock right now is on STAT6, just given the potential, as you mentioned, like downstream of IL-4, kind of dream of being an oral Dupixent. Let's start with that Phase 1. You have SAD/MAD data coming up in June. Can you kind of talk through, you know, I guess you guided that the three things to look at are the target degradation, safety, biomarkers. Can you kind of guide us on that first one on target degradation? What should we expect to see? What would be a good outcome to see on that?
Yeah. So, you know, when we set out these clinical expectations, we do it based on extensive PKPD studies that we do preclinically. We're probably the company that does most PKPD studies across species, across tissues, so that we can refine our target product profile. If you look at our preclinical data with STAT6, which I think is one of the most robust preclinical packages I have seen, you'll see that when you even degradation profiles of 70%-85% are able to give you a pretty compelling phenotype that can, in many instances, match dupilumab.
I think only once you reach that 90% degradation, 90%, 90% plus is where you consistently see in any type of readout, whether it's efficacy endpoints or Th2 biomarkers, you see consistently that we're either equal or numerically superior to dupilumab. For that reason, given that, you know, we're trying to build that first and best in class here, you know, our target is being able to reach 90% plus in blood and ideally in skin.
Yeah. If you don't reach 90% plus, like what does that mean? Like biologically, how could that happen? What do you think sort of the downstream clinical impact of that would be? Just more of a curiosity question.
Yeah. I'll answer your question in two ways. The first one, just to the question directly, as we've said, even 85%, I mean, 85%, 80% degradation in our preclinical model gave us some quite interesting phenotype. As I said, you know, I think when you evaluate STAT6 agents, you have to look at the totality of, at least so far, the preclinical data. If you choose one endpoint, let's say, I don't know, IgE in preclinical models of asthma or atopic dermatitis, you'll see that, you know, it can be more or less sensitive.
If you look, it can be more or less sensitive to the degrees of degradation. I think you can develop a drug. Likely that's where the small molecule inhibitor we're going to land, right, in a suboptimal pathway inhibition profile that might still be clinically relevant. I think the profile that we're going for is a Dupixent profile. I think if we have less than 90%, it would not be an ideal case for us to have a best-in-class profile. I would also say that this is the fifth molecule we put into the clinic. I'm not previewing any data. I'm just looking back. We've never seen a molecule that stopped degrading below 90%. It will be the first time.
Yeah. Let's talk about the skin degradation, because in your IRAK4 program, I think you had well over 90% plasma degradation, and it was pretty homogenous. In the skin degradation, it was like almost 30 percentage points lower and quite heterogeneous. How should we think about skin degradation just as a concept? Is there a different benchmark to think about there?
Yeah. I would start with why do we want to degrade the target in skin?
Yeah.
We have actually no pharmacology from other agents that show direct target engagement in skin, right? We know that if you look at other upstream biologics, you look at skin transcriptomic, for example, in AD patients, and you see a pretty profound impact. We do not know whether that is from target engagement in the skin or it is just a systemic—these are Th2 diseases or systemic diseases with local manifestations.
I would say that the reason why we are pretty bullish about wanting to have skin degradation is because we do not want to leave any potential kind of value on the table. It is unclear, to be honest, whether we need it, but I think we want to have it just to make sure we have the best profile possible. Now, your question is very valid.
Obviously, it's a question we've been dealing with for a few years, which is IRAK4 in healthy volunteers and in patients showed, you know, I would say a degradation of between 50% and 60% at the relevant doses, where in blood we would see 95% plus. There are two potential explanations for that. One is that we see less degradation. I think it's unlikely, but it's possible. The other one is IRAK4 levels in skin are extremely low. The dynamic range of the assay is very narrow. It's really hard to robustly measure a percent reduction.
Is STAT6 different?
STAT6 levels in skin are much higher. As we've also shown preclinically, we can measure and reduce STAT6 levels in the skin of many preclinical species quite effectively, including non-human primates. The compound distribution profile is slightly different. We have confidence that we'll be able to see robust degradation in skin as well.
Got it. Interesting. Let's talk about safety then. I'm curious on STAT6 as a target, what are the safety attributes we should watch out for? Are there anything else on safety with regards to just degraders as a whole or just this molecule in general that we should look out for as well?
Yeah. First, I would say that degraders have been actually an exceptionally well-balanced—I have had an exceptionally well-balanced safety profile. If you look in the industry across all programs, all the safety that has been seen in the clinic were safety that one could explain based on target biology. For example, with IRAK4, we have seen really good safety because we know that human genetics tell you that not having IRAK4 should be relatively well tolerated.
Other programs from other companies, including ours in oncology, what we have seen in terms of adverse events were all associated with well-understood biology of that particular target. Telling you that as a modality, it is a very, very well-tolerated modality. There is not a degrader safety profile. With regards to STAT6, you know, we stand on like three important pieces of information, right? I would start with pathway clinical validation.
We've shown robustly that STAT6 degradation, as much as we can tell, a one-to-one relationship with IL-4 receptor inhibition. And we know that obviously dupilumab is a drug that has been, you know, dosed to a million patients actually now, including children with a very good safety profile. I would also say that there is STAT6 human genetics that says if you have a gain of function of STAT6, the only phenotype that you see is severe allergic diseases.
So it's telling you that's the function of the target. There has been a heterozygous loss of function. Humans that have been identified recently also with no phenotype, actually, no adverse phenotype. And then I would say our preclinical tox have shown no adverse events at any doses or concentration. So we're going into the study expecting a very good safety profile. I mean, when we say that we want to have a Dupixent-like molecule, we mean that from both the efficacy and safety.
Yeah. Yeah, I love that. There are some investors that kind of have what I think are misconceptions around degraders, that degraders are, you know, larger small molecules. They break rule of five. They struggle with oral bioavailability. They might have increased risk for GI or liver tox because of these molecular attributes. What is your kind of response to that kind of conception that some people have?
Yeah. I mean, look, first of all, there are no Rule of Five. I think that's kind of a lazy observation, if I may say. I think what I would say is that these are generally larger than your traditional small molecule inhibitor. The reason why degraders, and that's good for companies like Kymera, haven't been commoditized completely, is because it does require different rules on how you build them into being like a pharmaceutical agent.
Companies like Kymera and others, I would say, we're not the only ones. I think we're the very good one. We've learned how to effectively make these molecules behave like traditional small molecules from a pharmaceutical perspective. To be honest, we're well past that question. That question used to be discussed at Kymera four years ago, maybe, but not now. We're more focused on making drugs against targets that we like. I think that particular question is for the kind of naive of the space.
Yeah. Appreciate that. In terms of biomarkers, I think you've talked about TARC and IgE as biomarkers that you'll look at both in the healthy volunteer setting and then in your Phase 1b in patients. You know, at least in the healthy volunteer setting, acknowledging that, you know, those outcomes are often pretty noisy, is there a minimum bar that you want to see on TARC and IgE, even in the healthy volunteer setting, to feel comfortable with the molecule?
Yeah. No, I love how this has become a controversial topic. I'm not sure how it happened. I was told that I've changed the narrative around it. I'm going to say what I've been saying for months, which is if you just look at the publications, you know, I think Regeneron has done a great job and Sanofi, they've done a great job publishing science, not just drug development. There is a paper on healthy volunteer. There are several papers on biomarkers on patients across all the indications. We have all the data out there. Like it's not about what I say. It doesn't matter what I say. It's actually what's in the publication.
If you look at the dupilumab in healthy volunteer publications where they have, you know, when they have like those response over time, as you've said, you know, you don't really see a clear dose response. You see a measurable effect in TARC. I would say in IgE, if you look at the first two weeks, it's not easy to see a real measure.
I think what I've been saying all the time is that we, given that we believe we can phenocopy in a broad sense the dupilumab, that you should expect from us a profile that is going to look like that. What I keep saying, which is only a fact, is that if a drug within its own dose response is not, it doesn't have a clear dose response, what I'm saying is that it's not trying to compare two drugs.
If an individual drug doesn't have a clear dose response, and I'm talking about the dupilumab, I don't want to get into comparing drugs across two different studies. The bar, you asked the question about the bar. It's hard, right? I don't know what the bar is. I just would say that I'll be surprised. I think we would all be surprised if there were no measurable changes in these biomarkers because they've been shown by the dupilumab and also other IL-13 drugs. I don't know that there is a bar there. I mean, if you look at the TARC data, they go anywhere from, I don't know, 10% to 35% within the first two weeks, right? I don't know where the bar is.
Okay. Makes sense. Let's talk about another controversy then.
Let's do it.
Can you defend your decision to do a Phase 1b single arm, no placebo, single dose in atopic derm?
Yeah. No, that's an easy one. The goal of our development plan is to get to market ASAP. Like we are committed to actually developing this drug because I think this is a, I said it on the call, this is a once-in-a-generation drug, hopefully, right? I mean, we still have a long way to go. I think the setup is this is one-in-a-generation drug, one-in-a-lifetime drug for people like me. We are committed to do the right thing by the drug first. If we want to get to Phase 3 ASAP, we need to get to Phase 2b ASAP, which, as you know, we are starting, hopefully, if everything goes according to plan, the first Phase 2b will start in 4Q. The second Phase 2b will start in 1Q.
We believe those Phase 2b's might be the only Phase 2 studies we'll ever have to run. We can do a series of Phase 3 studies after that. What we wanted to do before the start of Phase 2b, which, you know, we want to do ASAP, is to build a data set that will show us robustly that we behave like dupilumab. We know in AD patients, the strongest data set of dupilumab is looking at biomarkers in blood and, more importantly, in skin. We know that, for example, there is a strong correlation of biomarker changes in skin with extent of clinical response. We know that actually reduction in TARC has been associated with reduction in pruritus in dupilumab's Phase 2 and Phase 3 studies.
We know really well that if we inhibit and block these biomarkers, we can easily make a correlation between biomarkers and clinical endpoints. Given that this is a four-week study, we do not think we need placebo to show that. Placebo and biomarker, you can look at it, the papers are everywhere, are very, very minimal. There is no really placebo rates in biomarker. For a four-week study to move quickly in a Phase 2b without running a hundred patients' four-week study, because that is probably what it will take to do a placebo-controlled study, we thought we can show degradation in blood and skin, biomarkers in blood and skin that correlates to a clinical endpoint. We believe that it would be a robust data set that will not need any conversation.
Yeah. It's interesting because I think when we last spoke, you mentioned, you said this phrase, you're like, biomarkers don't lie.
I know. Some people love that sentence. Some people didn't.
Oh, okay. Interesting. I mean, because the investor controversy was that in AD studies, placebo has such a huge variability on EASI score reduction. I think people actually kind of don't appreciate that, biomarkers. We pulled the data.
You said the data, right? Yeah. Biomarkers is really very little placebo effect. We're talking about biomarkers in patients, right? Not to confuse the previous conversation. I would also say that it's true that the placebo rates in AD have increased a bit over time. I think that's mostly due to the fact that it's extremely competitive and patients maybe that might not meet all the entry points are recruited to some of these studies. I think if you run a highly controlled study, you should be able to reduce the placebo rates.
Yeah. How do you choose which dose you put into the Phase 1b ?
Yeah. So how we choose the dose, I mean, without going into the details, but we talked about what is the profile we're looking for, which is we want to have a degradation profile that degrades the target around 90% plus at a dose that is well tolerated. That's the dose that is going into the Phase 1b , which, as you probably gather, it's likely to start before we release the healthy volunteer data.
Got it. Makes sense. I want to talk about another topic. I know you might not comment too much, but I'm going to try. We noticed that you published some, I think it was 3,000 pages worth of patents on STAT6 degraders a few days ago. Can you comment on the structure and, you know, what that means for the kind of the future of the molecule?
You know, it's funny. We're trying to do all this under the radar. Now you want to bring it in front of everybody. No, you know, we have a, you know, we've been working on this target for multiple years. We have multiple patents out there. Yes, some, I believe, were published a few days ago. I don't remember exactly when. Some were published earlier. I think your comment about the number of pages, maybe the only comment I would make is, you know, we take our IP very seriously at Kymera. We have a very, I would say, you know, good strategy that is forward-looking. You know, we're very proud of the chemistry we've built.
Makes sense. All right. I want to spend a few minutes on your other pipeline candidates. You said you're going to disclose your next candidate in May. I think you've made some allusions to what it might be. I guess you're not going to tell us what it is, but can you just talk a little bit about your philosophy on what went into the decision of what you were going to work on next after the STAT6 and TYK2?
Look, it goes back to the same principles I've outlined before. There are, I think the reason why a few years ago we decided to go in immunology almost fully is because there has been so much validation of immunological pathways with, especially biologics, in the past few years. There has been such an underwhelming set of data from traditional small molecule inhibitor that, you know, the way I think about it, the time of degraders in immunology is now. We have a lot of activities on a variety of targets that I think each could be, you know, multi-billion dollar opportunities.
There are so many of them, to be honest, that if you think about target strategy well and you have the right platform to prosecute, and we have a unique ability to find binders to undrug protein right now at Kymera, that, you know, I think the target is going to be one that, you know, is on everybody's list because it's one of those transcription factors that you don't have to think about long to kind of appreciate where to position clinically. You know, I don't want to raise expectations too much, but I think it'll be appreciated broadly. It is another amazing molecule.
Got it. Interesting. I guess as you think about your pipeline development, like you have like STAT6 and TYK2. STAT6 goal is to drug an undruggable transcription factor. TYK2 is to drug something better than how it's drugged with traditional small molecules or allosteric small molecules. How do you think about what comes next and kind of like leaning, you know, between these two different types of approaches?
Yeah. You know, as I said, you know, if you think about marrying the power of the technology with the right target, you know, we're not limited by the type of target. I think what I said is we've ended up working in these couple of classes of these scaffolding proteins and transcription factors, but I wouldn't say that those are limiting.
You know, we have another early program that is going after a totally different target type. I would just say that the key, what I think will stay consistent is validated biology, us having the potentially best in pathway drug where you don't compromise on efficacy with an oral drug. You capture both most efficacy and most convenience with an oral drug with biologics-like efficacy or even biologics-superior efficacy, which I think will happen in some of our programs.
Got it. Makes sense. I want to just talk quickly about TYK2. As you know, investors do not love TYK2 for a few different reasons, but can you kind of defend why you chose that as a target to go after and why you feel good about your program?
Yeah. I mean, I think it's fair to say there is a bit of fatigue around TYK2, which, I mean, it's understandable if you think about TYK2 inhibitors, right? How many TYK2 inhibitors are needed to drug a target? This is a pet peeve of mine. How many drugs do we need? There are so many targets that are, you know, way over drugged at this point, right? With hundreds of companies. TYK2 is probably close to that. Not as bad as the PD-1 or the CD19, the CD20, but it's getting there. I think we're talking here about a different modality with different pharmacology. We're trying to replicate the human genetics data that has made this target one of the most compelling targets in immunology.
This target should work in, drugging this target properly should work in IBD, should work in psoriasis, in psoriatic arthritis, and in many other indications. I think inhibiting the function of TYK2 is not going to be enough. We are going to de-risk it in two different ways. In the Phase 1 , which, you know, hopefully we'll have data this year already, show that we can degrade this target fully, which is the phenotype that nobody has ever shown.
Then show that this full degradation of TYK2 is going to drive a biologics-like efficacy profile, you know, let's say in an indication like psoriasis or others as a proof of concept. I am totally comfortable for this program to be a show-me-the-data program, but we have the utmost confidence this is going to be another big program for us.
Got it. All right. We are at three minutes left. I have two questions. Obviously with STAT6, you spoke about the huge potential, you know, going after large mass market opportunities. You guys are first in class with this molecule. How are you guys thinking about the kind of strategic path forward for the molecule? Like, does it make sense for a company with your scale to be developing this forward? How are you thinking about, you know, the potential partnership strategy there?
Yeah. I think what I can say with comfort right now is that there is no scenario where, you know, partnering this program between now and the end of these big Phase 2b studies will accelerate or expand the potential of this program. We are likely going to be able to do it faster and better than any other company, given the investments we've made already and are continuing to make.
I think at the end of those Phase 2b studies where in front of us, we'd have potentially eight indications or more that we could, in theory, parallel track in Phase 3. We're talking about 21 Phase 3 studies if one wanted to parallel everything. The question would be, are we positioned to maximize value? I think it's a fair question to us then, and we can address it then.
Okay. Sounds good. I'll put it on the list. Just one last one to wrap us up. What do you think investors misunderstand most about the Kymera story?
Yeah. Look, I, you know, I do my job. Investors do their job. It's hard for me to say, especially in this context, you know, what they're missing. I think I hope that investors that invest in the science of companies, in the fundamentals, because not everybody does that, right? For the ones that actually invest in the science and the fundamental of the company, I think there is a strong appreciation of the quality of work that we do, the strategy that we have, and the targets that we have.
Again, not everybody likes every target. That's okay. I think there is a, I think right now, I feel like there is an underappreciation of what the monumental potential of degrading STAT6 safely means. You know, getting hung up on a, you know, relatively unscientific readout, which is the biomarker readout, instead of understanding that if we integrate STAT6 safely, this has the potential to be one of the biggest drugs in immunology.
Yeah. That's great. We have just a little bit of time left. I just want to check if anyone in the audience has any questions.
No, look at that. You've got multiple. Go ahead.
Have you looked at subcellular localization with any of your protein degraders and other limitations in the cellular context in which a protein can be degraded effectively?
That's a great question. We have looked at that extensively, especially with transcription factors that, as you know, are activated in the cytoplasms, usually by phosphorylation, and then go to the nucleus to bind to DNA. We have shown, I'm not sure if we've shown with STAT6, but I know we've shown internally that we can degrade STAT6 and we remove it from every compartment. Actually, we'll show also data from this new program because it's another transcription factor.
You mentioned that the protein degraders, they are always safe. I do not want to be controversial. The thalidomide was a molecule that grew, and it was very dangerous. Can you put some perspective?
I didn't say, I actually said that, you know, the safety of the degraders are based on the mechanism of the pharmacology of the target. Obviously, in that particular case, there are some substrates that are degraded that have a particular pharmacology, but nothing to do with the actual degradation modality, but it's the pharmacology of that particular drug.
As a follow-up.
I think we're way past time. Maybe we can do it after.
Thank you so much for joining us. Thank you for folks in the room and folks who dialed in as well.
Thank you.