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

Good morning. Thank you for attending today's Pipelines Live! 2022 Series with Kymera Therapeutics call hosted by Rich Law, Senior Analyst at Credit Suisse. On the call, we have speakers Nello Mainolfi, CEO of Kymera and Jared Gollob, CMO of Kymera. [Operator Instructions] I would now like to pass the conference over to our host, Rich Law. You may proceed, sir.

Thank you. Good morning, everyone. My name is Rich Law, and I'm a Biotech Senior Analyst at Credit Suisse. I am pleased to host Kymera Therapeutics today in our inaugural Pipelines Live! 2022 Series of senior leadership discussions. Nello, Co-Founder and CEO; and Jared, the CMO will be joining us today. We may have some time towards the end for questions from the audience. Please send me your questions to [email protected] or you can also post the questions on the dashboard. Okay. I've been anticipating this call for some time. So let's get started. Nello and Jared, welcome. Do you want to give a quick remark before we get started with the Q&A?

Sure. Thanks, Rich. Thanks for the opportunity to be here today. So maybe just a couple of minutes of company intro. I expect that many on the line are aware of the company, for the few that may not be aware, so Kymera was founded in 2016 with the focus on building a fully integrated business by investing in targeted protein degradation and evolving our pipeline and platform to support the generation of a new series of medicines based on targeted protein degradation. We -- in the past 6 years, we have focused on 2 key aspects: one, executing on a series of pipeline programs that, in our mind, we're able to capitalize on the power of protein degradation in a way that we believe is quite unique. So our programs are first-in-class programs that we believe have the ability to change how we think about treatment paradigms across several indications. But we've also invested in our platform to -- not only to become more efficient at developing drugs, but also to being able to develop new therapeutic hypotheses based on new things that targeted protein degradation can do, whether it's using novel E3 ligases, whether it's expanding the concept of degradation using molecular glue, whether it's using our broad heat finding capabilities. But again, with the goal of investing in the platform in order to deliver on our commitment to building a company that can go from idea generation all the way to commercialization on protein degradation. For people that are not aware of targeted protein degradation, it is a small molecule-based modality that allows us to target disease causing protein and removing them completely from the seller localization without any change on the genome. So it's the probably more powerful, more flexible technology that can add that proteome in a selective manner. We have closed Q1 with about $523 million of cash, which sets us in a quite unique place, especially in this environment, to fund the company into '25 and through several key inflection points. And I'm sure we'll go into them. But just at a high level, we have 3 programs. We just announced today that we have dosed patients in both the IRAKIMiD program within KT-413 for MYD88-mutant tumors. And we've also dosed patients in the KT-333 STAT3 program for both solid and liquid tumors. And so now we have 3 programs that are dosing patients in Phase I, and we expect to share data across both the oncology program as well as the KT-474 program later in the year. So I'll pause here. Obviously, there is much more to Kymera, but happy to go into the Q&A.

All right. Sounds good. Thanks a lot, Nello. Okay. I have a couple of general questions to start. Over the past couple of years, the past 2 years, there have been a lot of interesting developments in degrader because there's a lot of clinical data that came out. And we have seen some positive results and some unexpected ones across the industry. So how would you characterize the progression so far for degraders as a viable modality? And how would you -- and also, would you -- do you think that the degraders can be as successful as, say, like monoclonal antibodies or kinase inhibitors and so forth?

Yes. No, great question, Rich. So the short answer is degrader they've been in hundreds, probably hundreds of thousands of patients are ready. Degraders have been on the market for many, many years. And degraders are now increasing the impact because we have come up with technologies that allow us to specifically and rationally design degrader. So let me explain what I mean by that, and then I'll answer your question. So the class of [ image ] drugs that have been on the market for now, I believe, probably close to 20 years for different indications. Operate through a degradation mechanisms. And this drug, and if you think about Revlimid was, I believe the #1 small molecule drug in terms of sales for many years not sure it still is, but I do know it was and at least until recently. Also, if you look at how some of nuclear receptors are targeted even before the most recent degraders for Arvinas, these are small molecule degraders of androgen receptor or estrogen receptor. So the technology is well established. The pharmacology and safety have been well characterized. And I would say that what we have seen, including the more recent data is all the efficacy and safety that we've seen so far are either on target pharmacology or in some cases, off-target pharmacology. But we have not seen to date any class effect that one can look through the lens of being challenging. So I guess what I'm saying is the technology is clinically and commercially validated through several drugs, heterobifunctional degraders, which is the new way to specifically degrade protein as advanced with several molecules now, I believe I can count at least 5 molecules, maybe 6, in the clinic. And all of them have actually shown good target engagement and all safety has been in line with what's expected with those targets. I think the global success of protein degraders is going to be driven by our ability as an industry to use the technology for the right type of target for the right type of indication for the right type of patients. And what I mean by that is every technology has the right application, maybe the most simple analogy there if you think about mRNA and application to COVID, it just feels like almost a perfect fit. But if you look at antibodies, obviously, they've been targeted for extracellular proteins that have specific half-life that is in line with the right therapeutic potential of monoclonal antibodies. If you look at small molecules, they're being targeted towards drug targets that have a catalytic site that can be inhibited by a small molecule. Now with degrader, we can actually go as Kymera says after any target in -- any protein target in the cell. And so the trick will be selecting the targets where degrading that protein is the only or the best way to do it so that you can advance a clear therapeutic hypothesis into and through the clinic.

Okay. Got it. And -- for most of the company's history, Kymera has been focused on heterobifunctional degraders. But late last year, you guys made the announcement to also develop molecular glues. What drove that decision? And where are you now with the glue development.

Yes. So I mean I go back to what I -- hopefully, this answer will be shorter than the previous one. But -- as I said before, our goal, our vision is being able to use degrader mechanism to go after any type of proteins in the cell that cannot be targeted with other technologies. So we've shown that we have been quite successful to go after proteins that can be targeted with small molecules, but where a small molecule inhibition is insufficient to drive the right biological response. And I think IRAK4 is a great example. MDM2 for different reasons is another example. We've also shown that we're able to go after on drug targets that can be liganded with small molecule. An example is STAT3. We have other examples in our pipeline that we haven't disclosed yet. So traditionally, on drug targets but can be liganded with small molecule. We're also showing that we can use expression profile of E3 ligases to develop drugs with larger therapeutic indices. So we haven't shared that, but we will hopefully soon, what some of the examples are. So as you can see, we're using protein degradation to really push the envelope on innovation as well as on clear, hopefully, patient impact as we go into and through the clinic. There is -- and I -- we strongly believe that Kymera that a heterobifunctional-driven degradation is the most efficient degradation technology to selectively and specifically degrade protein. Now what I left out of all those classes of targets that we're going after is the, let's call it, undruggable or undrug targets that are not ligandable with small molecules. So unlike STAT3 that while it doesn't have a catalytic site does have a small molecule binding site that we can degrade. There are other transcription factors, attacker proteins that do not possess a well-defined small molecule binding pocket. And for those, we either decide as a company that we have so much to work on. We don't need to work in that space or decide as we've done with everything else, to build a comprehensive strategy, so not to be limited by technology but to be limited by biology. And so we use molecular glue approaches where we need the protein-protein interaction enabled by a small molecule molecular glue to target and degrade some undruggable, undrug proteins. And what I would say is that unlike many other companies in the space, we're not working on cereblon based molecular glue on the IMiD scaffold, but we're looking for E3 ligase and target protein interactions that are naturally occurring already and you would be surprised of how many E3 ligases bind very weekly to how many proteins. And then what we add there is small molecules that can enhance their natural affinity to then drive degradation. I don't know that we're in a position to disclose some of those programs, but we will, as we kind of evolve and move those programs into development.

Fantastic and I look forward to seeing what those programs are. And are you doing anything different in this market environment in this uncertain market environment from the inflation and potential recession? Are you doing anything different in terms of spending and investments?

Yes, it's a great question. So as I mentioned earlier, we are really well capitalized. Obviously, for the stage of the company, we have more than $500 million that will put us in those -- in the group of biotechs that doesn't have to raise capital in the short- or medium-term. Having said that, I think it will be irresponsible for us not to be -- not only aware of what's going on, but also respond to external environment. So we're taking measures without compromising our productivity, but we're taking measures to de-risk our operations and potentially even extend our ability to operate the company with -- in terms of timing with the cash that we have in hand. I don't want to go into specifics, but rest assured that we're not, obviously, either indifferent or we're not taking actions to -- to describe, I think, kind of maybe 1 unit generation type of external environment.

Okay. Yes. Yes, I have other questions on KT-474, so let's move on for that. For KT-474, you guys made a decision to extend the study from 4 weeks to 8 weeks. Why not go a little bit longer to better gauge the clinical efficacy?

Yes. Rich, it's a great question. And let me start with what was the study -- what was the point of this study? I've said this before, the point -- the goal of the study was to demonstrate that immunology focused protein degrader. So I think the novelty here is not just the indications or the disease areas but it's the fact that we're -- let's call it, we have several stakeholders in the human body that we need to address. We need to degrade IRAK4 in a wide variety of cell types. We know that based on preclinical where we know that based on also now clinical work. And so the question that actually Sanofi and Kymera had when we signed the contract, which is 2 years ago, roughly, was is degradation of IRAK4 in blood and skin consistent when you go from healthy volunteer where there is no real inflammatory process to patients, especially patients with skin conditions where we've seen an up-regulated target expression in the skin, for example, of HS patients. So the question was really simple. Is the gradation profile, the same or different as you go from healthy volunteers to patients. And the goal has not changed. So this is why in the short-term, this is why we're not extending the study. We're not adding placebo because the reason for the study has not changed. Now we have extended the duration from 2 weeks to 4 weeks for 2 reasons: one was because we realized that in 2 weeks, we have not reached steady state in the skin of healthy volunteer. And because these patients have skin conditions, we wanted to make sure that when we measure PD biomarker, we had reached steady state. And then because also we wanted to confirm that going from that -- I'm sure we will discuss, we have seen these non-adverse non-dose responsive small subclinical QT finding. We want to make sure that we -- that as plateau, as we've already seen, at day 7 basically because day 7 dosing, were the same. We want to make sure that as we extend dosing, we don't see anything different. So yes, we could expand the study we could add placebo, but then we would be running a Phase II study. And I think that's not the goal of the study. The goal is to actually go through this confirming PK/PD and safety and then move into a Phase II study ASAP at which will be powered well enough to answer all the clinical questions.

Okay. And that decision was that requested by Sanofi? Or was it something that you guys just voluntarily designed it to [ dare ]?

Yes. Thanks, Rich, for asking the question. No, this was designed by our team, was proposed by our team based on the data we had in hand. We then run it by Sanofi or run it by the FDA, and they both agreed that it made sense to do it. But this was from Kymera.

Okay. Got it. Sanofi paid $150 million upfront in mid-2020 and may take over the study after Phase I. Obviously, Sanofi has a lot of experience in the AD market and also for RA in drug development. What is the level of engagement from Sanofi so far for this program? And like, for example, how much have they been involved in the Phase I decisions and executions and helping Kymera due the POC.

Yes. Yes. So I mean, as you know, Sanofi pay a relatively meaningful number when the program was actually around DC. So it was clearly preclinical. And this just shows how much both confidence and expectations they had and obviously still have on this mechanism. I mean, as you've heard from their CEO a few weeks ago or a few -- even a few days ago in 1 of his interview. Sanofi has the ambition to become the #1 player in immunology. And I think they appreciate that you have to have a small molecule mechanism to conquer large market. Obviously, DUPIXENT is doing great. It probably would turn out to be the most -- the largest grossing drug in a few years yearly. But clearly, that's not enough. And it has some challenges being an injectable et cetera. So the expectation that Sanofi has for IRAK4 mechanisms are franchise expectations. This is not a drug for a particular indication, but for a broad variety of indications. There are some that are higher priorities as you've seen with DUPIXENT, that's kind of the approach they took of going into AD and then expanding in other indications. I expect that, that would be similar. I can't tell you right now what the first indication would be for approval. But -- and they've been really close to the company. They are very close to the company, both scientifically and from their leadership. And -- we have a very close collaboration. So everything that we have done has been well aware, obviously, before anything has been disclosed, and we make sure that every decision we made is run by their team. So far, there hasn't been any disagreements on anything that we have proposed and we have done. So it's been going really well.

Sounds good. And have they been providing the guidance in terms of just kind of based on their experience so far in AD and RA sort of the guidance in terms of how to think about these studies and so forth?

Well, I mean, as you mentioned, Sanofi will take over the development of KT-474, at the end of Phase I. And so they are obviously in preparation mode for Phase II and beyond. And so -- we have discussed for sure in the actions and they do have views about indications of interest. And then those will be disclosed at the appropriate time. We've discussed as they have ADHS, potentially array, you can think about lupus, you can think about IBD, there are so many indications. So the -- I think the data that we will generate also in the patient cohort will be informative, and we will also guide the prioritization exercises.

Okay. Yes. Got it. So Sanofi, I think you mentioned DUPIXENT, Sanofi is also co-commercializing Kevzara with Regeneron. Since these assets overlap with 474, KT-474, I would argue that the bar for investment is relatively high -- what is your understanding of what Sanofi is looking for when evaluating 474 as an investment?

Well, I mean, as I said, I mean, the kids are -- I'm not sure how well the drug is doing, right? So unfortunately, I don't have the number handy, but I don't think it's doing great in array. What I would say is that we are -- and I'm going to say we because I can't speak for Sanofi. So when I say we, I'm going to talk the collaboration, informed by also what Sanofi tells Kymera. We are looking for an active and well-tolerated drug that can potentially take over the biologics market and take over all the JAKs market in a variety of indications because we know that our safety profile of this mechanism will be superior to the JAK inhibitor -- JAK inhibition mechanism. So that's the level of commitment to this mechanism. And that is also one of the reasons that we have a broad partnership on the IRAK4 mechanism that goes also beyond 474.

I see. Okay. Yes, makes sense. Okay. Let's discuss some of the risks around the IRAK4 pathway. So it's been well documented that naturally occurring IRAK4 deficient children are at risk of serious and life-threatening infections. However, infections decline with age and aware for IRAK4 deficient adults. And I don't think there's any depth or after the age of 8, there is no invasive infections after the age of 14. What DUPIXENT just got approval in AD earlier this month for children of 6 months to 5 years -- 5 years old. How do you think about the development for KT-474 in atopic dermatitis where pediatrics is a fairly large portion of the patient population. For example, can you still develop the drug in pediatrics and say less cut it off at age 14 and under?

Yes. I think ultimately, Sanofi will have to play an important role in deciding what the development path of pediatrics looks like. Obviously, there's a very large opportunity in adults. I think for piece as you mentioned, adolescents really don't have much of a susceptibility to infection is predominantly in infancy and early childhood. And so I think the real question would be in children say, as you said, 5 or 6 years of age or younger, could it be developed there. I think there still is the potential for that. I think the knockdown that would be required for us to have efficacy. May from our -- what we've learned so far be in the 85% to 90% range, but it's not going to be 100% knockdown. And so it's not clear that 85% or 90% knockdown of IRAK4 would necessarily lead to infection susceptibility in very young children to the extent that you see in children who have complete loss of IRAK4 due to mutation. So I think that there really is no segment, which is really sort of off limit, I think at this point for development with this particular drug, I think more needs to be learned in adults. I think Sanofi will ultimately have the important call around to what degree to develop it in pediatrics and to what age to limit it to, if any.

Yes. And obviously, I learned from the studies, right? What is the potential risk? At this point, I think we -- that's not on top of our list of concerns.

I see. Okay. Yes, got it. It makes sense. Okay. Let's move on to the QTc prolongation that you mentioned during the first quarter earnings call. So you mentioned that you observed 10 millisecond to 20 millisecond on average of prolongation, but never exceeding the 30 millisecond. And you have served this in the MAD portion, so the multiple ascending dose portion of the study. Despite that QTc prolongation are quite common among many medications such as antibiotics, antidepressants and so forth, why do you think it was necessary to call it out, especially you didn't really qualify as an adverse effect?

Yes. No, Rich, it's a great point. So yes, obviously, and with respect, probably we could have done something different. But I think we're still convinced that this is a long game of developing drugs and building companies. And having a finding was not adverse that does we believe, is a real finding. It's not a noise. And given that it was detected in early clinical development, we thought it would be prudent for, I guess, both the credibility and the corners of the company and this team here today to share this finding, just in the event that later on in clinical development, things might look different, and we want to be transparent from the get go. We don't have any expectations that this finding will get worse. In fact, very, very rarely do you see a finding that is not adverse that is also self limiting. So we feel pretty confident about it and are frustrated by the unfortunate, I think, assumption that is made outside of the company that this is a big problem. But nonetheless, we decided to share it just to be, again, transparent and demonstrate that we're building this company to be around for a long time.

I see. And what gives you the confidence that the effect were not worse than, let's say, in the Part C of your longer study?

Yes. I'll let Jared comment on this too. But at the high level, I've read many, many reports and by some of your colleagues, I think what's missed sometimes, not all the time, is that the QT effect that KT-474 elicit is quite unique. And the uniqueness is actually all good. And what I mean by that is, I'm not aware of any drug that has a QT effect that -- first, that's not show up on a single dose and only takes a few days to appear. It's not dose responses. So you can increase the exposure and the dose by sevenfold and you don't see a difference. And also that it seems to be self-limiting. So once you reach steady state in bot, you seem to reach steady state in the signal. So it's very rare to find these. The concern for QT is excursion of QT above 60 milliseconds or the interval go above 500 milliseconds. We have never seen even a single time point in hours and hours of kind of QT data that we've accumulated in the Phase I study in the [indiscernible] study. We haven't seen anybody getting close. So I think some of this is perception. So we just need to analyze the data. So far, we believe that this finding while real, that's why we disclosed it is in a range that is so minimal that -- and it is self-limiting and [ non-dose responses ] that we don't expected to become something that will impact the drug development of this drug. Now if we knew at 100%, we wouldn't be running future studies. So future studies are to confirm what we understand so far. Going back to your question, in the 14 days of study, day 7 and day 14 looked exactly the same. So it will be extremely strange that you plateau and then you go up again, right? So we expect that it will stay around steady state because we -- and we know we've reached steady state in plasma, and the kinetics of these effects seem to correlate with plasma PK. And so we expect that it will continue to look the same. We -- yes, I will leave it at that. Jared, anything you want to add?

No, I think you've answered it.

Okay. Got it. So it didn't really change with the different time points, didn't change with the dose amount. And -- so how much buffer room does the data show before becoming like, let's say, a grade 1 adverse effect? Is there enough of a buffer there?

Yes. Jared, why don't you comment on this. My only point would be like this is not so much about how much power we have versus Grade 1. But what is the risk? So Jared, if maybe you can...

Yes, I think the key would be not to have too much focus on Grade 1. I think for the change in QT, the so-called Delta QT, as Nello mentioned, you need to get above 60, before there is a substantial risk for their being arrhythmia and 60 milliseconds -- greater than 60 milliseconds is Grade 3. There is no grading for anything less than 60 milliseconds. For the QT interval itself, the interval really needs to get above 500 before you really at risk for arrhythmia. Grade 1 is considered 450 milliseconds or greater our subjects have been certainly well below even 450 have been essentially within the normal range on the study. We haven't had anybody who's reached 450 or greater. But the only emphasis I would make is that for QT interval itself, if there was anybody in the future who were to be in the Grade 1 range for QTc interval itself, we don't see that really as being an issue or being a safety issue. It's really if you're starting to get into that 500 range or above 60-millisecond change where there's a risk of arrhythmia, I think that's where one starts to become concerned.

Okay. Yes. Okay. That makes sense. And you guys reported or you guys mentioned it to the FDA? And what was the discussion like -- did they -- did you guys discuss any monitoring for the QTc beyond what you would normally do? Had you not observe the QTc effect?

No, no. And in fact, we had requested a Type C meeting with FDA, we felt we wanted to be very transparent as we have a very open relationship with the [ derm ] division. And so we wanted to provide them with all of our safety, PK and PD data and also to let them know in conjunction with that what our plans going to be for modifying Part C. We put all that in writing. We shared with them all of our QTc data. We even requested that they have the FDA QT IRT group. This is their group that specializes in QT analysis be involved as well. So they also saw all of our data we got back from them a written response, which essentially indicated that they were simply aligned with our plans for Part C. They agreed with our going to 28 days of dosing. They agreed with our dose selection, [indiscernible] dose, equivalent to an exposure that we had with 100 milligrams in the fasting state. They agreed with our addition of exploratory clinical endpoints. And they also agreed with our cardiac monitoring, which is actually routine. We're doing all of this on an outpatient basis in Part C. So these patients will all be treated with oral drug for 28 days on an outpatient basis there's no inpatient monitoring. They'll have an ECG done either twice weekly on a weekly basis, all routine ECG monitoring that the FDA agreed to. So essentially, their response to us is so straightforward that we actually were able to cancel the actual face-to-face meeting because there was no need to have a conversation with us as they were aligned with our plan.

Okay. Got it. That's very helpful. And is there any -- I mean, what's the effect of QTc on the criteria for eligible patients for the study? Like for example, when you now exclude patients with history of cardiac complications like arrhythmia or something like that, just as a...

No. Yes, essentially, predominantly, what we do in terms of eligibility. The only real changes were to exclude patients with any history of QT prolongation at baseline or any inherited syndrome associated with QT prolongation. These are very rare patients also to state that if patients are on any drug that is known to prolong the QT interval, they have to come off that drug before going on to the study. Those were really the primary changes and eligibility criteria which really should not have much of an impact at all on our ability to enroll Part C.

Okay. Yes. Okay, makes sense. In our analysis, we also found QTc prolongation effects in Pfizer trial but it looks similar across their IRAK4 inhibitor [indiscernible] and placebo arm. So would this -- I mean, would it be safe to say that the QTc effect is not associated to the IRAK4 pathway? And if that's the case, what is your theory in terms of what's causing the QTc effect?

Yes, maybe I'll take the first part of that and then turn it over to Nello for the second part. But in terms of your observations around Pfizer study, the fact that they did see some QT prolongation, both in placebo as well as in the arm of the JAK inhibitor as well as the IRAK4 inhibitor really suggest that this was sort of a non-specific effect. And that probably relates more just to the normal variability that you can see in QTc interval over time. There's a normal sort of fluctuation you see in QTc, which is why if you're going to look at this rigorously you have to do these ECGs and triplet kit at each time point and normally have to have these overread by a cardiologist because the machine read QTc changes can be [indiscernible]. And so if you don't do it with that sort of level of rigor, which we did in our Phase I study you may end up seeing changes which are really which are really very non-specific. And so therefore, as you pointed out, we don't see that there's any evidence on the Pfizer trial that their IRAK4 an inhibitor was causing any QT effect. And that's in line with what we believe as well that the fact that we're seeing on QT really has nothing to do with IRAK4 degradation is really more of a compound-specific effect. And maybe Nello can speak more to our mechanistic data, but I'd also point to that.

Yes. No, I agree with you, Jared. Obviously, if you look at the data, you'll see some subjects QT going to like[indiscernible]. So you see that fluctuation can be relatively large. And so that's why we try not to be fixated on a number per se, but on the mean as well as on whether it now is increased or increased risk or not. With regards to the mechanism, I mean, we've said this before, I just want to remind everybody, we have not seen QT prolongation in any study so far, in any preclinical study in which we measure QT in animals, whether it was a 24-hour or 28-day or even more recently a 4-month chronic [ tox ] study we did not measure any QT prolongation. So it's possible that the instrumentation that we used in animals -- that one use -- in animals is not sensitive enough. Again, this is a very small signal or it's possible that dogs that we use are not -- less sensitive than humans. We will never know that, although we are doing some more studies. Also, I want to remind everybody that we've dosed preclinically, this compounds that much higher exposures, 30, 60, probably 100 fold above the exposure that we're seeing in humans. So even in those we didn't detect it, which again tells you something else about this plateau effect in case that even there, it's so minimal that we can't find it. Now -- so then how do we explain this? So we know with a high degree of confidence, although there is some noise out there that this has nothing to do with IRAK4. I mean we know it from human genetics which, to me, is the strongest piece of evidence. And disputing human genetics with obscure favor is not a good sign. Then we know from small molecule inhibitor, there has been in the clinic now. I think we've had at least 2 selective or some more selective inhibitors that have never shown QT prolongation. And including our own data, I think it's clear to us that as I do with IRAK4 now. Our rationale for this finding, which again, we did not expect. I want to remind you, we did not see in the SAD study, we did not see in the MAD dose 1, day 1 study. So again, it only appeared after 7-day of dosing. We believe that it's a mix between the compound 474 having a weak affinity for the herd channel. Again, the affinity, the ITCs, thousands of fold above what is the degradation of 474. And I want to repeat, we do not degrade the her channel. There is some binding activity that might be specific or may be non-specific, we're still trying to learn. So as I was saying, there might be some of that confounded by or maybe increased by the fact that upon multiple day of dosing, we do see probably higher -- much higher exposure in some tissues, including the cardiac issues that we see in plasma. And we believe that the exposure in some issues, including the cardiac issues, get saturated at a relatively early dose. And so at that early dose, we might have an engagement, an affinity of binding, let's say, with the her channel, there may be 10% to 20%, and that's enough to lead to a measurable QT effect. And it doesn't get worse because the tissue exposure is saturated. So let's hope we're confident about based on our data. But it's still studies that are ongoing to completely confirm these hypothesis.

Okay. That makes a lot of sense. Some investors look at Pfizer IRAK4 inhibitor data and see a lower efficacy compared to HUMIRA. And they see that as a sign that the IRAK4 pathway may not be as effective compared to targeting specific cytokines like TNF. What is your view on the IRAK4 inhibitor versus the degrader approach and compare that to targeting cytokines directly.

So maybe I'll start here, Jared, and you can continue. So actually, all the data that has been generated so far in the clinic, mostly by Pfizer. So we have, I would call it still an initial proof-of-concept in array. And from what we've heard, some efficacy also in HS although insufficient to advance the market in Phase III. To us, that is best case scenario. When we started this program 5 years ago, 4 years ago or so, we came into this field, knowing or at least expecting that IRAK4 inhibition will be insufficient to have clinical benefit in these complex diseases. And we demonstrated with our data and not only us, so for some other people in academia have shown that the only way to fully locate this pathway is by removing IRAK4 instead of inhibiting the kinase function. So by removing IRAK4 blocking the also so-called scaffolding function, we're able to have a complete blockade of [indiscernible] TLR, downstream signaling that has to go through the MYD88 complex in IRAK4. So to us, actually, that's best case scenario. We have proof-of-concept that the pathway is relevant. But we also have proof-of-concept that our kinase inhibition is not enough to have enough of a clinical benefit. So we're going into these studies actually with a lot of confidence that we'll be able to show that this mechanism will be superior to IRAK4 inhibition.

Okay. Yes, that makes sense. So I know you guys are expecting the expectations for 474 to be superior to biologics like DUPIXENT or HUMIRA and so forth. What do you think of the opportunity, the market opportunity, if 474 falls short of that goal?

Well, I actually think that our goal is to have a compound that is active and well tolerated. And with the compound that is active and well tolerated, I think you'll see that you will take over the biologics market. I mean you're seeing even in AD where JAK inhibitors with the black box have been approved, they are taking market share from biologics. So imagine if you have a drug that is active, let's say, the activity similar to biologic or similar to JAKs or plus and minus something that has never black box warning a high-risk profile, I think the market opportunities are going to be huge.

Right. Okay. Got it. And then staying in the context, we obviously see tremendous value for an oral and safe therapy given what Otezla has achieved in psoriasis, which is a very competitive market and very crowded with many potent biologics like Cosentyx, [ TreVia ] , SKYRIZI and so forth. Do you -- do you see Otezla as a good case study of what an oral therapy could achieve? And also, do you believe that Sanofi is also seeing the value in such a scenario where they could place themselves before the more potent biologics.

Yes. I mean Otezla is a good case study for probably lots of companies, right? You have a drug that is somewhat active, but it's well tolerated, and it's easy to take and has a huge market share in that patient population. So I expect that, again, the -- I think the strategy from Sanofi, again, I can't speak for them, and I don't want to is to take over the immunology space through small [indiscernible] active and well-tolerated small molecules. That will be the -- I think that will be the win in 5 to 10 years. I think pricing pressure will continue to be there, small molecule drugs will take over all this market because the prices will be lower, but you can still have you can still have high sales just based on really large volumes. So I think that's where the world will go, assuming we can develop good drugs, which is where Kymera is investing heavily. You've seen IRAK4. We have 2 other large immunology programs that we haven't disclosed yet. On top of STAT3, so we are huge believers that small molecule degraders will actually be huge players in immunology in the next 5 to 10 years.

Okay. Yes. And you mentioned the JAK inhibitors. So abrocitinib and upadacitinib were both approved earlier this year in atopic dermatitis. They're both perceived as potent, very potent compared to -- or more potent compared to biologics, but they have the JAK class box warning despite that both are -- have a cleaner profile compared to earlier generation of 30 JAK. How do you compare in terms of these 2 products to KT-474, in terms of competition in the oral space.

Well, I mean, as I said earlier, I do believe that -- so what are JAK inhibitors? JAK inhibitors are, first of all, great drugs that have profound activity now across the wide variety of diseases. So these are good drugs that unfortunately have shown some in some cases, really bad safety events, also rare. And I'm not going to comment on FDA strategy on black box. I have my own ideas, but it is what it is. And the reason why they're very active JAK inhibitors are because their pleiotropic anti inflammatory agents. They block the secretion and the signaling of the [indiscernible] -- in a way, while on a different pathway, our export degraders have similar kind of pleiotropic anti inflammatory effect. So we believe that JAK inhibitors are our direct competitors, just to be honest. And we believe that our risk reward will look much better than JAK inhibitors. That's the hypothesis behind this program.

I see, okay. Yes. So okay, why don't we move on to the other programs in the pipeline. Let's start with the MDM2 degrader KT-253, there have been high rates of adverse effects and safety concerns on targeting MDM2 for multiple inhibitors. There's some from Roche that get discontinued -- sorry, there's one from Roche that the that discontinued. Can you talk about how you think about KT-253, how that would differentiate in terms of safety and efficacy compared to inhibitors?

Sure. Yes, I think that one of the main drawbacks for the MDM2 small molecule inhibitors is that while they do inhibit the MDM2 253 interaction that leads to wild-type 253 upregulation, which is what you want, it's also limited by the fact that with the inhibitors, you could then get a compensatory sort of feedback loop when that happens, that leads to further MDM2 protein upregulation. And that positive feedback loop, which upregulates MDM2 expression than fights the effect of the MDM2 inhibitor. And therefore, you're never able to get quite the degree of 253 upregulation that you need to drive apoptosis over just cell cycle inhibition. And it also means that it's hard to use pulsatile dosing that you have to have more continuous exposure and coverage with the MDM2 inhibitors, which then leads to the classic dose-limiting toxicities of neutropenia and thrombocytopenia and GI tox that you see with the MDM2 inhibitors. So I think the MDM2 small molecule inhibitors are really problematic, both from a safety standpoint as well as from an efficacy standpoint. The degraders offer a really unique approach here by degrading MDM2 rather than just blocking the interaction with 253, you prevent this feedback loop. You prevent the upregulation of MDM2 in response to 253 upregulation. And by doing that, you get a much stronger upregulation of 253, which is much more likely to drive apoptosis and cell death in these 253 wild-type tumors. And it also enables just brief exposures, pulsatile exposure were just hours' worth of exposure and down-regulation of the target drive cell apoptosis. So this also allows us to dose potentially very infrequently with a degrader to mitigate the classic dose-limiting toxicities that you see with the inhibitors. So we think that the unique mechanism allows for enhanced efficacy and also a much better therapeutic index and safety window, which we think will be very transformative and allows for a very different value proposition for a degrader of MDM2 versus the inhibitors.

I see. Okay, very interesting. And what was the rationale to focus on AML and uveal melanoma?

Well, I mean, for us, we're very data-driven when it comes to understanding indications that are going to be sensitive to MDM2 degradation. You're right, there are some precedents out there with MDM2 inhibitors showing activity, for example, in AML, although that activity so far has not been sufficient for approval. Again, largely because it's hard for these MDM2 inhibitors mechanistically to be as effective as an MDM2 to greater and they're also strapped with the sort of safety issues. From our standpoint, we are using a biomarker-based approach in-vitro to really understand what tumor types be they liquid tumors or solid tumors are going to be responsive to MDM2 degradation 253 wild-type tumors that will be responsive. We've been able to show so far in various models of AML, both in-vitro and in-vivo that these can be very responsive to MDM2 degradation where even single doses in xenograft models of AML lead to durable complete tumor responses. We're in the process of really understanding and defining what the actual gene expression profile or biomarker profile is of these highly responsive tumors to MDM2 degraders. And those are the ones that we will focus on for clinical development. AML is certainly up there as a very real possibility. In uveal melanoma and other solid tumor malignancies, certainly not just restricted to uveal melanoma. We've also seen very strong apoptotic responses in-vitro. And further really evaluating defining which solid tumor types as well as which liquid tumor types will be most responsive to MDM2 degraders. And then our ultimate aim is to have a profile, a biomarker profile that will allow us to then identify and select for those indications and those patients within certain indications that will be most responsive to this approach.

Okay. Got it. So I think we have a couple more minutes left. So let's shift gears quickly to KT-333 or STAT3 degrader. You have 2 step 3 degraders that we know of the KT-333 and KTX-115. Can you talk about the development path for these? And then for the inflammatory disorders, there seem to be some overlap with KT-474. So how do you see this asset fit into that space with 474.

I just want to clarify 1 thing, and then I'll let Jared comment. So KT-333 is our investigational drug in oncology. And in fact, again, as I said earlier today, we shared publicly. Obviously, this has happened already that we dosed our first patient in the oncology trial. KTX-115 is a molecule that we've generated data on. It's not a development molecule yet. I think when we have a development molecule, we will we will define and characterize it with a KT number. Just to clarify, in case people expect that this code will show up in development. Jared, do you want to comment on...

Yes, maybe commenting on first -- so KT-333, which is now in Phase I, and which is now dosing patients is really being developed for oncology indications. Specifically, we're looking to develop this drug either as a monotherapy and STAT3 dependent heme-malignancyes, especially T cell malignancies like peripheral T-cell lymphoma, cutaneous T cell lymphoma and LGL leukemia, where we have compelling preclinical data showing a high degree of activity in association, for example, with JAK or STAT3 mutations. And also looking to develop KT-333 probably in combination with checkpoint inhibitors in solid tumors, but we've also generated very compelling preclinical data in syngeneic tumor models showing a very strong commentarial effect of this approach in solid tumors. On the inflammation side of things, as Nello indicated, we would be moving a separate compound forward potentially in both inflammatory and fibrotic disorders. -- the mechanism of action of a STAT3 degrader is obviously very different from KT-474, which is blocking IRAK4 and impacting the middle zone. So for the STAT3 compound or approach. We're looking at fibrosis and we're looking at Th17-driven inflammation, which is a different sort of universe of indications for development, which is separate from 474 IRAK4 were there, we're looking at inflammatory diseases driven by [indiscernible] cytokines and toll-like receptors, where there may be a little bit of overlap, we think that there really are distinct development opportunities in inflammation across these 2 programs.

Okay. Got it. Sounds good. And that's all the time that we have today. Nello and Jared, thank you so much. Is there any closing remarks you want to give before we sign off?

No. First, I want to thank you, Rich, for having us be an inaugural Pipelines meeting. Also I want to just share the excitement that we have at Kymera for these 3 readouts in the second half of the year, these are all, again, first-in-class mechanisms for which we're going deep on understanding PK pharmacology, safety and efficacy with a plethora of assays and readouts. So hopefully, now people know we will be sharing some really insightful data sets. And the rest of the pipeline, most of which is not being disclosed, I would say, just as exciting, it's not more. So there is a lot here brewing at Kymera and look forward to engaging with you further to talk about also a new program.

Sounds good. Thank you to Nello and Jared and all of you for joining us in our inaugural Pipelines Live! Series with Kymera. Please don't forget to sign up for next week expert call in atopic dermatitis. Thanks again, and enjoy the rest of the day. Thanks. Bye.

That concludes the conference call. Thank you for your participation. You may now connect your lines.