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

Good morning. I'm Bruce Jacobs, Kymera's Chief Financial Officer. It's my great pleasure to welcome everyone to Kymera's first ever R&D Day, which is being broadcast from our headquarters in Watertown, Massachusetts. As you may have seen this morning, we issued a press release with highlights of today's meeting. That release is also available on our website. Following the completion of today's session, we'll post both the R&D Day slide deck and the video replay of all presentations to the Events and Presentations section of our website. Our plan today is to spend the next 2 hours sharing a number of important program and platform updates, as well as new clinical data from the MAD portion of our IRAK 4 Phase I trial. We also hold time at the end of our prepared remarks, likely around 10:30 this morning to take your questions. You'll note there's a question submission bar on your screen that will be opened through the presentations this morning and during the Q&A session. We will collect those questions throughout the morning and take as many questions as time allows. Before I hand the podium over to Nello Mainolfi, Kymera's Founder and CEO, I need to make these comments regarding forward-looking statements. As you can see on Slide 2 of today's presentation deck are the forward-looking statement comments. Today, we'll make forward-looking statements, including express or implied statements about our expectations, plans, timelines for clinical development, reporting of clinical trial results and planned regulatory activities, the potential success of our development efforts and product candidates, including potential for approval and future commercial launch and other projections and expectations regarding our business and other upcoming events. Actual results may differ materially. The risks and other factors that could cause actual results to differ are discussed in today's press release and in the Risk Factors section of our most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission and other reports filed with the SEC. Any forward-looking statements represent our views as of today only. We may update these statements in the future, but we disclaim any obligation to do so. With that, I'll turn it over to Nello.

Thanks, Bruce, and welcome, everybody. As you see here from my background, where Kymera's headquarters is actually the labs that you might be able to see in the background. I want to thank, everybody, for being here today, even if virtually. We really wanted to do this in-person, but unfortunately, we're not quite ready yet. This is a big moment for Kymera, as this is our first public R&D Day on the anniversary of our 50 years since our funding, and it feels very special. I suspect many of you are here to learn about our KT-474 update, others to hear about our oncology programs that are now in the clinic, others to hear about our new development programs we're unveiling today or the exciting new platform progress and investments that we're making. I want to be clear. Today is really about all of the above and beyond. The goal of today is not only to tell you where we've been, but more importantly, where we are and where we're going and why we believe that Kymera has the potential to have a profound impact in a wide variety of diseases and indications and realize our vision to becoming a fully integrated global biopharma company. So going to the next slide here on Slide 4. I just wanted to take a very simple start with a very, I would say, simplified graphic. Nothing that I'm saying here or I'm showing on the slide here today is new, but hopefully helps contextualizing why the opportunity to edit a proteome is enormous. As we know that genome is essentially static and genomic abnormalities, while generally rare, can lead to serious diseases. So directing editing of the genome is actually quite powerful and potentially has very huge impact. But we have to keep in mind that it's also irreversible. And while in some cases, this might be desired, it is an area that we, as a society, have to be really thoughtful about. The proteome instead is much less static. It changes based on genetic or we can say, internal or epigenetic or we can say external events. So proteome alterations, as I said, it can be both driven by internal and external changes are responsible for all diseases of humankind. Because editing the proteome happens in a post-translational stage, it is reversible, hence, highly flexible and adaptable. This is important to keep in mind as we think about the broad potential application of a technology that is basically editing our proteome. So going to the next slide. Really, this actually is a really good foray into the context around this slide. Targeted protein degradation is, in fact, in this moment, the most effective technology and drug modality that allows us to edit the proteome. It is able to remove disease-causing protein from its cellular localization selectively without altering the rest of the proteome. Going a bit into more details, the ubiquitin proteasome system responsible for maintaining protein homeostasis can be co-opted by small molecules. You can see one here in the slides in magenta. This small molecule is able to bind both an E3 ligase, which is part of the ubiquitin proteasome system and a disease-causing protein simultaneously at the same time, allowing for the protein to be [attacked] for distraction. We call that technically ubiquitinated, but think about [attack] for distraction. And then actually, the protein is degraded by the proteasome. These molecules can do this very selectively and very potently. Additionally, due to their catalytic mode of action, each molecule can run this cycle several times since the molecule is actually not degraded in the mechanism. So as a result, we can generate a genetic like knockdown effect with the flexibility of small molecule modality. Importantly, this modality is also protein type and disease agnostic. So this gives you an idea of really the broad potential of the technology. So going to the next slide. For all the reasons that I've told you so far and that I've described to you, we believe that targeted protein degradation is the technology that enables the significant expansions of the druggable proteome, much more so than any other technologies developed to date. Chris De Savi, Head of Discovery, will go into the details of how Kymera is expanding our platform to really drag all target classes within a human cell later in the presentation. So it's not surprising moving to the next slide here, to note that while thousands of drugs have been developed with existing technologies, they're still very limited in the breadth of proteome impact. I think that we calculate that it's about 15% to 20% of the proteome that has been drugged by thousands of drugs that you see here on the slide. Protein degradation, though, especially since the elucidation of the mechanism of action of one of the first characterized degrader class, the image in 2010, has been growing exponentially. Currently, we have 4 drugs already on the market. More than 15 drugs are in clinical development. And based on the significant investments across large and small companies, we expect this number to continue to grow exponentially with the potential that we strongly believe in to really transform treatment paradigms. So in the next slide, I just want to take a moment to introduce the speakers today. You've heard from Bruce in the intro. He will join us in the Q&A session. You will hear from Jared, our Chief Medical Officer. I'm sure many of you know him already. I also want to be really thankful to Naimish Patel, Global Head of Development, focused on immunology and inflammation at Sanofi for spending a few minutes with us today. And then you'll hear from Ashwin, our Head of Development, from Juliet Williams, our Head of Biology, as well as from Chris, as I mentioned already, our Head of Discovery, later in the presentation. So going now a bit in the agenda. So what I'll try to do in the next 5 minutes is telling you about where Kymera has been, what we've done this year, what we're planning to do, what are the investments today. Then Jared will unveil for the first time, our MAD data from the KT-474 study. Naimish will tell us about Sanofi's view on the KT-474 development opportunities in immunology and inflammation. Then Ashwin will discuss our KT-413 IRAKIMiD program, our KT-333 STAT3 program, as well as he will discuss some really first time that we show data with our STAT3 degraders in a variety of immune inflammatory and fibrotic diseases. After a small break, we'll have Juliet, that will discuss our philosophy in selecting and prosecuting targets. And importantly, we'll unveil our new development program, MDM2. And then Chris will talk about our platform investments, both in terms of new data on our tissue-restricted E3 ligase, as well as new investments in molecular glues. And then I'll wrap up with a 2026 vision, where Kymera will go in the next 5 years. And then we'll have the remaining 30 minutes or so with Q&A, where you'll see us, Jared, myself and Bruce taking your questions. So I just want to start our, let's say, Kymera focused part of my presentation talking about our vision. This is something that has been with us since the beginning, since we founded the company, something that we feel very close to and very focused on. So our vision is to become a disease and technology-agnostic, fully integrated global biopharmaceutical company using targeted protein degradation to deliver medicines that will transform patients' lives. So with that in mind, I think this is important because everything that you see today, hopefully, will continue to demonstrate how we're building the company, how we're derisking our growth towards that vision and that goal. So here on Slide 11 here, I want to use just 2 minutes to do a brief introduction of Kymera. Many of you already know us, but for those that know us less and for everyone to just level set, I just want to say that I think it's fair to say that Kymera is a well-recognized leader in targeted protein degradation. It's focused, as I mentioned, on building a fully integrated business to deliver what we believe will be transformative therapies. We're currently internally focused on oncology and inflammation, but thanks to some partnerships that we have in place, we are already a disease-agnostic protein degradation platform. We also believe that to accelerate forward integration, there are opportunities to leverage the biopharma industry through the right type of partnerships. And so especially the ones with Sanofi and Vertex, we believe are a good example of what that looks like. Through really strong execution in the past 5 years, but I would say, especially this year, we've established several firsts for Kymera, but also for the TPD space in general. We have run the first placebo-controlled, randomized, healthy volunteer Phase I study with KT-474. And Jared will share the really exciting data today. We also were the first company that took a heterobifunctional degrader in the clinic against an undrugged transcription factor with our KT-333 against STAT3. And also, with KT-413 and IRAKIMiD degrader, we believe we have the opportunity to have the first targeted therapy in diffuse large B cell lymphoma. And these were all cleared INDs in 2021. I want to say we continue to be committed to innovation and to be the company that really take on ourselves to address holistically the challenge of drugging all target classes in the cell. You will hear from Chris later about our first in vivo proof-of-concept of tissue-restricted degradation, as well as our new molecular glue discovery unit. The point here is that Kymera really wants to own and deliver on the challenges that industry continues to face in providing meaningful therapies to patients across different diseases. And also, our cash position here that you see in the bottom of the slide with about $600 million allows us to really be thoughtful and strategic about our growth in the next few years. Going to the next slide, I want to take an opportunity to just highlight a few things. So as we go through the different presentations with the team, you'll be able to hopefully have the right context around it. So starting with our clinical pipeline, KT-474, we believe this molecule has the potential to be best-in-class, small molecule anti-inflammatory oral drug. We believe that the data that we've generated so far has strongly derisked that path. And hopefully, after you see the data, you'll agree with me. KT-413, as I mentioned, potentially first targeted therapy lymphoma, profound preclinical activity in a wide variety of models, both as a single agent and in combination. KT-333 is really the first molecule of what we believe will be a large franchise of STAT3 degraders in both liquid tumor, solid tumor, in inflammation and fibrosis. The next, going into our, let's say, pre-clinical pipeline. You'll hear from Juliet, our first disclosure of KT-253. This is a development candidate that is now in IND-enabling studies. It's a degrader of MDM2. And we believe this has the potential to be best-in-class p53 stabilizer. And hopefully, after you see the data from Juliet, you'll agree with me. And this has also a large potential in a wide variety of both liquid and solid tumors, as you'll see. I also want to highlight that we remain committed to have at least one new IND per year going forward. And so when we talk about what Kymera is going to look like in 2026, I think it will become clear, the type of company, discovery engine and platform that we're building. Slide 13. So going to the next slide here on Slide 13. I just want to say that we believe that our approach, our philosophy, our commitment to long-term value creation and continuous innovation makes us a very unique company, not just in targeted protein degradation, but I would say in the whole biotech ecosystem. But I think it's also helpful to highlight a few aspects that we believe are more tangible in terms of differentiation within the industry. So we start -- often start with target selection. We believe we have a very unique approach to focus on pathways where there is a high degree of validation, where key nodes have not been drugged or drugged well with any other modality where protein degradation is able to deliver the unique solution. In terms of platform, as I've already discussed briefly, but you'll hear more from Chris De Savi, we have built, first, a large toolbox of E3 ligase and E3 ligase binders beyond what's existing in the public domain to unlock novel opportunities. And you'll hear again our tissue-restricted strategy there, as well as now we're expanding the technologies to go after also new sets of targets. These will be undrugged, but also non-ligandable targets where we believe the molecular glue approach is best positioned. Clinically, I think we've demonstrated, and again, hopefully, you'll agree with me after you see Jared's presentation that we have a very innovative way to develop our molecules. And I don't -- we're not innovating for the sake of innovating. We want to develop our degraders in the best way possible, where we are actually understanding and developing these degrader medicines in the best way possible. We've talked about, first, in targeted protein degradation, that not only is an execution, but it's also a philosophy of doing things that are also difficult first. And again, on the last part, I think you've heard me say innovation a few times already. So I'll spare you one more sentence on that. We could not do any of this without our unique value and culture here at Kymera. This is a company that is constantly working on cutting-edge science of a new modality. And in doing so, trying to solve problems that have never been really faced or solved before. So how we operate and how we show up here every day? It's probably just as important, if not more than what we do. So we believe in core values where all decisions are data-driven in both science and business. We trust and respect our colleagues. We're energized by the challenges that we're facing. Our sense of urgency is [ dialed back ] to the maximum because we believe, and we know that patients are waiting for our therapies and every week, every day and every hour counts. We believe in open and transparent communication. We know that everybody is doing their best, but we're also here to help each other because we believe no single -- one single person has the solution to all the problems and challenges that we face every day. So I'm not going to go through all the slides, but I think I'll encourage you to take a moment, maybe afterwards, to read what we have on this slide because this is also what makes this company very special. Going on Slide 15 here. It will take too long to walk you through what the past 5 years have been. But what I want to highlight is that all our drug development milestones and execution has been both fueled and enabled by really thoughtful financing, both in terms of equity financing as well as partnerships. And our philosophy has always been to derisk and demonstrate that we earn the right to either the next partnership or the next financing. And so maybe just to capture the last ones that we believe are quite meaningful. We've just recently cleared our third IND in a few weeks ago. And also recently, we signed a partnership with 3 organizations; A-Alpha Bio and NYU and University of Washington, to launch this new molecular glue initiative. So my objectives for today and our objectives for today, some of which we've covered, many of which we haven't yet. I just want to make sure that at the end of the 2 and a half hours, we're all hopefully on the same page about why targeted protein degradation is uniquely poised to transform treatment paradigms, who we are and what we've accomplished so far, which we've discussed, rationale for our strategy and our approach, the power of Kymera's engine, what we've delivered in 2021, how we're evolving our pipeline and all of TPD and our vision for the company that we're building. So before I pass it on to Jared, I just want to take the opportunity to maybe introduce the clinical pipeline agenda. So Jared will, as I mentioned already, will talk about our KT-474 Phase I healthy volunteer study, discussing both SAD and MAD, but obviously, reminding you the MAD data is a new disclosure, and it's a very meaningful one. And then Naimish will discuss Sanofi's view of the potential there. And then Ashwin will talk about 413, 333, as well as the opportunities with STAT3 degraders in immune inflammatory diseases as well as fibrotic diseases. So I will pause here. I look forward to actually see all my colleagues present today and then see you at the end of it. And I'll pass it on to Jared for the next section. Thank you.

Thank you, Nello. I'm Jared Gollob, Chief Medical Officer at Kymera. I will be presenting results from the single and multiple ascending dose portions of the KT-474 Phase I trial in healthy volunteers. As shown on Slide 20, IRAK4 is a key component of the myddosome complex that mediate signaling through IL-1 receptors and toll-like receptors to stimulate production of multiple pro-inflammatory cytokines and chemokines. Since downstream activation of NF-kappa B as well as MAP kinase is dependent on both the kinase activity and scaffolding function of IRAK4, degraders of IRAK4 have an advantage over kinase inhibitors and being able to more completely block the IL-1R/TLR pathway. Clinical validation for targeting this pathway comes from the clinical activity of antibodies targeting IL-1 family cytokines across a wide variety of diseases, as well as from the activity of an IRAK4 small-molecule kinase inhibitor in rheumatoid arthritis. Human genetics indicate that IRAK4 knockdown should be well tolerated as adults with mutations leading to complete loss of IRAK4 are healthy and do not exhibit susceptibility to infections. Targeting IRAK4 forward with a degrader, therefore, has the potential to achieve a broad, well-tolerated anti-inflammatory effect that provides multiple development opportunities in TLR-IL-1R-driven autoimmune diseases. Some of those opportunities are shown here on Slide 21, including diseases characterized by Th1 and Th17 inflammation and neutrophils such as hidradenitis suppurativa, rheumatoid arthritis or by Th2 inflammation and eosinophils such as atopic dermatitis, which are among the indications that we and Sanofi are initially prioritizing for our IRAK4 program. Compared to an IRAK4 degrader, antibodies targeting cytokines or cytokine receptors are potentially limited in their efficacy by virtue of hitting only one or 2 cytokines in conditions where multiple different cytokines or chemokines are driving the inflammation. Furthermore, they cannot be dosed orally. Small-molecule inhibitors like the IRAK4 kinase inhibitors, even though they are showing positive early safety and efficacy in the clinic, have limited impact on the pathway. JAK inhibitors, on the other hand, while having a broad anti-inflammatory effect, have safety liabilities that may complicate broad applications. Our orally active IRAK4 degraders can provide a unique solution to all of these challenges. IRAK4 expression in autoimmune diseases can provide further insights into its role in disease pathophysiology. As seen on Slide 22, in a non-interventional study examining the expression of IRAK4 and inflammatory biomarkers in hidradenitis suppurativa, or HS, we showed that IRAK4 protein measured using immunofluorescence and mass spectrometry was upregulated in active skin lesions and perilesional skin relative to healthy subjects. As shown in the panels in the middle and right part of the slide, immunofluorescence demonstrated IRAK4 upregulation in both the epidermis and dermis of HS skin lesions relative to healthy subjects. Additionally, as shown here on Slide 23 in the heat map on the left, we found that multiple pro-inflammatory gene transcripts were upregulated in the skin lesions, including MYD88, toll-like receptors, IL-1 beta, TNF alpha, IL-6, IL-8, interferon gamma and multiple additional drivers of inflammation. Importantly, as shown in the heat map on the right, all of these upregulated genes correlated with IRAK4 protein expression. So I have shown you in these 2 slides that IRAK4 can be overexpressed in sites of inflammation in IL-1R/TLR-driven autoimmune disease and that there is a critical link between IRAK4 and the pleiotropic inflammation seen in HS, suggesting that IRAK4 targeting with a degrader should downregulate expression of these pro-inflammatory genes and thereby, impact the severity of disease in HS patients and in other diseases dependent on IL-1R/TLR pathway activation. Turning now to a review of the preclinical data with our lead IRAK4 degrader. Slide 24 shows that KT-474 is a potent and highly selective degrader of IRAK4. The DC 50 in human PBMC is 2.1 nanomolar. And proteomics analysis showed that at a KT-474 concentration 10-fold above the DC 90, IRAK4 was the only protein degraded out of more than 10,000 proteins analyzed. Its superiority over IRAK4 small molecule kinase inhibitor and blocking IL-1R/TLR mediated cytokine induction is shown in the right panel, where the KT-474 dose response curve for inhibition of IL-6 production by human PBMC stimulated with LPS plus IL-1 beta was significantly less shifted relative to the Pfizer IRAK4 kinase inhibitor. KT-474 also resulted in near-complete inhibition of IL-6 production, whereas the kinase inhibitor only reduced IL-6 by less than 50%. The anti-inflammatory effect of KT-474, and its superiority to IRAK4 kinase inhibitors was also shown in vivo in various mouse models of inflammation. Slide 25 shows the effect of KT-474 on IRAK 4 levels in whole blood and on measures of inflammation in intradermal challenge models using IL-1 family cytokines, including IL-33 and IL-36 and in a model of Th17-mediated multiple sclerosis. In these models, KT-474 outperformed an IRAK4 kinase inhibitor and was comparable to other potent corticosteroids or standard-of-care anti-inflammatory drugs at doses achieving greater than or equal to 85% IRAK4 knockdown in blood. Similar activity was observed in the mouse MSU gout model driven by TLR4 activation and in the imiquimod psoriasis model, driven by TLR7 and 8 activation. So far, I have shown you our rationale for selecting the pathway and this target with a greater advantage and our preclinical data pointing to specificity and superiority over IRAK4 small-molecule inhibitors. Now, I will dive into our clinical data. The ongoing Phase I study of KT-474 represents several important firsts for clinical trials with heterobifunctional degraders, including the first trial to include healthy volunteers, the first trial for a drug in development for inflammation immunology indications that includes a cohort of patients with autoimmune diseases, and the first randomized placebo-controlled study. The use of healthy volunteers in a randomized placebo-controlled design enables us to compile one of the most robust human safety and PK/PD data sets in the TPD field. As shown on Slide 26, the randomized placebo-controlled portions of the study in healthy volunteers with 3 to one randomization of active drug to placebo are comprised of an SAD portion, which has now completed dose escalation after enrolling 7 cohorts, as well as a parallel staggered MAD portion, consisting of 14 daily doses of drug that has enrolled 4 cohorts to date. Following completion of the MAD portion, the recommended Phase II dose will be tested in an open-label MAD cohort of patients with hidradenitis suppurativa or atopic dermatitis, to confirm PK and PD and show impact on inflammatory disease biomarkers in vivo. In addition to safety and PK, the key PD endpoints in the SAD include IRAK4 knockdown and PBMC and ex vivo response of whole blood to TLR agonists. While in the MAD portion, additional PD endpoints include IRAK4 knockdown and skin, as well as effects on scan and/or blood biomarkers of inflammation. I'll now turn to presentation of the results from the healthy volunteer SAD and MAD portions of the trial. As shown on Slide 27, in the SAD portion, we enrolled a total of 57 subjects across 7 cohorts at single oral doses ranging from 25 milligrams to 1,600 milligrams. The median age was 38, and approximately half of the subjects were female. In the MAD, we have enrolled 48 subjects into 4 cohorts at doses ranging from 25 milligrams to 200 milligrams. The median age was 37.5, and more than 3/4 were male. Overall, we have recruited more than 100 subjects to this clinical trial, which we believe is the largest in the evolving TPD field to date. After a single dose of drug, profound dose-dependent IRAK4 degradation was observed in PBMC using mass spectrometry, establishing proof of mechanism for KT-474. Here on Slide 28, we show the mean and median percent reduction from baseline for IRAK4 at the nadir, 48 hours post dose across each of the dose levels. A steep dose response is apparent, plateauing after the 600-milligram dose. Remarkably, at single doses of 600 milligrams to 1,600 milligrams, mean IRAK4 knockdown was 93% to 96%, with absolute IRAK4 protein levels approaching or exceeding the lower limit of quantitation for the highly sensitive mass-spec assay. In ex vivo, cytokine stimulation assay was used to establish proof of biology in the most direct manner by demonstrating the impact of IRAK4 lowering in PBMC in vivo on the ability of TLR agonist to stimulate myddosome dependent pro-inflammatory cytokine and chemokine production in whole blood ex vivo. As shown on Slide 29, whole blood samples were drawn pre-dose and at various time points post-dose into true culture tubes containing either LPS, a TLR4 agonist or R848, a TLR7 and 8 agonist. After overnight incubation, supernatants were separated from cells and then analyzed for multiple disease relevant cytokines and chemokines, as shown in the figure. Inhibition of ex vivo cytokine stimulation was associated with IRAK4 knockdown in PBMC of greater than or equal to 85% at 24 hours to 48 hours post-dose. Results for LPS and R848-induced cytokines in the top 2 dose levels are shown here on Slide 30 as mean maximum inhibition at 24 hours to 48 hours compared to pre-dose baseline. Broad inhibition of multiple cytokines and chemokines, IL-1 beta, IL-6, TNF alpha, IL-8, IL-12 and IL-17, among others, was seen for both LPS and R848, with maximum inhibition of up to 97%. These findings with both TLR4 and TLR7 and 8 agonists were consistent with a robust in vivo activity of KT-474, associated with greater than or equal to 85% IRAK4 knockdown in preclinical models of gout and psoriasis that are driven by TLR4 and TLR7 and 8 agonists, respectively. As shown here on Slide 31, this broad effect on ex vivo cytokine induction in Phase I is unmatched compared to other anti-inflammatory drugs, including IRAK4 kinase inhibitors, which only looked at several cytokines in response to usually just a single stimulus, whereas the effect of KT-474 was seen across 8 to 9 cytokines with multiple stimuli. Blinded safety analysis showed that single oral doses of KT-474 from 25 milligrams up to 1,600 milligrams were safe and well tolerated with no serious adverse events. As shown on Slide 32, the most common treatment-related adverse events deemed possibly or probably related by investigators were mild to moderate headache and nausea that were self-limiting. Turning now to the MAD portion of the study. Plasma PK results on Slide 33 showed well-behaved PK with predictable dose-dependent increases in exposure, with steady-state levels reached by day 7 and a three to fourfold increase in Cmax and AUC24 day 14 compared to day one. As shown on Slide 34, robust and sustained knockdown of IRAK4 in PBMC with low intrasubject variability was seen across all dose levels, with steady-state degradation occurring between day 7 and 14 that approached the lower limit of quantitation for the highly sensitive mass-spec assay in the 50 milligram to 200 milligram cohorts. This was followed by recovery towards baseline by day 28, 14 days post last dose. Slide 35 shows that near complete IRAK4 degradation of up to 98% was observed in PBMC at steady-state, with multi dosing as predicted based on the PK, plateauing after 100 milligrams, a substantially lower dose compared to greater than or equal to 600 milligrams required to maximize degradation following a single dose. Effect across all dose levels was highly significant relative to placebo. Flow cytometry was used as an orthogonal measure of IRAK4 levels to enable assessment of degradation in lymphocytes versus monocytes, as monocytes are a key source of pro-inflammatory cytokines in the blood and have the highest IRAK4 levels among the various PBMC subsets. As you can see on Slide 36, IRAK4 degradation in monocytes appear to reach maximum levels at 100 milligrams to 200 milligrams, with 94% reduction at day 14 in the 200-milligram cohort. As shown on Slide 37, weekly skin punch biopsies obtained pre-dose during the 14-day dosing period, showed high dose-dependent KT-474 levels in the skin that were continuing to increase on day 14 and showed only a modest decline on day 28, 14 days post last dose. Pre-dose levels in the skin on day 14 were approximately 10 to 14-fold higher compared to plasma, reflecting higher drug residency in the skin on repeat dosing. Proof of mechanism in the skin was achieved through demonstration of IRAK4 knockdown using mass spectrometry. As shown on Slide 38, baseline levels of IRAK4 in healthy adult skin were five to tenfold lower than PBMC. Dose-dependent reduction associated with increasing skin exposure was observed, with IRAK4 levels nearing the lower limit of quantitation of the assay by day 14 at the top dose of 200 milligrams, representing knockdown of up to 90%. Knockdown did not appear to be at steady state on day 14, suggesting that continued dosing beyond 14 days could result in further decline in IRAK4 levels. As shown on the right graph, IRAK4 was reduced to levels approaching the LLOQ in both PBMC and skin by day 14, showing that the effect of KT-474 on IRAK4 was independent of baseline expression level. Here on Slide 39, serial immunofluorescence images from a representative subject in the 50-milligram cohort shows near complete loss of IRAK4 signal in both the epidermis and dermis by day 14, with recovery by day 28. Ex vivo cytokine induction results were available through the 100-milligram MAD3 cohort. As shown on Slide 40, dose-dependent inhibition of multiple disease relevant cytokines and chemokines induced by either LPS or R848 was observed, comparable to the effect seen at the top SAD cohort of 1,600 milligrams, with greater than 50% inhibition of most cytokines and maximum inhibition of 85% at 100 milligrams. This robust inhibition was seen in conjunction with greater than 90% IRAK4 knockdown in monocytes. While cytokine results at 200 milligrams are not currently available, even greater inhibition is anticipated at that dose, given the substantial increase in plasma exposure and 94% IRAK4 reduction in monocytes. Blinded safety analysis of cohorts randomized 9 to 3 drug to placebo showed that multiple daily doses of KT-474 from 25 milligrams to 200 milligrams, leading to substantial IRAK4 knockdown for at least 21 days were safe and well tolerated with no serious adverse events. As shown on Slide 41, the most common treatment-related adverse events deemed possibly or probably related by investigators were mild to moderate headache and mild nausea or palpitations that were self-limiting and did not lead to interruptions in dosing. The palpitations were all considered possibly related because they happened while in the Phase I unit and in each subject was a single, self-reported transient episode during 21 days of in-patient observation that was not associated with any objective findings. Those subjects who reported palpitations [were not to] complete the study without any additional episodes. As shown in the summary on Slide 42, we've completed SAD dose escalation and MAD enrollment through the 200-milligram cohort and established proof of mechanism and proof of biology for KT-474 in SAD and at substantially lower doses in MAD. We've achieved marked, near complete reduction of IRAK4 in both PBMC and skin and strong inhibition of ex vivo cytokine induction at doses of 100 milligrams to 200 milligrams daily for 14 days. High sensitivity CRP levels in plasma fluctuated too much over time within the normal range for healthy volunteers in all dose groups, including placebo, to detect meaningful changes. Importantly, prolonged suppression of IRAK4 with multi dosing was safe and well tolerated. We are on track to initiate the open-label mad cohort of HS and AD patients in Q1 next year, with data readout planned for midyear, followed thereafter by start of Phase II studies in multiple indications. With that, I'll turn it over to Naimish for his presentation and thank him for being part of our R&D Day.

Hello. So I'm very excited today to discuss the Sanofi collaboration with Kymera around our IRAK4 degrader program. As we discussed at Sanofi's Capital Markets Day earlier this year, Sanofi's has really transformed its pipeline over the past 3 years with an emphasis on specialty care. And the core approach to Sanofi's R&D focuses on a deep knowledge of pathways, patients and platforms. We're looking to target core immune pathways that are central nodes or are central controllers of inflammation that lead to autoimmune disease. We aim to translate the science to human disease and keep a relentless focus on patients, taking advantage of the core expertise in key disease areas such as dermatology, atopic dermatitis in order to identify the right drug for the right patient. And finally, we believe to truly innovate in the immunology space, we must leverage novel platforms that get to previously undruggable targets in order to develop medicines that can change the practice of medicine. Within this framework, our collaboration with Kymera, developing a protein degrader for IRAK4 really leverages all 3 of these key areas. In terms of the Sanofi pipeline today, we have a rich immunology portfolio that extends through multiple therapeutic areas. IRAK4 is a key immune target that has potential in a number of key areas, such as dermatology, respiratory, gastroenterology and rheumatology. And thus, the greater molecule has the potential advantage to advance with TAs where we have high ambitions. Moreover, our presence in these areas and the deep knowledge of the patients, of the networks of the diseases, really make this collaboration an ideal fit for us and for Kymera. This slide -- next slide illustrates the pathways targeted by IRAK4. So at mucosal surfaces, invading pathogens or environmental irritates activate early mediators that generate danger signals that activate inflammation. An example of these mediators include IL-33, IL-1 alpha, IL-1 beta and IL-36. And also direct simulation by TLRs also activate antigen presenting cells. And these initial sort of activation or alarming events lead to downstream initiation of adaptive immunity, Type 1 immunity, Type 2 immunity and Th17 immune response. And eventually, the activation of these pathways will promote trafficking of cells and inflammation back to these mucosal sites. Now, normally, this is an important response to fight off these pathogens, but in autoimmune disease, these responses become excessive and lead to pathology and disease. And there are a number of diseases where these pathways are critical in dermatology, atopic dermatitis, hidradenitis suppurativa and even lupus are areas where these types of excessive inflammation can lead to disease. In airways and lungs, we think of asthma and COPD as key areas where excessive Type 17, Type 2 inflammation lead to pathology and in inflammatory bowel disease, ulcerative colitis and Crohn's disease. And in this sense, IRAK4 is one of those key signaling molecules, one of those key nodes that sits downstream of IL-33 signaling and really all IL-1 family signaling, as well as TLR signaling. Thus, IRAK4 is a key signaling protein or pathway in early activation of inflammation with relevance to multiple diseases. And so we're really excited about the potential of SAR444656 or KT-474, the first ever IRAK4 protein degrader in the clinic to treat autoimmune disease. And why is IRAK4 about the potential of SAR444656 or KT-474, the first ever IRAK4 protein degrader in the clinic to treat autoimmune disease. And why did -- why is IRAK4 itself so important in terms of protein degradation. It's a signaling protein that has both a kinase function and a scaffolding function. And the scaffolding function is a critical signaling function that isn't typically inhibitor or can't be inhibited by a simple enzyme inhibitor or kinase inhibitor. And to really inhibit IRAK4 function, you need something like a protein degrader that can inhibit both of these activities of the protein. And the preclinical data that our colleagues at Kymera have generated show this very clearly, where if we stimulate cells in-vitro with IL-1 family members or TLR agonist, we're able to inhibit these pathways with a kinase inhibitor, but the inhibition is much more potent with the protein degrader. And you see on the lower right-hand corner, as Jared has already presented earlier today, we're really excited that in our first Phase I first-in-human studies, we see a significant level of IRAK4 knockdown both in -- after a single dose and after multiple dose cohorts in a healthy volunteer study. So we can see the potential of IRAK4 inhibition as a best-in-class inhibitor of IRAK4 in multiple indications in dermatology, respiratory, GI and rheumatology. And we look forward to entering the clinic in this coming year with indications in both atopic dermatitis and hidradenitis suppurativa. And with that, I'll hand back to the team.

Hello. I am Ashwin Gollerkeri, Senior Vice President and Head of Development at Kymera Therapeutics, and I will be providing updates, including clinical plans for Kymera's IRAKIMiD degrader, KT-413. To begin with a little background on the targets, Slide 50 illustrates signaling pathways in MYD88 mutant DLBCL that are affected by IRAKIMiD degraders. Briefly, MYD88 mutations results in constitutive IRAK4 dependent NF-kB pathway activation, which drives tumor cell proliferation. It also results in upregulation of IRAK4 expression through the transcription factors, Ikaros and Aiolos, which in turn further augments NF-kB activation and downregulates type 1 interferon signaling, thereby preventing cell death. Although, MYD88 mutations are the primary drivers of NF-kB pathway activation, the majority of MYD88 mutant DLBCL tumors have additional genotypic alterations that further augment NF-kB signaling and thereby diminish dependence on MYD88 alone. Consequently, while inhibiting NF-kB activation by targeting single nodes would be expected to have some anti-tumor activity, a more robust effect on NF-kB signaling, coupled with the restoration of Type 1 interferon signaling could help circumvent tumor escape mechanisms and achieve deeper and more sustained anti-tumor responses. This therapeutic hypothesis provides the rationale for the development of IRAKIMiD degraders that simultaneously target both IRAK4 and the IMiD substrates, Ikaros and Aiolos for the treatment of MYD88 mutant tumors. Based on this mechanism of action, we believe our IRAKIMiD KT-413 has the potential to have substantial clinical impact in a number of indications as summarized on Slide 51. MYD88 mutations are found in more than 25% of DLBCL tumors with the prevalence in the United States estimated to be approximately 8,000 cases per year. This subset of DLBCL has poor survival following first-line therapy, reinforcing the need to develop more effective therapies that specifically target this mutation. Other B-cell lymphomas with the higher frequencies of MYD88 mutations include Waldenstrom's macroglobulinemia and primary CNS lymphoma, in which mutations occur in approximately 90% and 80% of cases, respectively. There are approximately 10,000 cases a year of Waldenstrom's macroglobulinemia in the U.S., for which more effective therapies are needed, especially in the setting of disease that is refractory or resistant to the BTK inhibitors, as well as for therapies of the first-line that can achieve complete responses. Primary CNS lymphoma with the prevalence of approximately 3,000 cases a year in the U.S. is characterized by an aggressive clinical course with a rapid disease progression following initial therapy, for which there are no effective treatments. In addition to these indications, there are others, where KT-413 can have significant clinical impact. However, for today, the focus of the presentation will be solely on MYD88 mutant tumors, which are our current priority. Now to turn to the preclinical data with KT-413, as summarized on Slide 52, KT-413 is a potent degrader of IRAK4 and the IMiD substrates, Ikaros and Aiolos, with single-digit nanomolar DC 50 values against all 3 targets with maximal growth of inhibition observed with approximately 80% target knockdown. As shown in the lower part of the slide, KT-413 is more potent and more active than an -- either an IRAK4-selective degrader compound or a clinically active IMiD in MYD88 mutant DLBCL models, supporting the hypothesis that simultaneous degradation of IRAK4 and IMiD substrates is superior to degradation of either target alone. Finally, although not shown on the slide, KT-413 has been shown to be more active than the non-selective IRAK4 inhibitor, CA-4948 in MYD88 mutant DLBCL cells. Slide 53 summarizes results of in vivo experiments and xenograft models of MYD88 mutant DLBCL, demonstrating profound antitumor activity with durable complete responses in animals treated with KT-413 on an intermittent schedule of once every 3 weeks. As noted on the slide, this level of activity is superior to that of an IRAK4 kinase inhibitor or the clinically active latest generation IMiD compound. The lower portion of the slide highlights the unique PK/PD properties of KT-413 that result in protracted tumor exposure and robust knockdown of the targets for approximately 72 hours, committing its tumor cells to apoptosis that lead to eventual tumor regressions. In addition to the robust single agent anti-tumor effects of KT-413 on the -- shown on the previous slide, Slide 54 summarizes the combination data with agents used in the treatment of lymphomas. In these experiments conducted in MYD88 mutant DLBCL models, suboptimal doses of KT-413, combined with ibrutinib, venetoclax or Rituxan, show deep and durable regressions, highlighting the potential of KT-413 combinations to be used in earlier lines of therapy in patients with MYD88 mutant lymphomas. Based on the preclinical data, we are eager to evaluate KT-413 in the clinic in patients, as shown in the next few slides. On Slide 55 shows study KT-413 [ TL-101 ], a first-in-human Phase Ia/Ib trial in adult patients with relapsed or refractory B-cell lymphomas. The primary objective of the study is to evaluate the safety, pharmacokinetics and pharmacodynamics of KT-413 administered intravenously once every 3 weeks. In Phase Ia, patients with relapsed or refractory B-cell lymphomas will be treated in escalating doses until the maximum tolerated dose or recommended Phase 2 dose are reached. The Phase Ib expansion will include preliminary assessments of efficacy of KT-413 in both MYD88 mutant and MYD88 wild-type relapsed or refractory DLBCL. Exploratory endpoints in both Phase Ia and Phase Ib will include pharmacodynamic assessments, such as knockdown of IRAK4, Ikaros and Aiolos as well as downstream effects in peripheral blood cells, as well as in tumor biopsies. Based on the observed safety, PK and PD and clinical activity of single-agent KT-413, the protocol will be amended to include evaluation of KT-413 combinations and to evaluate monotherapy kT-413 and other MYD88 mutant lymphomas. As described in Slide 56, the initial registration strategy is centered around accelerated approval of single agent, KT-413, in third-line or greater, relapsed or refractory, MYD88 mutant DLBCL that will be based on demonstrating robust activity in Phase Ib and in a single-arm Phase 2 study. Such a strategy for registration in the U.S. is supported by the regulatory precedent of multiple other agents having received similar approvals in recent years in this indication. Following the initial accelerated approval for KT-413 and subsequent full approval based on a confirmatory Phase 3 combination trial, label expansions will include single agent KT-413 for other MYD88 mutant lymphomas, such as Waldenstrom's macroglobulinemia and primary CNS lymphoma. In Waldenstrom's macroglobulinemia, there's a high unmet need for effective treatment following BTK inhibitors, which are considered standard in the first-line setting. In addition, the improved activity in the first-line setting compared with BTK inhibitors in the form of complete responses instead of just partial responses could provide a potential path for KT-413 in this line as well. In primary CNS lymphoma, although the greatest unmet need is in the second-line due to the lack of any approved therapies, there's a potential registration path for KT-413 in first-line, where current standard of care rarely achieves durable responses. Finally, expansion to first-line MYD88 mutant DLBCL will be based on subsequent trials combining KT-413 with standard of care agents. In conclusion, as summarized on Slide 57, KT-413 is a potent IRAKIMiD degrader with the potential to be the first precision medicine in DLBCL to target a genetically defined population of MYD88 mutant tumors. The clinical development strategy is supported by the profound anti-tumor activity observed in preclinical models with KT-413 monotherapy and in combination with standard of care agents. The registrational strategy is to enable a fast to market approach with accelerated approval, followed by confirmatory Phase 3 trial in patients with relapsed refractory, MYD88 mutant DLBCL. Label expansions will include KT-413 combinations with standard of care agents to target earlier lines of treatment in patients with MYD88 mutant DLBCL, as well as expansion of KT-413 single agent into other MYD88 mutant lymphomas, such as Waldenstrom's macroglobulinemia and primary CNS lymphoma. I will now provide an update and discuss the clinical plans for our second oncology clinical program, the STAT3 degrader, KT-333. As shown on Slide 59, the JAK-STAT pathway, mediate signaling, by an array of cytokines and growth factors and is a critical pathway for multiple inflammatory and tumor genic processes. Within the STAT family of proteins, STAT3 has been shown to have a crucial role in inducing and maintaining inflammation in tumor genesis. Although, it's [ importance ], disease processes is well recognized, as a transcription factor, it has been considered an undruggable target with conventional classes of therapeutics. With regards to its role in cancer, STAT3 has been -- has both tumor cell intrinsic effects resulting in the promotion of gene expression involved in survival, proliferation, stemness and metastasis, as well as tumor extrinsic effects that promote an immunosuppressive tumor microenvironment. Based on the impact of STAT3 signaling on tumors, opportunities for STAT3 degrader in oncology include as a monotherapy treatment for STAT3 dependent hematologic malignancies and in combinations with anti-PD-1 drugs for the treatment of both solid and hematologic tumors. As summarized in Slide 60, KT-333 represents a first-in-class opportunity to address a number of diverse oncology indications. These include peripheral T-cell lymphomas or PTCL, which is a heterogeneous group of lymphomas in which abnormal activation of the JAK-STAT pathway is found in many subsets. The prevalence of PTCL in the U.S. is approximately 13,000 cases a year, and there are limited effective treatments, especially in the relapsed/refractory setting. Cutaneous T-cell lymphomas or CTCL are also associated with constitutively activated STAT3 in the advanced disease settings. The prevalence in the U.S. is approximately 30,000 patients per year. And as with PTCL, therapeutic options are limited in the relapsed/refractory setting. In addition to the T-cell lymphomas, large granular lymphocytic leukemias or LGL-L are associated with activated STAT3 signaling in nearly all cases. There are currently no approved treatments for LGL-L and the prevalence in the United States is approximately 4,500 patients per year. Finally, based on the role of STAT3 in maintaining the immunosuppressive tumor microenvironment, the combination of STAT3 degraders, with immune checkpoint inhibitors has the potential to be effective in patients with tumors that are refractory to immune checkpoint inhibitor therapy across a range of solid tumor indications in which PD-1 and PD-L1 inhibitors are the current standard of care. Turning our attention to KT-333, Slide 61 shows it to be a highly selectively greater STAT3, as evidenced by proteomic analysis demonstrating that KT-333 concentration is tenfold greater than the DC 95. STAT3 is the only protein to be degraded among over 10,000 proteins evaluated, including other STAT family members. In vivo efficacy of KT-333 is summarized in Slide 62, showing weekly administration, resulting in robust anti-tumor activity with full regressions that are durable in animals bearing STAT3 dependent lymphomas. These regressions were associated with greater than 90% STAT3 knockdown in tumors. Although KT-333 leads to profound anti-tumor activity when given as a single agent, based on the known tumor extrinsic effects of STAT3 on the tumor microenvironment, additional preclinical work was initiated to study the combination of STAT3 degraders with immune checkpoint inhibitors. On the left slide -- left side of Slide 63 are results from mouse syngeneic colorectal cancer model, in which a STAT3 degrader resulted in an interferon gamma dependent gene expression signature that has been previously been identified as a predictor of response in cancer patients treated with pembrolizumab. These findings are consistent with STAT3's role in remodeling the tumor microenvironment and provide the rationale for combining STAT3 degraders with immune checkpoint inhibitors. As shown on the right side of the slide, the addition of KT-333 augmented the activity of a PD-1 inhibitor, resulting in complete regressions in a greater proportion of the animals treated. Furthermore, in the animals treated with the combination, there was no tumor growth when we challenged 1 month after the last dose, suggesting development of long-term immune memory. Importantly, in addition to causing tumor regressions, the combination extended survival relative to either PD-1 inhibitor or STAT3 degrader alone. Collectively, these data suggest that the addition of STAT3 degraders could significantly augment the clinical efficacy of immune checkpoint inhibitors. Based on the preclinical data with KT-333, we are eager to evaluate the compound in cancer patients. As shown on Slide 64, study KT-333, [ TL-101 ] is a first-in-human Phase Ia/Ib trial in adult patients with lymphomas, large granular lymphocytic leukemia and solid tumors. The primary objective of the study is to evaluate the safety, pharmacokinetics and pharmacodynamics of KT-333 administered intravenously on a weekly regimen. Phase Ia will enroll patients with relapsed or refractory lymphomas with an expansion into solid tumors at the maximum tolerated dose or recommended Phase 2 dose. The subsequent Phase Ib expansion will consist of separate cohorts of patients with relapsed/refractory PTCL, CTCL, LGL-L and advanced solid tumors. Preliminary efficacy will be evaluated in all cohorts in Phase Ia and Phase Ib and exploratory endpoints will include pharmacodynamic assessments, including the level of STAT3 knockdown and its downstream effects in peripheral blood and in tumors. Although KT-333 has robust single agent activity in preclinical models, there's also interest in assessing combinations with agents used in treating PTCL or CTCL and based on the data shown on the previous slide, combining with immune checkpoint inhibitors in patients with solid tumors and hematologic malignancies. Therefore, once the safety tolerability and PK of KT-333 monotherapy have been assessed, the protocol will be amended to evaluate combinations with standard of care regimens in PTCL or CTCL and with standard of care immune checkpoint inhibitors in solid tumors. As shown on Slide 65, the registration strategy for KT-333 includes plans to seek accelerated approval in patients with relapsed or refractory PTCL or CTCL, that will be based on demonstrating robust activity in Phase Ib and in a single arm Phase 2 study. This strategy is supported by recent regulatory precedents of a number of other agents having received accelerated approvals in these similar indications. The subsequent randomized trial of KT-333 monotherapy or in combination with standard of care will be needed for full approval in either of these indications. Since LGL-L is a rare indication without any approved therapies, health authorities will be engaged in order to seek full approval based on a single arm Phase 2 trial, neither the first or the second-line setting. Finally, in solid tumors, the regulatory strategy is to combine KT-333 with anti-PD-1 drugs that are approved in any one of several solid tumor indications. In summary, as shown on Slide 66, KT-333 is the first heterobifunctional degrader against an undruggable target to be evaluated in the clinic. Based on its ability to potently and selectively degrade STAT3, KT-333 has the potential to address that 3 different pathology across a variety of indications. The clinical development strategy for KT-333 includes accelerated approvals and STAT3 pathway activated hematologic malignancies with opportunities to subsequently expand into solid tumors in combinations with immune checkpoint inhibitors. I'll spend the next few minutes giving you a brief update on an area that we haven't discussed probably before, specifically around the opportunity of STAT3 degraders in immunology and fibrosis. As summarized on Slide 68, based on STAT3's role in mediating the activation of immune cells, fibroblasts and various epithelial, endothelial cell types, we believe that the STAT3 degraders can have profound activity in a number of inflammatory and fibrotic diseases. STAT3 gain-of-function mutations lead to poly-autoimmunity with clinical manifestations, including arthritis, scleroderma and eczema. And STAT3 activation is associated with disease severity in chronic inflammation and has also been implicated in conditions, such as interstitial pulmonary fibrosis, pulmonary artery hypertension, nonalcoholic fatty liver disease and diabetic kidney disease, which are defined by stromal modeling in the absence of overt inflammation. The potential inflammatory and fibrotic indications for STAT3 degraders are reviewed in Slide 69, and include serious life-threatening diseases, such as systemic sclerosis and idiopathic pulmonary fibrosis that are associated with STAT3 activation, and for which there are a limited number of modestly effective approved drugs. Additional potential indications in which a STAT3 degrader may be active, include atopic dermatitis and rheumatoid arthritis, which continue to have substantial unmet needs. The final slide, Slide 70, summarizes the results of multiple preclinical experiments demonstrating robust anti-fibrotic and anti-inflammatory activities of STAT3 degraders in mouse models of systemic scleroderma, arthritis and CNS inflammation. The tight skin model is spontaneous TGF-beta dependent model of fibrosis that is most representative of scleroderma, STAT3 degradation results in significant reduction in skin thickening and completely inhibits myofibroblast contraction in an in vitro gel contraction assay. In the collagen-induced arthritis model, which is a prototypical model of human arthritis, STAT3 degradation reduces the clinical signs of disease in a dose-dependent manner. The effects of STAT3 degraders also reflected in the significant reduction in Pathology scores and Periosteal Bone Growth, which is used as a model for aberrant bone growth and ankylosing spondylitis. Finally, on the right, I would like to draw your attention to the effect of STAT3 degradation in the experimental autoimmune encephalomyelitis model representative of multiple sclerosis. In this model, STAT3 degradation not only has a profound dose-dependent effect on the severity of disease, but also greatly reduces the incidence of disease and delays onset of encephalomyelitis in the animals. Collectively, these findings highlight the pleiotropic effects of STAT3 degraders in fibrosis and inflammation, demonstrating the potential for this approach across a broad spectrum of autoimmune diseases. I thank you for your attention. There will now be a short break, after which, Juliet will return and describe our discovery pipeline.

Thanks, Ashwin. Good morning, everyone. I'm Juliet Williams, SVP and Head of Biology of Kymera. I wanted to start by giving you a brief overview of how we at Kymera think about target selection principles and how these are applied to our discovery pipeline to deliver our goals of at least one new IND per year. My colleague, Chris is going to talk in great detail later this morning about our drug discovery investments to all -- to drug all target classes, well, here, I would like to focus more on our approach to target selection [ in advance ] of sharing details about our next clinical program. As those of you, who follow Kymera closely know, we're interested in targets, which have highly validated biology with a clear degrader advantage and where we can easily define, which patients to treat with a precision medicine approach. Additionally, we put priority on diseases or subset of diseases, where there is unmet medical need and also on nodes of well-validated disease pathways, which have yet to be drugged. So this leads us to our target types being split into 3 areas. The first group, depicted here as ID, come from well-validated targets that have been inadequately drugged, hence ID, with existing technologies. Here, degrading the protein has an advantage over current modalities. For example, if there's a feedback loop, which we can continuously suppress or a scaffolding function, which we can disrupt. Our IRAK4 degrader falls into this category. Our heavy investments in the next 2 groups, undrugged or UD, and tissue restrictive or TR are what most profoundly differentiates us from other companies. Targets in UD or undrugged are proteins that have not been drugged by any other modality to-date and STAT3 is an illustration of this. Targets in group TR, tissue restricted, are validated proteins of interest with clinically established drugs and known safety liabilities and limitations. Our approach here is to pair these targets with E3 ligases, which are differentially expressed either selectively in the disease tissue or absent in the tissues, where there are toxicities. This enables a greater therapeutic index, subsequently extending the depth of efficacy we can achieve in a patient and enabling a greater response rate across a population. As mentioned, this third group also differentiates us from most degrader efforts currently being undertaken in this field. Our platform and approach are disease agnostic, but currently with an internal primary focus on inflammation and oncology. For oncology is essential that we have a clear understanding of the precise patient population, clear single agent activity and large addressable unmet needs. For immunology, we focus on key validated signaling pathways, which again address unmet needs, often by enabling oral medicines by targeting downstream nodes. In both our oncology and inflammation portfolios, many of our programs represent what we believe a franchise opportunities. Targets from other disease areas, which reside in our portfolio benefit from differential E3 ligase expression, another clear degrader advantages. Our strength in these areas is currently enhanced by collaborator expertise. On Slide 74, we show we are well positioned with a robust pipeline to achieve 1 or more INDs a year, as we project into the future. And those INDs are predicted to come from the 3 categories of targets with distinctly defined degrader advantages, as I've already discussed. Of note, we have produced 3 FDA-cleared INDs this year and are well positioned to deliver several more over the coming years. Now I'm very excited to share with you our next clinical program, KT-253, a first-in-class MDM2 degrader, being developed for solid and liquid tumors. We have recently nominated this molecule as our development candidate, which is currently in IND-enabling activities and on track for an IND filing next year. Slide 76 is an overview of MDM2 as a target. MDM2 is the ligase, which controls P53, the largest tumor suppressor. P53 is functional in over 50% of cancers, both liquid and solid, and it's been well-established that many P53 functional cell lines are dependent on MDM2 for P53 stabilization and consequent survival, as depicted here in blue. The large number of cells dependent on MDM2 gives a high-level view of the potential breadth of opportunities in oncology for a potent and well-tolerated agent for this pathway. These cells include, but are not limited, to cancers, which have amplification and overexpression of MDM2. Destabilization of P53 by MDM2 enable cells to survive by blocking both cell cycle arrest and apoptosis. Stabilization of P53 by removal of MDM2 by degradation can cause cells to undergo cell death and/or cell cycle arrest. There are a handful of MDM2 small molecule inhibitors in the clinic with some clinical activity in a variety of tumor types. Unfortunately, the activity has been limited. And the main reason for this is that inhibition of MDM2 leads to a transcriptional feedback loop, as depicted here on Slide 77. This creates more protein, which in turn makes it harder for the occupancy driven small molecules to inhibit. As a result, small molecule inhibitors, which are constantly fighting that feedback loop, have been hampered with limited potency and multi dosing regimens, which leads to toxicities and limited efficacy. Degraders, on the other hand, block that feedback loop because they completely remove the protein and do so in a catalytic manner. This enables us to develop highly potent drugs that are able to induce the irreversible acute apoptotic response with just brief exposures, simultaneously allowing time for recovery of any normal cells, which may be affected and create an increased therapeutic index. So I've talked about the cancer genetic validation, the clinical validation and the degrader rationale, now I will show you data that will hopefully convince you that KT-253 is potentially the best-in-class P53 stabilizer with broad application potential. On Slide 78, I show KT-253 is an exceptionally potent and selective degrader of MDM2. On the left-hand side, we see the potency of subnanomolar, and this translates in the middle graph to vast superiority in P53 stabilization over small molecule inhibitors, such as DS compound in the plot. Consequently, our very selective MDM2 degrader has stark potency differences over the inhibitors in cell killing assays. You can see that from the graph on the right and the table below. In fact, our degrader is 200-fold more potent in this cell line compared to the most potent MDM2 small molecules in the clinic. Our extreme potency occurs because unlike small molecule inhibitors, which are occupancy driven, the catalytic activity of degraders is able to constantly suppress the feedback upregulation of MDM2, as shown here on Slide 79. You can see the MDM2 protein is barely detectable and this is in sharp contrast to small molecules, which, because they are constantly fighting the feedback loop, struggle to control the increase of MDM2, impairing P53 stabilization. As you can see in the plot below, in the presence of inhibitors, MDM2 levels increase. This, therefore, needs additional target coverage of the inhibitor to be effective. This mechanism of action enables the MDM2 degraders to be extremely efficient [ intriguing ] the acute apoptotic response. Slide 80 shows washout experiments. Even with just 4 hours of coverage, we can effectively show cell killing in this cell line, whereas the small molecule cannot. And Slide 81 shows the in vitro data translates in vivo. With a single low dose at 1 mg per kg, we show we induce PD markers of MDM2 inhibition, including apoptotic readouts, such as PUMA. This single low dose sends the established tumor model into deep regression for weeks. This allows time for recovery of any normal cells affected, providing that therapeutic index, which has plagued this field for years. Of note, clinically equivalent exposures of small molecules have no significant in vivo efficacy in this xenograft model. Slide 82 illustrates MDM2 dependency is seen across a large subset of tumor types. As shown, both here on the left, by genetically knocking out MDM2 across a panel of cell lines. And on the graph on the right, showing effects on cells by pharmacologically removing MDM2 with a degrader, which again shows marked superiority over small molecules inhibitors on the panel of ALL, AML, DLBCL and uveal melanoma cells. While the opportunities are very diverse, as shown on Slide 83, we plan to focus our development efforts on tumors, which are most susceptible to the acute apoptotic response elected by autograders, which is where we think we will be able to achieve the greatest therapeutic index and efficacy. Our initial disease areas of interest are AML, uveal melanoma and lymphomas, but there are other indications and subset of indications, which are prime for this response. To summarize, as on Slide 84, we are excited about our new protein degradation development program at Kymera, which we believe has great clinical promise. With KT-253, we have developed a molecule that has picomolar potency, 200-fold more potent than the most potent small molecule inhibitors in the clinic. Unlike small molecule inhibitors, or the greatest catalytic activity can block the feedback loop, allowing shorter exposures to send the cells into apoptosis. This not only affords superior efficacy in cells and in vivo, but also creates additional time for any normal cells affected to recover, and consequently, the potential for a large therapeutic window and better efficacy. Finally, there is broad indication space with intact P53 tumors, and we are specifically focused on the tumors, which are particularly sensitive to the acute apoptotic response, which we will select through our biomarker strategy. We look forward to sharing more details, as this program progresses towards an IND filing next year. Now, I will introduce Chris De Savi, who will be discussing Kymera's platform.

I'd like to thank Juliet for her presentation. My name is Chris De Savi, Vice President and Head of Drug Discovery, and I'll be sharing how Kymera's platform will expand the drugged proteome today. Several modalities have been developed to address aberrant protein activity. As shown on Slide 86, some of these modalities have had a tremendous impact on the treatment of human diseases. However, these modalities still face specific challenges that limit their therapeutic impact and reach. Small molecules are less effective against noncatalytic proteins, such as transcription factors or where scaffolding function is important. Antibodies are large, are limited to extracellular targets, but must be dosed parentally, and they can be expensive to manufacture. Oligo based therapeutics have significant challenges with drug delivery and in achieving oral bioavailability. As a result of these limitations, as much as 80% of the human proteome remains undrugged. Targeted protein degradation is a new modality that offers the potential to target a large percentage of previously undruggable targets, thanks to its mechanism of action and to its small molecule based technology. This therapeutic modality harnesses the body's natural cellular recycling machinery, the ubiquitin proteasome system to break down or degrade unwanted proteins. Kymera can co-op this innate cellular process using novel heterobifunctional molecules to direct the UPS towards specific disease-causing proteins, demonstrated with our first clinical program, KT-474. These molecules can be designed with high systemic exposure and good oral bioavailability. We have a bold ambition to expand the druggable proteome by drugging all target classes using TPD. One way to think about our discovery efforts is in 3 distinct categories on Slide 87. The first are targets that have been inadequately drugged with other technologies, where TPD provides a clear solution. We have identified and targeted proteins, where removal offers superior therapeutic benefit versus inhibition of enzymatic activity or blockade of a binding site. 2 examples demonstrating its concept are IRAK4 and our newly announced degrader program, MDM2. The second category are undrugged targets, specifically those where no other technology exists to drug the pathway or target of interest. These include proteins such as STAT3. Ligands for STAT3, while inadequate on their own, can serve as part of a heterobifunctional degrader. Using such an approach, Kymera has developed a first-in-class degrader with STAT3, KT-333, which selectively and thoroughly degrades STAT3. An additional area that Kymera is committed to with respect to undrugged targets is those that have no known ligands and potentially no accessible small molecule binding sites, these proteins have remained undrugged, even with current heterobifunctional molecules. We believe in creating a new surface on an E3 ligase by a small molecule that can engage the protein target of interest through a specific PPI is a solution to the problem. We call this small molecule molecular glues. The final category of targets are uniquely accessed using our proprietary human whole body E3 ligase Atlas, which allows us to systematically identify tissue sparing and tissue selective E3 ligases. This enables us to unlock clinically validated targets, where [ on target ] unwanted pharmacology limits the clinical utility of small molecule inhibitors. Kymera's proprietary drug discovery platform, as shown on Slide 88, enables us to move beyond empirical approaches to rationally design targeted protein degraders to drug all target classes in the cell nacelle. We have expanded our understanding of relationship between E3 ligases and target proteins to identify the properties that make a target both ligandable and degradable and determine how multiple factors impact potency, selectivity, PK and PD. By systematically defining these properties and relationships, we can discover degraders for the right target with the right pharmaceutical properties for the right patients. The key components of our Pegasus platform combine Kymera's broad understanding of a localization and expression levels of hundreds of E3 ligases in the human body with our proprietary E3 ligase binders toolbox, as well as our chemistry, biology and computational capabilities to develop protein degraders that address significant unmet medical needs. I'll introduce a few case studies, where we have used components of this platform to advance TPD drug discovery. We're also very excited to announce we have established a new center for molecular glue discovery. This center will focus on the identification of novel E3 ligases beyond cereblon and will enable the degradation of both undrugged and un-ligandable proteins through small molecule interactions. Kymera's E3 ligase whole-body Atlas is focused on identifying the expression profile of approximately 600 ligases across different tissues. We can determine expression across both healthy and disease tissue. And the graph here on Slide 89 here shows an example of diverse expression profiles using circle size as a relative abundance measure for E3 ligases and also selected targets across a panel of healthy tissues taken from our proprietary E3 ligase whole-body Atlas. This Atlas enables data-driven disease selective protein degradation strategies based upon all the [ met ] E3 ligases, which we view as a paradigm shift from relying on a limited number of E3 ligases typically exploited for TPD, and this does provide us with a distinct competitive advantage versus others in the TPD space. Using comparative analysis of expression patterns, we can identify selective pairings of E3 ligases with therapeutics targets of interest, including tissue selective or tissue restrictive pairings. And our vision remains to develop tissue selective degrader drugs to enable exquisite pharmacology in the right tissues and avoid safety limitations in healthy tissues. This will enable us to develop novel small molecule protein degraders with specific degradation profiles, which we believe will transform drug development. I'll show you for the first time some examples over the next few slides. Slide 90 shows an excellent example of one of the tissue selective E3 ligases that Kymera is working on now. This is not the E3 that we disclosed earlier in the year. We have comprehensively analyzed the expression profile of this ligase using both proteomics and transcriptomics analysis and have shown that it is localized to a specific cell type, our target cells and not expressed in several other cell types, tissues we don't want to be degrading in for this specific target. We have fully characterized this novel tissue selective ligase, have engaged in hit finding campaigns and identified unique chemical matter, which has the affinity for this ligase, well below 1 micromolar. Furthermore, we have also shown productive ternary complex formation against the identified therapeutic target, as shown in the AlphaLISA assay on this slide. We'll share more of the story in upcoming scientific meetings. In this next example, on Slide 91, Kymera is working on a well-validated and high-value oncology target, which we know has on-target heme toxicity. Through our platform, we identified an E3 ligase that is lonely expressed or absent in the target cell responsible for this toxicity, as you can see in the Western block -- plot on the left. Kymera's novel degraders for this high-value oncology target, have demonstrated potent degradation of the target type. It is also showing to not degrade the target in the key blood cell type. And finally, when comparing in vivo, this novel degrader containing is tissue selective E3 ligase ligand versus a well-known small molecule inhibitor, we're able to show that the degrader allows these blood cells to survive, while the small molecule inhibitor leads to substantial cell death. Thus demonstrating for the first time in vivo proof-of-concept of selectively degrading its target and avoiding known on-target heme toxicity. This is a significant advance that demonstrates the power of this platform to deliver truly differentiated protein degrader drugs. Our lead discovery group employs a full suite of modern hit finding approaches shown here on Slide 92. We are not limited by technology to solve a particular problem. We have implemented the most comprehensive array of screening technologies that we believe are unparalleled in companies of our size and stage. We use virtual screening and AI-enabled iteration to characterize the binding pocket of a target protein and/or E3 to evaluate ligandability and to also find small molecule ligands. There are examples in our pipeline of many successful efforts using this technology. We also use high contact screening such as DEL, ASMS or traditional HTS. While we use FBS and covalent screening for more targeted approaches, where we understand protein topology well. We have world-class X-ray and cryo EM capabilities to enable hit finding, but also ternary complex optimization. Our investment in this space is strategic and long-term to continue to solve problems that the industry is yet to solve in drugging the undrugged or difficult to drug high-value targets. In the panel on the left on Slide 93, I'd like to describe application of fragment structure and virtual screening approaches to identify ligands to a novel on Slide 93, I'd like to describe the application of fragment structure and virtual screening approaches to identify ligands to a novel Callan [indiscernible] E3 ligase, which was successfully made into degraders. The co structure of an initial fragment hit with KT of greater than 1 millimolar was solved by x-ray crystallography, revealing interactions within the degra [indiscernible] binding side of the ligase. Structure-guided rational design using insights from a fragment co structure and interactions of the degron peptide allowed improvement in affinity to approximately 30 micromolar. Iterative cycles of in silico library design, synthesis, and co-crystal structures further improve the potency to single-digit micromolar. Finally, iterative traditional medicinal chemistry optimization led to nanomolar heads with good physical properties and low molecular weight. All in all, the use of in-silico screening to desired libraries and extensive use of 18 cocrystal structures was highly efficient. With only approximately 200 compounds needed to get from one millimolar hit to several triple-digit nanomolar hits. This is actually quite remarkable. We've been able to identify several exit vectors for subsequent degrader design, which were then guided by further modeling and X-ray structures. We successfully made degraders of multiple proteins, including BRD4 and also in-house Kymera targets. So the right panel here highlights we are utilizing activity-based profiling to screen covalent compound libraries using chemo proteomics. One enormous advantage of this approach is the ability to find novel hits for E3's across a proteome within a single set of experiments. We can then rapidly characterize these interactions using high throughput crystallography. In this particular example, an X-ray structure of a novel, small novel covalent hit bound to a specific cystine residue of a tissue-sparing E3 ligase. Once optimized, these molecules will be used in multiple oncology programs where sparing bone marrow toxicity will be important for both efficacy and the safety of future therapeutics. So Kymera has built significant expertise in uncovering the molecular principles for the properties of this new class of small molecules and allowed us to design molecules with optimized pharmaceutical properties, not unlike traditional small molecules. So here on Slide 94, our proprietary chemistry utilizes [indiscernible] complex modeling, where we use cloud computing to evaluate millions of compounds to design both the right length and composition of linker, along with the most efficient vectors to enable efficient binding of both E3 ligases ligand and protein-ligand. We are using molecular [indiscernible] to accurately design and predict ADME and PK profiles of these complex molecules. We know that degraders typically occupy high molecular weight and lipophilicity space, properties that are not conducive to high oral bioavailability. Our experienced chemistry and computational chemistry teams utilize artificial intelligence-driven insights to understand these design parameters, driving clearance, permeability and efflux. As a result, we can design compounds in this space with high oral bioavailability, as you can see in this table. In another component of our platform, I'd like to show you how we have used mechanistic modeling at Kymera to accurately predict both human PK and PD from preclinical data here shown on Slide 95. We applied an indirect PK/PD response model to describe the mechanism of action of TPD. The biodistribution of drug to target tissue was accounted for in the PK model, while an E Max exposure-response model was used to describe the mechanism of action of TPD. A preclinical PK/PD study was conducted in dog to understand the kinetics of protein degradation in tissues at different dose levels. The PK and PD was used to estimate in vivo degradation potency and protein turnover rate in the target tissue. We then go ahead and humanize the PK/PD model by applying human PK parameters, adjusting species differences in potency and protein turnover rate, if needed to predict protein degradation in the clinic. As you can see from the graph on the right-hand side, this model accurately predicted human PD using preclinical PK/PD from dog in orange, as confirmed by the actual human PK/PD data in blue. We have actually demonstrated how to drug several inadequately drugged or undrugged proteins with heterobifunctional degraders. We've also shown our hetero bifunctional degraders are very potent, selective, safe, and efficacious in humans. On Slide 96, another area I want to talk about is expanding our pipeline into undrugged [indiscernible] proteins. We're finding specific ligands to proteins is challenging and forming new catalytic protein-protein interactions and eventually drugging these proteins could be enabled by small-molecule molecular glues. In fact, molecular glue suitability in targeting [indiscernible] proteins is by virtue of their mechanism of action. Rather than requiring a defined binding pocket on the undruggable target, these molecules leverage a weak pre-existing interaction between an E3 ligase and the [indiscernible] protein of interest. Through binding of a molecular glue to the E3 ligase, the protein-protein interaction interface of E3 ligase is remodeled, leading to enhanced interaction of the 2 proteins and facilitating degradation. Our approach is to move beyond the traditional and now in space of Cereblon IMiD-based molecular glues. Kymera has recently established strategic partnerships with several groundbreaking academic and biotechnology research teams, including Alpha Bio, University of Washington, and NYU. With these groups, we are identifying and characterizing novel E3 ligase substrate pairs for molecular glue interactions, exploiting natural affinity augmented with small molecules. We are utilizing genetic screening, structural insights, and pathway and computational biology to identify novel match pairs of E3 ligases and high-value undrugged targets. We have already transitioned several programs from the concept to the discovery stage and are looking forward to sharing updates in future scientific meetings. I have demonstrated to you the level of investment we continue to drive in our platform to expand the druggable protein with TPD on Slide 97. We have established know-how and technologies to drug inadequately drugged targets such as IRAK4 and MDM2. Undrugged targets such as STAT3 and have for the first time in TPD, drug targets in a tissue-selective manner using our E3 ligase toolbox. We've recently established a new discovery unit to identify molecular glue degraded drugs focused on undrugged, [indiscernible], high-value protein targets, and we hope to share with you further progress here at upcoming high-impact conferences. I'd now like to pass it back to Nello for his closing remarks.

Well thanks, Chris. What [Foreign Language], really a spectacular series of updates. So what have we shown you today? Let's try and recapture the presentations. First, we've shown you our first 5 years pipeline and platform investments. Hopefully, you will agree with me now that we've shown you 3 compelling clinical programs with large franchise potential. Hopefully, you agree after seeing Jared's presentation that KT-474 is really poised to be potentially the best-in-class oral anti-inflammatory drug. If you look at the degradation data in both blood and skin impact on biomarker as well as the safety profile, really, we can never ask for a better profile at this stage of development. KT-413, again, as I mentioned, is really positioned to be a unique therapy in diffuse large B-cell lymphoma. KT-333, really large potential right now, both in lipid tumor and solid tumor. In terms of our discovery pipeline, I hope you agree that this KT-253 is really an amazingly potent molecule with a really differentiated mechanism with large franchise potential, where actually our job next year beyond executing towards IND will be -- continue to expand the right type of indications that we want to go after. And then, as I mentioned, our commitment to at least one deeper year going forward. But this is not enough. We have much more that will continue to feed our pipeline. We have shown you the first tissue-restricted E3 ligase in vivo concept, leading to first tissue sparing biology. You've heard me say this sentence many times before. Hopefully, now you've seen the data. And this program is ready to go into development already next year. We've also shown you why we are moving into the molecular glue world because we're actually solving an actual technical problem. And this is all in the context of Kymera wants to own the challenge and the opportunity to drive all target classes in human cells. So just a refresher of our pipeline, I've already given it to you early in the presentation, but maybe here with an opportunity to look maybe more forward-looking. KT-474, what are we looking for next year? Hopefully, just as exciting patient data, where we confirm, knock-down, impact on biomarker, biomarketing skin, and then being ready with our partner, Sanofi, to start our Phase II studies. KT-413 and KT-333, we expect to see derisking proof of mechanism studies where we're able to demonstrate that these molecules are on track to get into the pharmacological doses in a tolerated way where we expect to see profound clinical benefits. MDM2, as already mentioned, IMD, but also continue to expand opportunities in a wide variety of indications where we believe this very potent degradation that breaks the feedback loop and leads to profound apoptosis, will allow us to really expand clinical opportunities. As I mentioned, continued commitment to novel programs, and I'm sure we will be here, hopefully not as late in the year next year to tell you what our new development programs are. So I've covered actually most of these already. So in 2022, we've already discussed 474, 413, the IMD for 253, hopefully, and we're very keen on this. First program in development for tissue-restricted E3 ligase platform, but also continued growth of both teams and capabilities. I know this will be expected, but it's important to realize that we cannot do this if we don't continue to build the teams and the capabilities. We're very focused on continuing to expand our leadership in TPD with disruptive innovation across the biotech, which also results in innovation and scientific contribution in medical meetings as well as in peer-reviewed publications. And as well as -- and this is key, going back to the culture slide, continued investment in providing our employees, collaborators, and partner with the best experience possible. So where are we going to be in 2026? So we have a very ambitious but also a vision that we believe is attainable. So we believe that 5 years from today, we should be on path to NDA for our first program, or at least one program. We expect to have at least 8 clinical programs at different stages of development across different diseases. We continue, obviously, to want to have a pipeline that is able to deliver at least one new IMD per year. We would like to see at least one tissue-restricted or selective degradation in humans, proof-of-concept as well as proof-of-concept of in humans of a degrader against a traditionally undrugged protein. We also want to continue to grow into disease agnostic as well as technology-agnostic pipeline and capabilities, again, continue to expand the platform to holistically address the [indiscernible]. Again, commitment to innovation and first-in-class science as well as being ready to have our commercial organization in place. So those are all key important milestones and commitments that we are making today and everything that we've been doing and everything that we will be doing in the next few quarters and years will be towards these type of goals and beyond. So I don't want to spend too much time on this slide, but just gives you a visual maybe representation of what Kymera's pipeline might look like 5 years from today, several programs, late-stage, definitely post proof-of-concept and towards registration, several programs beginning Phase II, proof-of-concept studies as well as some programs in early clinical development, across, as I mentioned, wide variety of indications and technologies. So I just want to wrap it up today here with what we hope you've taken from today. Obviously, there's been a huge amount of content. I realize that probably content overload is there. And so you'll see that the slides and this presentation will be on our website right after we complete the R&D Day today. And so I understand that there is a lot of information. So if I had to choose 5, 6 key things that I want to make sure people are taking away from today are really high-level key messages. The targeted protein degradation is positioned to transform the drug development landscape. Kymera is a medicine-focused company, company that has a commitment to develop and commercialize medicines with recognized leadership in targeted protein degradation. We believe we employ a novel and differentiated strategy and approach in terms of how we select targets, how we develop our programs, and also how we invest in our platform. We are committed to innovation. We are committed to execution and also to pursuing a real step-change in this treatment paradigm. There is a lot that we've accomplished, but we're nowhere near where we want to be. And so there is a lot that we want to accomplish. And so we have a very ambitious but achievable vision for the company. So I want to leave you on the last slide with a thank you. First, I want to thank everybody at Kymera that has been part of this amazing journey so far of really working in unchartered waters of novel drug discovery and development and has made all of these possible. So all the employees who have been part of this amazing journey so far. I would like to thank all the presenters today that have done an amazing job showcasing the excellence of how Kymera operates, and also our guest Naimish from Sanofi for spending some time with us today. Finally, I'd like to thank everybody in the audience that has spent the past 2 hours with us today, hoping that the next year, we will do this in person. As we get ready for the Q&A session, I just want to remind you that there is a box underneath the screen where you can submit your questions. Hopefully, you have already done so. If you're in a full screen, please exit your full-screen to ask the question. So I want to thank everybody again. And Bruce, Jared, and I will reconvene in a couple of minutes to take your questions here from Kymera. Thank you again.

Great. Welcome back, everyone. This is a Q&A section. Thanks for staying with us through the duration of today's R&D Day. I'm Bruce Jacobs again joined, as you all know, by Nello Mainolfi and Jared Gollob. So we've got -- we've taken all the questions throughout the day, try to collate them into categories. And then, obviously, we'll try to monitor it as we go through here and answer as many questions as we can. So the first series of questions are around the IRAK4 program, specifically with a healthy volunteer portion largely behind the company. What is our level of confidence in and enthusiasm for the molecule moving into Phase II?

Great. Thanks, Bruce. So maybe I'll start with this one. First of all, I want to thank everybody for being with us for the past 2 hours or so. I also want to remind everybody, we're all vaccinated and tested. So that's why you see us without masks in close proximity. So going back to the question. So we are very excited about where the program is, again, as I was telling actually my colleagues this morning, the position that we are in today is really as good as you can be for this program at the end, almost at the end of Phase I, healthy volunteer study. So we're very excited to now think about transitioning into our patient cohort. And then eventually, as you've heard from our colleagues at Sanofi initiating our Phase II studies. And you've seen the breadth of opportunities there, and I think our job is really prioritizing the opportunity. I just want to maybe take the opportunity to highlight the key take-home messages from the presentation today that I think we should really be focused on. First of all, we've shown that through multiple-day dosing, we can completely remove IRAK4. Obviously, technically, we stay close to lower limit of quantitation. But when you get to 98% or more, you're functionally removing the protein. It's important also that for the first time, we've demonstrated how KT-474 distributes in the body, and we're using the skin, which is both a surrogate tissue, but also a tissue target. And so you see there that we can measure really high level of compound, KT-474. And those high level of KT-474 [indiscernible], especially at the 200 mg dose, removed the target also in the skin almost completely, you saw that the curve at bay 14 was almost touching the lower limit of quantitation. It's important to also reiterate that this degradation of IRAK4 is functional. So not only we degrade the protein, but regrading the protein has a functional effect as measured by ex vivo cytokines. And we've shown data only up to MAP 3. And -- but just that shows you, they're also just up to the 100 mg dose, the level of inhibition was profound. And I think to me, actually, the most important aspect is combining degradation, functional effect, and safety. And we cannot be more excited about that whole package. We might touch on the safety a bit more. I saw some questions coming in later. So I'm sure we'll touch on it. But that package is as good as you could get at this stage of development. So we're very excited about where we are, and we're eager to move forward.

Great. Thanks, Nello. So the next question or category questions are largely based on our learnings so far in SAT and MAD, what we expect to see in the patient cohort of the trial? And what data will we be sharing and when?

Great. So maybe, Jared do you want to take this one?

Yes. So our plan is to go into an open-label cohort of patients with HS and AD following completion of a healthy volunteer MAD and to initiate that early next year. In the patient cohort, just as a reminder, we're dosing for 14 days, just as we did in the MAD portion in healthy volunteers, which means that we're not looking at clinical endpoints. The real aim of the MAD in patients is to confirm PK and PD. So we'll have opportunities, again, in the patient cohort to look at IRAK4 knockdown in the blood. But we'll also have the opportunity now to look, not just in the skin, but also in disease skin in these patients with active inflamed skin lesions, which will give us an opportunity to confirm that we can knock down the target robustly in diseased skin. And we'll also have the opportunity to look at various disease-relevant pro-inflammatory biomarkers in the skin as well as in the blood of these patients to further extend our learnings around the pharmacodynamic effect of our drug. And this will set us up nicely then to really be fully confident in a recommended Phase II dose that we will then plan to bring into patients in multiple Phase II studies in diseases like HS and AD toward the end of next year.

Great. Thanks, Jared. So you touched on skin. I had a few questions regarding degradation and skin. Specifically, can you discuss what you've seen so far, how that compares to what you might expect to see in the patient cohort and then over the long-term in dosing in Phase II and beyond?

Yes. I mean we're very excited really about what we were able to show in skin, as you mentioned in the presentation, we really showed for the first time, proof of mechanism in the skin. And we showed that we were actually able to degrade IRAK4 in the skin really to near the lower limits of quantification, really almost to undetectable levels at the highest dose of 200 milligrams. So we think that that's very encouraging. And that shows us that we can degrade in the skin, really to the same extent that we were able to degrade in the blood and peripheral blood mononuclear cells. We also saw some additional encouraging data points. We saw -- first of all, that skin exposure was higher than exposure in plasma, which really suggested that we're getting excellent distribution of the drug into the skin. And as you probably remember from the data that I showed, the skin exposures were actually still increasing at day 14. So even though we stopped dosing after 14 days, the data do seem to suggest that exposure, and we think degradation as well had not yet reached steady state.

Great. Thanks, Jared. One of the questions we got was to go in a little more detail around safety and tolerability, specifically the AE palpitations?

Yes. So maybe I wanted to start off by really just stating that we are really highly encouraged by the very favorable safety profile that we've seen in the study so far, both in the SAD and the MAD portions. It's important to realize that in the MAD, we are taking healthy volunteers and confining them in an inpatient Phase I unit for 21 days. And despite the fact that we're confining them for that period of time and really knocking down IRAK4 to almost undetectable levels in the skin and blood and that the only adverse events that we're seeing are really self-reported nonspecific adverse events, just a handful of them, headache, nausea, and palpitations, I think, really is a testament to the favorable safety profile that we're seeing. Specifically, with regard to the palpitations, it's also important to understand that, first of all, they -- we are not dose-dependent. We saw one episode at MAD2, and we saw several episodes at MAD4. It's also important to understand that these were single isolated transient events lasting no longer than 10 to 20 minutes and that these events were number one, self-reported. And number two, these events were not associated with any objective finding. So for example, in one subject who had palpitations for this very short period of time when the physicians went in and took vital signs, there was no increase in the heart rate. There were also no findings on the ECG at the time of those palpitations, again, sort of suggesting that these were subjective. And the fact that we only saw isolated episodes of these over a 21-day observation period, we can also attest to the fact that these were not really clinically significant. We also don't think this represented any sort of on-target pharmacology. If we look at our preclinical data, first of all, we know that in individuals who are completely lacking in IRAK4 people with no mutations, there are no cardiac manifestations. Secondly, we've also looked very closely in our 4-week GLP toxicology studies, both in rodents and in higher species, and we've seen no cardiac complications. And this includes dogs who were under telemetry. So continuous cardiac monitoring during dosing, at doses that were much higher than what we administered in the Phase I study and saw no findings. So I think overall, we're very pleased by the favorable safety profile and encouraged by what we can see regarding safety, even at doses that are giving us maximum pharmacology.

Thanks, Jared. Maybe if I can just add something. I also want to remind, I know it's in the slide. This is still a blinded study. So in every cohort, there are actually 3 placebo subjects. And so at this point, we remain blinded, and we will be unblinding the study once we complete it. And so obviously, Jared has touched on all the key points. I don't think that I need to add anything. So we this is all that we have for IRAK4 degradation, we're very happy about it.

Great. Jared, just a quick couple of questions on cytokines. Can you talk a little bit about any variability you may have observed between cohorts and differences in reduction levels?

Yes. I think in the MAD, where we look at the impact on cytokines in MAD2 at 50 milligrams versus MAD3 at 100 milligrams, we did see stronger cytokine inhibition at the higher dose, especially with the LPS stimulation. And this was not completely surprising to us, even though we had significant greater than 90% degradation in PBMC at both of those dose levels and monocytes, which are really one of the key cell types that are producing these proinflammatory cytokines, we really didn't max out on IRAK4 down-regulation until we started to get to the MAD3 dose level where we saw greater than 90% degradation of IRAK4 at that dose level, which is probably why we saw stronger cytokine response. We also think it's encouraging by the fact that in MAD4 at 200 milligrams, even though we did not have cytokine data to report today, we would expect even more robust impact on cytokines because at that dose level, we're achieving even greater knockdown in monocytes nearing 94%.

And can I -- maybe I'll add just one point here. Actually, two points. One, I think we probably haven't done this, but if you take a step back and you look at the composite data and maybe people in the audience have done that. I'm sure people have done that. You can probably tell that the MAD4 200 mg dose is the dose that gives us the kind of the most complete target engagement, both in terms of PBMCs, where maybe it doesn't differentiate from MAD3 in monocytes, in the skin, probably especially and given the exposure and the level of degradation, we expect actually that those to give us also higher cytokine impact. We don't have the data at the moment. But what I want to remind everybody is that this is a catalytic mechanism that is continuing to happen as we continue to dose the molecule. So what we see right now is a snapshot of 2 weeks of dosing. So it's possible to expect and upon multiple weeks of dosing, lower doses might be able to reach the level of target engagement that we want and we need. So this is why it's important for our Phase I study as we're planning, and we're still refining, obviously with Sanofi, that we will take more than one dose, just because we want to understand the pharmacology across longer time periods.

Great. Just one more question on the data, it relates to HCRP and can we explain the signal -- why we didn't see a signal, what implications, if any, it has for just the molecules development and effectiveness?

Yes. I think it's important to understand that we included CRP levels in Phase I, understanding that in healthy volunteers, CRP levels are normal. And so trying to detect an anti-inflammatory effect against a biomarker that's not elevated, is going to be challenging. But what we noted on the Phase I study in the MAD portion is that the CRP levels were indeed quite low within the normal range, but then they also fluctuated greatly over time. So it ends up producing a lot of noise that makes it very challenging to try to see any relay signal from that noise, especially when you're dealing with relatively small numbers of subjects. It's also important to note that CRP is actually produced by hepatocytes and not by immune cells. And while this production is likely mediated by multiple different inflammatory stimuli, it's not really clear how it's produced and stimulated in healthy volunteers. For us, really the sort of gold standard measure, therefore, in healthy volunteers is not really CRP, but the ex vivo cytokine induction. And that's where we're able to really directly measure the impact of down-regulation of IRAK4 and the impact on the pathway and the impact on inflammatory cytokine induction, which we think really is the sort of gold standard anti-inflammatory effect that you can measure in healthy volunteers. Now importantly, if you look at other IRAK4 targeted agents, including the IRAK4 kinase inhibitors being developed by Gilead and Curis and their Phase I studies with those IRAK4 inhibitors, they also looked at ex vivo cytokine inhibition, and we're able to see an impact there. They did not look at CRP levels in the plasma, probably for the same reason that we discovered in our own exploration, it's very challenging to really see any impact on CRP, again, when it's in the normal range and fluctuating wildly over time. Also importantly, the ex vivo cytokine induction was also used by other novel anti-inflammatory drugs in development in Phase I, including MK2 and ROR gamma inhibitors and AMIDs. And also in those trials, they use their ex vivo cytokine assay the same as ours, it did show an effect, but they also did not look at plasma CRP.

Thanks, Jared. So there's a couple of questions. These are the last on [indiscernible] for now, at least on the development opportunities for the molecule. And if we could spend a little more time talking about the likely indications that first will be pursued in Phase II and then in the future, additional indications that might be pursued.

Yes, maybe I'll take this one, Bruce. So hopefully, you've seen both our presentation and the one from our colleagues at Sanofi. And the way that we look at this mechanism and this asset is potentially a very broad anti-inflammatory drug. So while the universe of opportunities are broad, we've talked about respiratory, skin, rheumatology, and GI inflammation. And those are all indications that assuming the efficacy and safety profile continues to be supportive, we will be exploring in the clinic. Obviously, we cannot run 10, Phase II studies in parallel from the get-go. So our goal with our partners is to prioritize the first probably 2 or maybe 3 programs that we want to start as soon as possible and then learn from those and maybe actually dissect those programs in the biological context. So TH1, TH17, where we think about HS, potentially array, TH2, where we're thinking about AD. And then from those expanding in, again, GI, respiratory and other indications. So breadth of opportunities but being rational and data-driven as, I think we all need to be at this point of development.

Great. Thanks. So we're going to shift to MDM2. I have a handful of questions there. First group to provide more detail around how we envision selecting indications for this program? What would be most likely to be our first or most likely indication?

Sure. So maybe -- I mean, I know I've seen other questions about differentiation. So maybe we'll wrap it up. And then, Jared, you can touch on the indication. Like if I were in the audience, I would be asking, why degraded for MDM2 and what is the opportunity there, both biologically, mechanistically, and then in terms of market opportunities, which maybe summarizes all the questions that I've seen in the past 5 minutes. So why an MDM2 degrader? So the MDM2 program is another one that fits perfectly into our target selection strategy that has been with us for now 5 years, which is a pathway where there is a high degree of validation, where keynotes have not been dragged or drugged well where opportunities are broad. So p53 is -- actually, I looked up a few days ago, it was on a Time Magazine cover as one of the key tissue -- sorry, tumor suppressor gene, maybe the largest tumor suppressive gene. So it's been in the public domain as un-drugged node for maybe 20 years. So what have we done is a drug development industry to solve for stabilizing this tumor suppressor, that can be either mutated or wild type. We've come up with small molecule inhibitors that unfortunately don't work. I'm simplifying here. Obviously, there are companies working on those. They have had some clinical success and I wish them continued success. But the challenge with those molecules is that biologically, once you inhibit MDM2, you create a translational feedback look that increases the expression of MDM2. With the increased expansion of MDM2, you need to give more MDM2 inhibitors. And you actually never really catch up. What happens with those molecules than, you try and inhibit, but you do not quite inhibit the full MDM2, and you continue to dose and you generate toxicity. So the therapeutic indices of those drugs are very challenging. What we offer, and this is why such a beautiful here, a biological hypothesis for us. What we offer is a simple degradation of -- too many targets -- of MDM2 is able to completely remove the target, overcome the feedback loop, lead cells to apoptosis and drive tumor cells to death while we've done those again for weeks actually, and we allow healthy cells to recover. So we have a biological superiority of targeting MDM2 with a degrader from a, again, purely biological perspective, but also at the superiority, thanks to this biological superiority angle to have broader therapeutic indices because we don't need to fight this continuous dosing and feedback loop. So this is why it fits very well. This is a target that has been around for a while. We believe this is going to transform so many tumors, both liquid tumors, and solid tumors. And really, the challenge is given that more than 50% of tumors have wide p53, what are the tumors where this mechanism -- this drug is going to provide unparalleled, a clinical benefit. Maybe Jared, you can help me on this one.

Sure. We know that the sort of common approach to trying to select indications is to focus on tumor types that are p53 wild type, of course, but also have MDM2 amplification, gene amplification, and/or overexpression. And so some of the common examples there are certain types of liposarcoma, [indiscernible] tumor and different subsets of breast lung and bladder cancer. But really, we are taking this a step further. And for us, also selecting indications, really based on those that exhibit a rapid apoptotic response to MDM2 degradation. So really having a biomarker strategy for us to select appropriate indications. So far, we've identified AML, lymphoma, and uveal melanoma has 2 initial indications of interest, based on that additional sort of step. But we'll disclose others, I think, in upcoming medical meetings as we do more preclinical work.

Just one -- there is one follow-up question on MDM2, which relates to just the degrader bet -- you touched on a little bit.

I think we've covered these, Bruce. Why don't we move to the next one?

Got it. So just some general questions that came in, some programs, some corporate strategy. The first one is, can we talk about our views on future partnerships?

Yes, that's a great one. So we have a few minutes, but I'll try and be brief. So hopefully, what we were able to relay today is, again, as I said early on, if people were connected, Kymera is not just about IRAK4. It's not just about MDM2 or STAT3 or IRAKIMiD, but it's about taking this potentially transformative platform and build a series of transformative medicines. And I think it will be really silly of us to believe that we're going to be doing all of that. You've seen the molecular glue initiative that we've had for a while and now unveiled. You've seen tissue-restricted degradation. So there is unlimited opportunities as a company as we are today. So again, it will be silly to think that we're going to be doing everything on our own. Probably not even a large pharma can do everything that we would like to do. So the trick will be how do we accelerate forward integration to be a fully integrated business with the right type of partnership. So we have already a couple that are very meaningful Vertex working outside of oncology and immunology, Sanofi taking KT-474 in a wide variety of diseases, in a de-risked manner. But you can imagine that there could be down the road partnerships around either clinical opportunities in large diseases, there could be partnerships that are commercial, there could be geographical partnerships. There could be also platform partnerships. While I personally struggle with those because I think we're the best at both developing our platform but also to using it to discover this drug test, but we realize the opportunities are so large, especially with these novel E3 ligases that we might have partnerships in areas that right now we're not considering. So maybe closing this topic and might not be satisfying to the audience, but we don't have immediate plans in the next 12 to 16 months to partner any of our programs. But what I would say is that for a company like Kymera, it is likely that there will be other partnerships in the future. On the themes that I've covered.

Great. So Nello, you touched us a second ago in brief on the molecular glue effort. I had a few questions largely around what Kymera is trying to solve for with our effort, the extent of differentiation? And then there was a specific question about how one can design both selective and potent glues?

Yes. So great question. I would like to go back to our mission statement, which is dragging all target classes in human cells. And so we want to have all the tools in the toolbox to target all target classes in the human cells. And we realize that while hetero bifunctional degraders have so many opportunities, again, I just mentioned that probably even us as a company on our own, cannot fully prosecute. But there are targets that we are very excited about. There are traditionally undrugged that have not been liganded. And where we've actually experimented and realize that they're actually not ligandable with small molecules ligands. So just remember, to degrade the protein with the hetero-bifunctional molecule, you need to have a specific and somewhat relatively high-affinity binding event with the protein that you want to degrade. There are proteins that are very shallow pocket. They are very validated in terms of human genetics. That we want to be able to drive. We think these are of huge value both for patients and for Kymera and our shareholders. And we don't want to be limited by technology. So that's how we got into the space. I'm sorry, I went too long here. And this is why we want to work with Molecular Group. But we want to -- so what's differentiated is we only want to use it for the targets where this technology is really helping. For specific degradation, hetero-bifunctional molecules are still the best technology. And so what we've spent a lot of time, I was telling Lane, our CBO, yesterday, that this is 2 years in the making because we spent a lot of time with our collaborators in [indiscernible] and more recently in biotech to understand how do we do this rationally and prospectively? And how do we say, let's say, we want to go after -- I'm making this up, NRF2, how do we find which is the right E3 ligase? And then how do we build the molecular grow small molecule. And we have done that. We have built capabilities to prospectively design, rational, selective protein integrators. And we'll be talking about those, I'm sure, next year in some conferences.

Okay. Just a couple more as we're running quickly here out of time. The tissue-restricted E3 ligase, can you talk about when you'll disclose what -- more about that program, what indications you might pursue with it?

Yes. So our goal is to go with that program in development next year. We have several programs that are following that type of timeline. I'm not sure whether we will disclose that program next year. So that's something we have to decide. Just because this is something that is extremely proprietary and it's technologies that we want to keep as close to the best as possible. But this is one of the opportunities that we have. This is one E3 ligase. We have several others that the team is working on. And in the next probably few years, you will hear us disclosing several other programs where we use tissue-restricted expression to enable a new generation of targets.

Great. So we are just coming up on the hour. I knew we would not get to all of them. We did our best. But if you would like to reach this for follow-up, please do. I guess before we break, I'll just -- Nello, do you have any closing remarks.

So first of all, this has been really fun, what, 2.5 hours? I'm impressed that we were able to put a lot of our science in hundred slides in 2 hours of presentations. We're excited about where Kymera is going. Hopefully, you see that we -- feels like, I think, hopefully, you'll take from today, Kymera feels like a real drug development and eventually commercialization company, the commitment to not only the initial clinical programs, but to continue to double down on our discovery pipeline and platform, hopefully gives you an idea that we're here for the long run, and we're here to generate a lot of value. And so we're excited that this was our first public R&D Day. We've had tens of R&D days within the company but not one publicly. And we hope that everybody enjoyed it, we're available for questions, and we'll see you soon in the upcoming meetings and conferences.

And just one quick reminder. So we will post the slide deck from today just shortly after this presentation. And then for those of you who missed segments or who like this so much, they want to watch it again, we will also post all of the replays as well. So look for those on the Events and Presentations section of our website. Thanks, and everyone, have a great holiday.

Thank you.