Hello. On behalf of the Kymera team, I'd like to welcome everyone to our virtual Immunology R&D Day. I'm Justine Konigsberg, Head of Investor Relations at Kymera. Starting with slide three, I'd like to remind you that today's presentations will include forward-looking statements about our future expectations, plans, and prospects. These statements are subject to risks and uncertainties that may cause actual results to differ materially from those projected. A description of these risks can be found in our most recent 10-Q filed with the SEC. Any forward-looking statements speak only as of today's date, and we assume no obligation to update any forward-looking statements made on today's call. We have a full agenda today focused on our growing immunology pipeline, as shown on slide four.
Nello Mainolfi, our President and CEO, will begin today's discussion with an overview of our strategy and the opportunity to revolutionize immunology with small molecule degraders. Then, Jared Gollob, Amy Wang, and Juliet Williams will review our IRAK4, STAT6, and TYK2 programs, respectively, before Nello's closing remarks. The slide presentation will be available after the prepared remarks before the Q&A, and the replay will be available shortly after the conclusion of today's meeting in the IR section of our newly redesigned website under Events and Presentations. Following our prepared remarks, we are allocating about 40 minutes to take questions. There will be a live Q&A discussion where we will address questions. In addition, there's a question submission bar on your screen that will be open through the presentations this morning and during the Q&A session to submit written questions.
We will collect those questions throughout the morning and take as many as time allows. With that backdrop, I will turn it over to Nello.
Thanks, Justine, and thanks, everyone, for joining us here today. I'm Nello Mainolfi, Founder, President, and CEO of Kymera. First, Happy New Year from all of us here at Kymera. We're fortunate to be part of an industry that can change people's lives, and I truly hope and know that as an industry, this will be another amazing year of patient impact and innovation. We built Kymera to be a global medicine company that uses novel modality like TPD, targeted protein degradation, to change patients' lives across the world. We know that this technology is disease agnostic, and we continue to organically grow our capabilities on path to build a global company that addresses disease at a scale in a variety of therapeutic areas.
Currently, we've been focusing in oncology and immunology, and we're excited by the preclinical and clinical data we've generated so far in both areas, and we're even more excited about the upcoming data readouts. Today, at our first Immunology R&D Day, we're going to focus on what we've been doing in immunology, and more importantly, where we're going in this important and underserved therapeutic area. We're excited to share with you today our vision, our strategy of how Kymera will capitalize on what we see as a significant opportunity to change the way immunological disorder are treated. So going on slide seven, my goal is to really talk about how Kymera is harnessing this game-changing modality of TPD, how we've demonstrated reproducible and scalable innovation, and how we've successfully translated all of our programs in the clinic.
We'll talk about our unique target selection strategy, and then go deep into why we're focusing more and more in immunology, and what's the opportunity for oral degraders, and then go into our novel two new programs. So the inherent ability to combine the power of genetic, like, knockdown with the flexibility of small molecules, the power to drug classes of targets that have been elusive to other therapeutic modality, the use of affinity rather than occupancy-based catalysis, the promise of all of these have made TPD one of the most exciting new therapeutic modalities of the past several decades. We have founded the company to harness the transformative power of the technology and deliver, doing so, a new class of medicines. We focused, as you will hear soon, on high-value undrugged targets. We have created a highly productive discovery engine that delivers scalable and reproducible innovation.
All of our IP has been generated internally at Kymera, and importantly, we're well capitalized to pursue all the programs that you've seen, and the one you'll see today, within the cash runway that we've guided externally of first half of 2026. We're very proud at Kymera to have built an organization that continues to deliver industry-leading innovation. We have advanced four programs in the clinic. We've demonstrated flawless translation of PK and PD and safety from preclinical species into the clinic across all of them. We have demonstrated early proof of concept of meaningful clinical impact on patients in both oncology and immunology. All of this continues to validate our target selection strategy, our molecular design, really how we design and characterize our molecules.
We're on track to continue with this amazing pace of productive innovation and expect to deliver up to 10 new INDs within the first 10 years of Kymera. So going to the next slide, I just wanna maybe highlight some of the key principles of what we do here at Kymera. And first, I'd like to share that we're really a medicine product-focused company... and believe that any platform will be only as good as the products that it generates. For this reason, we believe that target selection is the most important ingredient on how we've built and continue to scale Kymera. And we believe their approach has been quite unique in the space. We like to focus on undrugged or poorly drugged targets.
We focused a lot on transcription factors and scaffolding proteins, but we go in pathways that have been clinically validated, where ideally, there is clinical validation on nodes in the same pathways that have been drugged by other modalities, and importantly, where there is human genetics data for the target that we're going after. We also wanna have a clear line of sight to an ability to demonstrate in the clinic, early on in the clinic, the superiority of our modality over existing drugs in that pathway. Importantly, we wanna be able to serve large patient populations that will lead to large commercial opportunities. You will hear this theme over and over again in our presentation. Slide 10, if I had to comment on one area of our recent history that I'm most proud of, it's our ability to deliver scalable and reproducible innovation.
This is not important just for the execution across the program so far, but also because it speaks to our ability to reproduce this translation in new programs that we're advancing towards the clinic now, and the ones that will be advancing in the future. So as you can see on the slide, starting from IRAK4, complete degradation of IRAK4, as predicted from preclinical species, has led to impact on patients with HS and AD. In these slides, you see reduction of AN counts in HS patients. In the IRAK4 program, we have shown that one can degrade IRAK4, Ikaros, and Aiolos at the same time, at the desired levels, and also safely, which was already predicted by our preclinical work.
In MDM2, in the MDM2 degrader program, KT-253 has shown us that by degrading this target, you can actually see strong antitumor effect without the typical hem tox of MDM2 blockade with small molecule inhibitors. Again, as predicted by our preclinical models. And finally, also with our STAT3 degrader, KT-333, we have demonstrated that we can reach up to 90% degradation in blood and tumor in the clinic, that results in strong antitumor effects in a variety of tumor types. In this case, you see in a Hodgkin lymphoma patient, also here, as predicted by our preclinical studies. I think it's very rare that a new company with a new modality can show these levels of fidelity of translation and reproducible and scalable innovation across the whole pipeline.
Moving to slide 11, we wanna draw your attention to a summary of where we've been, where we're now, and where we're going on our path to fulfill our mission. In the early days, on the left, we were focused on building capabilities in TPD, refining our target selection strategy, and building strategic relationships that will allow us to forward integrate the company. More recently, as I just showed you, we've been really focused on demonstrating our ability to translate our target selection strategy, our molecular design, and our preclinical data into the clinic. As we've discussed, I think we've done a tremendous job there. In fact, with our partner, Sanofi, we've initiated two phase II studies in two large indications in immunology. I'm a big believer that companies have to earn the right to grow and build the next phase of growth.
I think we have earned the right to plan our next phase, which is focusing on programs with large clinical and commercial opportunities, staying true to our target selection philosophy. As you'll see soon, our next phase will see more focus in I&I. To be clear, we will not be doing just I&I, but I will explain to you why we believe this is the time to increase investments in this space. Also, you will see us completing several proof of concept studies and launching several registrational studies in the next 3-4 years. In doing all of the above, staying true to our mission, to building an independent, fully integrated global biotech. So let's go into why we're increasing our investments in immunology.
If we look at this just from a market size perspective, you'll see on the slide that the market of drugs that target immune inflammatory pathways is by far the largest in industry, with a cumulative value of about $250 billion. As you see, the market is dominated by more than 75% by injectable biologics. So it is clear that there is a huge opportunity to provide millions of patients with safe and effective orals. In the next slide, I'll explain to you why oral degraders, we believe, is the differentiated and best solution for this unmet need. So going to slide 13, here's why. So let's start on the top left.
It is important to recognize that in the past 10, 15 years, key pathways responsible for immune inflammatory diseases have been validated, in the majority of cases, by understanding the role of key signaling cytokines. In fact, I think it's fair to say that antibodies to those cytokines have transformed and revolutionized treatment of immune inflammatory diseases. However, these monoclonal antibodies are injected. They're costly and inconvenient. In fact, in a survey that was run by our industry colleagues at J&J, 75% of patients on biologics said that they would switch to orals with an equivalent profile. So why haven't traditional small molecule inhibitors solved this problem? And this is a very important point. The reason is that small molecule inhibitors are not able to block these pathways fully. They cannot match the saturating blockade of a biologic.
You can see an example here on the slide comparing a TYK2 small molecule inhibitor with an IL-23 biologic in psoriasis. So what we need is an oral agent that can deliver the pathway blockade of a biologic and the convenience of oral dosing, and this is where we come in. Degraders are the only modality, in our opinion, that can deliver biologic-like activity, convenience of oral dosing, low cost of manufacturing, and importantly, because of this profile, access a much broader patient population. This is what we believe we can deliver here at Kymera in I&I, and this will be the focus of our presentation today. So let's go to the next slide and apply this concept to IRAK4. This is a program that many of you know well. IRAK4 is a scaffolding kinase downstream of IL-1 family cytokines.
These cytokines have been validated in a wide variety of diseases: HS, AD, asthma, gout, and others. IRAK4 small molecule inhibitors cannot block the pathway fully because IRAK4 has also a scaffolding function, and only by removing the protein you can block both the kinase and scaffolding functions and deliver full pathway blockade. So in this case, a degrader of IRAK4, by blocking the pathway fully, should have the biological and clinical activity of the combined IL-1 family cytokines biologics, anti-IL-1, 18, 33, and 36. This is what's really exciting about this program and why we and Sanofi are aggressively advancing KT474 in our phase II studies, initially in HS and AD. So biologics-like pathway blockade with an oral degrader. There is no equivalent or better way to do this.
On slide 15 and 16, I wanted to take a moment to reflect on what we've learned from this program and why this is important, especially today. You will see some compelling preclinical data on our new programs, and it is important for everyone to see how well KT-474 has translated in the clinic and how much confidence we have that this will happen also for our two new programs. To remind everybody, KT-474 is the first hetero bifunctional degrader to have been dosed to healthy volunteers and then to HS and AD patients. It's also the first to show profound clinical impact in such complex immune inflammatory diseases because we're degrading and not inhibiting a master regulator of inflammation, IRAK4. So we've seen in our experience so far, strong PK/PD correlation and impeccable translation from our preclinical studies into the clinic. We've seen robust safety.
We've demonstrated in a phase 1 study already substantial differentiation versus small molecule inhibitor, and in doing so, demonstrating profound patient impact, as Jared will show you soon. So on slide 16, I just wanted to take a moment to go a bit into the details of our PK/PD translation and why this is important, again, for this program and for our new programs. So on the left, you see that the correlation... the concentration, sorry, needed to achieve our 85% degradation in dogs was around 3 nanograms per mL, and we projected that in human, a similar concentration will be needed to achieve also 85% degradation. On the right, you'll see from our healthy volunteer MAD study, we're able to show that even in the lowest dose of 25 mg per day, we were achieving a concentration just above 3 nanograms per mL.
In fact, it was about 4.4. And these show that at 4.4, so above 3 nanograms per mL, we were already reaching 90% degradation or more, again, at the lowest dose. Obviously, you see that with higher doses, we completely depleted IRAK4 effectively and safely to deliver that complete pathway blockade that we talked about. So the strong translation is the result of extensive work to understand PK/PD correlation across multiple cell types that we've done at Kymera preclinically, that allowed us to go into the clinic with a high degree of confidence. And as I said earlier, you'll see soon that you can expect the same level of understanding of our novel programs that are about to enter into clinical development.
So here we are, finally, unveiling the work that we've been doing for the past few years, our two new programs. Our first-in-class STAT6 oral degrader program. This target is the obligate and specific transcription factor in the IL-4/IL-13 pathway and will have the potential, as you'll see, of a dupilumab-like profile in an oral pill. And our first-in-class TYK2 oral degrader program, which with a loss-of-function-like profile, can set a new standard in the TYK2 class and match biologics-like efficacy. So let's spend some time introducing each of them before the team goes into more details. Starting with STAT6, we selected this target because it sits in one of the most validated pathways in immunology and because it is critical and specific transcription factor in this pathway.
Meaning that by degrading it, and only by doing so, we can selectively block this pathway fully, and importantly, this pathway only, and potentially phenocopying upstream biologics like dupilumab. As the team will show you, there is strong pathway validation, both clinically and in terms of human genetics. We will show you data that will convince you that our degrader blocks this pathway equally or better than dupilumab in our preclinical studies, and that the enormous opportunity that we have in front of us to change how Th2 inflammation is treated. This is about having a drug like dupilumab, which is going to be a mega blockbuster drug, and now think about that profile as a simple daily oral pill. That's really what this program is about. As you can see, we have multiple indications that have been validated, such as AD, asthma, more recently COPD, EoE, and others.
What I'm passionate about is that with an oral, we have an opportunity to be first line and best line therapy, access broader population, and early disease states. This is going to be a huge program. We're putting a lot of resources to really own the space from all the angles: chemistry, biology, indication, expansions, et cetera. On slide 19, as I was saying, dupilumab is expected to be a, a $20 billion drug by the end of this decade. Importantly to note, that this is still with a relatively low penetration assumptions. As I mentioned, we have an opportunity to reach beyond this type of profile. And I believe we can do that, and we can actually do more. With an oral option, we have the potential to access biologics-ineligible patients. We can go earlier in stages of diseases.
There is more that we can do with this program in Th2 inflammation, both clinically and commercially, and we can't wait to start our clinical development later this year. Moving on to TYK2. So what's the opportunity for a TYK2 degrader? Very simple in our view: validated target, validated pathway, large clinical and commercial opportunities in diseases like psoriasis, IBD, lupus, and others. But small molecule inhibitors, like the approved TYK2 inhibitor, Sotyktu, are not delivering on the human genetics promise. Some have selectivity limitations, some have potency limitations, all of them have pathway engagement limitations. With our degrader, we can finally replicate the loss-of-function profile and deliver the full pathway blockade that we believe in the clinic will lead to biologics-like efficacy. Market opportunity for IL-23 interferon biologics are enormous. Our goal here is to be the drug of choice and go where and beyond biologics are used.
So another mega blockbuster opportunity is in our hand. So now you've seen three programs focusing on delivering on our vision of best-in-pathway drugs by having biologics-like profile in an oral drug. So the next slide is our portfolio of first-in-class oral degraders that we will talk about today. Three fundamental pathways with clinical and genetics validation, where Kymera's technology can deliver, for each, the best-in-pathway drug. For IRAK4 in oral, they can have the combined activity of the upstream single cytokine biologics. For STAT6, as I said, the Dupi-like oral drug. For TYK2, the best-in-class agent with biologics-like activity. These are also, importantly, complementary pathways that have potential synergies that we think about as we continue to build our pipeline.
I truly believe that we're building the best-in-industry oral immunology pipeline, staying true to our target selection philosophy, focusing on best-in-class oral drugs, and entering large markets with the potential for best efficacy, convenience profile. I want to remind you that our IRAK-4 program is partnered with Sanofi, and we have an option to share 50% of the US market, while STAT6 and TYK2 are both wholly owned. For my last slide, so far today, you've heard about our vision and plans for our growing immunology pipeline. You will hear an update on our IRAK-4 program from Jared, and then you'll hear from the team, compelling data sets for both STAT6 and TYK2 programs, and then I'll come back for some concluding remarks. Jared?
Thanks, Nello. Good morning. I'm Jared Gollob, Chief Medical Officer at Kymera. I'm excited to provide an update on our first-in-class KT-474 program, sharing how it fits with our strategy, and importantly, how everything we have learned at Kymera with the first TPD program in immunology should increase the probability of success for our emerging oral immunology pipeline. As shown in slide 26, my presentation will review the TLR/IL-1R pathway biology and validation that make IRAK-4 an attractive target in the innate immunity space, lay out the development and commercial opportunities for a therapeutic targeting IRAK-4, and why we believe degrading IRAK-4 is the only way to effectively block TLR/IL-1R signaling. Then summarize the important learnings from the KT-474 phase I trial and the status of the ongoing phase II trials in hidradenitis suppurativa and atopic dermatitis.
IRAK4 is a master regulator of innate immunity, mediating myddosome signaling by all IL-1 family cytokines, as well as by most TLRs. As shown in slide 27, the production of multiple different cytokines following TLR and IL-1R activation is dependent upon both the kinase and scaffolding functions of IRAK4. Therefore, complete blockade of signaling downstream of IRAK4, which can only be achieved through removal of the protein, has the potential to achieve a broad anti-inflammatory effect. There is genetic de-risking of chronic IRAK4 suppression, as adult humans who lack IRAK4 due to null mutations are healthy. Clinical validation for targeting this pathway comes from IRAK4 small molecule inhibitors and from antibodies targeting individual IL-1 family cytokines that all signal through the IRAK4 protein in diseases that include AD, HS, RA, TPP, and others.
Therefore, we believe that removing IRAK-4 will be able to have the combined activity of all the known anti-IL-1 family biologics, achieving our best in pathway objective. Slide 28 shows examples of the many development opportunities and potential large patient impact for an IRAK-4 degrader in immune inflammatory diseases across dermatology, respiratory, GI, and rheumatology indications, where there is clinical, biologic, and/or genetic evidence for the role of TLR, IL-1R activation in disease pathogenesis. Importantly, as I noted earlier, IRAK-4 degradation leading to full pathway inhibition has the potential to deliver a superior therapeutic profile compared to suboptimal biologics acting upstream of IRAK-4. As shown in slide 29, there are multiple lines of evidence supporting why removal of the kinase and scaffolding functions of IRAK-4 through protein degradation is superior to kinase inhibition alone or any other modality.
Functionally, only degradation can inhibit TLR/IL-1R-mediated inflammation in a manner that is context-independent with regards to immune cell type and stimulus. The scaffolding function of IRAK4 is critical to the recruitment of additional myddosome components following MyD88 activation and to mediating NF-kappaB activation required for cytokine induction. We and others have generated a plethora of preclinical biological data demonstrating the difference between blocking the kinase function and the IRAK null phenotype generated by our degrader, and I encourage you to click on the link in this slide to have access to the broader data set. Clinically, in HS and AD patients treated on the KT-474 phase I trial, IRAK4 degradation in blood and skin lesions led to a systemic anti-inflammatory effect associated with preliminary evidence of clinical improvement, whereas an IRAK4 kinase inhibitor failed to show activity in a placebo-controlled phase II trial in HS.
KT-474 is a potent and selective IRAK4 degrader. It is important to note here, as it will be relevant for our new programs, that preclinically, we extensively study the degradation kinetics across multiple disease-relevant cell types to best translate the degrader profile into humans. As shown in slide 30, KT-474 is highly selective and effective at degrading IRAK4 across multiple different immune cell subsets in blood, as well as in a variety of other tissues, including skin, where degradation in keratinocytes and fibroblasts has been demonstrated. As shown earlier, the opportunities for this pathway and target in I&I are numerous, based on pathway biology and its role in autoimmune disease pathophysiology. We and Sanofi have decided that the initial development indications for KT-474 are the inflammatory skin diseases HS and AD.
As shown in slide 31, these chronic diseases include inflammatory skin disfigurement, as well as debilitating symptoms such as pain and/or pruritus that severely impact quality of life. Both are highly prevalent and often manifest in either childhood or young adulthood, with a substantial proportion progressing to moderate to severe disease, requiring systemic therapy for disease control. The inflammation in both diseases is highly pleiotropic and associated with IL-1 family cytokines, TLR stimuli, and cytokines and chemokines produced in response to IL-1R and TLR activation. Active agents in these diseases are largely injectable biologics that have provided a clinical benefit to subsets of patients and validation of the TNF, IL-17, and IL-4/IL-13 pathways, but are used by only a small fraction of patients who might benefit from these treatments, due either to safety concerns or restricted access to injectables.
JAK inhibitors, while active, have safety issues and monitoring requirements with black box warning that have limited uptake. Both HS and AD therefore provide an opportunity for KT474 by virtue of its broad anti-inflammatory activity, convenience of once-daily oral dosing, favorable safety, and potential for best in pathway profile. As shown in slide 32, the objectives of the KT474 phase I trial were to first establish the translation of PK on target pharmacology and safety from preclinical models to healthy volunteers, using single doses followed by daily dosing for 14 days, and then to show that an active dose administered to HS and AD patients for 28 days can impact inflammation as well as clinical signs and symptoms. All these objectives were met, including preliminary demonstration of clinical proof of concept in moderate to severe HS and AD patients, leading to publication of the results last November in Nature Medicine.
As shown in slide 33, up to 98% degradation of IRAK4 was achieved in healthy volunteer peripheral blood mononuclear cells by day 7 of a 14-day once-daily dosing regimen, with the effect plateauing after 50-100 milligrams.... This level of IRAK4 degradation was associated with functional TLR pathway inhibition, as shown by greater than 50% inhibition of multiple disease-relevant pro-inflammatory cytokines in a whole blood ex vivo TLR4/8 stimulation assay. We want to highlight here that both the plasma concentration needed for maximal degradation and the doses needed to reach that concentration were almost perfectly predicted by our preclinical team based on extensive work performed before entering the clinic. We believe this gives us the confidence that the impressive preclinical profiles you will see soon for our new immunology programs will also translate just as well in the clinic.
As shown in slide 34, in HS and AD patients treated with 75 milligrams of KT-474 in the fed state, which was the equivalent of 100 milligrams dosed in the fasted state to healthy volunteers, KT-474 concentrations in biopsied skin lesions after 28 days of dosing were much higher than steady-state trough levels in plasma at day 28. While IRAK4 was overexpressed in HS and AD skin lesions relative to healthy volunteer skin, the KT-474 exposure achieved in skin lesions was able to normalize IRAK4 to the level seen in healthy volunteers. This was associated with a downregulation of pro-inflammatory gene transcripts in skin lesions. While HS and AD patients were dosed for only 28 days in an open-label study with a placebo control, we were able to detect preliminary evidence of clinical efficacy with regards to both skin lesions and symptoms.
As shown in slide 35, a high score response rate of up to 50% was observed in moderate to severe HS patients, in conjunction with an up to 66% mean reduction in pain. This clinical effect peaked either by or after day 28 and was maintained through the 2-week follow-up period after dosing completed, consistent with a sustained effect of KT-474 on IRAK4 degradation in blood and skin observed after dosing was stopped. Slide 36 shows a similar effect in moderate to severe AD patients, with up to 37% mean reduction in EASI score and up to 66% mean reduction in pruritus observed by or after day 28.
Taken together, the internal consistency in this phase 1 trial between IRAK4 degradation in blood and skin lesions, systemic anti-inflammatory effect, and preliminary signal of clinical efficacy absent a placebo control, provides confidence around this initial proof of concept in HS and AD. Based on these promising phase 1 results, Sanofi has now moved KT-474 into phase 2 randomized, double-blind, placebo-controlled trials in moderate to severe HS and AD. As shown in slide 37, the treatment duration is 16 weeks for both studies, with clinical endpoints including safety, as well as measures of skin lesion burden, disease severity, and symptoms. Top line data for both trials are expected in the first half of 2025.
I have shown you today how KT-474, our oral IRAK4 degrader currently in the clinic in phase 2 trials, sets the stage for the newer entries into our immunology pipeline, as it exemplifies our approach to target selection and clinical development, and therefore provides an important read-through to what we expect to achieve with STAT6 and TYK2. Key features of the IRAK4 program include biologic de-risking through clinical and genetic pathway validation, a compelling biologic and clinical rationale for developing an oral degrader, and multiple development opportunities in large, high unmet need indications that make this a pipeline in a product.
We successfully executed on the largest, most comprehensive phase 1 targeted protein degrader trial in healthy volunteers and patients with HS and AD, demonstrating proof of concept for the TPD platform, as well as further validation of KT-474 as a potential best-in pathway IRAK4 targeting degrader therapeutic in TLR/IL-1R-driven inflammatory diseases. Enrollment onto Sanofi's phase 2 trials in HS and AD began last quarter, and we look forward to readouts from those studies in the first half of 2025. I'll now turn it over to Amy for her presentation on our exciting new STAT6 program in immunology.
Thanks, Jared. I'm Amy Wang, a senior director in Kymera's Immunology team and the biology project lead of the STAT6 program. I'm very excited to share with you the story of our first-in-class oral STAT6 degrader, KT-621, and why we believe it has the potential to have the best-in-pathway profile with dupilumab-like efficacy and the convenience of a oral drug. What we will cover today are the well-established STAT6 biology and target rationale, the clinical development and commercial opportunities, the strong degrader advantage of exciting preclinical data package, and the next steps. On slide 41, briefly on biology, STAT6 is the specific transcription factor required for IL-4 and IL-13 cytokine signaling. As you can see on the right, there are two types of IL-4 receptors: type one, consisting of IL-4 receptor alpha and gamma C; type two, with IL-4 receptor alpha and IL-13 receptor alpha one.
IL-4 signals through type... both type 1 and 2 receptors. IL-13 signals through type 2 only. Upon IL-4 and 13 binding to the receptor, the downstream activated JAK kinases phosphorylate and activate STAT6, leading to allergic Th2 inflammation. As many of you already know, STAT6-regulated cytokines are clinically validated targets for allergic diseases, as demonstrated by the clinical efficacies of the biologics targeting IL-4 and 13, such as dupilumab.... Unlike JAK kinases that can be activated by multiple cytokine pathways, STAT6 is specifically activated by IL-4 and 13, making it a perfect target to selectively block IL-4 and 13, like dupilumab. The pathogenic role of STAT6 is also supported by human genetics, that gain-of-function mutations with STAT6 cause severe early allergic, early onset allergic diseases in human, and STAT6 knockout in mice is protective in multiple allergic diseases.
Also, STAT6 knockout mice develop normally, are viable and fertile, supporting the safety of STAT6 degradation. On clinical pathway validation, dupilumab that blocks IL-4 and 13, by binding to IL-4 receptor alpha, showed broad clinical efficacies, and has been approved in atopic dermatitis, asthma, and other Th2 diseases. It has also shown positive phase three data recently in COPD. Because STAT6 is the absolutely essential transcription factor for IL-4 and 13, STAT6 degradation can fully block IL-4 and 13 signaling, and can achieve dupilumab-like pathway inhibition, as you'll see soon.
On patient impact, over 150 million patients in just the U.S., Europe, and Japan suffer from Th2-driven diseases, and dupilumab is a great drug that has validated this pathway in many of these diseases, as you can see on this slide, including atopic dermatitis, prurigo nodularis, asthma, COPD, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, and others. With our STAT6 degrader, a drug that can have full pathway inhibition like dupilumab, combined with a simple QD oral profile, we believe we have the potential to access many more patients worldwide than current injectable biologics, and can transform the treatment paradigm of Th2 diseases. As for every program, we'd like to focus on why a degrader is superior to other modalities. As many of you know, we call it our degrader advantage.
In the case of STAT6, it is the specific transcription factor in the IL-4 and 13 pathway, which means a STAT6 degrader can selectively block IL-4 and 13. It is also the essential transcription factor in the IL-4 and 13 pathway, which means a STAT6 degrader can fully block IL-4 and 13, and also it is a transcription factor. Transcription factors has historically been difficult to drug. It is challenging and unlikely for occupancy-based approaches, such as traditional small molecule inhibitors, to achieve the selectivity, potency, and maximal inhibition on the transcription factor in vitro and in vivo to the level of a degrader. All these make STAT6 a perfect target for the degradation approach to develop an oral drug with dupilumab-like efficacy and safety profile. Starting from slide 44, we will show you our really compelling data and why we're so excited about this opportunity.
KT621 is extremely potent degrader of STAT6. As you can see, the picomolar degradation potencies across all the disease-relevant human primary cell types we have looked at. It is one of the most potent hetero-bifunctional degraders we have ever designed and tested at Kymera. In the table, you can see STAT6 degradation across hematopoietic cells that are involved in all Th2 diseases, epithelial cells from the skin and from the lung that are involved in the skin and respiratory indications, smooth muscle cells from the lung and from esophagus that are involved in the respiratory and GI indications, and the vascular endothelial cells that are important for inflammatory cell infiltration in all Th2 diseases.
For all these human hematopoietic and tissue cell types, KT-621 showed potent and full STAT6 degradation with picomolar DC50s, as you can see in the table, and those dependent degradation curves on the right. As we've shown you earlier, for IRAK4, it is critical for us to understand degradation across all disease-relevant human primary cell types in preclinical settings to build the right translational package for human dose prediction. Here on slide 45, showed our degradation selectivity. In PBMC treated with a concentration as high as 100x DC90 of KT-621, as you can see in the graph, STAT6 is the only protein that KT-621 degraded out of the 10,000 or so human proteins that were detected by mass spec. No other STATs were degraded to any extent. This demonstrated the exquisite degradation selectivity of KT-621.
Next, we wanted to prove selectivity not only through proteomics, but also through pathway biology. Here on slide 46, we tested KT-621 for its functional selectivity against all the other STATs in cytokine assays, as shown in the table and in the graphs. KT-621 only inhibited STAT6 function, as you can see on the right, in the IL-13-induced pSTAT6 assay in human PBMC with a 42 picomolar inhibition potency and did not impact any of the other STATs, as you can see the complete flat, those response curves in the bottom, in the bottom graphs. This demonstrated the exquisite pathway selectivity of KT-621 for STAT6 against all the other STATs.
So we've shown you the potent degradation and excellent selectivity of KT-621, and here we want to show you how this potent degradation impacts IL-4 and IL-13 pathway, and how KT-621 compares with dupilumab in all the important Th2 in vitro functional assays. As hopefully you already know, we like to be very comprehensive in our biological characterizations. So we looked at IL-4 and IL-13-induced TARC release in human PBMC. We looked at IL-4 and IL-13-induced CD23 expression in human B cells, and CD23 is a B cell activation marker and correlates with IgE class switch. And we also looked at IL-13-induced periostin release in human bronchoalveolar and esophageal smooth muscle cells. And these tissue cells only respond to IL-13, not to IL-4. TARC, IgE, and periostin are all well-established PD biomarkers used in the clinic for Th2 diseases.
As you can see in the table and in the graphs below, both KT-621 and dupilumab fully block IL-4 and IL-13, but KT-621 showed more potent IC50s compared to dupilumab, in some cases more than tenfold. And all the IC50 of dupilumab we obtained in our own assays are aligned with Regeneron's published data. Now, let's take a moment to summarize what we've seen so far. With the powerful targeted protein degradation platform at Kymera, we designed a degrader of STAT6, KT-621, that can have the selectivity, potency, and maximal inhibition, comparable or even superior to a monoclonal antibody like dupilumab. This is quite compelling in our view. Now let's look at in vivo data starting from slide 48. KT-621 potently degrades STAT6 across multiple preclinical species. It can degrade STAT6 to full depletion with low oral doses.
In the graph on the right, showing in vivo degradation in dogs, you can see dose-dependent degradation to depletion from 0.2 MPK to 12.8 MPK oral doses, with doses between 1-3 already leading to maximal STAT6 degradation. We don't show the data here, but it is important to highlight that in all preclinical species, KT-621 induces potent STAT6 degradation with a very rapid degradation onset within only a few hours post a single oral dose. Thanks to the study, like the one showing here, and many preclinical PK/PD studies we have done, we're able to predict low and developable efficacious doses in human of KT-621, and potentially a rapid onset of action to relieve disease symptoms. On slide 49, as part of a non-GLP safety study, we had the opportunity to look at STAT6 degradation in disease-relevant tissues in non-human primates.
It is important to note that in this study, with a dose as high as 300 MPK daily for 14 days and reached concentrations that were over 40-fold over our efficacious concentration. KT-621 was well-tolerated, with no adverse event or relevant finding. In the graph, you can see at 10 MPK, which was the lowest dose level in this safety study, KT-621 fully degrades STAT6 in all disease-relevant tissues, including blood, spleen, skin, and lung. Again, de-risking our path to human translation and POC. On the next two slides, we'll go over our preclinical efficacy study and show you how KT-621 compares with dupilumab in both a skin and a lung model. On slide 50, we show a two-week atopic dermatitis model induced by topical application of low-calcemic vitamin D3 analog, MC903. This is a complex model, but with prominent Th2 inflammation.
It was done in the IL-4, IL-4RA humanized mice to ensure response to dupilumab and efficacy comparison. KT-621 was dosed QD orally for 11 days. As you can see in the graph in the middle, a 2, 8, and 32 MPK oral doses led to about 70%, 80%, and 90% degradation in the spleen. Dupilumab was dosed 4 times subcutaneously at 25 MPK twice a week, which was republished by Regeneron to ensure constant IL-4RA saturation and full IL-4 and 13 blockade. Its effect is equivalent to that of 300 mg every other week in humans, which is the most aggressive dose regimen in humans. As you can see in the graph on the right, the prominent Th2 inflammation was demonstrated by the greatly elevated total serum IgE in the PO vehicle and subq IgG4 control groups, compared to the no MC903 group.
KT-621 robustly and dose-dependently inhibited total serum IgE elevation, comparable to dupilumab. It is worth noting that a dose that led to about 90% degradation gave similar efficacy compared to the IL-4RA saturating dose of dupilumab, indicating full IL-4 and 13 blockade in vivo by KT-621 in this skin model. On slide 51, we're showing what is considered the most relevant preclinical model for Th2 inflammation. It is a 1-month lung inflammation model induced by intranasal house dust mite administration, unlike ovalbumin, which is commonly used in mouse models but does not induce airway inflammation in human; house dust mite is a real-world allergen that can induce asthma in humans. This intranasal house dust mite model has dominant Th2 inflammation and was used by Regeneron for the preclinical development of dupilumab. Again, this study was done in IL-4/IL-4Ra humanized mice to ensure response to dupilumab and efficacy comparison.
KT-621 was dosed QD orally for 31 days at the same three dose levels, 2, 8, and 32 MPK, leading to 72%, 85%, and 91% STAT6 degradation, consistent with the previous skin model. Dupilumab was dosed 9 times subcutaneously at 25 MPK twice weekly. Here, we strictly follow the dose level and frequencies published by Regeneron to ensure IL-4Ra saturation and full IL-4 and IL-13 blockade. Again, its effect is equivalent to that of 300 mg every other week in human, which is, as I said, is the most aggressive dose regimen in humans. In the graphs below, you can see the dominant Th2 inflammation, as demonstrated by the greatly elevated total IgE in the serum, TARC and periostin release in the bronchoalveolar lavage, and eosinophil recruitment to the lung, all are well-established Th2 biomarkers. KT-621 inhibited all these readouts at all three dose levels.
A reminder that the first two graphs use the log scale to ensure better visualization of the low values. For all these Th2 readouts, KT-621 showed comparable or superior efficacy compared to dupilumab. To summarize our efficacy data, in both the skin and lung models, KT-621, when reaching 90% degradation, gave similar or superior efficacy compared to the IL-4Ra saturating dose of dupilumab, indicating full IL-4 and IL-13 blockade by KT-621 in both of these models. Importantly, 90% STAT6 degradation is predicted to be readily achievable with low oral doses in human, based on our PK/PD data in multiple preclinical species. To summarize, we have shown you that STAT6 as a target has validated and de-risked the biology. It is the specific and essential transcription factor in the IL-4 and IL-13 signaling pathways, the central driver of Th2 inflammation.
It is validated by human genetics and by dupilumab across multiple indications. It is the perfect target for the degradation approach to block this pathway. A STAT6 degrader has an attractive competitive profile. The worldwide IL-4 and IL-13 biologic market is predicted to grow over $23 billion in the next few years. We believe our STAT6 degrader, KT-621, with dupilumab-like efficacy, good safety, and a simple QD oral profile, has the potential to disrupt this market in an unprecedented way and transform the treatment paradigm of Th2 diseases. Specifically on KT-621, it showed full IL-4 and IL-13 functional inhibition with picomolar IC50s superior to dupilumab. It showed robust efficacies in both the skin and lung models, equal or superior to dupilumab. Both itself and STAT6 degradation were well-tolerated in multiple preclinical safety studies at doses and concentrations that were over 40-fold of our predicted human applications concentration.
We're currently in IND-enabling studies and expect first in human in the second half of 2024. We really believe our STAT6 degrader, KT-621, is the, is the first-in-class drug with the best-in-pathway potentials. With that, I'll pass it over to Juliet to share with you an overview of our exciting TYK2 program.
Thank you, Amy. My name is Juliet Williams. I'm Head of Research at Kymera, and I'm excited to talk about our oral TYK2 degrader. This is a first-in-class TYK2 oral degrader with what we believe has the best potential to have the best-in-class profile. What we will cover today is TYK2 biology and target rationale, clinical development, commercial opportunities, degrader advantage, preclinical data, and next steps. As you can see from the schematic here, TYK2 is required for type I interferon, IL-12, and IL-23 cytokine signaling, and these cytokines are clinically validated targets for autoimmune and inflammatory diseases. This is one of the most elegant stories of human genetic validation that has resulted in improved drugs. In fact, people with loss-of-function variants show that TYK2 is protective in autoimmune and inflammatory diseases. So it's not surprising that the target and pathway have extensive clinical validation.
Starting from the target, the TYK2 small molecule inhibitor, Deucravacitinib, was recently approved in psoriasis. In terms of broader pathway validation, there are several IL-23 targeting biologics in the clinic, such as ustekinumab and others, with approvals in psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis. Type I interferon targeting agents include anifrolumab with approval in systemic lupus. The impact of being able to target TYK2 optimally is large. There are numerous indication opportunities across multiple immunology therapeutic areas, with a total potential patient impact of more than 20 million patients. And this ability to be effective across multiple indications has been de-risked by the biologics and small molecule inhibitors. We believe, and we will show you today, that TYK2 degradation differentiates from inhibition and leads to full pathway inhibition, with the potential to deliver biologics-like activity with the convenience of oral QD dosing.
We believe that this will allow our molecule to reach broader patient populations and sets up this program as another potential mega blockbuster drug. So on this slide, slide 57, we talk about why we believe a TYK2 degrader can transform this space. First, TYK2 scaffolding function is well established. It's responsible for cytokine receptor surface expression and activation. We have shown with IRAK4, the scaffolding function can be best addressed with a degrader approach. So unlike small molecule inhibitors, only TYK2 degradation can fully recapitulate the human TYK2 null biology because we completely remove the protein. We are therefore able to achieve full pathway inhibition of type I interferon, IL-12, and IL-23, while sparing IL-10. Unlike Deucravacitinib, which inhibits IL-10 by inhibiting JAK1, KT-294 does not inhibit IL-10 signaling. That's important, for IL-10 is important in intestinal homeostasis and particularly relevant when treating diseases like IBD.
Compared to TAK-279, Takeda's investigational TYK2 inhibitor, because we fully remove the protein, KT-294 fully inhibits all possible scaffolding functions, including fully inhibiting type one interferon, which completely recapitulates the human TYK2 complete deficiency, which no other small molecule inhibitor can do. Pharmacologically, we also differentiate. As you know, small molecule inhibitors cannot reach steady-state full target inhibition. As we have shown with IRAK4, we can build degraders to reach full target degradation at steady state, and you'll see this in the next few slides. We believe that all of the above will lead to superior pathway blockade relative to existing small molecule inhibitors and potentially reach biologics-like activity. I'll go through all of these points separately now in the upcoming slides. On slide 58, we will address the scaffolding function and the human loss-of-function phenotype.
TYK2 complete deficiency severely impairs IL-23, type 1 interferon, and IL-12 signaling, but spares IL-10. TYK2 scaffolding functions are demonstrated by differential pathway inhibitions by complete TYK2 deficiency. This is a kinase dead variant in humans. That's demonstrated in the table below. Humans with complete deficiency of TYK2 have strong pathway inhibition for the IL-23, IL-12, and type 1 interferon pathways. However, those with the kinase dead variant do not have IL-12 and type 1 interferon suppression. And the safety of TYK2 degradation is supported by complete deficiency in humans, where these individuals are generally healthy, with only some increased risk of mycobacteria, viral infections that are relatively mild, curable, and tend not to recur. Removing TYK2 using a degrader is the only small molecule approach to eliminate all scaffolding and catalytic functions of TYK2, fully recapitulating the human TYK2 null biology.
On slide 59, we summarize KT-294 data supporting how it recapitulates the TYK2 loss-of-function profile. First, on the left, our proteomics data demonstrates how selective we are. We just degrade TYK2. In particular, we highlight that we are extremely selective of the JAK family members. On the right-hand side, you can see we achieve picomolar degradation in human PBMCs and keratinocytes, and low nanomolar inhibition of our functional assays across a range of cell types. We have potent efficacy on the IL-23 and IL-12 signaling pathways in PBMCs, and potent inhibition of the type 1 interferon pathway in PBMCs, but also in specific B-cell assays. You can also see when we look at inhibition of IL-10 and IL-22 pathways in various assays, we demonstrate that we spare these pathways completely, and I'll expand upon this in the next slide and discuss why this is important....
I just showed you that KT-294 spares IL-10. In this slide, I will show you how it differentiates from dupilumab, which inhibits IL-10 through its JAK1 inhibition. IL-10 has essential roles in intestinal homeostasis, such as epithelial repair and mucosal healing. So that's important in diseases such as IBD. In fact, loss of function mutations of IL-10 cause early onset refractory colitis in humans. On the left, we show Western blots demonstrating that when TYK2 is not present in a cell, we can induce phospho-STAT3 with IL-10, showing TYK2 is not necessary for IL-10 signaling. We also show dupilumab can block that pathway signaling exclusively due to its ability to inhibit JAK1 and not through TYK2. In the graph in the middle, again, we have an assay where we induce phospho-STAT3 in monocytes with IL-10.
You can see in this context that our degrader has no effect on phospho-STAT3 because it doesn't inhibit the IL-10 pathway. However, in contrast, dupilumab potently inhibits IL-10 signaling, as shown with the decrease of the orange data points. Similarly, on the graph on the far right, here we have monocytes where we use IL-10 to suppress LPS-induced TNF-alpha. You can see we have no effect on this IL-10 suppression of LPS-induced TNF-alpha release. However, dupilumab inhibits IL-10's function of suppressing LPS-induced TNF-alpha release, and you see an increase in TNF-alpha, and that's demonstrated by the orange data points. Beyond the differentiation versus the only approved TYK2 inhibitor, dupilumab, we also look at how the degrader can differentiate biologically versus another TYK2 inhibitor currently in clinical development, which is TAK-279. This is a selective TYK2 inhibitor over the JAKs and does therefore spare IL.
So we were interested to know because we fully removed the protein, eliminating all catalytic and scaffolding activities, if there are any biological differences between our degrader and TAK-279. In our experiment, we used a concentration of TAK-279 that was expected to fully occupy TYK2 and a concentration of our degrader, KT-294, that was fully expected to degrade TYK2, and asked if there are any biological differences between the two compounds. The concentrations were determined based on the IC95 of the interferon alpha phospho-STAT2 assay, which is the most difficult assay to inhibit out of all the TYK2-related cytokine assays. And we show, looking at RNA seq data, our degrader has superior inhibition of the interferon pathway signature genes. That's on the left with the 21 gene signature score. And we also see differences in the innate immune pathway, as shown on the right.
And this is due to the fact our degrader fully removes the protein and all possible scaffolding functions, phenocopying human null phenotypes. Note in the clinic, TAK-279 doesn't achieve clinical exposures of more than about 77 nanomolar with 35 mg repeat dose, which is close to their Phase III 30 mg dose. So at clinically relevant exposures, it's very likely that TAK-279 does not even reach these levels of pathway inhibition that we show here. So this is probably one of the most important slides that I'll share with you today for this program. Here we show that our TYK2 degrader, KT-294, can fully deplete TYK2 in vivo. Specifically, we show here that in non-human primates, upon repeat daily low oral doses, KT-294 can degrade TYK2 in a dose-responsive manner and reach full degradation of TYK2 in a well-tolerated manner.
As you will see on the next slide, this type of target engagement is unprecedented in the TYK2 space. Pharmacological pathway engagement is an important additional differentiator of our degrader versus the small molecules in the clinic. We have now observed over several studies that the levels of TYK2 pathway engagement correlate to efficacy. This slide shows clinical efficacy in psoriasis correlates to target engagement, and that TYK2 small molecule inhibitors do not reach maximum target engagement. Here we show the percentage of people who reach PASI 75 at week 10-16 with the antibodies and small molecules in the clinic. You can see there is correspondingly greater efficacy if there is greater pathway inhibition. The biologics inhibit the pathways fully and enable PASI scores of PASI 75 in 90% plus of people, whereas dupilumab achieves no more than 60% inhibition-...
TAK-279, no more than 80%, which reduced the percent of the population with PASI 75 score. We predict that with our degraders easily reaching more than 90% degradation with daily oral doses, phenocopying loss-of-function phenotype could lead to biologics-like activity, clearly differentiating from all other small molecules in the clinic or on the market. So to summarize, a TYK2 degrader and its loss-of-function-like profile has biological differentiation and expects clear clinical differentiation over small molecule TYK2 inhibitors. For psoriasis and psoriatic arthritis, we believe we will have the best anti-IL-23 profile, being able to inhibit the pathway over 90%, compared to a maximum of the small molecules of 80%. For IBD, we believe we will have the best overall profile, with superior IL-23 pathway inhibition, and in addition, spare IL-10, which is necessary for intestinal homeostasis.
Indeed, Tucera, which inhibits the IL-10 pathway, is no longer in IBD clinical trials. For lupus and interferonopathies, we believe both with our superior interferon biology and superior pharmacology of inhibiting the pathway, that we will have an advantage over the small molecules. To summarize what I've shown you today, our oral TYK2 degrader, due to its ability to replicate the TYK2 loss-of-function phenotype that is superior to small-molecule inhibitors, has the potential to be the best-in-class mechanism for this target. TYK2 has well-validated biology. It's a member of the JAK family required for type one interferon, IL-12, and IL-23 signaling. TYK2 is a very well-credentialed drug target, both by human genetics and also with targeted agents in the clinic, validated by upstream biologics and other small-molecule inhibitors across multiple diseases.
The biologics market for type one interferon and IL-23 is estimated to grow to over $20 billion. As shown to you today, our TYK2 degrader, with a potential best-in-class profile and biologics-like activity, can disrupt this large market. Specifically, the KT-294, we have shown you that it's a very potent degrader in the picomolar range, that it recapitulates the human null phenotype biologically, and can degrade the target fully in vivo with low doses, providing a path to full target engagement in the clinic, unlike current small molecule inhibitors. We are on track for an IND and a first in human in the first half of 2025.
I want to close my presentation by reiterating, with TYK2, as we have shown for IRAK4 and STAT6, we have chosen a key target in a validated pathway with large clinical and commercial opportunities, where we have clear line of sight to best-in-class profile, an oral drug with biologics-like activity. With that, I'd like to now turn the call back to Nello for its closing remarks.
Thanks, Jared, Amy, and Juliet. Doesn't matter how many times I see this data, I continue to be blown away. I've rarely seen, if ever, such compelling data sets. So I hope all of you will appreciate what you've seen today and can draw a line from these preclinical data sets into real clinical and commercial value creation, given the well-understood biology of these pathways and our track record of clinical translation. The title says it all: Trying to solve big scientific problems at global scale with small molecule oral degraders. So the next slide, just to recap really our strategy, we've shown you today how our strategy is applied in immunology and what enormous potentials this new class of oral degrader drugs have from patients around the world.
Our target selection principles, undrugged, poorly drugged targets in pathways with clinical and human genetics validations, with large global patient impact, continue to guide us and deliver really exciting programs. So in slide 68, just to summarize where we are, the opportunities and the path forward, for KT-474, IRAK4 degrader, we're currently in phase II studies in HS and AD, with potential to go beyond in a wide variety of other indications. We're excited to read out data from these two trials in the first half of 2025. To remind you, the opportunity here is to have the best-in-pathway drug compared to IL-1 biologics, oral, with a broad anti-inflammatory profile. This program, as many of you know, is partnered with Sanofi, as I said earlier. Sanofi is now fully responsible for all phase II activities.
Before phase III, we will have an option to co-develop and co-commercialize in the U.S. and sharing profits and costs 50/50, while we will have tiered royalties in the rest of the world. For STAT6 and our KT-621 program, whereas, as Amy said, we're in IND-enabling studies with the goal of filing an IND and initiating our phase I very soon in the second half of the year. As I mentioned, the clinical opportunities are vast, from large diseases like AD, asthma, COPD, to others like EoE, PN, and many others that we intend to enter, which at this point, we will not be disclosing. The opportunity here is to change, as has been said already today, how Th2-driven inflammation is treated with an oral drug that has the activity of a biologics, like dupilumab. Important to note that this is a wholly owned program.
Finally, for TYK2, where we expect to be in the clinic in the first half of next year, 2025, the opportunity is to deliver a best-in-class TYK2 agent that will have a clinical profile that can compete with existing pathway biologics. In diseases that we all know are impacted by this pathway, IBD, psoriasis, psoriatic arthritis, lupus, and others. This is another really exciting opportunity for us, and like STAT6, this is also wholly owned program. So slide 69, we truly believe we're building the best in class in industry oral immunology pipeline. We're targeting these undrugged or not fully drugged nodes in key validated and critical pathways. In addition, these are biologically complementary pathways that we intend to build synergies across as we advance our drugs in clinical development.
Obviously, if we are able to deliver in the clinic the profiles we've shown you today, and we fully have the confidence that we'll be able to do that, this program is of enormous market potential, each with multibillion-dollar sales potential based on the current market of approved drugs in the targeted disease areas. On slide 70, finally, looking at our immunology pipeline in full, you will see we have truly an exciting series of programs with truly trajectory-altering data readouts in 2025. We'll have 2 phase II studies read out from HS and AD with KT-474. We'll have key de-risking and validating phase I study data with our STAT6 degrader, KT-621, where we'll have an opportunity to demonstrate our dupi-like profile. We'll also have phase I data with our TYK2 degrader, KT-294, which will allow us to de-risk and confirm our best-in-class profile in the TYK2 space.
Again, all of this happening within our guided cash runway of first half of 2026. As you can expect, our team is working hard in a lot of exciting areas of immunology to advance the next wave of programs in the clinic. These are all areas where, again, an oral degrader will change treatment paradigm. So it will be in areas like plasma cell biology, humoral immunity, respiratory and GI inflammations, and others. We will share these as they approach clinical development, as we always do, as we plan to do with our STAT3 program in I&I. So the next slide, just to give you a more complete view of our clinical and soon-to-be clinical pipeline.
So today we focused really only in immunology, but I didn't wanna leave you without showing you also exciting data readouts that we'll have in 2024 from our ongoing clinical oncology pipeline, both with KT-333, our STAT3 degrader, and KT-253, our MDM2 degrader. We have data from our comprehensive phase I campaign in dose escalation. In both of these programs, we've already shown early proof-of-concept data, so this will be the comprehensive data and late, late-stage development plans that we, that we will be disclosing around midyear of 2024. So stay tuned for those two. So on, on the last slide here, obviously, we had a very data and information, information-rich series of presentations. I'm sure you can tell by our tone today, we're extremely excited about where we are and where we're going at Kymera.
We're happy to engage all of you today, in the next few days, and weeks, and months. I wanna leave you with the goals for the year. As you've heard already, Sanofi is running our phase II study, so we wanna make sure to support them as well as we can to complete the enrollment of both the HS and AD studies this year in 2024. We wanna make sure we're able to initiate clinical dosing for our STAT6 degrader, KT-621, our phase I study, and we wanna have KT-294 IND ready by the end of the year. And then, as I just mentioned, we will have additional oncology proof-of-concept data for KT-333 and 253 during 2024. So I'd like to finally thank the Kymera team. They are the ones responsible for driving the science you're seeing today.
I also would like to thank all of you for the attention. We'll now break for a couple of minutes and meet you all again for a Q&A session. Thank you.
... Ready for Q&A. Operator?
For the Q&A section of today's session, we will be utilizing the Raise Hand feature. If you would like to ask a question, simply click on the Raise Hand button at the bottom of the screen. Once you have been called upon, please unmute yourself and begin with your question. If you have dialed in, please select star nine to raise your hand and star six to unmute. Please limit yourself to one question and a related follow-up. Our first question will come from Eric Joseph with J.P. Morgan. Please unmute your audio and ask your question.
Okay, great. Well, thanks for taking the questions. Thanks for hosting this R&D Day. Certainly lots to digest here. A few questions from us. I guess for both of these novel degraders that you're highlighting today, can you talk a little bit about sort of the E3 ligase that's engaged here, and the extent to which it shares similarities with that of KT-474? I'd also like to get a sense of, when you-- for the STAT6 program, you've highlighted, you know, a lot of data looking at the proteomic profiling. I guess beyond the STAT6 family of degraders, are there other transcription factors or proteins that are engaged? Maybe a little more clarity you could offer there.
And then on the TYK2 degrader, can you talk a little bit about sort of how much additional clinical headroom you think remains in psoriasis on top of KT-294, and to what extent you've explored that in non-clinical models, given the, you know, the higher degree of pathway inhibition you're seeing with your degrader compound versus Takeda's? Number of questions in there. I'll leave it there.
Yeah, no, that's a lot.
Yeah.
I had to write it down. But thank you for the question. So I'll start, and then I'll pass it to the team. So on the E3 ligase, we're not gonna comment on which E3 ligase we're engaging. Rest assured, as we've done in the past with all of our programs, we always make sure that the E3 ligase that we use is, first of all, expressed at relevant levels in all the disease-relevant cell types. As Amy showed you, and Juliet, for both programs, we have extremely robust degradation in all the relevant cell types. So we always make sure that we use the right E3 ligase for the right program.
We de-risk the chemistry, the biology, and so I would say it's consistent with all the work we've done on IRAK4, without going into the details. And the reason is, you know, again, we spend a lot of time and resources to build exceptionally competitive programs. Hopefully, you all will agree, and so we wanna be able to continue to retain that knowledge. On the selectivity, just quickly, at STAT6, I think Amy highlighted the on the proteomics, the other STAT, just because they are the, you know, the homologues that people will think about. But obviously, all the other proteome is also in the noise. As Amy said, this is the...
One of the most compelling selectivity profile we've ever seen in this company over the past seven years, both in terms of proteomics as well as, a functional pathway engagement. On the TYK2, which is a great question, I'll pass it, to, to maybe both Juliet and Jared. Maybe, Juliet, you can comment a bit more on, you know, why we believe there is a strong biological differentiation, and then, Jared, on what that clinical translation might look like.
Yeah. So, you know, as I showed in the presentation today, by completely removing the protein, i.e., eliminating all scaffolding effects, we have a biological differentiation. We also believe we have, again, a great pharmacological differentiation as we so deeply inhibit those pathways, which none of the small molecule inhibitors are able to do, because none of the small molecule inhibitors, being occupancy-driven, recapitulate human loss of function, completely removing the scaffold and all biological functions.
Maybe, Jared, on the clinical headroom.
Yeah.
I mean, maybe generally, you can comment on psoriasis, but generally.
I think generally speaking, I think we believe that, you know, the biologic differentiation, which we think is quite clear relative to the small molecule inhibitors, will translate into clinical differentiation across multiple different indications, whether it be psoriasis, or, you know, lupus, or even, inflammatory bowel disease. I think both because we have the superior pharmacologic engagement with the degrader relative to small molecule inhibitors, but also this greater impact on the interferon pathway, in addition to having a very strong effect on IL-12/IL-23. So I think that there still is plenty of room for development, you know, in psoriasis, for example, even though there are active drugs, I think we can be more active, you know, given our biological differentiation, relative to the other small molecule inhibitors, including the TAK compound.
I think there are real strong opportunities for us in lupus, for example, which is an interferonopathy, where that interferon component is essential, where we've shown preclinically that the TAK compound, you know, has inferior impact on the interferon pathway compared to our drug.
... and then of course, in inflammatory bowel disease, where because we spare IL-10, we think relative to the non-selective TYK inhibitors like Tucera, we can be quite active even in inflammatory bowel disease. So we're very confident in being able to be active, you know, across multiple different indications, including psoriasis.
Thanks, Jared. The only thing I would add, Eric, is, you know, and we'll, we'll talk about, I'm, I'm sure dupilumab and, and, and the IL-4/13 pathway. I mean, we're in the early innings of understanding where the- even in the case of TYK2, where this biology is most relevant. I think it was obvious and, and made sense for the first indications to be the ones that others have pursued. But the IL-23, IL-12 interferon biology is broadly reaching across so many disease types and tissue types, and I think it is our opportunity here to build on this best-in-class profile. For sure, biologically, we have a best-in-class profile, and obviously, to be determined clinically, to, to, to go even beyond what, what is being explored right now in the clinic. Maybe I, I'll close it there. Maybe next one-
No, that's great. Well, thanks for taking the-
Yeah. Sorry. Thanks, Eric. We'll see you soon next week.
Our next question comes from Marc Frahm from Cowen. Please unmute, unmute yourself and ask your question.
Hey, thanks for taking my questions and walking through all the data on all the programs. Maybe just following a little bit on some of the topics you were discussing with Eric just before. Just, Nello, how do you think about kind of indication prioritization, particularly for the STAT6, right? You know, Dupi will have been on the market in some of these early ones, where it's generating lots and lots of sales today for, you know, maybe as much as a decade. But, yeah, there's newer indications that it will be adding and other places that you, I think, even alluded to in the presentation, where maybe it's... you know, you, you're not even behind 'cause the development programs are really just starting. Just how do you approach that?
Is it best to go after those big early indications or the more modest, but still healthy-sized indications that maybe it's not as entrenched?
Yeah, I mean, you know, I'll start by saying that, you know, as you know, this is an area rich of opportunities and, you know, dupilumab is, I would say, you know, the best in pathway drug that is approved so far. As you know, there are many other drugs in this pathway, you know, all injectables that are pursuing areas of exploration that dupilumab has already gone through. So we're gonna be just a bit more careful with disclosing our plans today, just because I think we wanna be able, as Amy said, to be not only first line, but also best line in all of these opportunities. And so we have to be really thoughtful about the sequencing of development.
What I will say, and I'll try and answer your question a bit, too. What I will say is that personally, I've never seen in my experience, this is 20-year plus, is an oral small molecule that can match or be superior to a monoclonal antibody in terms of potency, distribution, in vivo profile, efficacy. So I think we have something unique in our hands, and I feel like this utmost responsibility, to do the best job possible to develop what could be, in our view, one of the best, biggest drug in industry. So the sequencing is gonna be really important. I think we have to go into diseases that have, large opportunities. I think we will have to go into atopic derm, we will have to go into COPD, we'll have to go into asthma.
But there are other indications that, you know, and other diseases that have been reported by even patients that take the drug, there are secondary comorbidities. For example, in AD patients, we know that a lot of patients benefit from the drug, in case the comorbidity might be food allergies or other type of Th2-driven inflammation, GI inflammation. So there are opportunities that we will be pursuing based on the emerging biology that is both clinical and preclinical, that we're building here at Kymera. I think as we get into phase II studies, which will happen as early as 2025, right, early as probably next year, you know, we will be able to talk about some of the details.
Our next question comes from Bradley Canino with Stifel. Please unmute your audio and ask your question.
Hey, thanks, everyone. Appreciate hearing the updates today as well. Maybe just for the STAT6 degrader, you know, if I'm to contrast that with IRAK4, where you obviously had the interesting PD effect in your early studies, you even had that early clinical signal in patients, but the mechanism has to be validated by your own phase II. With STAT6, are you going to be able to look at any of the phase I PD data with higher clinical relevance? Thinking of things like IgE levels, chemokines, and such.
Yeah, I'll let, actually, Jared answer this one. My—the only thing I would say is that the linearity of biology between the IL-4 receptor alpha and STAT6 is basically completely aligned. And so I think our ability to show blockade of the pathway is 100% validation of our later clinical development. Now, obviously, there are nuances. Maybe, Jared, you can address how we can think about early validation.
Yeah, I think there are, Brad, you know, early biomarkers that can be looked at even in healthy volunteers, that can tell you whether you're impacting, you know, the IL-4/IL-13 pathway. So there are circulating biomarkers like TARC and IgE, that can be looked at and have been looked at even with dupilumab in prior phase I studies, where you can get a sense in healthies, not just that you're knocking down the target, for example, in blood and skin, but that you're also impacting the function of the pathway by looking at those biomarkers, even in healthies. We also plan, you know, on having an accelerated development path here for STAT6 and moving, you know, quickly from healthy volunteers into patients, to be able to show early proof of concept, you know, in indications of interest to us.
I think that will give us an opportunity, you know, early in development, to not just show impact again on STAT6 and on biomarkers, but also on clinical endpoints in patients after we show that initial proof of concept in healthy volunteers.
Maybe the only thing I would add, maybe a, an abused sentence in the field, but I think it's extremely relevant here. I think we get to stand on the shoulders of giants in the space. I think the work that Regeneron and Sanofi have done in this pathway is exemplary on how one develops a novel drug in a, at that point, you know, novel pathway and unlock a wide variety of diseases. So we are fortunate to being able to follow all that work and obviously bring this, this, this novel drug that we believe will be, you know, disruptive and superior to what's out there.
Appreciate it. Thanks.
Thanks, Brad.
Our next question comes from Gospel Enyinna with Morgan Stanley. Please unmute your audio and ask your question.
Good morning, everyone. This is Gospel Enyinna. And we have two questions. The first one is, what can you tell us about the size and scope of the planned phase I studies? How many patients do you intend to enroll, and what would be the split between patients and healthy volunteers? And additionally, do you plan to nominate additional I&I programs in the near term, or will I&I pipeline expansion depend on the initial data from STAT6, TYK2, and your IRAK4 programs? Thank you.
Yeah. Thanks, Gospel. Good to see you. You know, these are gonna be pretty quick, so I'll take them probably myself. On the first one, we're not talking about clinical trial designs at this stage, as I mentioned earlier for the reasons I mentioned earlier. We're happy to do so as we get into those studies. On the expanding immunology pipeline, I mean, you know, what I will say is that Juliet and her team are doing an amazing job, as you're seeing today, right? These are data that have been generated in the past, you know, two, two, two and a half years. You know, creating and generating and advancing novel programs that address these undruggable targets in extremely relevant, validated pathway with large opportunities.
We have other programs that are, you know, I would say... I mean, it's hard to say just as exciting as this one because, you know, it's difficult to continue to deliver that, that level of excitement. But I, I think I will say that just as exciting as these, that we'll be announcing, we'll be disclosing, you know, in the next few quarters and, and probably, you know, around this time next year. I think what I said earlier, which I think is important, we are committing to a heightened investment in immunology, and you're seeing the results of it. I think we're building what I truly believe to be the best in industry oral immunology pipeline. I truly believe that.
But we also have activities in other disease areas, so stay tuned that, you know, as early as next year, we'll have other exciting programs to share.
Awesome. Thank you.
Our next question comes from Eliana Merle with UBS. Please unmute your audio and ask your question.
We can't hear you, Eli. I don't know if you're muted. No. Can you guys let her know? Oh, there you go.
Can you hear me now?
Yeah, there you go. Yes.
Okay, awesome.
We hear you.
Love that. Maybe just taking a step back, can you elaborate a bit more on your broader priorities and strategy for the company overall? Just you have a lot of different potential areas across oncology, your platform work with novel E3 ligases and molecular glues, and then, of course, here, I&I. Maybe just how are you thinking about the prioritization across these? And I guess, are there certain programs or areas that you think make more sense to keep wholly owned versus others that make more sense for collaborations? Should we think of, say, the IRAK4 collaboration with Sanofi as maybe a template that you might seek with further programs, or just curious your thoughts on how you're thinking about the strategy there going forward.
Yeah. No, thanks, Eli. It's a great question. So I will start with saying that, our strategy has been consistent, and it's been refined. Our strategy is focusing this really powerful modality on undruggable targets. And you've seen, we're really narrowing the scope on transcription factors because these again, we gotta do things that other technologies can't do or multifunctional proteins in pathways that have been validated in areas that we believe have meaningful patient impact. And now, what I will say, how has the strategy been refined? I think what we've learned is that these degraders can have really compelling profiles, especially in pathways where there are again validated biologics where we can deliver the same level of pathway blockade.
We have learned through our own experience and the evolving space in immunology, that this area right now feels really ripe for this concept. I think the programs you're seeing today, I mean, I think they're gonna be huge. They're gonna be huge programs for patients, for us, Kymera, for our shareholders. I think it feels like the really, an area where we found that win-win combination of technology potential impact. So this is an area where we are spending a lot of time, resources, and we're gonna be in the clinic spending a lot of time and resources. I would say that immunology right now, in the next 2 to 3 to 5 years, will be where we spend a lot of time and resources in the clinic.
That does not mean that we're not working in other areas. We have exciting programs in oncology that we have data this year. And as long as the profile continues to deliver high potential patient impact, those will continue to be areas that we put a lot of resources and time on. Now, as a company, we're not gonna be able to develop on our own all of these programs, you know, realistically, all the way through registration. And so we'll find opportunities where we can create those win-win partnerships, where it makes sense, when it makes sense for particular programs. I think where you won't see us doing collaborations, are the ones that, you know, we did with Sanofi many years ago.
I think it made sense to do it at that time, but you know, for programs that have large opportunities, you know, we're well-capitalized, we know what we're doing here, and so we wanna be able to drive maximal value. Before we start thinking about, you know, commercializing a $20 billion, potentially $20 billion drug, how do we do it? What is the best combination of internal versus external resources? So I don't know if that answered your question, but that's what the way we're thinking about our growing pipeline.
Mm-hmm. Great. That's, that's helpful. Thanks.
Our next question is from Michael Schmidt with Guggenheim. Please unmute your audio and ask your question.
Hey, guys. Thanks for taking my questions. Happy New Year, and, you know, thanks for the detailed update. Couple of questions on KT-294, the TYK2 inhibitor. So, do we know if the role of the scaffolding function does it differ in the various possible disease states? And if so, could that inform your development plans early on? And then secondly, the TYK2 inhibitor class, obviously, so far has avoided black box warnings. That is, for example, associated with the JAK1 inhibitors. You know, how confident are you in the potential clean safety profile with a much more potent degrader approach relative to the inhibitors that are out there? Thanks so much.
Thanks, Michael. So maybe I'll answer the second one, and maybe, Juliet, you can talk about the different scaffolding, if there are different scaffolding functions in different, disease contexts. I think we have data that shows, that shows that. So on the second one, I mean, I think the way we view the safety of this drug and of this mechanism is, you know, continue to look at human genetics. We know that, you know, there is loss of function in humans, with TYK2, and we know that they're actually healthy adults with some susceptibility to, to mild infections, but beyond that, no, no other, you know, major concern. And so again, as, as we've done in the past with IRAK4, our North Star is following human genetics, which actually supports a degrader approach, supports the elimination of the protein.
So, Juliet, you want to talk about the scaffolding?
Yeah. So, I mean, we've looked with our degrader in multiple different cellular contexts. So we understand that in all of those contexts, the scaffolding role is important. And then what we've also done in some contexts is look at downstream biology, and we've shown that compared to small molecule inhibitors that disrupt some scaffolding functions, by completely removing the protein, we're really able to disrupt more biology, really recapitulating that human loss-of-function profile. So we believe that, again, with our degrader being catalytic and enabling us to capture all biology scaffolding functions, that we will have something differentiating.
I was just gonna... If you guys excuse me, looking at the slides. So if you guys—actually, the slides are now on our website, so everybody can look at them. On slide 61, you'll see that we basically have done the RNA experiment, right? Looking at full inhibition versus full degradation, and then look at how all these genes moving, and you see that both in interferon and in innate immunity, we see a separation of the biology. That's not a potency difference, but it's a biological difference. So now then, you think about the interferon innate immunity, where do they play? Obviously, they play across the board in all of these diseases, and that's really what we're gonna be exploring in the clinic with this program.
Thank you.
For the interest of time, so we can get all the questions answered, if you could please limit it to one question. Thank you. Our next question comes from Kelly Shi with Jefferies. Please unmute your audio and ask your question.
Thank you for taking my question, and congrats on the progress. Maybe just a quick follow-up on the safety, and I also have a IRAK4 question. It's just: do you have a non-human primate safety data?
... to share. And also, I think my main question is on IRAK4 program in HS. Curious, based on the IRAK4 associated cytokine profile in comparison to IL-17 signaling pathway, do you anticipate KT-474's treatment efficacy, mostly achieved in similar patient base for IL-17 drugs or in broader patient base? Thank you.
So maybe, Amy, you can comment on the non-human primate, you know, the doses and the exposures?
Yeah
-on STAT6.
We have done non-GLP safety study in multiple clinical species. So we've done it in non-human primate, and with dose as high as 300 MPK daily for 14 days, as we show in the presentation, and we reached a concentration really high, 40-fold over our predicted human applications concentration. And KT-621 was very well tolerated, no adverse event, no relevant finding.
Thank you. Jared, do you want to take-
Sure. I think, I think on the KT-474 question, and IL-17, we know IL-17 targeted drugs are active in HS, clearly. KT-474, you know, has a different mechanism, because it's impacting signaling through toll-like receptors and IL-1 receptors. It has a broader anti-inflammatory effect. So not only is it blocking signaling by multiple different IL-1 family cytokines and by TLR agonists, it's also preventing the elaboration of multiple different cytokines, including IL-17, TNF, interferon gamma, that are driving HS. So our expectation is that KT-474, by having a broader anti-inflammatory effect, could be at least as good as IL-17 targeted agents, you know, if not better.
We don't really look to compare our drug to a more targeted IL-17 type drug, but rather we look at the opportunity for IRAK4 as potentially even broader because of that pleiotropic effect on multiple different cytokines that are driving the inflammation that one sees in HS.
Maybe just to add a small thing.
Yes, thank you.
I mean, we're... Yeah, we're not running a study right now to compare it to an IL-17 biologics. We're really running a study to evaluate the clinical activity versus placebo, and that's really our key, hopeful, good outcome for the study. Just to be clear. Thank you.
Great. Thank you.
We're trying to also have one answer instead of several, so we save time as well. That's on me.
Our next question comes from Thomas Smith with Leerink. Please unmute your audio and ask your question.
Hi, everyone. Good morning. This is Will on for Tom. Our question is, do you have a sense of if there are specific levels of degradation for STAT6 or TYK2 that you believe is necessary to drive a clinically relevant, therapeutic effect? And then a second question being that today's announcement really does seem to reaffirm the focus on INI. Can you provide just some color on how you're thinking about resource allocation between INI and oncology going forward in the next couple of years?
Great. So maybe, Amy, you can comment on the level of degradation in the preclinical species, and then I'll answer the second question.
Yes. You can see from our presentation that in both the skin and lung preclinical model, efficacy model, we've shown that 90% STAT6 degradation is sufficient to show comparable or even superior efficacy compared to dupilumab. And so that's kind of like our efficacy target. But in the preclinical, we're targeting, like IRAK4, we're targeting depletion, and then we can evaluate those in the clinic.
Yeah, I think what's actually – I found it. Sorry to do the double answer.
You're fine.
What I found actually quite compelling is even the lowest dose in all of our models, which is usually around 70%, right? It's all active, and not that far from dupilumab. So that shows you that these compounds are quite potent, and we'll have so much room in the clinic to evaluate doses and related efficacy. To your first question, you know, as I mentioned, we've decided, this is three years ago, to invest further in immunology for the hopefully the reasons that you're seeing today and hopefully you'll see in the next few years.
Obviously, this is now an area that has and will have the majority of our spend going forward, just based on the number of programs and the indications that we're pursuing. But again, I will reiterate that it's not gonna be the only area that we will be focused on. As I said, we have exciting oncology programs, and I think the ability for us to continue to grow the company. It's only going to be based on our ability to execute, be successful for patients, for us, change our cost of capital, and grow this company to become a disease-agnostic protein degradation company. That has to be our goal.
Now, what we've decided to do, and hopefully everybody agrees, that in the short to medium term, we wanna be able to, you know, drive that success in areas that where we built a lot of capabilities, and that's where the immunology focus is coming from.
Our next question comes from Kalpit Patel with B. Riley. Please unmute your audio and ask your question.
Yeah. Hey, good morning. Thanks for taking the question. Just one more question here on safety. I know you have the non-human primate data, maybe those are shorter term.
... data, but how should we think about long-term depletion of STAT6 given its maybe potential expression in normal tissues? You know, aside from risk of infections, is there anything else that you would recommend watching for when you inhibit this pathway?
Thanks, Karl. Good to hear from you again. Yeah, no, it's a great question. So the way we think about this, so we have obviously preclinical data. As you mentioned, obviously, it's limited time. I think the most compelling part of safety for this pathway, in our view, is that, you know, STAT6 and IL-4 receptor are linear, meaning that they have a direct interaction. So there is no IL-4 receptor signaling without STAT6. And so we have now years of safety on blocking IL-4 receptor fully for years, and because the biology is totally coherent, again, there is no IL-4 without STAT6, and there's no STAT6 without IL-4, we expect that blockade of STAT6 will be as well tolerated as blockade of IL-4. Obviously, the time and data will tell.
I cannot guarantee as, as you guys know, but that's where our rationale is coming from.
Can I just add that actually, our molecule is extremely selective, as you can see from both the proteomic data with degradation selectivity and also the functional selectivity against all the other stats. So that actually adds to the variable safety as well.
That's true. Thanks.
I think it was also mentioned earlier, but the STAT6 knockout mouse, you know, has no phenotype, so that also gives us confidence that we can degrade STAT6 deeply, chronically, without there being any safety consequences.
Thanks. Great. Next question? We've got, what, a few-
Our next question comes from... Our next question is from Kripa Devarakonda with Truist. Please unmute your audio and ask your question.
Hey, guys. Thank you so much for taking my question, and thank you for the presentation. It was very educational. You know, I think this question has been asked a couple of times before, but I'll just put it in another way. You know, based on what you've seen before, do you believe there is something inherent in either the biological pathways or the proteins that are involved in immunology that makes it more amenable to TPD? And sort of a similar question is, you know, you've targeted both the kinase and scaffolding part, which is challenging with small molecule inhibitors, and also now a transcription factor, which also historically has been challenging.
So, how, as you choose the targets, you know, how much do you focus on there is biology and there is genetic evidence there, but it's challenging and no one else can do it, versus, you know, indication, unmet need?
I think it's so it's a great question, Kripa. It's both. It's one, you know, as I said earlier in the presentation, I think a platform is only as good as the targets that the platform goes after and as good as the products that it generates. And that's just the reality of it. So for us, target selection is the most fundamental exercise that we run at Kymera probably every month, Juliet, at this point, where we brainstorm about what's the next target. And for us, it has to solve two problems. One, they need to be targeted where only protein degradation can deliver the best solution. And so, as you see us, we don't go after targets that can be equally drugged by other modalities.
So we have found ourselves that scaffolding proteins, transcription factors, are things that other modalities don't go after, can't go after. But then there has to be an overlap between the technical solution and the disease solution. And so what we're trying to marry here, an example is STAT6, right? And drug transcription factor. I've been in pharma before Kymera, and STAT6 had been discussed for a decade in the pharma industry. Nobody has been able to do it, right, so far. Why has it been discussed for many years? Because of the disease, right? We, we've learned the IL-4/13 pathway is validated. Again, Dupilumab probably will be the biggest drug in industry soon. And so now we can marry the technical challenge with impact on disease, and that's really our target selection strategy.
So we are trying to marry two in every program that we develop. In immunology, so why in immunology, the question? There's not something unique in immunology. I think what we found that is unique in immunology today, as I shared earlier, is that, you know, almost all drugs are biologics, 75% are biologics. The small molecule inhibitors work, they don't work as well, and we believe, and we've shown already some early data, and today even more data, that a degrader can match that biologics profile. So it's like now you're marrying three things, right? The target, the disease, and the ability to be commercially competitive.
Our next question comes from Adam Vogel with Wells Fargo. Please unmute your audio and ask your question.
Hey, team. Thank you for taking the questions today from us. Congratulations on all the exciting developments, too. Maybe on KT-294's ability to avoid IL-10, how does this come into play as you think about prioritizing IBD indications, or maybe even more broadly across the other indications you touched on today? You know, is this something you're thinking about in terms of indication, selection, and ability to differentiate?
... Thanks.
Yeah, I mean, I think what you're pointing to, the fact that IL-10 sparing is important, we think, for success in IBD, and the fact that Deucra was not able to spare IL-10 might be one reason why that drug was not active in IBD. This obviously becomes an important indication opportunity for us, where IL-10 sparing can be joined with strong anti-interferon activity and strong anti-IL-12/23 activities. We think that's a great opportunity for this particular degrader. But with that being said, we think that there are a multiplicity of opportunities here for development for this drug based on other biologic differentiation as well, that we've, I think, discussed in other questions.
So yes, IBD is of great interest to us, in part because of that IL-10 sparing advantage, but we think there are also very compelling opportunities in lupus and psoriasis and in multiple other indications. Again, coming back to the biologic differentiation versus small molecule inhibitors, and how that differentiation can really drive development opportunities for us with this particular compound.
Our final question comes from Susan Chor with Bank of America. Please unmute your audio and ask your question.
Hi, thank you for the question. I'm on for Geoff Meacham from Bank of America. So I know you've already gotten a number of questions on safety, and just in line with that, where do you anticipate your drugs when they reach the clinical treatment landscape in terms of line of therapy? Do you think that this has the potential to move earlier, you know, before TNF alphas, or, you know, anti-steroids? And can you speak to maybe the safety and efficacy and, you know, how those play in? Thank you.
Yeah. So generally, maybe I, I'll answer this question. Thank you. It's, it's a, it's a great question. So generally, what we're trying to bring forth today in a more, let's say, cohesive message is, how the space of oral degraders in immunology is coming together here at Kymera. And the value proposition we're bringing forth is, is around oral degraders that have biologics-like profile. So if you go there, if you go with that profile in the commercial space, and again, I'm talking years ahead in, in many cases, I, I think we will be. We, we have the potential to be in, in a, in a dominant place where, we, we can, we can choose, to be, competitive, with the existing first-line biologics because we might be able to match their efficacy profile, but also bring the convenience.
I think going earlier, let's say, in moderate disease or mild disease, that is, I would say, a dream that we have, especially in the STAT6 pathway, that, you know, as a potential expansion, given... You know, assuming, again, the efficacy and the safety, because there are so many patients worldwide with Th2 inflammation, and whether it's, you know, one drug or multiple drugs, that will allow us to accomplish that. But I think there is a unique opportunity to really address tens of millions of patients that have many of these diseases that are not addressable right now by first-line biologics, because of expenses and access and all these issues. So it's definitely on our mind, and I think will be part of the story of this company going forward. So I think this was the last question.
I want to thank everybody for joining us today. I know it was early in the year, it was early in the year for everybody. Hopefully, you've enjoyed and our enthusiasm was visible, and we're happy to follow up with all of you in the next few days, as I mentioned. And, you know, we're excited about where we are today. We have a lot of upcoming, interesting, new disclosures, both in 2024 and 2025, and so we'll look forward to catching up then.