Kymera Therapeutics, Inc. (KYMR) Earnings Call Transcript & Summary

Hi guys, I'm Ellie Merle. Thanks so much for joining us here at the UBS Healthcare Conference. Very happy to have Kymera Therapeutics presenting for us today at the UBS conference. With us from Kymera is Nello Mainolfi, President and CEO and Founder of Kymera. And with that, Nello, I'll pass it over to you for a presentation.

Thanks, Ellie. Thanks for the invite, and pleasure to share a bit of an update from us today. So I'll just talk through the slides, and maybe I'll -- just to help, I'll call out the slide number as I know, you -- the audience would be able to move through the deck on their own. So maybe the best way would be to start the Slide 5, just to give a brief overview of where the company is. So we founded Kymera in 2016. As many of you know, the goal has been to build a fully integrated biotech that would be able to take a targeted product degradation, which at that time, was still a relatively early modality into a stage where we would be able to take several drugs with this modality into and through the clinic, and eventually into the market. So our goal is to build that fully integrated business. And in a way, own the challenges as well as the, obviously, the opportunities that this technology can provide. We're at this point, a clinical stage company, we started our first Phase I study in February of 2021 with just over 100 full-time employees here in the Boston area, and we have also 200 to 300 FTEs in different parts of the world at different CROs and CMOs. We closed our first quarter with about $435 million, and this was thanks to some financing, both private and public, and partnerships that we closed in 2020. And this balance allows us to think very thoughtfully and carefully about how we're both building, scaling the company and also how we're thinking about next financing. So we're very aggressively expanding our capabilities, both in discovery, development, but also in our platform and technologies. And as I mentioned, we're going to be looking at potentially increasing our balance sheet, mostly driven by key data-driven inflection points. So as I mentioned, we are a company that is invested heavily in both the platform and pipeline in a way that we believe is quite differentiated. I would say, just at the high level, our pipeline has been focused on key pathways and key targets that will allow us to fully capitalize on the power of the technology to go after translational hypothesis that cannot be addressed by other modalities. And also, our platform has been trying to pursue opportunities that are not available even to the current state-of-the-art of TPD, as you'll see in a few minutes. We're internally focused in oncology and immunology, mostly, but thanks to our partnerships, I think, it's fair to consider Kymera a disease agnostic protein degradation company. In fact, we work on 7 different diseases, 5 of which are outside of oncology and immunology, as I mentioned, thanks to our partner, especially Vertex. We look at partnership as many companies as an opportunity to accelerate our growth and to create those win-win opportunities. So everything that we've done has had a goal in mind, but GSK has been a really technology-driven collaboration around their state-of-the-art high content screening capabilities. With Vertex, we had really unique opportunity to invest in a derisked manner in working in areas outside of oncology and immunology. And for Vertex, we believe an opportunity to access our platform and especially around novel E3 ligases and tissue selective or restricted E3 ligases that we're using in that partnership with Sanofi has been really driven by our desire to develop what we believe it to be potentially a best-in-class anti-inflammatory agent. And so develop it very aggressively in a wide variety of diseases. I'll touch on this in the next few slides. So we've done quite a few firsts for both us and protein degradation this year. We've launched the first placebo-controlled randomized study in healthy volunteer with KT-474. Actually, the first time also that a hetero bifunctional degrader has gone in healthy volunteer and eventually in the immunology patients. And we also plan to have 2 more clinical starts in the second half of the year. And we're very much looking forward to our plans to share our Phase I healthy volunteer study readout in the fourth quarter. We believe this would be the richest data set in terms of safety, PK, pharmacodynamic impact on disease-relevant biomarkers, impacting, hopefully, up to 70, 80 or more subjects' data. So lots to discuss as we go into the fourth quarter. So going to Slide 6, just to give everyone a sense of our publicly disclosed pipeline. So as I mentioned KT-474 is our IRAK4 degrader for immunology and inflammation and this is a program that we are co-developing with Sanofi. Kymera is driving through the end of Phase I, which, again, will include also a patient cohort. And then Sanofi will drive further development from the beginning of Phase II in a wide variety of diseases. And Kymera will have the opportunity to then go back in co-developing 50-50 in the U.S. So again, here, the opportunity is broad. We have both the human genetics derisking, the preclinical tox derisking as well as the Phase I derisking that will allow us to potentially develop this molecule in a wide variety of diseases right now on our priority list. We have atopic dermatitis, HS, RA and potentially other diseases. That will be initiated hopefully soon after the end of the Phase I study. The next program that will enter the clinic in the second half of the year is our IRAKIMiD program. As we've shared recently at ASCR, the hypothesis there is in a patient population that is quite refractory to standard of care malignant mutant lymphomas. We have found that by targeting 2 contiguous vulnerabilities in the MYD88 IRAK4 pathway and in the IMiD-driven IRAK4 pathway, we're able to drive the synergistic biology that seems to give us preclinically really best-in-class effect. We have shown superiority to all, both IMiD as well as clinically active IRAK4 agents that are out there. So hope to have there a really first targeted therapy in lymphoma as well as other diseases, as I'll mention in a minute. The third program to enter the clinic, this is also in the second half of the year, it's really going after the traditionally untrackable transcription factor, in this case, STAT3. We're going to initiate the studies in oncology by going after a selected populations in liquid tumor and then expanding in solid tumor, especially considering the -- especially some really exciting data that we've seen in combination with PD-1. What we don't often talk about is that probably most of the work that is ongoing today at Kymera, which is in our discovery pipeline and platform, and what we've decided to do in order to share more of what Kymera is besides this exciting first 3 programs is to host an R&D Day in the second half of the year, where we will disclose the next program that is entering the clinic at this point, the clinical entry is planned for next year. And this is a new pathway and a new program that we'll talk about. And also, we'll talk more about indication expansions for the existing programs as well as some early proof of concept of our tissue restricted, the E3 ligases that we hope to share that R&D Day. So before we go into the specifics, on Slide 8, I just want to take 1 minute to just level set on what is targeted protein degradation and where Kymera comes in, in this technology. So targeted protein degradation is a modality that is fully adopting a pharmacology that happens in ourselves every single day. So we use as a driver of our pharmacology, the ubiquitin proteasome system. And the ubiquitin proteasome system is a system that is there to maintain protein homeostasis. So basically, to maintain the right level, the healthy level of proteins in our cells. And it does it through a series of proteins that you see on this -- on Slide 8 in blue, that recognize protein substrates, in this case, in green, and then through a protein-protein interaction, drives the ubiquitination and degradation. So it's a very well-functioning system, highly catalytic. So what does Kymera do? It's introducing a bispecific molecule, in magenta there on your screen, let's say, in species 2. And this hetero bifunctional molecule, as we call it, again, you can envision it as a bispecific molecule, the job is to buy specifically to an E3 ligase and to, ideally, a disease-causing protein, in green. And then all that the molecule does is create spacial proximity between the UPS system and the disease-causing protein. And the rest of the pharmacology is purely driven by our cell machinery. So the protein is ubiquitinated and integrated. The molecule can go off and do this again. So what are we doing that is different? We use small molecules to actually only bring 2 proteins together, this is a catalytic system. You don't need to inhibit the function of a molecule, but you only need it to really bring -- to really bind to protein and bring them together. And also, the real other potential is the fact that you can have a prolonged impact that goes well beyond the presence of the molecule just because the protein degradation, it needs protein resynthesis for bringing the protein back online. So on Slide 9, just to share with you why we at Kymera are so excited and why this technology has had so much attention from large companies, companies like us that have been founded around this concept as well as the broad healthcare system. So when we founded Kymera, really the technical challenge and the opportunity was -- in the past 20 years, lots of new technologies has come to bear, but we're still dragging about 20% of the proteo. So -- and these technologies have been transformative. If you go beyond small molecule, you go to antibodies, oligo-based therapeutics like antisense and gene and cell therapy, again, we're still driving about 20%, mostly because we're limited by either technical ability to drag or ability to reach tissues. So the beauty about in principle of protein degradation is that you can have the power of knockdown strategy of genetic knockdown with the flexibility of small molecules. So you can knock it down, you can almost knock it out as we've demonstrated preclinically in many disease contacts, but you can do it by oral dosing if you need, and the drug distributes systemically and reaches all organs. So what Kymera has done, and I'm trying to go through this relatively quickly. When we founded the company, as I mentioned, our goal is to really own the -- both the challenges and the opportunity, and we have really a long view on protein degradation. We are -- we have invested in areas that will probably take some time to realize, but the really opportunity, once it realizes, can be really transformative. And so we decided to focus on 3 key areas that we believe were fundamental to the long-term success of the company in protein degradation. One, coming from the knowledge that existing the 3, 4, 5, 6, E3 ligases that have been used and really the only one that has been clinically proven so far is insufficient to drive degradation in a therapeutic manner. I'm not talking about academic proof of concept, I'm talking about therapeutically, we know that it's insufficient to track all targets that we want to go after. So we spend a lot of time, and I would save money to try and understand what is the IRAK3 ligase for the right target and how do we develop that. The second part is understanding the relationship between compound exposure, degradation and protein resynthesis in disease-relevant context, what we call PK/PD, is something that I think Kymera has put front and center, not only internally, but also in our communication. If you think about the preclinical data, the noninterventional study that we've done in HS and AD patients, and hopefully, as you'll see later in the year in our clinical investigation. And then last but not least, our investment in chemistry and in really adopting a comprehensive toolbox of technologies to access small molecule binders to proteins that go across the spectrum. So we don't believe in one technology, but we use chemoproteomics, DNA-encoded library. We use fragment screens. We use all sorts of in [indiscernible] and in silico, AI technologies just to get to the key question, how do we find a ligand to an untrackable protein. And what goes with that is also optimizing properties to identify these degraders to be real effective drugs. So just 30 seconds on our E3 ligase toolbox. I know I've talked about this enough, probably at other conferences that I don't want to sound too redundant. But just one thing that I want to highlight is we have proprietary knowledge about the expression localization and function of E3 ligases. We have unique insights into their interplay of the biology of E3 with the biology of the targets that we're going after. And so when we talk later in the year about our next program, you'll see how those insights are playing into our selection of targets and also our selection of the patient population that we want to go after. So we've talked in the past about our ability to spare, for example, bone marrow from degradation through identification of E3 ligases that are not in the bone marrow. And we'll have much more to say also in the next few months on what other therapeutic hypothesis we're launching into the clinics in the next few years. So I'm going to just move to Slide 14, and hopefully, yes, I was clear enough in the page number in the past few minutes. And this -- just to showcase also our target selection hypothesis and maybe colposcopy because these will remain constant as we continue to grow and scale this company. So what is very important for us, is obviously, working in a high unmet medical need area, working in pathways where there is a high degree of validation. And we look at that as both human genetics validation, but also as human pharmacology validation. So other drugs in those pathways have shown to be disease relevant. But where key nodes have not been drugged or drugged well by any other modality. When -- if you degrade the protein, you're not providing an incremental improvement, but you're providing a transformative improvement. That's our goal, and that will continue to be our goal as we continue to build this company to be the fully integrated business. So if you look at the IRAK4, the IL-1/TLR pathway and JAK-STAT pathway, you can say that there are drugs that target each cytokine that signal through the receptor. Actually, you know that there is a clinical proof of concept where we also drag that targets IRAK4 kinase function. What we show that by degrading IRAK4 and blocking all myddosome complex, we have the superiority of over the IL-1 family blockers because we can block all of them with a single molecule. We have the superiority over the kinase inhibitor because we bought fully rather than partially the pathway. And we have the convenience of the once-a-day oral drug. For JAK-STAT pathway, in a similar way, lots of drugs, multibillion-dollar franchises in this pathway, but no one has been able to track well the key oncogenic transcription factor. There also is a big immune modulators in both immuno-oncology as well immunology. And so you will see here that protein degradation is really the only way to target this target well in a cell agnostic manner. What I mean by that is that we can do it in both in the tumor cells as well as in immune cells. That is very, very important. So if we go to Slide 16, I don't -- I won't spend too much time on this. As you know, we're in Phase I for this program. Why is an IRAK4 degrader is superior? We know that the kinase function blocks only partially the downstream series of events. We demonstrated through in vitro and in vivo assays that by degrading IRAK4, you block fully the downstream activities. And so you -- and namely the NFkB downstream signaling, is really only blocked by an IRAK4 selective degrader. And so this allows us to really think about a wider variety of diseases. And we believe that this is really the potential to be a best-in-class anti-inflammatory agent. And the reason why I say that is because if you look at the human genetics on IRAK4 and what is the phenotype of human genetic -- of humans missing the IRAK4 gene, you see that it's the most benign profile than any other human genetics nor mutation of any other target out there in immunology, including the JAK-STAT pathways and others. So if you go to Slide 17, you see that the areas that Sanofi and Kymera have agreed to prioritize are areas where there is high unmet need, high biological validation as well as high commercial opportunities. And especially for AD and HS, we believe that we might have a small molecule oral drug that can really change the treatment paradigm in those diseases. We -- RA, potentially lupus, potentially asthma, GI inflammation, those are all other diseases that we're discussing with Sanofi about prioritizing. I will go quickly through the next few slides because I know this data have been presented in other meetings and conferences. But just to level set on Slide 18, the KT-474, which is our lead molecule in this franchise, is very potent degrader of IRAK4, and is a super selective degrader of IRAK4. And I want to just to make sure everyone keeps this in mind when we think about this drug in the treatment landscape in immunology and outside of immunology. So on Slide 19, why is an IRAK4 degrader superior to a small molecule inhibitor? We've shown it by using TLR, we've shown it by using IL-1 activator of the pathway that when you block IRAK4 with a kinase inhibitor, you partially block the downstream signaling, in this case, in green. And in gray, you see a partial blockade of IL-6, which is actually a secreted cytokine of this pathway. If you use an IRAK4 degrader, you are able to block almost fully that pathway. On Slide 20, this is recent data that we just presented at a recent information conference. I'm not going to go through the data one by one, but I think this continues to validate that by actually activating even in vivo in this pathway, so we've shown in the past the gap model, we've shown in the past so -- an IL-1-driven model. In the past, we've shown a TLR-driven model. Here, what we've shown is actually activation through other cytokines, IL-33 and IL-36, which are well known to be relevant in many diseases. I mentioned some of them earlier, and so here, you see that our ability with the degraders in vivo to block information driven by these cytokines is not only full, but also continues to be superior to a clinically active drug like the Pfizer molecule that has a positive proof of concept in RA. So again, continue to show that derisking element. And also in a pretty complex model like the Th17 MS model, we continue to demonstrate how relevant this biology is and how competitive it is even with an approved drug, FTY, which, from my past, I actually know pretty well. What we can do in terms of drug development, we can knock down our export fully and that full arc for knockdown is well tolerated by animals, and we've seen this in multiple tox studies, in multiple PK/PD studies. This is a 14-day daily dosing orally that shows that we can basically take IRAK4 below level of quantitation. If we go to Slide 22, which -- this is actually the first time that we're showing this data. We've had been the data for a while, but we decided to start talking about this. Again, it goes to the commitment that we have to understanding PK/PD of this technology. So what this tells you, this is a comparison between a single dose in a dog versus a multiple dose in a dog. And what are the differences that you might see in PD? And obviously, the differences are well understood. Obviously, this is a daily oral drug where the only relevant PK/PD is the one that you see on the right there in the multiple ascending dose, where you reach steady state levels of both PK, of distribution and then eventually degradation. And you see in a dose response for 0.3 mg per kg to 10 mg per kg, we're able to basically knock down IRAK4 substantially all the way to 85%, 90% and in the skin, all the way to 95% plus, upon repeat dosing. What you see in a single dose is, obviously, that the PK to PD is different because you basically are not able to reach the steady state. And what this tells you that even upon single dose of these compounds, then at 24 hours, you're able to see, even in the absence of the steady state level -- reaching steady state level, we're able to see up to a 60%, 70% degradation. But important, again, to notice how important it is to reach the steady state distribution in a multi-day dosing study. And so again, we've shown this in both blood and skin, as we've continued to do in all our preclinical as well as clinical study. And this allows me to go into the next slide, which tells you what we're planning to do in our Phase I study. As you know, this is divided in 3 portions: There is a single ascending dose portion. There is a multiple ascending dose portion. The MAD is divided in 2 parts. There is a healthy volunteer and then a patient cohort. So what I'd like to do, you see the enrollment numbers. This is why we had -- we're excited by sharing the data eventually because probably no one has seen 100 people work the data in TPD at this point, all in one presentation. So this is what's the exciting also about the Phase I study that we're able -- that we've been able to design and so far execute on. But maybe what I'd like to highlight is what we expect to get out of each phase. So for the SAD portion, the important thing for us is to show that we can have an orally bioavailable compound that distributes well in plasma, that is able to demonstrate initial degradation. You've seen the differences between SAD and MAD in the previous slide in dogs. And more importantly, the PK profile and the PK/PD profile enable us to plan these drugs' future development as a single daily oral drug. So once-a-day oral drug. And so the PK profile and the PD profile and the safety from the SAD will be critical for us to then plan future clinical development. For the MAD, I would call that the real proof of biology. So the goal is, upon repeat dosing to see more than 85% degradation, at least 85% or more, in both blood and skin upon, again, 14 days of daily dosing. We like to demonstrate that the knockdown has an impact on disease-relevant biomarkers, that -- both in skin and in blood. And those disease-relevant biomarkers that we're using are the ones that we know are disease-relevant, that have been shown to be disease-relevant, whether it's the IL-1 family cytokines reduction, whether it's C-reactive protein in vivo and as well as the goal is obviously to establish the maximum effective dose. And then after this, we plan to take the top dose of the MAD and demonstrate that in patients, and this will be up to 20 AD and HS patients. The goal is to demonstrate that with -- in patients, we see the similar level of knockdown and cytokines impact. The goal of this study of the patient cohort is not to get an endpoint that is clinically relevant in disease context but to actually derisk our Phase II dose choice. So if we're able to show that also in patients, the PK/PD is maintained, then going into Phase 2 will be much more derisked about picking the right dose. So for us, why we have such a comprehensive Phase I study because we believe that these will be maximum derisking for this program. We know that downstream effector of this pathway is, when blocked -- or even upstream, when blocked, are disease-relevant in randomized, placebo-controlled studies, we know that we can block many of them. And so if we're able to do that with a drug that is safe, tolerated and it hits the target at the level that we know to be therapeutically relevant, we believe that we have derisked the late development substantially. So that's really the top process behind the study. On Slide 24, very quickly, these are the time lines so we are in the SAD portion of the study, we're trying to initiate the MAD in the second half. And so as you see, the healthy volunteer portion will be shared in the fourth quarter and then the patient portion will be shared in the first part of next year. So going on Slide 26 and change gear a bit, our investment in the IRAK4 TLR franchise in oncology, and this is -- has evolved into the IRAKIMiD program. I mentioned earlier, we've shown it recently at ACR, if you knock down IRAK4 and also you degrade Ikaros and Aiolos, you have a double hit in the MYD88 mutant lymphoma, and you have this really profound preclinical activity that gives us confidence that we're going to have a single agent to take all the way to registration. Having said that, on next Slide, 27, MYD88 mutant lymphoma is not the only indication that we're planning to go after. It will be the first indication. We have built a molecule just around this concept. But we know that we can go -- not only we continue to explore MYD88 mutant populations, but we're also outside of those. And so for many of the mutant populations, obviously, Waldenstrom's has 90% plus mutation, 70% in primary CNS lymphoma have MYD88 mutation. We know that there is a hypothesis of IRAK4 long form in AML and MDS. There has been somewhat validated by another company. We also know that images are active in AML and MDS. We are actually planning to share studies in the second half of the year about what is an IRAK4 degrader. There's a selective IRAK4 degrader versus an IRAKIMiD degrader versus a clinically active molecule look like in AML and MDS later in the year. So that will be another data set to look at for as we progress this program. In terms of activity, just going to Slide 29. The beauty about this biology is that by degrading these 2 targets in these 2 pathways, you are able to have profound activity in MYD88 mutant lymphoma regardless of the co-mutations. And this is very important because especially in these patient population, single-agent activity is really difficult to have unless you go after other vulnerabilities. And once you have co-mutations, the reliance on co-vulnerabilities from the cancer cells becomes bigger. And so our ability to block both of these pathways is critical to drive that level of effect. Just going to Slide 31. This is showing some patient-derived xenograft model. We have other data that we're planning to share actually soon enough later in the year on comparing IRAKIMiD with clinically active agents, both against the IMiDs as well as IRAK4 but even in MYD88 mutant lymphoma, where we continue to show superiority. Maybe for today, just a key take-home point is that KT-413 in both cell line-derived xenograft and also in this case, patient-derived xenograft is able to drive a full activity even in a dosing paradigms that are once a week, once every 2 weeks or even up to once every 3 weeks, which is the type of dosing paradigms that we're considering taking in the clinic. So our development plan is to both file an IND and initiate our Phase I in the second half of the year. The goal is to really enter into the relapsed/refractory B-cell lymphomas, including MYD88 mutant early on and then expand in MYD88 mutat indications -- population to pursue a registrational study, but also, as I mentioned, in other indications that we believe that biology is very relevant. So moving to Slide 34, maybe the last 5 minutes spent on at STAT3 and then we just wrap up. So why are we excited about this target? So there is about 35, at this point, probably, 1,000 papers linking STAT3 to a wide variety of diseases most in oncology, lots in inflammation, some in fibrosis. So we obviously know that this pathway has been clinically validated in many diseases. But the ability to block this pathway, again, at the central node will give us different pharmacology. I just want to make sure that we appreciate that this is not a JAK inhibitors plus, it's just a different pharmacology. JAK or TYK2 signal through the wide variety of downstream factors. None of them sign only to STAT3. So we need to expect different biology from STAT3, and we believe we have uncovered a lot of it but there's still more to do. But we've uncovered a lot of it that we are investing into. And so if you go to Slide 35, it gives you a bit of a -- I would say, an overview of maybe more of our investment and focus more than flushing out the broad opportunities that this target gives us. And so I would say that in cancer, we've divided in 2 main buckets. One is in areas where STAT3 mutations or activation is a driver of that disease. And we've shared some of the data, I'll share again today. That STAT3 degradation impact and [ force ] the STAT3 in those tumors is absolutely sufficient to bring those tumors in full remissions. That's what we've seen preclinically. There are other context where the role of STAT3 has an effect both on the cancer cells and on the immune microenvironment. And an area that we're exploring broadly, and I don't have actually slides for it today, it is -- we've demonstrated that STAT3 has an impact on PD-L1 expression, but we also demonstrated that in the tumor micro environment, STAT3 increases inflammation. And so you wouldn't be surprised to see that if you take statutory and you go into indications there are refractory to PD-1, you actually see a very interesting synergistic effect. And we're going to share more of that later in the year. In immunology and fibrosis, as I mentioned, again, the phenotypes are different from the upstream inhibitors, but they're actually quite profound in a wide variety of diseases. And there, what we're doing, and it's a bit behind the oncology molecule, is really prioritizing the indications that we're going to go after. And fibrosis and chronic inflammation seems to be an area where STAT3 degradation is quite affected. So just a couple of slides on STAT3. Just a reminder, this is a very selective degrader. We only degrade STAT3 disease around KT-333, which is our molecule that is in IND-enabling activities, planning to file an IND before the end of the year. Very specific of STAT3, you see there is this [ pricing ] variance of STAT3 that we also agreed with this molecule. All the other stats are in the north. So that's where I say this is a very different biology than any upstream inhibitor out there. But this biology is super powerful when sales rely on STAT3 downstream effectors. And so you see we only dosed 3x this degrader in these tumor models to show full remissions. And that -- those remissions are basically continue upon decision of dosing. And so these are the type of transitional hypothesis that we're pursuing clinically as soon as next year in a wide variety of both live within solid tumors. So actually going into that. So our Phase I is a multicenter Phase I dose escalation study, where we actually will be both liquid and solid tumor. And then we're looking at expansion cohorts to then plan registrational studies, as you see in many of our oncology programs these days. Maybe on Slide 39 will be the last one. So lots, obviously, is happening in -- at Kymera. We've already shared some of the initial data set that we said we were going to share this year. For 474, we've shared the noninterventional study, we shared more preclinical data, clearly, something to look forward to our -- initiating the MAD and also that 80-plus possibly subject data set to show that full mechanistic proof of concept and proof of biology of IRAK4 degrader in healthy volunteer, and then eventually in patients. For 413, we actually have quite a bit more coming, obviously, besides the IND submission and hopefully, clearance, and the Phase I start. I think, hopefully, you'll find exciting the data that we'll share around novel indications and comparison against some of the clinically active agents out there. And for 333 and for STAT3, again, similar, we have actually many -- several data releases preclinical at this point, but in a wide variety of indications and contexts. So look out for that as we go through the year. And then again, a reminder for our R&D Day, we're excited about sharing new programs and activities that we've been doing for a while but haven't really talked about broadly. So I'll pause here, Ellie, and see if there are any questions either from the audience or from you.

Yes. Thanks, Nello. Did I hear correctly, you're going to talk about a novel tissue-specific E3 ligase at the R&D Day this year?

Yes. So our goal is to talk about the work that we've been doing in that area. And yes, for sure, we will talk about novel E3 ligases and how the impacts are in next 3 to 5 years clinical investigations, I would say.

Okay. Got it. I appreciate your being very coy about it. And then just in terms of the IND filings both for STAT3 and IRAKIMiD, both guided for the second half of this year. Can you give us any more granularity as to when specifically -- where are you in the IND-enabling work? And I guess what IND-enabling work is remaining for each of the molecules, respectively?

Yes. No. So we're very kind of excited about where we are with both of those programs. The time lines what we've shared, I think, we're all cylinders firing on making sure that we can accomplish these key milestones within the second half of the year. I don't know that I want to share more than that. We're pretty aggressive with our time lines. So I really have no room to share more, I think, at this point, it is what it is.

Got it. And then just in terms of the start of the multiple ascending dose portion for the IRAK4, how should we think about the time frame there? And how you're thinking about the safety profile, given this is, as you say, the first hetero bifunctional degrader in healthies?

Yes. So our plan is to collect enough SAD data to then think about and use modeling and data that we have, both clinical and preclinical, to design starting dose of MAD and eventually later doses. And as you know, we will share the data set with FDA to then proceed towards the MAD study. So at this point, everything is still on track. We -- again, we've said that we plan to start the MAD in the second half of the year. We also said that we plan to share the healthy volunteer, substantial part of the healthy volunteer SAD and MAD in the fourth quarter. So obviously, in order to do that, we'll have to start the MAD, I would say, relatively early in the second half in order to accomplish that data release. But we will share. Once we move to the next phase, we will obviously communicate it.

Got it. That's helpful. And with slightly less than 1 minute left, I'll turn it over to the audience to see if there are any questions, please put them in the box on the webcast. But I guess while we wait to see if any questions come in, I will ask you one quick one on the biology of IRAK4. I think some of the genetics work that you've highlighted is really interesting when we compare, say, to the JAK, other sort of maybe like the JAK1/2 class or maybe the TYK2, can you talk a little bit about some of the work here and why this drives your confidence in the efficacy and safety profile of IRAK4 degradation?

Yes. No, thank you. So again, our hypothesis is human genetics and human pharmacology. So human genetics tells you if you're an adult and you don't have IRAK4, you have a competent immune system, and you are a healthy adult. That's -- there is 100 patients -- 100 subjects' data out there in publications, peer reviewed publications. And if you look at, again, other pathways in inflammation, whether it's human genetics data, you'd see those -- I don't know that there is any phenotype that looks like IRAK4, meaning that you have a fully competent immune system and you have no comorbidities. And so to us, that is why we invested in this pathway and in this target. And then if you combine it with the broad anti-inflammatory effect that we've seen both preclinically with the degrader, and to be honest, also clinically, with, obviously, a less active IRAK4 inhibitor in array, I hope that we really have the best of the 2 worlds, and we have the potential win-win for patients in a wide variety of diseases.

Okay. Great. Well, thank you so much for the time today. And thanks, everyone, on the line, for joining us, and talk to you all soon.

Thanks, Ellie. Talk soon.

Thanks. Bye.