Kymera Therapeutics Q1 2025 Earnings Report

Kymera Therapeutics EPS Results

• Actual EPS: -$0.82
• Consensus EPS: -$0.92
• Beat/Miss: Beat by +$0.10
• One Year Ago EPS: -$0.69

Kymera Therapeutics Revenue Results

• Actual Revenue: $22.10 million
• Expected Revenue: $11.38 million
• Beat/Miss: Beat by +$10.72 million
• YoY Revenue Growth: +114.60%

Kymera Therapeutics Announcement Details

• Quarter: Q1 2025
• Date: 5/9/2025
• Time: Before Market Opens
• Conference Call Date: Friday, May 9, 2025
• Conference Call Time: 10:00AM ET

Kymera Therapeutics (NASDAQ:KYMR), a biopharmaceutical company, focuses on discovering and developing novel small molecule therapeutics that selectively degrade disease-causing proteins by harnessing the body's own natural protein degradation system. It engages in developing IRAK4 program, which is in Phase II clinical trial for the treatment of immunology-inflammation diseases, including hidradenitis suppurativa, atopic dermatitis; STAT3 program for the treatment of hematologic malignancies and solid tumors, as well as autoimmune diseases and fibrosis; and MDM2 program to treat hematological malignancies and solid tumors. The company develops STAT6, a Type 2 inflammation in allergic diseases; and TYK2, a treatment for inflammatory bowel disease, psoriasis, psoriatic arthritis, and lupus. The company was incorporated in 2015 and is headquartered in Watertown, Massachusetts.

Kymera Therapeutics Q1 2025 Earnings Call Transcript

Key Takeaways

• Chimera introduced its next immunology program, IRF5, emphasizing its strategy of using targeted protein degraders to develop oral therapies with biologic-like efficacy in immune inflammatory diseases.
• The lead STAT6 degrader (KT-621) showed preclinical dupilumab-like activity; Phase Ia healthy-volunteer data are expected in June, Phase Ib atopic dermatitis results in Q4, and Phase IIb trials in AD and asthma will start in late 2025/early 2026.
• The first-in-class IRF5 degrader (KT-579) achieved potent, selective target knockdown and superior efficacy versus standard of care in lupus and RA preclinical models, with IND-enabling studies underway and Phase I planned for early 2026.
• Chimera decided to pause its TYK2 degrader (KT-295) to prioritize the high-value STAT6 and IRF5 programs and extend its cash runway (currently ~$775 million) into the first half of 2028.

Presentation

[Justine Koenigsberg, VP - Investor Relations at Kymera Therapeutics]

Good morning, and welcome to Chimera's immunology innovation day, our virtual event to introduce our next immunology program, IRAV five. I'm Justine Koenigsberg, Chimera's head of investor relations. Please note that we are hosting today's event in lieu of our regularly scheduled quarterly update call. However, we have reported our results and filed our 10 Q this morning. For additional details on our Q1 results, please reference our press release issued this morning, which is available in the IR section of our website.

[Justine Koenigsberg, VP - Investor Relations at Kymera Therapeutics]

During today's presentation, you'll hear from our team about our strategy, our pipeline advancements, and our next high value immunology program. Joining me this morning are Nella Manalffy, our founder, president, and CEO Jared Gollop, our chief medical officer and Veronica Campbell, our senior director of immunology and project team leader of our newly introduced program IRAF five. Here's a snapshot of today's agenda. Nella will begin with an overview of our strategy and the opportunity with small molecule degraders. Then Jared will provide a high level overview of our STAT six program, and we'll conclude with our prepared remarks with a discussion of our newly introduced IRAF five program before we open the call to questions.

[Justine Koenigsberg, VP - Investor Relations at Kymera Therapeutics]

If you'd like to ask a question, please use the raise hand icon, which can be found at the bottom of your meeting window. To help us move efficiently through the Q and A discussion, we ask that you are ready to unmute your line and turn your camera on when called upon. A replay of today's event, including a copy of our corresponding presentation, will be available soon after the call concludes in the Investors section of our website. But before we begin, I would like to remind you that today's presentation 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.

[Justine Koenigsberg, VP - Investor Relations at Kymera Therapeutics]

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. With that, let's begin. Nello?

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

So thanks, Justine. Very exciting to be here today to share not only a pipeline update, but also our new program, IRF five, which Veronika will do in a few minutes. I thought I'll take a few minutes here to just give you an update on our strategy, where we're going, some important decisions we're making and upcoming milestones. So just to remind you, Chimera was founded about actually just very recently, nine years ago, with the goal of building an industry leading pipeline of medicines using a novel modality called targeted protein degradation. We believe with this modality, we can give rise to a series of new programs and medicines that can overcome the challenges that industry has faced for the past twenty years.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

In order to do so, we built some unique capabilities. I will start with the fact that we have become a key leader in the space of targeted protein degradation. We in doing so, we built some really unique capabilities of heat finding and optimization of oral degraders. We have we've always had and continue to refine a unique target selection strategy based on pursuing traditionally untracked targets in highly qualified and validated pathways. And that has allowed us to build a portfolio that is poised to really disrupt treatment paradigms.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

We have made a conscious choice a few years ago to focus in immunology. And the main reason has been, as I'll explain in a few slides, that in that particular space, in this place and time, we've been able to combine really the right target with the disruptive potential of targeted protein degradation, delivering for the first time in industry oral drugs with biologics like efficacy. And this is really a unique opportunity for Chimera and for patients. So Chimera is founded and continues to thrive on three key pillars. One is a clear vision.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

So we have always believed that with a new technology, not only you have an opportunity, but you have a responsibility to building a fully integrated company. So we are now building deep development capabilities to advance our programs into Phase II and Phase studies with an eye of becoming a commercial stage company. We've been fortunate to always be well capitalized. We now have, as of the end of Q1, dollars '7 '70 '5 million with now an extended runway into the first half of 'twenty eight. We have brought five new molecules in the clinic since 2020, and we are on path to being able to deliver 10 molecules in the clinic by 2026.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

We have dosed at this point way more than 300 between healthy volunteer patients across our pipeline. And one thing that we're very proud of is our ability to continue to demonstrate impeccable translation from our preclinical studies into the clinic with achieving in all of our programs more than 90% degradation with the desired efficacy and safety profile. So just a quick summary about targeted protein degradation. So the the main feature of the technology is the ability to use small molecules to remove protein. So you have almost a a genetic like knockdown or knockout effect with the flexibility and the convenience of oral small molecules.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

So we're able to go after proteins that have not been drug or drugged fully for the past decades with a simple oral drug that we're able to design, synthesize, and develop here at Chimera. So why immunology? Why is this such a unique opportunity for us and I would say for patients? So we well, the team did a work in the past year or so looking at the most common the 10 most common immune inflammatory diseases. And those are, you know, AD, asthma, COPD, as you can see from the slide, HS, multiple sclerosis.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

And if you look at the seven major markets, that's about one hundred and sixty million patients that are impacted by these diseases. And if you look at the number of patients that are right now are accessing advanced systemic therapies, it's really around five million. So we basically have a three percent penetration of advanced systemic therapy into these wide variety of immune inflammatory diseases, again, in the seven major markets. So I don't think we have a problem of innovation in immunology. There is plenty of great drugs in many disease areas.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

We have a problem of allowing patients to accessing these highly effective drugs. In fact, of these five million patients, twothree of these patients access biologics. So only onethree access oral drugs, and these oral drugs often are not able to deliver the type of efficacy that biologics can. So we have an opportunity to expand access and expand the reach of highly innovative drugs with oral degraders that have the efficacy of these advanced systemic therapies. And so when you try to put a number on the market, obviously, it's really hard to do.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

If you look at the five three percent, the 5,000,000, it's a $100,000,000,000 market or more than $100,000,000,000 market. So we're talking about ninety percent plus of patients that we believe could be poised to receive our novel oral systemic therapies, and that's a very large number that, obviously, it's even hard for us to quantify. But our job here at Chimera is to develop, again, as I said, oral drugs that can not only displace biologics because they ideally and hopefully will have a similar efficacy, safety profile and the convenience of oral drugs. But more importantly, we can now offer a convenient, highly effective advanced therapy to the ninety percent of patients that right now are not treated, whether it's for access, whether it's for pricing, whether it's for convenience. And so here in this slide, it's really highlighting what are the challenges and the opportunities.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

So biologics, as we all know, have transformed treatment paradigms. They have transformed many diseases and how doctors treat diseases. But the challenge that come with them is obviously they can be very expensive. They can be complex and expensive to manufacture and as well as to prescribe and reimburse. They have often, not always, immunogenicity issue.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

They have cold storage issues. So you if you're taking a biologics with you on a vacation, you have

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

to think about cold storage. And obviously, they bring the inconvenience route of administration often painful and again, inconvenient. In an industry survey that was done, I think as recently as, I believe, year and a

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

half, a few hundred patients were asked if you had an option to switch from a biologics to an oral drug with the same profile, you know, would make that switch? And seventy five percent of patients said yes. So there is clearly not only an opportunity, but there is a clear unmet need for patients to access oral therapies that will have a biologic like profile. So the question would be why wouldn't traditional small molecule oral drug capture that need? And the answer that we try to depict here is in the bottom of the slide.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

A traditional oral small molecules follow a traditional PKPD profile. So the efficacy is driven by the ability of the drug to block that pathway 20 fourseven. And because the PK and the PD of a small molecule drug is really connected, you see a sigmoidal curve mostly that depicts that correlation. So you're not able to block the pathway constantly twenty four seven, but you have a peak to trough PD effect. And this is very evident when you look at targets, for example, like FIC two, where while you're blocking the IL-twenty three pathway in principle well, you're not able to deliver the type of activity seen with an injectable IL-twenty three antibody.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

And that's really because of small molecules' inability to block the pathway fully. With a degrader that we've shown extensively, both preclinically and clinically, we can block the pathway fully at steady state, maintaining that degradation consistent. And that, as we've we've shown, can mimic biologics like pathway blockade. So there is in the next couple of slides, I just wanted to share with you two key features of Chimera that I believe has made us a leader in developing unique programs, especially now in immunology. One is really around the capabilities that we built.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

I believe we're the best company today at finding small molecule ligands to undrugged or difficult to drug protein. We're some of the best structural biology capabilities, and we've published on these extensively in peer reviewed journals on understanding ternary complex interactions of our drugs with the proteins and the e three ligases. And we've shown consistently our ability to translate in the clinic our deep understanding of PKPD in different tissues in the in preclinical species and then in humans, which really derisks the translation into patients and hopefully into disease outcome. And all of these capabilities have resulted in some really important accomplishments in the past few years. We've delivered at this point, I believe, more than nine development candidates for, against, un drug transcription factors.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

We've shown now extensively that our degraders are very potent, very specific, orally bioavailable with a great and even distribution across tissues. And we've shown over and over again, as I mentioned, our ability to translate these profiles effectively into the clinic. So another key feature, so we've talked about capabilities, another key feature of Chimera strategy is how we think about target selection. And we have these key four pillars that have been the same since day one. We go after targets that have not been drugged or drugged well before, where there is strong human genetics for the target, and importantly, where the pathway has been validated with other agents, usually upstream of our targets.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

We usually, if not always, have a clear path to show clinical differentiation early in our development strategy as well as now we're very, very keen on programs that have access to large clinical and commercial opportunities. So if you look at our targets today that we're actively pursuing, STAT6 and IRAF5, two un drug transcription factors where Chimera has delivered the first development candidate or for stat six, actually, the first clinical entry and soon the first clinical data. These have been targets have been pursued for decades, and really, the technology has been missing. And here, we have first in class drug targets with strong genetic validation. ARIC4, the target that has been drugged but not well with traditional small molecules.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

The beauty about our strategy is also that we're going after these pathways that have beenthat have complementarity. So not only these are stand alone important programs, you know, after IL4A13, type one interferon cytokines, B cells, autoantibodies, IL1 TLR pathways. But also, you can imagine that eventually, these pathways can be synergistic in how we think about further development in combination, etcetera. And this is probably even more appreciable if you look at the Slide 13 here, where we're looking at where we're developing these assets in which not only disease area, but also in which indications. So you see, for example, for STAT6, we have a big effort in atopic diseases, which are more often in dermatology and respiratory.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

And here, you see seven or eight different diseases. For IRAD5, which I would say it's more traditional immunology, rheumatology, you see more in GI and rheumatology, IRAD, lupus, etcetera, while IRAD4S places in each of these disease areas. So not only we can actually capture almost capture almost the totality of potential immune inflammatory indications, but then you can imagine when there is overlap, a potential strategy down the road could be combination of these assets. This is a slide that captures the concept that was made before about the unmet need in the space, and this actually puts number to the concept. We can use stat six, and the concept can be applied to the other programs.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Again, if you look at the seven major market, we have more than one hundred million patients that are diagnosed with Th2 diseases. And you can see the most prevalent there, AD, asthma, COPD, chronic rhenizitis, etcetera, the the number of patients that have access to advanced systemic therapy right now dominated by dupilumab is really around a million patients. So we have, you know, almost a hundred million patients, if not more, that I believe, we strongly believe, would benefit from an oral drug that has the efficacy and the safety of an injectable biologics. So an oral drug that can change how doctors prescribe medicines for patients with these diseases. And so that's really what we're trying to do, not only for STAT6 but also for IRAF5 in diseases that are, as

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

we

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

said, complementary to the STAT6 diseases. This is really around SLE, RA, Crohn disease, UC, etcetera, and both Veronica and Jarrod will share more. And then IREC4 with, again, the more traditional IL-one TLR driven diseases. So hopefully, this slide give you a sense of the opportunities we have in front of us with oral drugs that are really best in pathway to combine the convenience overall drug and the efficacy of a biologic. So in this slide, I just we will actually go through the upcoming milestones soon.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

And so I don't want to spend too much time going through the details of the slide. I just want to say we have the next eighteen months with the rich of milestones. We have stat six upcoming data in June, which we're very excited to finally get there. We have Phase Ib data at the end of the year. We have two Phase IIb study to start.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Veronika will tell you about IRF V. So maybe I'll give you an update on a couple of programs that will not be the subject of the later presentation. So first, on IRAK4. As you know, Sanofi is progressing KT474 in two parallel Phase IIb studies in both HS and AD. We continue to expect these studies to be completed in 2026, in first half mid-twenty twenty six with data shortly thereafter.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

As you know, IREC4 was our first immunology target. And early success in that program has allowed us and has actually given us the impetus to invest even more in immunology and allowed us to build what we believe it to be one of the best, if not the best, immunology pipeline in this industry. And so while Sanofi has been advancing April, we've had additional ongoing effort at KMR under the collaboration. We've said that in the past. As a result of these efforts, we're pleased to announce today that we have recently achieved their preclinical milestones resulting in $20,000,000 payment that we expect to receive in the second quarter.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

So a validation of both the strategy and the work that both teams have been doing in the past few years. Secondly, I'd like to touch on the disclosure that we released this morning in the press release around our decision around TYK2. So first, I'll say that it's, I think, widely accepted that we're in a very volatile market period, not only biotechnology, but I would say the broader market. And with that, we believe that Chimera is exceptionally well positioned to navigate this uncertain environment. We have what we believe, as I just said, probably the best oral immunology pipeline in industry.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

We have multiple upcoming catalysts that we'll go through later in the presentation. We have an incredible research team that continues to deliver novel programs. You've seen IRF5. You'll see more in the near future. And we have a strong balance sheet of $775,000,000 as of the end of Q1.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

But obviously, we can't just sit and be complacent. We continue to look for opportunities to ensure that our human as well as our capital resources are always prioritized towards the highest return activities. And in fact, it's this with this philosophy that we've continued to optimize our resource allocation strategy. You've seen changes that we made in the past around our oncology investments. And so it's really with this spirit of prioritizing and funding the highest return activities that we're announcing today, our strategic decision not to advance our TYK2 degrader, KT295, into clinical development.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Now I just want to take a moment to explain that well. First, I would like to say that we have completed IND enabling studies with this drug, and we have seen no adverse events in any of our studies, in any of our doses. So this was as a successful IND enabling campaign as you wish. And we continue I'm a continue to be a strong believer in the differentiated case for a degrader in this highly validated pathway. At the same time, in this current environment, resource allocation is very important.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

And we believe resource allocation and particularly our people to programs with the highest probability of success is paramount. So at this point, we've decided to pause on our take two efforts and redirect those resources. So this this decision will allow us to address two important point. One, we're able now to dedicate more human capital as well as our finances to what I believe it to be one of the largest potentially one of the largest programs in industry, our stat six programs and six to one. I would say the stat six franchise and six to one.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

That is really at the cusp of key inflection points. We also can use some of these both human and and and financial capital to to to fund IRAF five and other efforts that we have in other areas. And then secondly, what this decision has allowed us to do is to extend our cash runway from mid-twenty twenty seven to the first half of twenty twenty eight. So this is very important because now our cash runway is well beyond important inflection points, especially, I would say, well beyond the Phase IIb readouts for six:one. So I mean, you all know it's never easy when we make this resource allocation decision.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

But I hope I was able to convey our strategic thinking around this decision and then happy for myself and the team to take questions in the Q and A at the end. So I thought I'll pause here now and pass it on to Jared for him to go through our STAT6 program.

[Jared Gollob, Chief Medical Officer at Kymera Therapeutics]

Thanks, Nelo. This is a very exciting time for Chimera from a development perspective. We are well positioned to achieve multiple clinical data readouts that we believe will further validate our approach and strategy. Before we formally introduce our IRF5 program, I'd like to give you a brief update on our ongoing and planned clinical trials for KT-six twenty one, our first in class oral STAT6 degrader program and the first STAT6 targeted medicine to enter clinical development. The IL4IL13 pathway drives Th2 inflammation and is highly validated by dupilumab, an injectable biologic targeting IL-four receptor alpha that inhibits IL-four and IL-thirteen signaling and is approved for the treatment of multiple different Th2 allergic diseases, including atopic dermatitis and asthma.

[Jared Gollob, Chief Medical Officer at Kymera Therapeutics]

STAT6 is the obligate and specific transcription factor in the IL-fourthirteen pathway and is therefore the critical signaling node controlling Th2 inflammation. For this reason, blocking the function of STAT6 is expected to phenocopy IL4, IL13 targeting. There is also compelling genetic validation for the criticality of STAT6 in driving Th2 allergic diseases and the safety of reducing its expression, including the following. First, the pathogenic role of STAT6 is supported by human genetics showing that gain of function mutations of STAT6 cause severe early onset allergic disease in humans. Second, a recent publication found that human heterozygous STAT6 loss of function mutations protected against severe Th2 asthma, showing for the first time how decreased STAT6 protein levels can be protective against Th2 diseases.

[Jared Gollob, Chief Medical Officer at Kymera Therapeutics]

Additionally, STAT6 knockout in mice is protective in multiple allergic disease models, and STAT6 knockout mice develop normally, are viable, and are fertile. So the human and mouse genetics tell us that STAT6 is a compelling target for treating IL-four, IL-thirteen driven allergic diseases and suggest it can be safely knocked down. Only the unique pharmacology of STAT6 degradation has the potential to fully block IL-four 13 signaling with an oral daily drug, and thereby phenocopy the activity and safety of an upstream biologic like dupilumab. Historically, the development challenge has been to design oral small molecules that can fully block STAT6 around the clock and thereby inhibit the IL-four 13 pathway to the same extent as biologics. We believe the only modality that can do this are degraders.

[Jared Gollob, Chief Medical Officer at Kymera Therapeutics]

Furthermore, if an oral STAT6 degrader can truly block the IL-four 13 pathway to the same extent as, say, dupilumab, this has the potential to transform the treatment paradigm for all of the different Th2 allergic indications that have already been derisked by dupilumab. Dupilumab has transformed the lives of patients with dermatologic, respiratory, and gastrointestinal tissue diseases and has become one of the largest drugs in this industry. We think we can change the treatment paradigm and reach an even broader patient population with an oral drug targeting STAT6 across all the indications derisked by dupilumab and perhaps open up new opportunities in additional allergic indications beyond these. We have a robust preclinical data set to support this program, and I'll walk you through this at a high level. Preclinically, KT621 was shown to be exquisitely selected for STAT6 and shows no functional inhibition of other STATs.

[Jared Gollob, Chief Medical Officer at Kymera Therapeutics]

It degrades STAT6 at low picomolar concentrations across all disease relevant human primary cell types evaluated, including lymphocytes, myeloid cells, epithelial cells, and smooth muscle cells, among others. We've shown preclinically that KT621 is more potent than dupilumab at blocking IL-four and IL-thirteen pathway functions relevant to Th2 disease manifestations in cell systems and is equal or superior to dupilumab at blocking Th2 inflammation in preclinical disease models. This was demonstrated in the mouse house dust mite asthma model at doses achieving 90% or greater STAT6 degradation. Overall, the preclinical data generated highlight the best in pathway potential of KT621 given its dupilumab like activity and the convenience of an oral pill. In higher species, including dogs and monkeys, we have shown with oral daily dosing that we can fully degrade STAT6 at steady state in all relevant tissue types, and we did not observe any adverse safety findings in four week GLP tox studies in nonhuman primates and rodents.

[Jared Gollob, Chief Medical Officer at Kymera Therapeutics]

In light of the enormous potential for KT61 to transform the treatment paradigm for patients with Th2 allergic diseases, we have adopted an accelerated development strategy that begins with phase I studies in healthy volunteers and AD patients to quickly enable demonstration of clinical proof of concept and informed dose selection for phase 2b dose range finding studies. Our plan is to run two sentinel phase 2b trials in AD and asthma starting in Q4 twenty twenty five and Q1 twenty twenty six, respectively. That will enable dose selection for subsequent Phase III registrational studies, not just in AD and asthma, but also across multiple other dermatologic, respiratory, and gastrointestinal indications derisked by dupilumab. The Phase Ia healthy volunteer SADMAD study has been completed, and we're on track to report data next month. The primary objective is to show we can robustly degrade STAT6 in blood and skin, which we define as a reduction of 90% or more at doses that are safe and well tolerated.

[Jared Gollob, Chief Medical Officer at Kymera Therapeutics]

Given the extensive clinical pathway validation by dupilumab, all the human stat six genetics data, and the preclinical data we generated showing dupilumab like activity with 90% stat six degradation in disease models of asthma and AD, we believe that if we can achieve this study objective, it will largely de risk the program and meaningfully increase the probability of success as we move into patient studies. We're also looking at how KT621 impacts several circulating Th2 biomarkers, including TARC and IgE. Our expectation entering the trial was that the effect would likely be comparable to what has been reported in healthy volunteers for dupilumab. Though as we have said, we believe the best opportunity to show a significant effect on Th2 biomarkers will come in patient studies, where baseline levels are greatly elevated due to IL-four 13 pathway activation. Importantly, while completing the phase one healthy volunteer study, we were able to initiate the first KT621 trial in AD patients well ahead of what we had initially planned.

[Jared Gollob, Chief Medical Officer at Kymera Therapeutics]

The ongoing Phase Ib trial, named BROADEN, is a single arm open label trial that will enroll about 20 moderate to severe atopic dermatitis patients. Patients will be administered KT621 once daily for four weeks. The key study aim is to show that robust stat six degradation in blood and skin lesions by KT-six twenty one has a dupilumab like effect on multiple Th2 biomarkers in the blood and on the transcriptome of active AD skin lesions. The study will also assess KT621's effect on clinical endpoints such as EASI and pruritus NRS. We expect to report the Phase Ib data in the fourth quarter.

[Jared Gollob, Chief Medical Officer at Kymera Therapeutics]

So in summary, we believe that targeting STAT6 for degradation with KT621 is the only oral small molecule approach with the potential to achieve a dupilumab like profile with once daily dosing and are approaching KT621 development with a strong sense of urgency and focus on execution. This program has enormous potential to dramatically change the way we can treat patients with inflammatory diseases and expand their access to transformative drugs. We're excited by the progress we've made in completing our Phase Ia healthy volunteer trial and initiating our Phase Ib trial in AD patients, and look forward to sharing data next month for healthy volunteers and later this year for AD patients, and gearing up for the start of Phase IIb trials in AD and asthma. I'd like to pause here and introduce Veronica Campbell, the research lead on the IRF5 program. With her team, she's done a terrific job advancing this exciting program to development candidate and into IND enabling studies, and we are excited to share the details with you now.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

Thanks, Jared. I'm Veronica Campbell, senior director of immunology at Chimera. I've worked at Chimera for eight years, and I'm proud to be part of this pioneering team working to develop transformative treatments for chronic immunological diseases. As a project team lead, I'm very excited to share with you the story of our first in class IRAF five degrader, KT five seventy nine, and why we believe it has the potential to be the first IRAF five targeted oral therapy to deliver transformative activity in several rheumatic and autoimmune diseases superior to standard of care drugs including several biologics. Today I will cover first how Chimera's TPD approach has a unique opportunity to provide a novel oral therapy against what has been historically undrugged transcription factor.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

From there, I will describe the well established biological function of IRA five and the genetic and clinical pathway validation. Next, the clinical development and commercial opportunities IRA five presents. Then I'll describe the exciting preclinical data package for our development candidate KT five seventy nine. And finally, the expected timelines and next steps for the program. I'd like to start by introducing our latest first in class oral development candidate KT five seventy nine.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

KT five seventy nine is a highly potent selective oral degrader of IRA five, which is an essential signaling node in genetically and clinically validated immune pathways, driving inflammation in multiple autoimmune diseases with significant unmet patient need. I'll share details in the coming slides on the robust activity of KT five seven nine in primary cell systems, including patient donor cells, and preclinical efficacy models of RA and lupus. In addition, KT five seven nine has a highly encouraging safety profile in preclinical tox studies where it was well tolerated at up to 200 fold above the predicted human efficacious dose. Our compelling preclinical characterization of KT five seventy nine is consistent with the innovative science we've shared across our immunology pipeline and positions this program well on the path of development. The program is currently in IND enabling studies, and we're on track to initiate phase one testing in early twenty twenty six.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

Consistent with Nalo and Jared's discussion of our rigorous approach to target selection, IRA five meets all our criteria of what we think makes a compelling target for oral TPD approach. IRA five is an undrugged target with strong human genetic validation and supporting biological functional data within pathways that have been clinically validated. As seen in the pathway image on the right, IRA5 is a central node activated downstream of pattern recognition receptors that can recognize foreign or self antigens and is critical for mounting a pro inflammatory response. For example, downstream of endosomal TLR seven, TLR eight, and TLR nine activation, IRA five regulates type one interferon responses, pro inflammatory cytokines such as IL 12, TNF, and IL six, and antibody production. Its expression is cell and activation specific, making IRA five an attractive target with potential to block immune dysregulation while sparing normal cell function.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

IRA five is a highly validated target through human genetics and clinically pathway validation. IRA five functional risk variants that have been identified associate with increased susceptibility to lupus, Sjogren's, RA, IBD, and systemic sclerosis. For clinical validation, the IRA five regulated pathways have been validated by multiple cytokine biologics and B cell targeting agents, highlighting the importance of pro inflammatory mediators like type one interference, TNF alpha, IL 12, and IL 23 in autoimmune disease pathogenesis. I will expand on these two points in subsequent slides. IRA five has been challenging to drug to date likely due to its multiple complex activation steps, splicing isoforms, and high degree of IRF five, IRF family member homology.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

As previously reported, TPD is well suited to deplete undrugged transcription factor targets like IRF five, where a single and specific binding event drives molecule activity and can disrupt all IRA five signaling. Let's discuss IRA five more in disease context and as a master regulator of innate and adaptive response. IRA five is selectively expressed in dendritic cells, monocytes, macrophages, and B cells. Pathway specific IRA five dysregulation is cell and stimulant dependent. In autoimmunity, it is activated by pattern recognition receptors that can recognize nuclear self antigens in the body to initiate and amplify both innate and adaptive immune responses.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

By increasing pro inflammatory cytokines like TNF alpha, IL six, IL 12, IL 23, type one interferons, and pathogenic autoantibodies. This can lead to immune complex formation and propagate subsequent inflammation in autoimmune diseases such as lupus, systemic sclerosis, and dermatomyositis, among others. Therefore, targeting IRA five offers the opportunity for a transformative and multipronged approach to treat these complex and heterogeneous diseases. Now let's look further into the genetics associated with IRA five. Literature shows the pathogenic role of IRA five is supported by human genetics where multiple genome wide association studies identify IRA five as an autoimmune susceptibility gene.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

Specifically, if you look at the bottom left chart, meta analysis of GWAS studies have shown IRA five to be a strong risk locus in lupus with risk haplotypes of functional variants identified in patients that associate with high serum interferon alpha levels, anti double stranded DNA autoantibodies, or anti RNA one binding protein antibodies. Beyond lupus, genetic associations and functional variants have also been identified in RA, IBD systemic sclerosis, and multiple sclerosis. Looking at mouse knockout studies, IRA five knockout mice are viable and fertile with normal B cell development. In the bottom chart showing a mouse model of lupus, IRA five plays an essential role in lupus development and pathogenesis that is interestingly independent of type one interferon pathways, as

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

shown in

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

the survival curves below where Riches et al knocked out IRA five and showed increased protection versus the knockout of interferon a receptor that results in modest protection against lupus. Additionally, knockout studies demonstrated attenuated disease in other mouse models of lupus, RA, and IBD, showing biological functionality and supporting therapeutic potential of IRA five degradation. As previously mentioned, IRA five is only expressed in a limited number of cell types and only activated by specific stimuli. This indicates that IRA five degradation has the potential to selectively block inflammation to restore immune regulation. Dendritic cells, monocytes, and macrophages when activated by members of the TLR family or other pattern recognition receptors like dectin, mediate a pathogenic immune response via many pro inflammatory cytokines, including TNF alpha, IL six, and type one interferons.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

In addition, IRA five is activated by endosomal toll like receptors in B cells resulting in pathogenic autoantibody production. There are many agents which are approved in targeting some of these pro inflammatory mediators like anti TNF alpha, anti IL twelve twenty three, anti interferon alpha, and some which target B cells directly, further validating the target. The multifaceted functions of IRF five, which occur in specific cell context and upon specific stimuli, point to superior efficacy and tolerability profiles compared to current agents for autoimmune disease with the potential to be best in class to treat complex diseases like lupus, Sjogren's, NRA, IBD, and others. The development opportunity for targeting IRA five is vast, and there are numerous potential indications across multiple immunological therapeutic areas with a total potential patient impact of more than ten million patients. KT five seventy nine, our oral IRF five degrader, is designed to block the source of multiple pro inflammatory mechanisms and improve on effectiveness, durability, and tolerability over currently approved agents in diseases such as RA, lupus Sjogren's, systemic sclerosis, IBD, among others listed on this slide.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

Our IRF five degrader has the potential to be a transformative oral therapy superior to oral and biologics standard of care across all indications on this slide as a result of its broad but cell specific mechanism. Now let's look at the exciting profile of KT579 and its impact across the biological mechanisms and pathways just discussed. We have an incredible opportunity with KT five seventy nine given its potential to have an enormous impact on the treatment of autoimmune and rheumatic diseases. As we walk through the preclinical characterization, we hope you will share enthusiasm for what we believe is another high value target to emerge in our pipeline. I will show you the potent selective activity of k t five seven nine in normal human primary cells, donor cells from lupus patients, and in vivo disease models of lupus NRA.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

I'll start with KT five seven nine's effects in human primary cells from healthy donors. KT579 is an exquisitely selective degrader. As you have seen from our programs over and over, we look at concentrations well above that achieving maximal degradation of our intended target. IRA five is the only protein degraded out of the 10,000 or so proteins that were detected by mass spec. No other IRA family proteins were degraded to any extent.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

Looking at specific cell based assay degradation of IRA three and IRA seven, which are IRAF five's closest family members, again, we see no degradation even at concentrations as high as 10 micromole. Additionally, as seen on the right, KT five seventy nine is a very potent degrader of IRAF five. KT five 70 nine demonstrated picomolar to nanomolar potencies across functionally relevant human cell types evaluated, including B cells, dendritic cells, macrophages, and monocytes, all key players in the pathogenesis of inflammation associated with IRF five. As seen with our other degrader programs, it is critical for us to understand degradation across all relevant human cell types in preclinical settings to build the right translational package to predict our human efficacious doses. Next, we wanted to demonstrate selectivity not only through proteomics, but also through downstream pathway activated biology and IRF five cellular mobilization.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

KT five seventy nine selectively depletes IRF five over other key transcription factors within the same pathway axes and downstream of TLR seven and TLR eight activation. This is an important aspect of KT five seventy nine given the high sequence homology between IRAF five, IRAF three, and IRAF seven. As seen in the staining on the slide, depleting IRAF five with low nanomolar concentration of KT five seventy nine leaves these other critical transcription factors completely intact. These data provide additional evidence that the functional inhibition we've observed in subsequent slides is driven through IRA five depletion only and highlights how selective the compound is. In addition, we show we can degrade IRF five both in the cytoplasm and the nucleus as shown in the bottom panel.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

Here we see that k t five seven nine demonstrated potent inhibition of key pro inflammatory cytokines and type one interferon production downstream of TLR four, TLR seven, and TLR eight and nine activation in primary cellular assays shown in the table and graphs. For example, we show k t five seven nine can block IL 12 and interferon beta production in monocytes and block the production of TNF alpha and IL 23 in PBMCs. These data highlight KT five seventy nine's broad and potent activity that is both cell and stimuli dependent. Additionally, transcriptomics analysis demonstrates that KT579 dampens type one interferon response in select interferon stimulated genes that are reported to be elevated in systemic autoimmune diseases such as lupus and Sjogren's. Type one interferon responses can be induced by endosomal TLR seven and TLR eight activation via single stranded RNA nuclear self antigens.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

On the left, differential gene analysis demonstrates that KT five seventy nine can block the type one interferon at least as effectively as an anti TLR seven eight inhibitor, efemedrine, at concentrations predicted to be clinically active. On the right, we see that KT579 can achieve comparable inhibition to ephemedrine of select ISGs that have been associated with increased disease activity in lupus. Turning now to KT579's activity in patient derived donor cells. We examined KT five seventy nine's impact on lupus patient derived PBMCs. Endosomal TLR seven eight activation can be IRA five dependent, and KT five seventy nine effectively block TLR seven and eight induced proinflammatory cytokines and interferon beta production.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

These data include some patients with IRA five common functional variants where we observed similar activity on both IRA five degradation and downstream functional effects. By inhibiting pro inflammatory cytokines and type one interferon, we hope to reduce inflammation, suppress the development of autoantibodies, and ultimately mitigate the progression of autoimmune diseases like lupus independent of IRF five genotype. We plan to share more of these data in subsequent presentations. Continuing with the lupus patient samples, on this slide you can see how KT five seventy nine significantly inhibits IgG production in B cells cultured with CpGB with or without KT five seventy nine for seven days. In lupus, double stranded DNA nuclear self antigens or anti double stranded DNA complexes can activate endosomal TLR nine in B cells, leading to B cell activation, differentiation, and pathogenic autoantibody production.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

This data really shows the promise of an IRA five directed treatment to reduce the B cell mediated inflammatory cascade in lupus patients. And finally, let's turn to the in vivo preclinical data. In the first model shown here, we evaluated KT five seventy nine's activity in mouse acute TLR models that elicit a potent inflammatory cytokine response. In these studies, KT579 dosed orally once a day for four days achieved deep degradation of IR5, here measured in the spleen. Importantly, as we discussed with other programs in our pipeline, degraders require higher doses in mouse models compared to other species due to higher plasma protein binding and lower affinity, while in higher species like NHP, which is more translatable to humans, we can achieve full degradation at much lower doses.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

Then on the fourth day, TLR seven or TLR nine stimulants were administered systemically and KT five seventy nine activity was compared to a TLR seven eight inhibitor m five zero four nine as shown on the charts to the right. As expected, only KT five seven nine led to dose dependent inhibition of cytokines in both models, blocking both TLR seven and TLR nine induced cytokines, including TNF alpha and also IL six, IL 12, and interferon beta, which are not shown here. This demonstrates KT579's advantage in blocking both TLR7 and TLR9 activities, which should translate to greater efficacy in several autoimmune diseases. This potential advantage is further supported by mouse TLR knockout studies where TLR seven and TLR nine double knockout led to greater impact on disease onset and severity in mouse models of lupus, for example. In addition, these acute studies allowed us to select active doses for use in chronic mouse models of lupus NRA.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

In the next few slides, we will go over our preclinical efficacy studies and show you how our IRA five degrader KT five seven nine compares to existing agents in lupus and RA models, phenocopying IRA five knockout studies. To start, MRL LPR mice have a susceptible genetic background and single gene mutation in FAS, quickly developing lupus like symptoms and manifestations. Disease biomarkers can be detected as early as eight weeks of age. Treatment began at week ten and ended at week nineteen when mice are expected to present with extensive kidney pathology. KT five seven nine daily oral dosing was well tolerated at both doses of fifty mgs per kg and two hundred mgs per kg for the duration of treatment.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

KT five seven nine demonstrated sustained and near complete reduction of proteinuria and a % survival at both doses, achieving at least 85% degradation with activity superior to approved or clinically active drugs such as affameterin, dugravacitinib, cyclophosphamide, and an anti interferon a receptor mouse surrogate antibody administered at the top dose reported in the literature. Additional endpoint readouts are currently ongoing. Next, we evaluated the impact of IRA five degradation in the long term NZB w one spontaneous lupus model using an earlier potent and selective IRA five tool degrader. This degrader was used for proof of concept in this model while characterization was ongoing for our development candidate k t five seven nine. NZB w one mice have a polygenic background and spontaneously develop lupus that present with high levels of circulating anti double stranded DNA, anti ANAs, proteinuria, and immune complex mediated glomerulonephritis similar to human lupus.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

Treatment was initiated at week twenty one during early onset of disease. Daily oral doses of an IRA five degrader for four months were well tolerated, and doses that achieved greater than 80% IRA five degradation led to sustained reduction of proteinuria and near complete reduction of circulating serum, anti double stranded DNA autoantibodies, generally better than standard of care, cyclophosphamide approved anti interferon a receptor one surrogate, and clinical stage testing agents efemedrine and dupervastatin. These are really exciting results that demonstrate the ability of an oral IRA five degrader to achieve similar activity on IRA five to genetic depletion. We will be testing KT five seventy nine in this model, and we expect it to look very similar to this given the similar potency of the drugs. And we plan to share the results at a subsequent presentation.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

Next, in the antigen induced arthritis mouse model of RA, daily oral dosing with KT five seventy nine that achieved approximately 90% degradation led to significant reduction in joint swelling comparable to tofacitinib. IRA five degradation fetocopies IRA five knockout and leads to reduction in ankle swelling, circulating pro inflammatory cytokines as shown here with IL-twelve, and infiltrating inflammatory pathogenic Th one T cells evaluated by flow, which is also shown here on the right. These data exemplify the potential for an oral IRA five degrader to impact multiple inflammatory biologies in autoimmune diseases. As part of KT five seventy nine's preclinical characterization, we looked at degradation of IRF five across several preclinical species. As shown on the chart to the right with daily dosing for seven days, we observed KT five seventy nine can robustly deplete IRAF five at steady state with low oral doses in nonhuman primate.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

Importantly, the degradation was measured twenty four hours after the last dose. KT five seventy nine was also very well tolerated with no adverse effects or relevant findings up to 200 fold the predicted human efficacious exposure in our non GLP toxicology studies in both nonhuman primate and rodents, derisking our path to human translation and proof of concept. In summary, I've shown you that first, IRA five has the potential to be the first broad anti inflammatory that effectively addresses immune dysregulation while sparing normal cell function. And both human and mouse genetics, along with preclinical validation, indicate a best in class profile for IRF five in treating lupus, Sjogren's, RA, and other diseases. Next, KT five seventy nine stands out as a highly selective potent oral IRA five degrader.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

Also, our in vivo study showed that IRA five deprivation leads to robust cytokine inhibition and demonstrates superior or comparable efficacy in lupus and RA models compared to approved drugs in this space. In addition, KT five seventy nine achieves complete degradation across multiple preclinical safety species and relevant tissues maintaining a favorable safety profile. At last, we're very happy that this program is progressing in IND enabling studies, and we expect to advance KT five seventy nine into the clinic in early two thousand twenty six as we believe the first oral IRA five degrader. With that, I'd like to now turn the call back to Nello for his closing remarks.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Thank you, Veronica. It's always exciting to hear these stories even if I've heard that multiple times internally. I think when we do this public disclosure, it's just an exciting time to put all our data out there and show how productive the team can be, and more importantly, the level of sophistication that the team goes when we build these preclinical packages. So very excited to take this program in the clinic. So why don't I maybe complete this presentation today by going through our pipeline and spending a bit more time on the upcoming milestones.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

And then we look forward to take questions from the audience and the analysts. So first, as we've repeated now multiple times, obviously, KT-six 21 is moving very rapidly. As we've said, likely much more rapidly than we anticipated, which is a great problem to have. We've been able to complete our healthy volunteer study in really dosing in March. We are collecting the last small data points, and then we're really excited to being able to share our Phase one healthy volunteer data in June.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

So that's an important date on your calendar. As you also know, we have started our phase 1b AD study, in April. And again, kudos to the team, the six to one team, for being able to do that, as I said, very rapidly. We're now recruiting patients, and we expect to be able to share data from this study in the fourth quarter of the year. The team is already gearing up to initiate these two large phase 2b studies.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

So, we'll start the AD study in, fourth quarter of twenty five and the asthma study in the first part of twenty six. So, very busy with all these activities. So important two data readouts, healthy volunteer in June and then AD patient data in the fourth quarter of the year. And then we'll embark in these large studies that will obviously take longer than the Phase Ib study, and we'll share more details about expectations around timing and data readouts as we get closer to them.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

For

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

IRAE5KT579, as Veronica said, the preclinical package both on safety and efficacy looks extremely impressive. And so we're expecting to file an IND towards year end, starting our Phase I early next year with data with Phase I data already next year. And then as we mentioned with AREC4, we expect to have data in 'twenty six for both HS and AD. So thank you, everybody, for taking the time. I know it was during the morning on a Friday, but hopefully, you'll appreciate the level of details that we shared today.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

And we're happy to reconvene and take questions once we get together in a couple of minutes.

[Operator]

Thank you. At this time, if you would like to ask a question, please click on the raise hand button, which can be found on the black bar at the bottom of your screen. If you've joined by phone, please dial 9 on your keypad to raise your hand. When it is your turn, you will receive a message on your screen inviting you to join as panelist. Please accept and wait until you are promoted to panelist.

[Operator]

Please unmute your audio, turn on your camera, and ask your question. As a reminder, we are allowing analysts one question and one related follow-up today. We will now pause a moment to assemble the queue.

[Operator]

Your

[Operator]

first question will come from Derek Arkela with Wells Fargo. Please unmute and ask your question.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Hey, Derek. We can't hear you. Can you, unmute if you haven't?

[Yvonne Kumi, VP - Senior Quantitative Analytics at Wells Fargo]

Hi. Can you hear me?

[Jared Gollob, Chief Medical Officer at Kymera Therapeutics]

Oh, yes.

[Yvonne Kumi, VP - Senior Quantitative Analytics at Wells Fargo]

Yeah. This is Yvonne for Derek. Thanks for taking our questions. Just a quick one from us. Can you talk a bit about your confidence on targeting STAT6 in AD and of showing an effect in the four week study?

[Yvonne Kumi, VP - Senior Quantitative Analytics at Wells Fargo]

Like, should we be expecting a relatively noisy dataset given it's such a short study? Thanks.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Yeah. Thanks for the question. So, obviously, the the underpinning of this program is that IL four and thirteen mass signal through stat six to propagate the signal and to impact downstream Th two cytokines. So we've so the derisking and the expectation that we've set on this program are purely driven by the data that's been shown in AD already by the past I four and thirteen agent, which is dupilumab, which is actually the only drug that blocks both I four and thirteen. So we know with that drug, even in four weeks, you can actually generate quite compelling differentiated dataset.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

The first one is that even in four weeks, you can impact both circulating and skin biomarkers of t h two information very robustly. And, actually, if you look at the the data for weeks in terms of disease scores and others clinical endpoints, while they don't they do not reach maximal effect, they are quite robust. And and so we given all the preclinical data that we've generated on this on our program with k t six two one and the fact that all the models and assays that we run this compound through, we've shown a doopy like effect, in some cases, even a doopy better effect, we we expect that we'll be able to see really robust data. But first, in biomarkers because that's really what the study is being powered on, but but also clinical endpoints.

[Yvonne Kumi, VP - Senior Quantitative Analytics at Wells Fargo]

Got it. Thanks.

[Operator]

Your next question comes from the line of Jeet Mukherjee with BTIG. Please unmute and ask your question.

[Jeet Mukherjee, Analyst at BTIG]

Hey. Good morning. Can you hear me?

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Yeah. We can see you even, g.

[Jeet Mukherjee, Analyst at BTIG]

Great. Thanks for

[Jeet Mukherjee, Analyst at BTIG]

taking the

[Jeet Mukherjee, Analyst at BTIG]

question. Maybe just one question around the decision not to advance the, the tick two program. You obviously talked about the decision in the, you know, context of being capital conscious and the macro backdrop, but it appears you've swapped tick two for perhaps IRF five. So was there anything there in terms of the molecule's profile or just the evolving competitive landscape that influenced your decision? Thanks.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Yeah. No. Great question. So I think it's important to maybe spend even a bit more time as you're suggesting. So we remain I can say personally, I remain confident in the in the tick to opportunity with a d grader.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

I think the the the decision is really around in today, where we are with both resources, both human and capital, we feel like being able to power up even more so at six to one program given that it's really accelerated in terms of pace. And, obviously, I can't speak to the data, but, obviously, we have a lot of confidence going into these larger studies. Given the risk reward in that program, we feel like that's the place where we wanna go and put a lot of resources in. I think the RFI program is actually quite different from from TIC two. TIC two, it's it really is true to to reflect that the TIC two space is, you know, is is obviously, there is a lot of competitive intensity.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

We we look at not just TIC two, but I always look at all the other I twenty three drugs out there, including the quite impressive GHA peptide. Obviously, the barium despases has been raised. We think IRAD five is a totally different program. I think that's gonna be a best in class drug for a wider variety of diseases, and that's a program we wanna go all in would be first the competitive intensities right now in that program in those pathways is close to zero. And we have an opportunity to have a highly differentiated profile.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

So that's again, there is obviously competitive intensity and risk reward conversations that have happened within the company on how programs have been prioritized. I think we are alluding to is fair. But at the same time, I would say the main driver is we have the the largest program in industry in our hands, probably, maybe if you remove the GLP one drugs, and we got a resource at the maximum that we can do in this point in time.

[Jeet Mukherjee, Analyst at BTIG]

Thanks for taking the question.

[Operator]

Our next question will come from Mark Fram with TD Cowen. Please unmute your line and ask your question.

[Marc Frahm, Biotechnology Equity Research Analyst at Cowen]

Thanks for taking my questions. Beyond the IRF five burn that you disclosed today, just, you know, as you get into the clinic, what does that minimum kind of target profile in terms of degradation look like? And, you know, as we get to clinical data, as you highlighted and, you know, with your kinda intro Nello, you know, the the bar in some of these other diseases where you've you've started going after orals, you know, things like psoriasis, like, is extremely high. There really isn't much room even there or, to some extent, AD to push efficacy higher. But, you know, some of these diseases you're talking about for IRF five, there there's certainly much more room for clinical improve for efficacy improvement.

[Marc Frahm, Biotechnology Equity Research Analyst at Cowen]

How important is that to to ultimately show versus just kinda matching available therapies but offering, you know, oral convenience?

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Yeah. I think it's a great question. Maybe I can start, and others can follow. So first, I think that's very insightful question. I will start with just looking at our preclinical data.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

As you could appreciate, I know we've only just gone through it, and we didn't have a lot of time to digest. At least so far, it looks like once we at least 80% degradation and above is able to deliver some really best in class profile. So we're actually doing more work to to understand is it even less than 80% degradation sufficient to drive the activity that we've seen. So I I guess, to answer your question, there's even more work that we're doing. I think if you look at and just in both lupus and IRA, but I will start maybe with the lupus model, clearly, targeting IRA five in this quite translational models of lupus seems to have, by far, the best effect, which I think if you look at approved therapies in lupus, you know, that right now, they don't really work very well.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

So there is clearly unmet need on the efficacy. So being able to deliver both efficacy and convenience that that is superior to existing and even clinically active drug, I think, is really what we're trying to deliver there. So maybe even, you know, one step over some of the conversations we've been having in the past few months. And then the team with Veronica's leadership has come up with a an extremely well behaved molecule that we believe would be highly differentiated in the clinic. But I don't know, Jared or Veronica, if you guys wanna add.

[Jared Gollob, Chief Medical Officer at Kymera Therapeutics]

I mean, I think I would only add that importantly. You know, we we know that, number one, we can achieve greater than ninety percent knockdown of viral five across multiple different species, including higher species like nonhuman primates. And that in in in our fourteen day studies, you know, that can be achieved with very favorable safety. So I think that's very important. It's also very interesting to note in terms of your question around, well, how much knockdown do we really need even if 90% or greater is saved?

[Jared Gollob, Chief Medical Officer at Kymera Therapeutics]

It's very interesting that these sort of heterozygous iron five knockout mice are actually fairly well protected from diseases like lupus. So it's possible we might not need that much knockdown for efficacy, but we know we can achieve that degree of knockdown, high degree of knockdown, and that that would be safe. So that's gonna be very important for us.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

Yeah. And I I think our expectation is, again, that we would see superior efficacy, and that's because of the multiple biologies that we can hit with higher f five. Right? As we talked about during the presentation, being able to impact autoantibody producing cells, type one interferon, and then also pro pro inflammatory cytokines that will be very important when you go after complex and heterogeneous diseases like those, like like lupus. So I think even compared to, let's say, anifrolumab, we would expect to have a lot more efficacy.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Great. Thanks, Lauren.

[Marc Frahm, Biotechnology Equity Research Analyst at Cowen]

Yeah. Thank you.

[Operator]

Our next question will come from the line of Ellie Mel with UBS Securities. Please unmute and ask your question. Hey, guys.

[Eliana Merle, Analyst at UBS Group]

Just on IRF five, just a quick search. There's obviously a lot of literature showing that this plays a critical role in a lot of diseases. But curious how you're thinking about balancing the safety here. It looks like there's some data showing that IRF5 can act as a tumor suppressor. I mean, obviously, we're new to this target, and it seems like it's involved in a lot of diseases.

[Eliana Merle, Analyst at UBS Group]

But just can you explain why you're comfortable with the safety here? And I know in the last question, you mentioned that you can even get disease protection or modification perhaps with the 50% degradation just from a clinical development perspective, even if early on 90% degradation is safe? Would you also explore moving forward with, say, 50% degradation, 90% with multiple dose levels, and thinking about the long term safety profile? Thanks.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Yeah. So I'll let actually Veronica address kind of the first part of your question. I just wanna touch a high level. So the beauty about IRAD five, which, you know, will require a few days of of work from everybody to kind of get up to speed is is that what Veronica said multiple times that is cell specific. Like, it's really only expressed in a subset of cells, and it's also really only activated in the presence of diseases.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

There are multiple other IRFs that are contributing to, let's say, immune surveillance from a safety perspective, from an infection perspective. So it's really one of those only great targets, and that's why it's been pursued, you know, without much knowledge because with a lot of failures by the whole industry in the past ten years, at least, that we know of. Because it actually combines this broad anti inflammatory effect, that twelve twenty three I l six t and f IgG type one interferon, but in a context specific manner. And that's really why, you know, even in these preclinical studies, we can you can remove the target completely. We've gone 200 fold above that dose and have not seen any activity.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Veronica, do you wanna Mhmm. Take that? I know you had the answer to that question better than I do.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

Yeah. No. No. Thank you for the question. You know, that was part of our due diligence in the beginning.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

We evaluated the targets, some of the studies that you mentioned, and we would look across TCGA aggregate studies. There's actually very little evidence that loss of I r f five associates with cancer. And in fact, when you look, it seems like gain of function is associated with with with cancer. And the one report that pops up is from from one lab. There has been no follow-up work.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

And with a target that's more highly expressed in heme cells, it's it's sort of hard to believe that, you know, loss in a breast cancer, you know, epithelial cell will will lead to keep lead to cancer. So there has been really no follow-up there. And, with our our our broader analysis, we don't really see a risk in that area.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Thank you. Thanks, Varani.

[Eliana Merle, Analyst at UBS Group]

Great. Thanks.

[Operator]

Your next question comes from the line of Sudan Noganathan with Stephens. Please unmute and ask your question.

[Sudan Loganathan, Managing Director at Stephens Inc]

Hi. Good morning. And thank you this morning again for this detailed presentation and for taking my questions. You know, my first one is on the, IRF five program. You know, in your preclinical work or any of the, literature out there, did the degradation of IRF five trigger any feedback mechanisms that may have activated IRF four, my d 88, not one two, or any other IRS that could be a means of causing, like, an untargetable relapse in a disease state, you know, whenever treated in in humans going forward.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Yeah. No. That's a great question. So this is something we pay a lot of attention to across our our programs. Right?

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Do we see a either a resist an evolving potential resistant mechanism or other pathways coming into play? We haven't seen any of that in our studies. I mean, as Veronica showed, some of these are probably some of the longest studies that we've run preclinically. You see the the lupus model is a four month study. I think mice were dosed hundred and six days in a row, if I remember correctly.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

And with that, we haven't seen during the study and, obviously, you know, the the the mice are taken down at the end. But but even when we've when it's happened that we've in other studies, we've we've we've dosed and then stopped dosing, we have not seen any kind of flares or rebound of of these inflammatory pathways. It's it's the beauty about these inflammatory pathways is that these are not overexpressed or activated in inflammatory processes or sorry. They're not overexpressed. They just signal through.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

There is just a signal that that moves into a particular pathway. In this case, let's say, through IRAF five. And so the reason to kind of a an increase of protein expression that you're slowing down or removing, which will make the cell kind of react with producing some other protein. So, anyway, the short answer is we haven't seen it. We don't expect to see it.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

We haven't seen it for any program so far.

[Sudan Loganathan, Managing Director at Stephens Inc]

Great. I appreciate that. And just if I can squeeze in a follow-up, you know, just in regards to the stat six program and the degradation. I think you've mentioned before, obviously, also achieving a pretty high level of stat six degradation, hopefully, in in the in human population as well in in your trial. You know, between the different indications you're going after with stat six degradation, does the level of that degradation need to be, you know, exceeding 90% for all the indications, or, you know, is it different between each ones to get, you know, a clinical benefit specific to each type?

[Sudan Loganathan, Managing Director at Stephens Inc]

You know, for instance, with AD, you know, in the skin and blood, you know, are there kind of targets between the two different tissue types there in when it comes to looking at the statics degradation to form a clinical benefit?

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Yeah. It's a it's a great question. I mean, I think that there there is kind of two answers. One, we our goal of our phase one study was to hopefully being able to achieve 90% plus in blood and skin. The reason for that is there two.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Right? One, preclinically, we've shown in mice that if we get to ninety percent plus, we have a dupi like effect. The second reason is why do we wanna have also the same target in skin is because we don't wanna be left with the question of what if we had more than 90% degradation in skin. What would the activity look like? So that's why we wanna we would like to target a profile that has similar degradation in both blood and skin so that we maximize that probability of success.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Second part of your question, which actually was Elliot's question that I don't think I answered, is what is the level of degradation needed for particular diseases for both sat six and we'll throw in IRAF five as well? I think that's why we're so keen on running, at least for stat six for now, imminently, this phase two b dose ranging studies. It's the ability to correlate a degradation profile with a clinical outcome that will allow us to select the right dose for phase three. So right now, we are for stat six, at least, we're going based on our preclinical data, we're going into the clinic with the expectation that ninety percent plus is the desired profile. But once we run a phase two b study where we'll be able to ask the questions of multiple dose and multidrug degradation profile, you know, we might learn then that that, you know, the mid less than nine is sufficient.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

I don't know if we expect that more than nine is needed, but, you know, that's why we run the the those ranging studies. It's really to establish those relationships.

[Sudan Loganathan, Managing Director at Stephens Inc]

Great.

[Sudan Loganathan, Managing Director at Stephens Inc]

I appreciate the details here, and thanks again for this detailed presentation today.

[Operator]

Your next question you.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Who's next?

[Operator]

Your next question comes from the line of Vikram Purohit with Morgan Stanley. Please unmute and ask your question.

[Vikram Purohit, Analyst at Morgan Stanley]

Great. Good morning. Can you hear me?

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Yeah. We are here, Vikram.

[Vikram Purohit, Analyst at Morgan Stanley]

Thanks for taking the questions and for the presentation. We had a follow-up question on IRS five. I mean, you've alluded to how, challenging this target has been through, your prepared remarks and also through the responses to the last few questions. But we were wondering if you could speak in a bit more detail about, prior competitive approaches that may have been attempted for IRS five and where specifically these approaches may have faltered and how five seven nine has been engineered specifically to address some of the missteps that Yeah. Other others others in the space may have faced in the past?

[Vikram Purohit, Analyst at Morgan Stanley]

And I'll I have a follow-up, but I'll save that for for post your response.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Okay. And I think that's a great question. So the the main challenge with IRAF five actually, I would say from a chemistry perspective, this is probably being the hardest program in the company. And the reason is identifying a highly specific IRF five binder or for others as being inhibitor is extremely difficult. There is a high sequence homology.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Veronica showed you IREF one and seven versus five three and seven, sorry, versus five. And we were, I would say, also lucky to find, thanks to the great team that we had, a molecule that is basically 100% specific to IRF five. That's not bind to any IRFs. The other point is IRF brings, you know, this kind of complex activation. And and I think you have to really inhibit all type of IRAF fives where the type right of bio the right type of biology.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

And with that drug, we bind to basic and degrade all types of IRAF fives. And so it has been has been a really difficult target to drug. I think it's probably underappreciated how difficult there's been. And and this is a highly I think, you know, this program has a a has a lot of a lot of focus on by, I think, the external immunology community because this would be the first time that we finally hit this target selectively and well.

[Vikram Purohit, Analyst at Morgan Stanley]

Great. And then as a follow-up, on the development program, how broad of an initial development plan do you think you will end up pursuing for May? Is it reasonable to expect something like 06/21 where you started with the two sentinel sentinel indication, excuse me, and then go from there? And, relatedly, you mentioned a mid twenty twenty eight runway. How how far in development do you think you could get with a $5.07 9 through that time point?

[Vikram Purohit, Analyst at Morgan Stanley]

Thanks.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Alright. So I'll high level. So first, I think it's it's it's a bit early for us to get into the actual development plan, but but but what I would say is that there is a plethora of opportunities where I think there was an earlier comment from one of your colleagues that there was quite quite apt, which is this drug can actually really, really make a difference for many patients with these, let's call it, rheumatological immune inflammatory diseases. And so I I I we believe that this is gonna be also a relatively broad development program with more than one indications that would be prioritized. I think the runway just to be clear, I think we've said first half of twenty eight.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

You gave us mid twenty eight. I'll take it if you also give us the money. But I think what we said it's it's it's all good. What we said is that we plan to start phase one early next year. We plan to complete phase one within that year.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

So you can expect that we'll have some meaningful clinical data within this runway.

[Vikram Purohit, Analyst at Morgan Stanley]

Very helpful. Thank you. Appreciate it.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

I see Eric ready already to the next slide.

[Operator]

Your next question will

[Operator]

come from the

[Operator]

next question will come from the line of Eric Joseph with JPMorgan. Please unmute and ask your question.

[Eric Joseph, Equity Research Analyst at JP Morgan]

Thanks. Thanks for taking the questions. Just on IRF five, can you talk a little bit about the relative infection risk given the broader or more pan pro inflammatory cytokine suppression profile here? To what extent are you able to model that pre clinically perhaps? And then in what sounds like lupus or actually being one of the lead one of the focal indications with this approach, have you preclinically looked at the comparative efficacy of five seven nine versus some of the b cell depleting or modulating approaches to the extent that this is also feasible to do in mice models?

[Eric Joseph, Equity Research Analyst at JP Morgan]

Thanks.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Great question. I'm gonna let you guys answer on the infection risk. We have tons of answers. I don't wanna give all the answers. Veronica, you wanna go first?

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

And then, Jared, maybe you can speak to that and some other aspects of it.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

Yeah. No. No. Thanks for the question. We don't think that IRF five will work like a broad immunosuppressant.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

Right? And and the reason for that is because it's really selectively expressed in very key immune cells. You know, those those four that I listed is really where it's highly expressed. And not only that, but it's also specifically activated through certain stimuli. So I think that combination, when we look into these certain autoimmune diseases, will be an advantage because we won't have this broad immunosuppression against against all all all stimuli.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

Really, only the ones with that are elevated in those autoimmune diseases that we're going after.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

And that means immune surveillance. You can talk about the other IRA.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

Right. Exactly. So we will be leaving, like we showed, IRA three and seven intact, and those are really important for viral infections. Right?

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

Those are actually Those are actually the transcription factors that drive high type one interferon response. So by leaving those intact in IRF blocking IRF five, we don't think we'll have anything as severe as, let's say, sapnello anifrolimab. We we probably would expect it to look less. Right?

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

Because there, you're blocking all type one interferon response. So that's just an example. Yeah.

[Jared Gollob, Chief Medical Officer at Kymera Therapeutics]

And then, Eric, I think your your second question was around comparison to B cell depleters. I mean, the data that Yeah. Veronica showed so far, the comparisons that have not been to the B cell depleters per se, but we have looked at comparisons in those lupus models to DUCRA, so TYK2 inhibition, TLR seven eight inhibition with a athemetiran, you know, alpha induron receptor antibodies, you know, we've been at least comparable, probably better actually in our activity in those models compared to all those standards of care, even cyclophosphamide. And I think probably looking at B cell depleters will be something that we can do in the future. I think it's important to recognize that, you know, IRF five impacts multiple different components of inflammation.

[Jared Gollob, Chief Medical Officer at Kymera Therapeutics]

B cell is one part of that inflammation, but there's also the dendritic cell component. There's also the T cell component that is stimulated by macrophages and dendritic cells. So we would anticipate that we would have a broader effect and potentially could be even more active than the more sort of selective D cell depleter.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

And and safer, I think. Yeah. I think also better tolerated.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

And it's actually known that anti c d twenties, as an example, don't perform very well in these lupus models.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Okay. Any anything else, Eric?

[Eric Joseph, Equity Research Analyst at JP Morgan]

No. No. No. Appreciate the thanks. Appreciate you taking the questions.

[Eric Joseph, Equity Research Analyst at JP Morgan]

Thanks for the updates.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Thank you.

[Operator]

Your next question will come from Faisal Khashid with Leerink. Please unmute and ask your question.

[Faisal Khurshid, Senior Research Analyst - Emerging Immunology at Leerink Partners]

Hey, guys. Good to see you. Thanks for taking the question. So we're still early in our few days of work. I think you said no to understand the target.

[Faisal Khurshid, Senior Research Analyst - Emerging Immunology at Leerink Partners]

But I saw that there is a one other kind of disclosed development program for IRF5 that's an allosteric modulator. Could you talk a little bit about, like, how you kind of see the potential benefits of a degrader approach over an allosteric modulator?

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Yeah. I mean, as I mentioned earlier, yeah, there are disclosed programs. We haven't seen any data, so I always don't comment on those because they're just a word on a slide. But but I think the main the main, really, challenge has been, can you do it selectively? And then can you block all the functions of IRED five, including all despising variants.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Right, Veronica? And I think it's really hard to do. I I I'm not gonna say it's impossible to do. I'm gonna say, we believe in our hands. It's extremely hard to do with an inhibitor.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Then you put on top of it the fact that with an inhibitor, if if the need is to block IRAD five at high level continuously, you know, obviously, we made the case that D graders allow you to do once a day or on track with a low dose with inhibitor to to stay on top of that target twenty four seven is gonna be really difficult. But I think for this one, it's really the selective context independent inhibition is gonna be hard, but we'll see.

[Faisal Khurshid, Senior Research Analyst - Emerging Immunology at Leerink Partners]

Got it. Great. Thank you

[Faisal Khurshid, Senior Research Analyst - Emerging Immunology at Leerink Partners]

for taking the question.

[Operator]

Your next question is from Jeff Meacham with Citi. Please unmute your audio and ask your question.

[Nishant Jadav, Managing Director at Citi]

Hey, guys. This is Nishanth on for Jeff. Thanks for the questions and really helpful presentation. So first on I r f five, so there has been, like, genetic links between certain I r f five isoforms and lupus susceptibility. So are there any concerns that five seven nine could exacerbate disease in sub subset of patients and whether you have designed this, kind of, degrader to target specific isoforms to avoid this effect?

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Veronica, you wanna take it? I think the second one was if we get all the isoform

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

Can we selectively target certain isoforms that are expressed in these variant patients? Yeah. That's really difficult to do because, the isoforms are really cell specific expression. Right? So, that would be really hard to do.

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

What we do know is that, you know, five seven nine can degrade all the different isoforms that that are expressed, whether it's, you know, those that are caused by the variants or not, which might actually be important in these autoimmune diseases because there are also other mechanisms besides the variants that can turn I r f five on. So we believe that, really, you know, the best is to try and block all of the different isoforms for IRA five. But we have not seen any

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Yeah. We wanna get all isoforms because we wanna get the broader population and also the we in our hands already, we know that there is biology that is this is relevant that has nothing to do with the with the despising isoforms activation. Right?

[Veronica Campbell, Senior Director - Immunology at Kymera Therapeutics]

Right.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Right. Pathway activation. Mhmm. Next one. I'm trying to catch up.

[Operator]

Your next question will come from Michael Schmidt with Guggenheim. Please unmute and ask your question.

[Michael Schmidt, Senior Managing Director & Equity Research Analyst - Biotechnology at Guggenheim Securities, LLC]

Hey, guys. Good morning. I just wanted to come back to k t six two one and and stat six, especially sort of, you know, heading to the June update, coming up here very soon. How important will be interpretation of some of the PD marker analysis in this phase one healthy volunteer study, especially given that, as you mentioned earlier, the biomarkers in in healthy is really very low at baseline and also asking because there was a lot of variability, especially with TARC in some of the the Dupi studies. So how meaningful is interpretation of these biomarkers in in the June dataset?

[Michael Schmidt, Senior Managing Director & Equity Research Analyst - Biotechnology at Guggenheim Securities, LLC]

And perhaps then following up on your upcoming phase one b study in in patients. Yeah. So what are some of the things that that you're trying to address in this study sort of ahead of starting your randomized phase two, trial later this year? Are there any particular outcomes you're or, questions you're trying to answer in patients before starting the phase two? Thanks.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Yeah. You know, I I kind of I I was thinking about a rapid way to give you an answer on all the questions, which is, you know, we made the case from the beginning for this program that a stat six degree that should perform like dupilumab. And so I would say the expectation across the studies is to perform like dupilumab. In the healthy volunteer study, obviously, dupilumab didn't look at stat six degradation. But, you know, whatever they saw in biomarkers, you should expect it from us.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

In the one b study, they did a nice twenty eight day study of both biomarkers and clinical endpoint. I would say we expect to see a Dupi like effect. That's probably the quickest the quickest way to answer this question. In addition to dupilumab, the beauty about working in protein degradation that if you're good, you can actually understand what's going on. You just don't look at some biomarkers after you dose a drug, but you can see, okay, what is the level of pathway blockade that where it can can achieve in blood and skin?

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

And so we we're gonna be able to look at the gradation of statics in blood and skin. Obviously, safety is gonna be paramount for this for this drug in this in this environment, in this in this landscape. But in terms of biomarkers, I would just say that we expect to have 2P life because that's what we've seen all all along in our preclinical study, and we've been saying for for a while.

[Michael Schmidt, Senior Managing Director & Equity Research Analyst - Biotechnology at Guggenheim Securities, LLC]

And and maybe just a quick follow-up. Can I ask a follow-up? So, you know, on dosing in particular, Dupixent is typically given at a high initial loading dose, and then, there's a a lower maintenance dose. How do you think about that in context of the sort of k t six four, six two one, you know, you know, dynamics? You know, is is is that something that you're evaluating too for the phase two perhaps?

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Well, you know, obviously, I can't speak to the data. I just would go to preclinical data with the k 621. We're able to achieve in preclinical models, you know, the full extent of the desired degradation in in hours. And so based on the data, we've never built a loading dose model preclinically, and we, you know, we hope that will be the case in the clinic too.

[Michael Schmidt, Senior Managing Director & Equity Research Analyst - Biotechnology at Guggenheim Securities, LLC]

Helpful. Thank you.

[Operator]

Your next question will come from the line of Yifan Zhu with Jefferies. Please unmute and ask your question.

[Yifan Xu, Senior Associate - Biotechnology Equity Research at Jefferies]

Hi. This is Yifan from Jefferies for Kelly. Thank you for taking my question. Maybe another question on the stat six program. Could you please provide some additional color on the dose level used in the phase one b phase sorry.

[Yifan Xu, Senior Associate - Biotechnology Equity Research at Jefferies]

Phase one b trial because this is a single arm trial. How does it compare to the highest dose tested in the health volunteer studies? And how might it relate to the potential dose that you are going to use in the upcoming phase two b trials? Thank you.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Yeah. I mean, thank you. It's a great question. We we can't really comment on the dose. I think what we've said is we have a target in terms of degradation, and we believe that is an important target, which, as we said, 90% blast in blood and skin.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

And there is a the the target that we'd like to explore in in patients, but I'm not gonna speak to the dose and the profile. I think once we once we share our healthy volunteer data, we can talk a bit about the profile. But then as we as we share the data from one b, we'll talk about the dose as well likely.

[Yifan Xu, Senior Associate - Biotechnology Equity Research at Jefferies]

Okay. Thank you.

[Operator]

Your next question will come from Andy Chen with Wolfe Research. Please unmute and ask your question.

[Andy Chen, Director, Senior Equity Research Analyst at Wolfe Research]

Hey. Thank you for taking the question. On IRF five, do you see this concept as a conceptual equivalent to a combo therapy, including belimumab and anifrolumab and perhaps also Humira? Is this like a dual biologic or maybe triple biologic? So in terms of the studies that you've that you have done in vivo, do we have reasons to believe that you're it it would act like a dual drug or even even a triple drug?

[Andy Chen, Director, Senior Equity Research Analyst at Wolfe Research]

So I noticed that in the mouse model you tested, you you tested ducravacitinib and IFNAR separately, but can you combine them in mice, and would you see better efficacy that way? Thank you.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

So I'll take a quick and then maybe Jared and Veronica, you guys can can add. So so I think that as we've said, the beauty of BI RAD five is that you can actually yes. You can imagine having a multi asset combo in a single drug in a context specific manner. Right? Like,

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

if

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

you think about anti TNF or anti twenty three or anti interferon, these are antibodies that block those cytokines independently of what's going on in your body. This is why they work well, but they also have, in many cases in some cases, they have some side effects because you probably don't want to remove all of your type one interferon consistently all the time. So the beauty about IRFY, why it's a broad anti inflammatory agent, but also well tolerated is because we only do it in those setups, in those disease context. Maybe, Chad, do you wanna comment about from a medical clinical perspective? What would that mean?

[Jared Gollob, Chief Medical Officer at Kymera Therapeutics]

Yeah. No. I mean, I think the fact that we that we can have this sort of broad effect that's context specific and hopefully, therefore, have a safety profile that would be very favorable, you know, should allow us even as a single agent to potentially have activities that are equivalent to combining multiple different drugs. I think with that being said, I think Nelo, you know, earlier in his presentation talked about how these various pathways that are in our pipeline are complementary, right, whether it's TIC two, IRF five, now IRF five, you know, IRF four, and stat six, one could think about, you know, combining these, right, across certain diseases if there are potential synergies that could be obtained, especially if a drug like IRF five ends up being safe and well tolerated. That really opens up EV optionality, especially as an oral drug for combining several different oral drugs from within our pipeline or combining our oral drug with other standard of care agents that are out there.

[Jared Gollob, Chief Medical Officer at Kymera Therapeutics]

Again, I think we our expectation based on the data that Veronica showed in the preclinical models is that we should have substantial activity even as a single agent. So it's not as though we're obligated to combine it, but we certainly have that optionality.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Great. I think we've Yeah.

[Jared Gollob, Chief Medical Officer at Kymera Therapeutics]

We're operator, we're we're smidge over time. Maybe one last question, and then we'll we'll wrap up.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Thanks, Andy. Thanks, Andy.

[Operator]

Your last question will come from Kalpit Patel with B. Riley. Please unmute and ask your question.

[Kalpit Patel, Senior Biotech Research Analyst at B.Riley Securities]

Yeah. Hey. Good morning, and thanks for squeezing me in here. Noah, I just had one question on the degradation kinetics that that you may show here with the stat 60 greater in in patients by by the year end. You know, for the IRAD four program previously, you you know, the in that in that paper that was published, there was a rebound of the protein between day 14 to day 28, you know, which you attributed to the variability and the method used, the testing method used, and the storage conditions.

[Kalpit Patel, Senior Biotech Research Analyst at B.Riley Securities]

So I I guess going forward, what steps are you taking to ensure that the kinetics, you know, will more accurately reflect the true target knockdown rather than any measurement or sampling hand motions?

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Yeah. Maybe just to thanks for the question. Just to kind of make sure we're all on the same page. So with with our report, what we've shown is into in in the in the healthy volunteer studies, we were able to show robust degradation using mass spec technology that would follow from, obviously, day one to day 14. When you go into this broader study, the patient study, we it's really hard to use mass spec because the isolation procedure, it's difficult to use in multiple sites that you're using.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

So we ended up using flow. And flow, what happens is, unfortunately, that the in in some cases, the the sample can can deteriorate, and so it makes it more difficult to measure the the effect on the of the degrader with time. And so what what we have what we have planned for, obviously, the existing study of six to one and the and the phase one b study is that we'll have, you know, several opportunities to ensure that we can measure protein levels well. And I think, I can't speak it because, you know, I will speak about the data as well. But I think once we share the healthy volunteer data, it might be easier for me to comment more on your question.

[Kalpit Patel, Senior Biotech Research Analyst at B.Riley Securities]

Okay. Thanks very much for choosing our question.

[Operator]

There

[Operator]

are no more questions at this time. I'd now like to turn the call over to Nello Manolfe for closing remarks.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

Thank you. First, I wanted to thank everybody for attending our call. I wanna thank the team at Chimera for putting together a great story today. Obviously, we have a lot of more opportunities ahead of us to engage further on some exciting milestones that we're reaching soon. In the meanwhile, if you have further questions, you know where to find us.

[Nello Mainolfi, Founder, President & CEO at Kymera Therapeutics]

We we wanna make sure that the richness of the data we shared today can be appreciated with fullest. So, again, thank you for everybody everybody for attending. The slides are on our website so you can review in your own time, and we'll see you actually soon.

Participants

Executives

• Justine Koenigsberg, VP - Investor Relations
• Nello Mainolfi, Founder, President & CEO
• Jared Gollob, Chief Medical Officer
• Veronica Campbell, Senior Director - Immunology

Analysts

• Yvonne Kumi, VP - Senior Quantitative Analytics at Wells Fargo
• Jeet Mukherjee, Analyst at BTIG
• Marc Frahm, Biotechnology Equity Research Analyst at Cowen
• Eliana Merle, Analyst at UBS Group
• Sudan Loganathan, Managing Director at Stephens Inc
• Vikram Purohit, Analyst at Morgan Stanley
• Eric Joseph, Equity Research Analyst at JP Morgan
• Faisal Khurshid, Senior Research Analyst - Emerging Immunology at Leerink Partners
• Nishant Jadav, Managing Director at Citi
• Michael Schmidt, Senior Managing Director & Equity Research Analyst - Biotechnology at Guggenheim Securities, LLC
• Yifan Xu, Senior Associate - Biotechnology Equity Research at Jefferies
• Andy Chen, Director, Senior Equity Research Analyst at Wolfe Research
• Kalpit Patel, Senior Biotech Research Analyst at B.Riley Securities