Hi, good afternoon, everyone. I'm Eliana Merle. I'm one of the biotech analysts here at UBS. Very happy to have Kymera Therapeutics here with us today, presenting as part of the UBS Targeted Protein Degradation Day. Joining us from Kymera is Nello Mainolfi, President and Chief Executive Officer. Nello, thank you so much for making the time. Very timely, we can discuss the latest update with 474 , which I think is exciting. But maybe just to kick it off, can you give us an overview of your protein degradation platform and discovery capabilities? And given there's so many companies in this space, I guess, what aspects of your platform and technology do you believe are unique and differentiated versus other companies?
Yeah. Thanks, Ellie, for having us. I guess it's good to be back to 2020 with the Zoom calls, but it's all good. Thanks for doing this, this day focused on protein degradation, which I think deserves to have a platform that allows you to go into new nuances of strategies, technologies, teams, and people, so I'm really glad you're doing this. So to answer your question, so first of all, you know, we founded the company in 2016 with the goal of using TPD to unlock a whole new generation of targets. We've been fortunate that we've de-risked and validated so many pathways, so much biology, so many targets, but I think the technologies have lagged behind.
If you, if you look at many technologies that we've developed as an industry in the past 10, 15 years, they all have big limitations, whether it's getting into the cell for biologics, for antibodies, or, you know, getting the right delivery for oligo-based therapeutics. What we saw with TPD was the opportunity to go after targets that had been undrugged or poorly drugged. And so I would say that the main thing that is very unique about Kymera, I would say, it's our target selection strategy. We have taken the concept of protein degradation as a validated therapeutic modality when we started the company. We didn't feel the need to develop programs to validate the technology. We felt the need to develop programs to bring innovative medicines to patients.
And so our target selection has been focused on targets that have been undrugged, poorly drugged, where protein degradation is either the only or the best way to go after. And if you look at IRAK4 with an evolving story, you know, we were the first of the companies to go after a target that had small molecule that had gone and failed in the clinic, but where we believed, through data, that protein degradation would be the modality to unlock the value of those targets and of this particular, in this particular pathway. If you look at our commitment to the STAT protein, STAT3, and more recently, STAT6, targets that have been undrugged in the industry for decades, with, you know, fully validated biology, and we've committed to unlocking the value of those targets.
And obviously, I can go on and on. So I think that is a key, unique aspect of what we do. Another aspect is our ability to develop chemistry for these difficult to drug targets. All the chemical matter that we use at Kymera is developed internally. We don't use literature, small molecule binders or inhibitors to target our target classes. We develop them internally through always evolving and always getting more sophisticated hit finding approaches. If you see behind me, this is a cryo-EM structure of KT-333 with STAT3 and VHL is the E3 ligase. We have a picture, in fact, the other one in the background is another version.
On this side is things that I can show you, but we have ternary complex structures of every program in our pipeline and in our discovery engine, which speaks to the nuances and the sophistication of our approach to develop these first-in-class degraders. You know, our commitment to doing translational work. I think hopefully you'll agree with me that you know, all the programs that Kymera has taken into the clinic and also in this space, I think we're ahead of the industry. We've taken four programs in the clinic in less than four years, since 2020, since we became a public company, and all of our programs have translated with a high degree of fidelity in terms of PK, PD, safety, and efficacy. So those are the key pillars of, I think, that makes, I believe, Kymera a very unique company, not only in the degrader space, but I would say in biotech.
Absolutely. Yeah, you certainly have moved at quite a rapid pace of bringing new degraders for novel targets into the clinic. What should we expect in terms of that rate going forward? I guess, at, like, every J.P. Morgan, maybe we'll learn some new targets.
So we have an internal commitment to have, you know, at least one new IND per year with a new molecular entity. And, you know, we've been on track, you know, on an average since we set out this goal, which was around 2020. So you should expect at least one new IND per year. In some years, we'll have probably many more than one, and maybe in some years less. But generally, you know, I would expect next year, probably not around J.P. Morgan, but a bit later, well, we plan to disclose a new program that will be a new addition to our pipeline, and we expect those disclosures to be consistent, you know, year after year.
Great. Well, I could certainly ask you about your platform all day, so for the sake of time, I'll move to IRAK4. Can you walk us through this latest update, and maybe specifically, like, what was learned in this interim analysis?
Yeah, so maybe just to take a step back. So if you look at the existing study design, at least what's on ClinicalTrials.gov or on our website, let's use HS as an example, you see that there was there still is, you know, up to today, a one dose group and one placebo group. I think for people that follow drug development in general, you would expect that before going into phase 3, you know, you would have required to likely run a dose ranging study. And so, you know, the update, when we say we're expanding the study, the current study to accelerate development pipeline, what we actually mean is that we expand the existing study to add more doses, so that this is the only phase 2 study before a phase 3.
The overall timelines are positively impacted in a dramatic way, although obviously the current study's expanded, it probably will take longer to complete. That's maybe a bit of the backdrop. What I would add to your question, obviously, I can't go into the details of what was seen or not seen, but the only thing I can say is that Sanofi elected to run an interim analysis of the data of safety and efficacy. This is not uncommon for a company, especially in pharma, to run an interim analysis to also make investment decision, and so we're happy that this interim analysis look at the data has led to an investment, a further investment decision into the program.
Philosophically, these types of interim analyses, should we think of them as having maybe a higher bar or, like, you know, kind of... Historically, some interims will be, say, for futility, others might be, you know, you've shown exceptional efficacy. Can you characterize sort of where this falls on that spectrum?
You know, again, I don't wanna upset our partners. It's not. There's not much I can say. What I will say is that there was a clear bar that Sanofi had questions around that wanted to clear, and it looks like, based on their decision to expand the investment, that bar was clear.
Okay, maybe I'll ask the same question another way. I guess, what's your, like, view on the likelihood of success, and maybe kind of like, how is your confidence now in IRAK4 disease biology in AD and HS, relative to a couple of weeks ago?
I mean, you, as you know, I've always been a big fan, a big champion of this program, not just because I'm the CEO of Kymera, but also because I actually started this program in 2017. Because we and I believe that this could be a cornerstone of small molecule orals in inflammation, given the breadth of the mechanism. Obviously, we cannot guarantee success, but I have high degree of confidence that this molecule and this target will be relevant in a broad variety of diseases, and the recent data only continues to support my confidence.
In broad strokes, I guess, can you characterize the changes? So it seems like additional dose levels. Anything else that you can talk about in terms of the changes in the study expansion we can expect?
Yeah, it, you know, hopefully, we'll see the amendment on ClinicalTrials.gov, you know, relatively soon enough, and at that point, we'll be able to add more color. The only thing I think we aligned with Sanofi that we'd be able to comment on is the fact that, you know, the real spirit of the expansion is adding more doses, and that's what's gonna change. That's, that's gonna be the major change.
Understood. Maybe turning to the disease biology, what gives you confidence in IRAK4?
Well, you know, I think it goes back to the pathway. When we talk about Kymera target selection, you know, the mantra is that we like to go after targets that have not been drugged or drugged well, like IRAK4, in pathways that have had deep degree of validation, sorry. And so, you know, going to the pathway degree of validation, there are drugs that are approved that target upstream cytokines. So IL-1 family cytokine, IL-1, IL-18, IL-33, and IL-36, these are cytokines that must signal through the myddosome complex and IRAK4. TLR, it's a whole other area as well, and we have a plethora of positive data looking at upstream biologics. If you look at the IL-1 alpha, beta.
Biologics from AbbVie that had some really impressive data in HS in a phase 2 study in TNF alpha refractory patients. We've seen encouraging data from the IL-33 in asthma, in respiratory diseases. We've seen other data in RA, in gout, in macrophage activation syndrome, which is a smaller disease. So we have a series of validating data set in phase 2 and phase 3 with single cytokine blockers. So it's only pretty rational. This is why I always thought it wasn't a big bet. It's only rational that if you have a drug that blocks the cytokines downstream of them, so you have a potential to have the activity of the combined IL-1 family cytokine blockers, it's only rational that this drug should work. Now, obviously, the drug is only gonna be as good as its ability to block the pathway the way that we believe it needs to be blocked to have the combined activity of these biologics. And if you look at our data in phase 1, we degrade IRAK4 fully in blood, robustly in the skin. We change cytokines systemically in the skin. We have early data in patients with some impressive impact on pain profiles, and then scores in HS, if you look at AN counts or HiSCR50 or EASI scores in AD. So all the data is pointing to this drug being really active, so that's where the confidence is coming from.
Cool. Are you considering starting a study in an additional indication prior to getting the AD and HS phase 2 data?
I'm definitely considering. The question is whether Sanofi is considering it. So, all I can say is that... No, it was a good question. Sorry, for throwing a joke in there. We have discussed at length with our partner, and there is a team, a combined team that has prioritised a series of indications. At this point, you know, it's really up to Sanofi to make that decision. And, and we-- To be honest, we've been so focused on this, this, this, this discussion of recent time around the interim analysis and the expansion of the study, that we really haven't had the opportunity to even ask them this question recently. So I'm sure it'll come up again, and I'll be able to give a better answer next time.
I mean, you referenced a couple where single cytokines have shown efficacy in indications that are mediated by IRAK4. I guess, is there any that kind of pop out that.
I'm a.
In particular?
Yeah, I'm a big believer in IRAK4 in respiratory diseases. I think both asthma and COPD are great opportunities. I think GI inflammation, which is an area that still requires the right oral, is another opportunity. I think traditional rheumatology also makes sense. I mean, lupus makes a lot of sense in terms of pathway biology. Obviously, IRAK4 is at some degree of validation, even with the small molecule inhibitor. So, I mean, those are areas that I'm personally very interested in. Many of those are areas that Sanofi has expressed interest, too. So, hopefully, soon enough, we'll be able to see some work in those areas as well.
What do you see as potential, like, theoretical safety concerns with degrading IRAK4 or anything specific with the molecule?
I don't see, personally, any specific areas of concerns. We know that adults that lack IRAK4 are pretty healthy. They have a competent immune system. In our own safety data up to phase 1 that I can speak to, we've seen good safety. So, I think we're feeling pretty bullish about this program.
Understood. Well, turning to some of your earlier programs, maybe specifically STAT6, can you elaborate on the rationale for a degrader and of STAT6, and specifically, where you see the disease biology pointing to in INI?
Yeah, I mean, you know, STAT6, some would argue, is the perfect target for the platform. It's a specific selective transcription factor for IL-4/13 biology. So the IL-4 receptor, once activated, recruits STAT6 to the receptor. So there isn't any steps, there isn't anything else between the receptor and STAT6, so it's as specific as you want. It's also a particular transcription factor, as most of them, really difficult to inhibit, given that they really only get phosphorylated and then go and bind to DNA. They don't have. They're not evolved to bind small molecule, let's put it that way. And so, we believe that with a degrader, where we can, use a silent binder approach, right, a binder that doesn't need to inhibit the protein, it's the best methodology or technology to go after such a target.
In addition, we've shown it internally at Kymera, that it's almost impossible to block IL-4/13 completely with a non-degrader of STAT6. So let me put it this way: you need to completely remove the function of this transcription factor 24/7 to being able to compete with Dupixent in terms of efficacy. Obviously, if you compromise on lower degrees of efficacy, then maybe other technologies could come in play. But given that our philosophy at Kymera, and we hopefully did a good job in January to outline it, is to develop a new generation of orals in immunology that have biologics-like efficacy. For that type of TPP, Target Product Profile, you need a STAT6 degrader.
And in terms of which diseases, you know, I would say that Dupixent, so blocking the IL-4 receptor alpha, has actually created a whole new disease area because it's shown what can be done. And this disease is Th2 disease that has skin manifestation, like atopic derm, has respiratory manifestation, like asthma or COPD, has GI manifestation, like EoE, but also has other manifestation, like food allergies, other manifestations, like alopecia areata. There are so many manifestation of Th2 inflammation that are driven by this pathway, and so our job is to actually deliver an oral small molecule that will hopefully be responsibly priced, that will be able to help hundreds of millions of patients in the world that suffer from Th2 disease.
Absolutely, and I hear you. I mean, it does sound like the ideal target as a somewhat oral Dupixent. I guess, what do you see as, like, the potential risk on the safety side, and how should we think about, like, you know, what gives you confidence in the safety?
Yeah, you know, we, as you can imagine, we've been working in this program for years. We're the first company to bring any type of agents against STAT6 in the clinic, so we should know more than most about this particular question. So I can tell you what we know. What we know is, if a human gain-of-function against STAT6 leads to severe atopic diseases, allergic diseases, you would expect that if STAT6 role went beyond this Th2 biology, the gain of function could lead to other phenotypes. So this is telling you already, this is one of the data point that is telling you that STAT6 role is really around Th2 inflammation and atopic diseases. What we know is if you have mice that lack STAT6, they're developed normally, they're viable, they're fertile.
What we've shown internally at Kymera, that we haven't been able to see any biology outside of IL-4 receptor, IL-4/13 signaling through STAT6. I'm not saying that could never exist, but we have looked, we have looked beyond, we've looked at all the papers that are out there, and all that we've been able to show is that IL-4 receptor and IL-13, signaling must signal through STAT6, and we haven't been able to see any other biology meaningfully signal through STAT6. Also, obviously, in terms of safety, we've run extensive safety study at Kymera, and I can speak to everything that we've done through non-GLP tox, and we haven't seen any adverse events in any of the studies that we've run with our molecules, including non-human primates and exceptionally high doses. So, so far, again, everything that I've tried to outline is telling us that we should expect to have really good safety. But, you know, this is the first time that that target is drugged, so we'll always have a keen eye on anything that might come from our evaluation of safety in humans.
Makes sense. That's helpful context. So you're moving into the clinic with STAT6 this year. What's your most recent commentary on what we should be able to see at this data in the first half of next year, and what we should look for?
Yeah. So, I mean, what we've said is that we're gonna run. We've only disclosed the phase 1 high-level design, which, what we've said is gonna look, you know, similar in terms of conceptually to the IRAK4, KT-474 phase 1 study, will include the SAD and MAD, will have degradation in blood and skin, as well as, you know, we'll try and measure any measurable cytokines that we can impact versus pre-dose. Others have shown, including Dupixent, that TARC levels can be modulated up to 30, 40%, IgE probably a bit less, bit more noisy, but that has also been shown to be able to modulate. So obviously, we'll look at those, and of course, safety and PK.
Great. Maybe just can you elaborate a little bit more on, like, what you would view as maybe informative for the hypothesis around disease biology? So, the specifics around the cytokines that you're able to measure.
Well, I mean, as I said, I mean, So this biology is so well understood, and even pre-clinically, we've done, I think, such a nice job demonstrating that degradation of STAT6 in all contexts that we've looked at is either, you know, equal or even slightly superior than an upstream biologic. So, I don't believe that there is a lot we need to show in our phase I to validate these hypothesis. I think we're very focused on the PK and PD, so degradation in blood and skin will be critical, the safety will be critical. Again, on cytokines, as I mentioned, we might be able to measure TARC and IgE because others have, but again, I will caveat that in healthy volunteers is a bit or quite a bit noisy. But, you know, if we obviously can measure that, we will definitely look into that. And then, you know, with that package, going into patients ASAP will be what we really must do.
Makes sense. In terms of your updates this year, I guess what should we expect from STAT3 and MDM2 in oncology?
Yeah. So as we reported recently, you know, those studies are still recruiting patients. I would say for STAT3, I believe we've said this publicly, that, you know, we're not dose escalating anymore. We're doing a small expansion, really focused on Hodgkin's lymphoma, where we're seeing a really impressive early signal. And so hopefully by the end of the year, we'll be able to share the complete data set of this phase 1A finally. We've been fortunate that the safety has been so good that, you know, we ended up escalating well beyond what we expected as we went into the study. So the goal is by the end of the year to be able to talk about that as well as next steps. With MDM2, obviously, we're still in the midst of those escalation, so it's a bit more difficult for me to say that by the end of the year, we're done. I mean, that was the initial plan, but also there, if we continue to see good safety, the expansion, sorry, the escalation might take longer. As you know, we are escalating both AML as well as in solid tumors. For sure, we will have an update on our biomarker-driven, forward-looking strategy on how hopefully we'll be able to use all the work that we've done to eventually, prospectively recruit patients to our studies, and that will be an update that for sure will happen in the second half.
Okay, interesting. So we'll see the data sort of cut by those that express the biomarker versus not?
No, I think it will be that the biomarker data will be mostly focused on all the work that we've done, especially pre-clinically, to generate the biomarker-based hypothesis. Then in terms of clinical data, we plan to update as we get, you know, towards the end or at the end of the phase 1A dose escalation.
Got it. In terms of your TYK2, maybe walk us through the rationale here. I know there's TYK2 inhibitors. Why do you think degraders can be better?
Yeah. So, also here, I like to go back to human genetics. If you look at loss of function of TYK2, and then you look at kinase dead TYK2, these are very different profiles. Now, small molecules, because some of them are allosteric, they're able to impact also somewhat the scaffolding function of TYK2. So TYK2 has a well-characterized scaffolding function, and that is really outlined, again, by the different phenotype of kinase dead and loss of function. So loss of function is impaired IL-23, IL-12, and Type I interferon. Kinase dead, really only IL-23. So, we have that goal in terms of complete blockade of IL-23, IL-12, and Type I interferon, 24/7, which obviously, any small molecule approach would not be able to do, or any catalytic inhibitor will not be able to do.
So what we hope to being able to have is really a biologics-like type of efficacy, and we believe that because we are, we hit IL-23 completely, but also IL-12 and Type I interferon, we should be able to have a biologics-like, Stelara-like efficacy. And this is gonna be a quick and relatively easy question to ask in early clinical development. We have no intention to invest heavily in this program unless we're able to show that we have a really differentiated and superior profile. And as we believe we're able to do with IRAK4, we believe that we should be able to do it with TYK2, where the small molecules already have activity, so it's a bit of a different bar here, but we believe biologically differentiated with a degrader.
Makes sense. And how's your work on novel E3 ligases going?
You know, this is an area that we've invested heavily, as you know well, even well before we were a public company. What we have learned through you know, a lot of hard work and investments is that it's actually much more tractable to have tissue-sparing E3 ligases that you can ligand than tissue-selective E3 ligases. Meaning, it's a lot easier to say, "I have an E3 ligase that is not expressed in GI and in the heart," than saying, "I have an E3 ligase that is only expressed in the liver," right? And so with that understanding in hand, you know, we are working on a few programs that should be able to finally deliver a pharmacologically more, let's say, pharmacologically sparing degrader program, but we're not quite ready to disclose when and what.
Understood. Since we're two minutes over, I'll just ask one last question. Of your discovery work, what are you most excited about?
Yeah, look, we have a lot going on under the hood, as people would say. We have a large commitment in immunology. We believe that there is a need for oral drugs in areas like autoantibody-driven diseases or, you know, immune resetting, that obviously these other technologies have shown the concept, but I don't think those are commercially viable in terms of the scale that we're interested in technologies. So that those are two areas where we have a lot of investment. I would also say that we're investing outside of immunology and oncology, but it's too early for us to talk about some of those targets.
Okay. Well, we're certainly excited to see your programs play out, and exciting work on the platform and clinical studies. Well, thank you, Nello, so much for joining us, and thank you everyone on the line for attending. We will talk to you soon.
Thank you. Thanks for having us.
Yeah, of course.