Good morning, and thank you for joining us to discuss the KT-621 phase I healthy volunteer results. I'm Justine Koenigsberg, Head of Investor Relations at Kymera. Joining me this morning with prepared remarks are Nello Mainolfi, our Founder, President, and CEO, and Jared Gollob, our Chief Medical Officer. For today's discussion, Nello will begin with an overview of our immunology strategy and the opportunity with small molecule degraders. Then, Jared will walk you through the KT-621 phase I trial and results. Following our prepared remarks, we will open the call to questions, where we will also be joined by Bruce Jacobs, our Chief Financial Officer. If you would 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&A discussion, we ask that you're ready to unmute your line when called on. In addition, we ask that you please limit your questions to one and a relevant follow-up to be sure we have enough time to address everyone's questions this morning. A replay of today's event, including the corresponding presentation, will be available soon after the call concludes in the investor section of our website. Before we begin, I would like to remind you that today's discussion will include forward-looking statements about our future expectations, plans, and prospects. These statements are subject to risks and uncertainties that may cause actual results to differ materially from those projected. A description of these risks can be found in our most recent 10-Q filed with the SEC.
Any forward-looking statements speak only as of today's date, and we assume no obligation to update any forward-looking statements found on today's call. With that, I would like to turn the call over to Nello.
Thank you, Justine, and thank you, everybody, for joining us this morning. Today is an important milestone for Kymera. It's also an important day for industry, and we believe for patients with Th2 diseases. Today marks the first clinical data for a STAT6 agent. KT-621, our once-a-day oral STAT6 degrader, after demonstrating an impressive preclinical profile with potency, efficacy, and safety in line or superior to dupilumab, has now delivered above and beyond our expectation in this first in-human study. In doing so, we believe, significantly de-risking the program and further validating its oral biologic-like profile. As the first STAT6 targeted medicine to advance into clinical testing, this is a great example of how using the power of targeted protein degradation with the right target allowed us to design and develop a compound poised to disrupt conventional treatment paradigms. Across every measure, the KT-621 phase I results were exceptional.
You will hear us describe this morning: KT-621 delivered complete STAT6 degradation at low doses, had a biomarker impact that we believe is at least comparable and, in some cases, superior to dupilumab, and doing so with an exceptionally clean tolerability profile. Before we jump into the data, which we are very excited to do, I'd like to take a few minutes to briefly highlight our INI strategy and the compelling rationale for an oral STAT6 medicine, to give you context for the data that Jared will walk you through. On slide five, I just want to summarize here. Kymera was founded with the goal of building an industry-leading pipeline of medicines using targeted protein degradation to overcome many of the challenges that our industry has faced over the past 20 years. Today, Kymera is a leader in the TPD space.
We have built unique capabilities, including how we identify small molecule ligands to undrug proteins, how we design and optimize exceptionally potent, selective, and orally active degraders against undrugged, high-value targets. We've married those capabilities with a unique target selection strategy of pursuing traditionally undrugged targets in highly qualified and validated pathways. The combination of bringing industry-leading capabilities to targets and pathways of immense value has allowed us to build a portfolio, including our STAT6 program, that's uniquely poised to disrupt conventional treatment paradigms. With our core focus in immunology, we've been able to combine the right target with the power of targeted protein degradation, delivering for the first time in industry oral drugs with biologics-like efficacy. That's really the value that we are here generating for Kymera, but ultimately for patients.
On slide six, I just want to highlight a few things that we believe we've done very uniquely. We've built a platform, a discovery engine that is able to deliver reproducible and scalable innovation. That's key for platform-based companies. I just talked about our hit finding and chemistry capabilities. I would add some of the best and most exciting in-industry structural biology capabilities that really allowed us to go after these traditionally intractable proteins. We have consistently demonstrated our ability to translate our preclinical findings into the clinic. This clearly is exemplified in the data we're sharing today. We believe it de-risks into patients and later into disease outcomes. We've delivered more than nine development candidates across our research efforts, five INDs, and those more than 400 humans, as I mentioned, with impeccable preclinical to clinical translation.
With these capabilities and a strong balance sheet, with KT-621 as an anchor of our pipeline, we're committed to building a fully integrated global commercial company. We're well on our way to doing just that. On slide seven here, you really see summarized with nice graphics our target selection strategy, which I've already explained. Strong genetics, clinical validation in the pathway and against the target. Target is undrugged or poorly drugged by other technologies. The target is going after diseases with large clinical and commercial opportunities. Importantly, we have a clear path to an early clinical differentiation. This results in what today's pipeline looks like. Starting maybe from the bottom, our more advanced program is in partnership with Sanofi in two phase II-B studies in HS and AD with data next year.
This program and this pathway, the IRAK4 pathway, has implications well beyond HS and AD. The next program that we just recently disclosed, the target is IRAK5, a traditionally undrugged transcription factor. We've identified what we believe to be the first development candidate, KT-579, which is in IND-enabling studies. It's going to go into the clinic early next year with clinical data ready in 2026. This, we believe, is a unique target to go after with a novel mechanism that is proven genetically and has pathway validation for a wide variety of immune inflammatory diseases. Obviously, the focus of today, KT-621, we've completed our healthy volunteer study a few weeks ago, and we're sharing the data today. We've started our phase I-B study in AD a few weeks ago. We'll share data in the fourth quarter.
We're initiating two phase II-B studies, one in AD, one in asthma, late this year, early next. Very busy year, very exciting year. Why immunology? There are about 160 million patients in the seven major markets that suffer, that have been diagnosed with the top 10 immune inflammatory diseases. They're in the bottom of the slides: AD, asthma, COPD, HS, MS, et cetera. This is just to give high-level numbers. Out of these 160 million patients, only 5 million patients, so about 3%, receive advanced systemic therapies. Advanced systemic therapies are targeted therapies that address the cause of disease. Most of these are injectable biologics, 2/3 of this. Then we have basically more than 100 million patients, I would say more than 150 million patients all over the world that do not have access to this systemic therapy for many, many reasons.
Probably one of the biggest reasons is that especially injectable biologics are only used in particular regions in the world and only for very severe patients. If we can develop drugs that have biologics-like efficacy, but the convenience, the simplicity of an oral small molecule, we are set up to disrupt the market tremendously. We are talking about hundreds of billions of dollars of value that is out there to be created with profiles like ours. Why are biologics having a hard time penetrating into these big indications? It is quite simple. Obviously, they work well. They are quite safe most of the time, but they are expensive. They are challenging to prescribe and reimburse. They sometimes have immunogenicity. They sometimes have loss of activity because of some level of immunogenicity. If you are on a biologic and you are on a vacation trip, you have to have a cold storage chain.
You have to bring a syringe with an ice pack, et cetera. So complicated for a chronic therapy and can be inconvenient and painful. In a survey that was done not by us, actually, but by another large company in the space, 75% of patients on a biologics that are receiving benefits for a biologic said that they would shift to an oral with a similar profile. That's an important data. What's more important is similar profile. Traditional small molecule oral small molecules have not delivered biologics-like profile, mostly because of the challenges of PK/PD correlation. As you know, every oral drug, you take it, you reach a maximal PK in the first few hours. By the time you take the next dose, most of the drug has been cleared. Most of the effect has gone away. You're chasing this PK/PD correlation.
What are we bringing to the table? We're bringing an oral drug that has steady-state complete pathway blockade, thanks to the catalytic mechanism that does not rely on PK/PD relationship. That's really the potential disruptive nature of oral degraders that can lead to biologics-like efficacy. With this summary, let's talk about STAT6, the perfect target in immunology, at least in my view, and the holy grail, I believe, in the space. We're going to spend the next 4-5 minutes going over each of the reasons why we believe this is really the perfect target. Starting on slide 12, it's about strong pathway validation and strong human genetics. You couldn't find out there really better than this. STAT6 is a key transcription factor downstream of IL-4 and IL- 13. IL-4 and IL- 13 have to signal through STAT6 to produce downstream effect.
If you block STAT6, your function are going to block IL-4 and IL- 13. This pathway, as you know, has been validated by several upstream biologics. The most notable is dupilumab. It's an IL-4 receptor alpha antibody. It's been approved in multiple indications, seven indications. I think there is one more that might get approved also, and generates about $14 billion of yearly sales, is expected to reach $25 billion. The largest blockbuster in immunology. Here is the opportunity to have an oral drug that might be able, we believe, to match that profile. Strong human genetics, this is our North Star. Human gain of function of STAT6 caused severe allergic diseases. It's telling you STAT6 is actually just doing that. A human heterozygous loss of function are healthy and protected against Th2 inflammation. STAT6 knockout mice are viable, fertile, and healthy.
We have all the data together to say that STAT6 degradation should lead to a dupilumab-like profile in Th2 diseases. Let's go to the undrugged, poorly drugged. Again, we've talked about the holy grail nature of this target. Small molecule inhibitors have had a really hard time drugging this target over the years. I go back to even if you're able to do so, and even internally, we've generated an extensive data set on small molecule inhibitors versus degraders. We've shown that only a degrader, thanks to the fact that we can suppress the target continuously without any rebounding with each dose, only by degrading the target continuously, we're able to match dupilumab-like pathway blockade. That's really the opportunity that we're bringing to the table here. We've talked about Th2 diseases.
There is more than 130 million patients, again, seven to eight indications, dermatology, respiratory, and also some GI. About 1% penetration of biologics into this market. If you just look at moderate to severe, it's a bit higher than that. We're talking about a drop in the bucket if you look at opportunities. The disruptive nature here is not that we're going to fight with dupilumab to replace dupilumab. Sure, that's one of the strategies. What we're really keen on is going after the other 100 million patients that are not on any systemic advanced therapy. That's the value of this program. On to slide 15, let's talk about our development plan. This is really high level, but just speaks to two priorities we have: time to registration, breadth of opportunities. Today we'll talk about the healthy volunteer study.
In fourth year, we'll talk about the phase I-B study. The important thing is that we have two parallel phase II-B studies, one in AD, one in asthma. Each of these studies, hopefully, will deliver a phase III dose that we can use for AD and one phase III dose that we can use for asthma. Probably they'll be the same dose, we'll see. Each of these phase III doses can be used also for other diseases. The AD dose could potentially be used for other derm indication, potentially also for the GI. The asthma phase III dose can be used for other respiratory indications. A very forward-leaning development plan that speaks to the breadth, but also the efficiency. This slide is to really summarize quickly our preclinical data.
Exceptionally selective degrader of STAT6, highly potent in human cells, more potent than dupilumab. In non-human primates, degrades the target completely in all the relevant tissues. In a preclinical mouse model of allergic asthma, about 90% degradation leads to dupilumab-like, if not superior, profile. That is what we had going into our phase I study. With safety, we've run multiple safety studies, toxicity studies preclinically, and never seen an adverse event at any doses or concentration. An amazing setup going into the healthy volunteer study. Slide 17, we'll talk about our objectives going into the study. Our objectives, as I showed in the previous slide, 90% degradation leads to a dupi-like profile. Ninety percent degradation plus in blood and skin, good safety.
Ideally, we were looking for a dupi-like profile in these Th2 biomarkers with all the caveats of noise and low baseline levels of these biomarkers. We were expecting to have a dupi-like profile as we had seen preclinically. What we have seen today, Jared will walk you through all the data, but what we have seen is way beyond the best expectations that we could have had. We have seen complete degradation in both blood and skin at relatively low doses, 50 mg or beyond. We have seen a pristine tolerability. We have a placebo-like safety profile, even at doses 16x above the first dose that reached 90% degradation plus, which was our initial TPP. Again, you will see that our impact on biomarkers, I believe, has gone well beyond our best expectations with surpassing, at least numerically, what had been shown with dupilumab in healthy volunteers.
Jared will tell you more about it. Really amazing setup for our study. I'll let Jared walk you through the data. Just to summarize, you know I've talked about these holy grail STAT6. We've talked about 62 1 as an amazing target, an amazing degrader of STAT6 that has shown a really compelling preclinical profile that I believe has increased the attention in the industry for the opportunities of STAT6 targeting. Now our phase I data continues to draw the line of these flawless, not only execution of studies, but also delivery of best expectations instead of data. Not only speaks to the healthy volunteer milestone, but also how important it is for the ongoing and future studies.
I think it's the perfect setup to continue to draw the line for these amazing opportunities that degrading STAT6 has for patients with Th2 diseases. I'll pause here, pass it to Jared, and then we'll wrap up at the end.
Thanks, Nello. It's a privilege to be able to present on behalf of the entire Kymera KT-621 team, these exciting phase I results from the first STAT6 targeted drug to enter the clinic. As Nello indicated, the data exceeded our most optimistic expectations, and we believe greatly de-risk the next stages of clinical development for a drug that has the potential in the coming years to profoundly alter how we treat Th2 allergic diseases. The agenda for my presentation is shown on slide 20.
I'll start with a description of the trial design and demographics of enrolled subjects before moving on to a detailed summary of the plasma pharmacokinetics of KT-621, pharmacodynamics of single and multiple doses of KT-621, including impact on STAT6 levels in blood and skin and on circulating Th2 biomarkers and safety. As shown on slide 21, KT-621 was tested in a phase I a randomized double-blind placebo-controlled single and multiple ascending dose trial in healthy volunteers. In the part A SAD portion, eight subjects randomized 6 to 2 to a single oral dose of KT-621 or placebo were enrolled per cohort. A total of 48 subjects were enrolled onto six cohorts with doses ranging from 6.25 mg- 800 mg. In the part B MAD portion, 12 subjects randomized 9 to 3 to once daily oral dosing of KT-621 or placebo for 14 days were enrolled per cohort.
A total of 70 subjects were enrolled onto six cohorts with doses ranging from 1.5 mg- 200 mg, with the 12.5 mg cohort enrolling 10 instead of 12 subjects. The primary and secondary endpoints were safety and tolerability and pharmacokinetic measures, respectively. Exploratory pharmacodynamic endpoints in SAD included STAT6 levels in blood, whereas in MAD, the endpoints were STAT6 levels in blood and skin, as well as Th2 biomarkers in blood. The demographics of enrolled subjects shown on slide 22 were generally well balanced between the placebo and treatment arms in SAD and MAD, with median age of 32 - 34.5 years. Plasma PK on slide 23 showed rapid absorption with Tmax of two to four hours and a half-life of nine to 36 hours. There was dose proportional increase in exposure after single or multiple doses with low to moderate variability.
Steady state was achieved by day four of once daily dosing. The kinetics of STAT6 degradation in peripheral blood mononuclear cells, as measured serially by mass spectrometry through day 14 following single doses of KT-621, are shown on slide 24. Robust STAT6 degradation occurred as early as four hours post-dose, reaching its nadir at 4-8 hours depending on the dose and maintained as long as through day five before recovering by day 14. Remarkably, as shown on slide 25, greater than 90% mean STAT6 degradation was achieved across all dose levels, including the lowest dose of just 6.25 mg, with greater than 95% mean degradation and reductions of STAT6 below the lower limit of quantification, or LLOQ, in multiple subjects at doses greater than or equal to 75 mg.
Recall that we wanted to see at least 90% mean STAT6 degradation in this phase I trial, as that degree of knockdown with KT-621 was associated with dupilumab-like activity in mouse models of asthma and atopic dermatitis. We were pleased to see that we could achieve this level of activity with single doses as low as 6.25 mg. However, even more impressive was our ability to completely degrade STAT6 with single doses of 75 mg or greater. I want to take a moment to describe in further detail how we measure STAT6 degradation. The results we're sharing today are based on a highly sensitive and quantitative mass spectrometry assay that can measure STAT6 protein levels in blood and skin. When the subject's STAT6 level is below the LLOQ of the assay, there is not enough STAT6 remaining for us to accurately quantify the amount.
The estimated value used for calculating percentage reduction from baseline is therefore imputed as one half the LLOQ. At 95% or greater degradation, we are usually at or below the LLOQ. Therefore, any remaining protein is largely undetectable. As a result, we define complete degradation for a cohort as either a mean reduction of 95% or greater or most subjects with levels falling below the LLOQ or both. As shown on slide 26, multiple daily doses of KT-621 also resulted in rapid deep degradation at the first time point measured eight hours post-first dose for all doses above 1.5 mg, with steady state nadir reached as early as eight hours and recovery starting at four days post-last dose. You can see on the graph on the left that all dose groups at or above 50 mg had most subjects falling below the LLOQ.
As shown on slide 27, mean STAT6 degradation greater than 90% was achieved at all dose levels above 1.5 mg, with complete degradation associated with reductions of STAT6 below the LLOQ in the majority of subjects at doses greater than or equal to 50 mg. The effect of multiple daily doses of KT-621 on STAT6 levels in the skin was assessed on serial skin punch biopsies using mass spectrometry. Baseline STAT6 levels in skin were five-fold lower compared to peripheral blood mononuclear cells. As shown on slide 28, steady state maximum STAT6 degradation was achieved by day seven at doses greater than 1.5 mg, with recovery observed 14 days post-last dose.
As shown on slide 29, complete degradation with greater than or equal to 95% STAT6 knockdown and reductions of STAT6 below the LLOQ in multiple subjects was achieved at doses greater than or equal to 50 mg, showing a strong correlation between skin and blood degradation. We believe this is the first demonstration that an oral degrader can reach complete target degradation in both blood and skin. Turning now to Th2 biomarkers in blood, we measured the effect of KT-621 on multiple clinically validated Th2 biomarkers. As shown on slide 31, these include TARC, IgE, and Eotaxin-3, all of which are known to be regulated by IL-4/IL-13 signaling and are associated with various pathological features of Type 2 inflammatory diseases. TARC drives the chemotaxis of CCR4-expressing Th2 cells to sites of inflammation.
There is evidence that basal levels of TARC in healthy individuals are at least partially dependent on IL-4 receptor alpha. IgE activates mast cells and basophils to produce allergic inflammatory mediators such as IL-4 and IL-13. IL-4 itself promotes B-cell class switching, which drives more IgE production. Eotaxin-3 drives the chemotaxis of CCR3-expressing eosinophils to sites of inflammation and is a highly specific chemokine downstream of IL-4/IL-13 pathway activation. These biomarkers are not typically elevated in healthy subjects without overt Th2 allergic diseases. The most robust effects have been seen with IL-4/IL-13 pathway targeting drugs like dupilumab in patients with Th2 diseases, including atopic dermatitis, asthma, and chronic rhinosinusitis with nasal polyposis, where one or more of these biomarkers are often greatly elevated and the impact of treatment is assessed over multiple months.
Despite the limitations of assessing drug effects on TARC and IgE in healthy subjects, both were followed and reported in healthy volunteers receiving dupilumab. As shown on slide 32, dupilumab had a non-dose-dependent effect on blood TARC levels at some, but not all doses, with a median reduction of up to 35%. A number of variables may have contributed to the absence of dose dependency, including high inter-subject variability regarding baseline TARC levels and response of TARC to IL-4/IL-13 pathway inhibition, both indicative of multiple factors involved in TARC regulation in healthy subjects. IgE was also followed but showed minimal to no change within the first week and only a modest 10%-15% reduction after four weeks. In patients with Th2 diseases treated with dupilumab, IgE reduction is minimal within the first two to four weeks, and months of treatment are often required to see robust reduction.
This is consistent with a relatively long half-life of IgE and the longer turnover of IgE-producing B cells and long-lived plasma cells. In our phase I trial, baseline blood TARC and IgE levels were in line with what has been reported in the dupilumab healthy volunteer study. As shown on slide 33, TARC reduction was achieved across all KT-621 MAD dose groups during the dosing period and seen as early as three days from the start of dosing, with median reduction of up to 37% by day 14. In multiple dose groups, including those with the greatest median reduction from baseline, the day 14 reduction was greater than day seven, raising the possibility that KT-621 had not yet reached its maximum effect on TARC by the end of dosing. All dose groups showed at least partial recovery two weeks after the last dose.
These results are comparable or superior to what was seen with TARC in the dupilumab healthy volunteer study. As shown on slide 34, there was a minimal effect of KT-621 on IgE levels compared to placebo over the 14 days of dosing, consistent with what is known regarding the longer time frame required for drugs targeting the IL-4/ IL- 13 pathway to show an effect on circulating IgE and also in line with what was observed with dupilumab in healthy volunteers. As shown on slide 35, KT-621 had a robust effect on Eotaxin-3 across all dose groups during the dosing period that occurred as early as three days from the start of dosing, with median reduction of up to 63% at day 14.
As was seen with TARC in multiple dose groups, it appeared that KT-621 had not yet reached its maximum effect on Eotaxin-3 by the end of dosing, and at least partial recovery had occurred by two weeks after the last dose. These results are superior to what has been reported with dupilumab in patients with asthma or chronic rhinosinusitis with nasal polyposis at even 52 weeks. KT-621 was well tolerated and had a safety profile indistinguishable from placebo. As shown on slide 36, there were no serious adverse events, very few treatment-related adverse events that were mild, no treatment-related discontinuations, and no clinically relevant changes in vital signs, laboratory tests, or ECGs with daily dosing up to 200 mg, which is 16x above the lowest MAD dose with greater than 90% degradation.
At this point, it is important to highlight that we've shown that KT-621 can degrade STAT6 completely in blood and skin and can have an impact on Th2 biomarkers that is in line or superior to dupilumab with a placebo-like safety profile. This is not only a profile that exceeded our expectations, but importantly, de-risked our ongoing and future studies in patients. It's gratifying to be part of the team that for the first time validated that STAT6 targeting can be achieved safely and effectively in humans. At this point, I'll turn it back over to Nello for some concluding remarks.
Thanks, Jared. What a data set. Maybe just before we wrap up the presentation today’s worth, kind of going back a bit into the history of the program, right? This has been a multi-year program. We start with STAT6 is a perfect target for potentially for the first time developing a biologics-like oral drug. We found and discovered KT-621 that generated a very compelling profile preclinically. I would probably say that it added a lot of excitement around the STAT6 space in general across the industry. Today, we’re looking at data that, to be honest, surpassed even my most optimistic expectations. We had to go to 1.5 mg dose to see a dose that degraded less than 90%. Actually, that’s what we had to do in this phase I study to identify the bottom of the curve of this dose response.
Complete degradation in blood and skin at all doses equal or above 50 mg, safety, you know, pristine tolerability profile. And then really, this was always an area of questions, you know, how reliable are these biomarkers read out in healthy volunteer study? I think I would still argue that there is a high level of noise, but I hope you agree with me that we're showing here a really robust profile, even in healthy volunteers, that compares favorably with other biologics. I wouldn't say just dupilumab. We couldn't be in a better place than we are today, as I've said earlier. This speaks to the confidence that we have now in our ongoing phase I-B study and the confidence that we have planning our phase II-B studies.
To be honest, the acceleration that we've had across all of these studies with the knowledge of this amazing profile that KT-621 had. I just want to conclude by first thanking the KT-621 STAT6 team for a multi-year amazing effort to deliver flawless execution and amazing data all the way from preclinical to clinical. Thank all of you that were on the call today. We're happy to take questions today and in the upcoming few days and weeks. Thank you again.
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 have joined by phone, please dial star nine 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 a panelist. Please accept and wait until you are promoted to panelist. Please then 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. Our first question comes from Eric Joseph with JP Morgan. Please turn on your camera, unmute your audio, and ask your question.
Okay. Great. Congrats on these data, team, and thanks for taking the questions. I guess first on dose response, I'd be curious to kind of get your views on the dose-responsive relationship, particularly at the higher end of the dosing range evaluated in the MAD. If you could, maybe just talk us through at this stage some of the doses that you are either evaluating currently as part of the broadened trial or that you might look to evaluate in the phase II studies upcoming in AD and asthma. Thanks.
Thanks. Thanks, Eric. First, before I answer the question, I want to remind everybody the slides should be on our website. I know we spent obviously a lot of time generating the data. We went through it quickly. It's a lot of data, so I want to make sure you all have access to the data and to the slides ASAP. To answer your question, again, 621 has been an amazingly potent molecule in all the studies that we've run from mice to rats to dogs to non-human primates to humans. As I said actually just a few minutes ago, all the doses that we tested in the SAD reached more than 90% degradation. When we went into the MAD study, we had to actually spend some time trying to figure out what was the lower part of the dose response.
We had to go all the way down to 1.5 mg to find the dose that gave less than 90% degradation. Actually, you see even the 1 mg had a robust, in some cases, impact on Th2 biomarkers. Telling you how relevant STAT6 is in this pathway. I think it once we were, I guess, so fortunate that the compound was so potent that, to be honest, how we started to understand dose differentiation was not so much about percentage degradation, but was about how many subjects were below the lower limit of quantitation. For example, at the 50 mg dose, more than 50% of subjects were below the lower limit of quantitation. At the 100 mg dose, 100% of subjects were below the lower limit of quantitation. That should read 100% degradation.
We do not write that because we have a way that it is a bit more scientific, as Jared explained earlier. In a way, the differentiation across the doses, once you reached 25mg or 50mg, became how many subjects are below the limit of quantitation. To answer your second question, I wrote it down. The doses that we are exploring, the only answer I am going to give you is that multiple doses MAD or TPP. I would probably say all doses besides the one and a half MAD or TPP, right? Our original TPP was 90%+ degradation in blood and skin. You see we have multiple doses in there. We had a rich choice of dose and doses to take into the phase I-B and eventually into the phase II-B. For now, we are going to leave it at that. Thank you. Next question.
Our next question will come from Vikram Purohit from Morgan Stanley. Just one moment. We'll have Vikram shortly. All right, Vikram, please unmute your audio and ask your question. Yes, please go ahead.
Great. Thanks. Good morning. Thanks for taking our question. I guess two questions from our side. First, I guess given the levels of degradation you're seeing and given some of the half-life commentary you made, do you have plans to think about a dosing interval extended beyond once a day in future studies in AD and asthma and beyond? Secondly, I guess now that you have the healthy volunteer data in hand, how would you kind of anchor expectations for some of the clinical endpoints from broaden? So EZ, NRS, I'd just be curious to see how your views around some of those endpoints and what you'd guide us to might have changed there now that you have these data out. Thank you.
Thanks, Vikram. Great questions also. Starting with the first one. Maybe I think what's important to remember is that there is a pharmacological need, and then there is a compliance need, and then there is a risk need when you select those regimens. For us, obviously, once you have good safety, which we do, excellent safety, then you think about pharmacology risk as well as compliance. Obviously, once a day dosing, we've done plenty of research, continues to be the most sought-after oral therapy paradigm. Obviously, once a day, twice a day is problematic, but once a day is thought to be the best way to do it in terms of compliance. There is also the pharmacology question, which is very important for degraders that might be not appreciated.
If you have a drug that works as well as KT-621, you see after a single dose, we can keep the target, that knockdown for several days. You actually might be able to miss a dose in your clinical studies or even once the drug is approved and actually see no effect on, should not see any effect, I should say, on the pharmacology. That is an important thing because we all know we've all taken drugs. We all have forgotten to take one dose at some point. If you do it less frequently, once you miss that one dose, I think it becomes problematic. That is what I was talking about, the risk. To be honest, before we really know what is the best dose and paradigm, we need to translate our degradation profile into a clinical outcome.
I think after that, one could get more creative. I continue to believe that once a day oral is the best way to move forward. The second question, I just want to remind everybody. We said nine months ago or so, I cannot remember, at some point a lifetime ago, we talked about this study being really focused on degradation and safety. Obviously, we have delivered that. We said that in order to really assess biomarkers, we need to go into patients. I committed that I will continue to say that, and I will continue to say that. That is the context where we are going to have more robust data because the baselines are higher and the pathway is activated. I think we have, I would say, overachieved on the healthy volunteer biomarkers.
That does not take it away from the fact that to have a real scientific conversation about impact on biomarker will have to happen in patients. That continues to be the north star of this study. It is really powered on biomarkers. Given the biomarkers we have seen today, hopefully everybody will feel like, okay, we are going to see some robust biomarkers in patients. I believe given the way the study is designed, we will obviously look at clinical endpoints and we have high expectations. I will continue to say that the biomarkers is really the must-have data and the clinical endpoint is the kind of nice-to-have data. I will also parallel with the phase I healthy where the degradation and safety was the must-have data and the biomarkers were the nice-to-have data. I will apply kind of the same concept.
There in patients, biomarker at the must-have, must-meet bar data, and then the clinical endpoint will be the nice-to-have data. Obviously, the expectation is to have a dupli-like profile across the board. We'll continue to do that.
Great. Thanks so much.
Our next question will come from Faisal Khurshid with Leerink Partners. Please unmute your audio and ask your question.
Hey, Nello. Thank you for taking the question. In the presentation, you kind of spoke to the dupilumab expectations on the biomarkers that you showed. Can I ask you for the phase I- B study? Can you kind of help set the expectations for what you want to see on these biomarkers and then for the clinical data as well?
Yeah, maybe I'll let Jared, who's also on the line today, we stayed in our offices to do a quick, to quickly move into Q&A. So you don't see Jared, but you'll see him soon. Jared, do you want to take this one?
Sure. Yeah. If you look at the dupilumab studies where they've looked at biomarkers like TARC and Eotaxin, depending on the Th2 allergic disease that was in that particular study, even though these endpoints go out in 16 weeks, they're looking serially at biomarker impact, including at four weeks. When we think about our phase I-B study where we're going to be dosing for four weeks, we look to the dupilumab results at four weeks in various disease contexts in order to give ourselves a sense of where we would set the bar. If you look at TARC, for example, in AD, and you look at the results of dupi at four weeks, you see about a 70%-80% reduction in TARC at four weeks. Now, do we know that we're going to hit exactly that particular level of inhibition?
You have to remember that's a point estimate and there's a range of effects of dupilumab. That's the general ballpark that we'd be looking at if we want to say that we have a dupi-like effect in AD patients at four weeks. We'll be looking at other Th2 biomarkers as well, including Eotaxin. We mentioned during the presentation that if you look in asthma and chronic rhinosinusitis with nasal polyposis patients, you see about a 40%-50% reduction in Eotaxin. That takes about 52 weeks to see that maximal effect. At four weeks, you see about a 30% or so change. In AD patients, Eotaxin is not the ideal biomarker. One tends to see more effects on Eotaxin in the respiratory setting.
Our focus in the AD patients will be mostly on TARC, although we'll be looking at a variety of different Th%2 biomarkers, both in blood and in skin. In terms of that benchmark, I think that TARC effect of 70-80% at four weeks, which we're seeing with dupi, is about what we would be looking to see with four weeks of KT-621 treatment in AD.
The beauty of it, I do not know if the overhead switches camera, yeah. The beauty of it is that in the skin we will have this really nice transcriptomic, at least we hope to have a really nice transcriptomic profile that has been widely established by biologics, and I think mostly by dupilumab. That is a rich data set in the lesions of AD patients. That is really where the value will be, really in the skin because that is where the disease is.
Got it. That's super helpful. Thank you. We'll look forward to the 4Q update then.
Thank you. Next one.
Our next question comes from Kelly Shi with Jefferies. Please go ahead.
Hi, this is Evan from Jefferies for Kelly. I have two questions. One is that for biomarkers like IgE, TARC, and CCL26, can you give us, can these biomarkers give us a sense whether KT-621 might work better in certain indications, like CCL26, like pointing to asthma and AE might pointing to AD? Also, since your healthy volunteer data really better than your expectation, are you considering expanding your phase II indications at this stage? Thank you.
Great question. Let me start with saying something very important. Biomarkers in healthy volunteers are a mechanistic readout of pathway engagement. They have no impact. They should have no impact on, to be honest, on translation into patients or selection of indications. Basically, what you do, you block the pathway. Subjects that are healthy volunteers have extremely low levels of these biomarkers. If you block the pathway really well and these biomarkers are generated in those individuals by this pathway, you'll see a reduction. I think all we're seeing by the data that we're sharing today is that we block this pathway probably as well as one could ever imagine, for sure, as well as an upstream biologic like dupilumab, if not better. That's all we're saying today. We have no intention to use these biomarkers to select and prioritize indications.
All we know is that now we have all the data that we need to continue to accelerate this program. What these biomarkers and the degradation, more importantly, tell us is that we have for the first time, I believe, in the immunology history, a small molecule oral drug that seemed to mimic the activity of an upstream biologic. More importantly, this upstream biologic is the largest drug in immunology and probably the second or third largest drug in the world. For the first time, there is a small molecule that can potentially challenge that type of profile. That is all it is saying. Yes, to answer the second part of your questions, we are moving as fast as we can. I think we are moving as fast as anybody has ever done this. We are in a phase I-B study. We are already planning our phase II-B studies.
We're planning to run two parallel phase II-B studies. I can assure you there is nothing that we can do faster, even if we had $10 billion of cash today, as what we're doing for the KT-621 program.
Thank you.
Our next question will come from Marc Frahm with TD Cowen. Please go ahead.
Thanks for taking my questions and congrats on the data this morning. One on dosing, just going forward, the dosing. I know you're not disclosing the exact doses, but can you maybe speak to the dose that was advanced in phase II-B versus the and where that kind of falls in the range or the phase I-B and where that falls in the range of what you're planning for the phase IIs? Is that at the top of the range of the phase IIs? Is that the bottom of the range? Just kind of where does that fall? We've talked a little bit about this with some of the other targets before, but just the mechanics of target engagement and the timing of altering the pathway is a little bit different with degradation than some more traditional approaches to drugs.
Just given that and what you're seeing here with the biomarkers, can you maybe speak to not just where you might end up at the end of a month relative to a dupilumab, but the trajectory to get to there within a month? Would you expect this to be maybe faster, onset of action from a clinical perspective, or about the same?
Yeah, great questions, Marc. The first one, again, I'd like to continue not to comment. Obviously, the phase I-B, it's a dose that is robust that you've seen. We have several that really hit the target well. The phase II-B will obviously likely, almost certainly, contain the phase I-B dose. I think this is a highly, obviously, this is a potentially transformative program in an area that is getting quite competitive. To be honest, I'm not going to give our, let's call them competitor, any information that I don't need to give my investors. I will start there. On the kinetics of efficacy, I mean, it's a good question. We're curious to answer that question. I'll remind you that with dupilumab and most of these biologics, there is a loading dose. The goal of the loading dose is to get to steady state ASAP.
Obviously, with some of the doses, we get to loading, sorry, we get to steady state at four hours. For sure, we hit the target really well, really quickly, again, depending on doses, but from 50% on, we're hitting that target at four hours. We're curious to see whether there is a contribution of kinetics or whether it's really the biology that is dominating the effect. That is a question for the phase I-B and studies beyond that.
Thank you. Congrats again.
Thanks, Marc.
Our next question comes from Derek Archila with Wells Fargo. Please go ahead.
Hey, good morning. Thanks for taking the questions. Congrats on the update here. Just to follow up to the last question, I guess, what do you think is on the table in terms of onset of efficacy and maybe depth of response relative to dupi? I guess maybe not giving quantitative, but what's your confidence level, Nello, about potentially at least maybe showing dupi-like efficacy or maybe superior? Just a follow-up in terms of, I guess, what do you make? You talked about not giving information to competitors. I guess, what do you make of kind of the Sanofi deal for Nurix's STAT6 candidate this morning? I don't know, share any color in terms of the overall strategic interest in this target broadly.
Thanks, Derek. Good to see you again. On the dupi, look, let's start with that's the danger of having amazing data that we move the bar again. I just want to maybe level set. The biology of STAT6 tells you that you can block the pathway as effectively as blocking IL-4 receptor alpha. Dupilumab is one of the most amazing drugs. I give credit to Regeneron for discovering an amazing drug and actually to Sanofi for developing it with them. That blocks that pathway better than any other biologics that has tried in the past 10-15 years. If you just stay grounded on the biology, blocking STAT6 fully should replicate blocking IL-4 receptor alpha. We would be the most excited organization ever to reach a dupi-like profile with an oral pill. The bar is not moved.
The biology has not changed. We want to see the clinical data to then hopefully being able to continue to say this, that we have a dupi in a pill. I know some people do not allow me saying it. I want to kind of generate the clinical data in patients to continue to being able to say that. On our partner, Sanofi, reminding everybody that obviously they have an amazing franchise with Regeneron that they need to account for. If you can access the most advanced and best drug in the space, obviously, you need to continue to protect that franchise. It is obviously a testament to the value of this program that they are continuing to invest with other companies that are quite a bit behind us with the molecules that we have not been able to see any data, really relevant data, right?
We're the only company that has shown head-to-head studies against dupilumab. Obviously, they should be able to do the same. You can make the cross comparison with 6 2 1, but we haven't seen that. I think it just shows you that I think the whole industry, even if we needed more conviction after this data, is going to be super interested in a STAT6 agent. We strongly believe degraders is the only way to do this, and this is initial data to make that case. It's an exciting time to be at the forefront of a new class of drugs, hopefully.
Thanks, Nello.
Thank you.
One moment, please. Our next question will come from Michael Schmidt with Guggenheim. All right, Michael, please go ahead.
All right, there we go. Yeah, hey, guys, thanks for taking our questions. Yeah, really exciting data, obviously. I think it's really interesting that you have a really wide dynamic range in terms of doses and activity, starting at one and a half up to 800, essentially. Can you talk a bit more about the safety tolerability profile? I know you're saying there haven't been any SAEs or SAEs or any dose response, even around AEs, but perhaps any comments around lab measurements? Are you seeing anything there that's interesting, even if non-clinically relevant? Just curious if you could provide some more color on that. Yeah, just again, going back to the dose selection strategy based on that wide therapeutic range, philosophically, how are you thinking about it in the phase II studies, perhaps?
Are you thinking about picking doses that are in the middle of the range that are closely correlated or things that are probably further apart to cover the spectrum of the dynamic range? Thanks so much.
Yeah, thanks, Michael. I'll take the second one, and I'll let an actual MD take the first one. I don't play an MD on the phone here. On the second one, again, I think the goal of the phase II-B is to ask the question of what are different levels of target engagement, STAT6 degradation, give you in terms of efficacy and safety profile. You should imagine that, I know this is going to kind of sound silly, we're going to take a high dose, a mid dose, and a low dose with possibly, I don't think we'll go beyond three doses for now. I don't think so. Kind of trying to ask that question. Obviously, we have a very, very steep dose response curve, as you see. We have lots of doses that hit the target really well.
We know exactly what we need to do to ask those questions. Jared, do you want to take the first one on the safety?
Yeah, I think, look, in terms of safety, as an MD, I can happily say that safety here is pretty boring, which is a good thing, actually. As I mentioned, there were only three treatment-related adverse events. They were all mild. Two of them were in placebo. One was in drug. The one that was in drug was just mild tiredness. With regard to the laboratory tests, everything was essentially normal, benign, including ECG. I know we get asked a lot about ECGs. We did not only safety ECGs, but also 24-hour Holter monitoring at various time points in both SAD and MAD. All of that was unremarkable. Fortunately, the safety profile was pristine. We referred to it as being indistinguishable from placebo.
Thank you. Thanks, Jared. Next question.
Our next question will come from Geoff Meacham with Citi. Please go ahead, Geoff.
All righty. Morning, guys. Thanks for the call, hosting the call, and congrats on the data.
Let me get the video there. There we go. Nello, I guess at the end of the SAD or the MAD, the question is, how quickly do STAT6 levels or Th2 biomarkers return to the baseline? Curious about the clinical consequences of this. The second question is, when you look at your animal studies or even degradation kind of pathways genetically, are there other targets that correlate with STAT6? I'm just trying to think towards more of the refractory populations, for example, in AD, and maybe whether that's going to be a tougher population to study. Thank you.
Thanks, Geoff. Again, as always, good question. I was looking down because I have the slides in front of me here on the left. If you look at, for example, slide 26, we can pull it up for you, but you guys might have the deck in front of you. For the really robust doses, we retain pretty robust, almost complete degradation, roughly four days beyond the last dose. You can see here on the slide, day 18, you can see we still have quite robust degradation. Really, day 28, which is two weeks after the last dose, we go back to baseline. I believe that's true also for the biomarkers. I think what's this telling us?
That this molecule, besides having the flexibility, right, of once-a-day oral, once-a-day oral that you can potentially skip a dose, I do not want to keep saying it and encourage our patients to drop a dose one day. I am saying having that flexibility to being able to do that also has the hallmark of oral medicines, which is on and off, right? That is the beauty of these therapies. You can jump in, come in, and hopefully be active, have a response quickly. When you decide to stop therapy, you do not have to wait four weeks or four months. You have to wait probably a couple of days. That is very important because that is what patients want. They want the flexibility to, and prescribers. They want the flexibility to know that when they are on therapy, they have a really good therapy. When they are not, they are not.
That is the beauty of small molecules.
Perfect.
The other question, Nello, about related pathways to STAT6.
Oh, sorry. Yeah. Sorry, I forgot to note that. Thank you for staying on. Yeah. I think the beauty about STAT6 is that it is one of the few transcription factors. I think this data continue to prove what we've been saying for years now. It's one of the few transcription factors that is really specific for the IL-4 receptor alpha. I would expect that we should have activity where dupilumab has activity. I wouldn't expect necessarily that we're going to be active in a different population, let's say a population where the disease is skewed more towards Th1, for example. This is a Th2 drug. There are 100+ million plus patients with Th2 diseases. I would call this our expectation, this is to be a canonical Th2 drug. I think that's an amazing place to be, especially not only from the efficacy.
Obviously, we know dupilumab is going to be a $25 billion drug in a few years. Also from the safety, dupilumab is one of the few drugs that is actually not considered an immunosuppressant because this pathway is really in the Western world, it's not really used for much of anything at this point. Besides, again, allergic responses. That's the beauty of this target versus others. They might have more pleiotropic activity.
Awesome. Thank you.
Cool. Thanks, Geoff. Next one.
Our next question comes from Tazeen Ahmad from BofA Securities. Please go ahead.
Hi, guys. Congrats on the update. I think most of my questions have already been asked. Maybe to keep one a little bit general, now that you have this validation, how would you say you could differentiate from other degraders outside of the timeline, assuming that you're in the lead in at least this indication? Are there any other areas that we should be looking for going forward as other degraders, whether they be STAT6 or otherwise, try to experiment with trying to do indications similar to yours? Thanks.
Yeah. Great question, Tazeen. I'm glad you were able to jump on. I would just say two important things. Obviously, we have a STAT6 degrader. We've shown extensive preclinical data. Hopefully, people looked at the ATS. We had an ATS poster where we show for the first time a therapeutic dosing in the house dust mite model, where we actually outperformed dupilumab on that particular study. That is the first time there has been shown a therapeutic paradigm, again, in that particular model. Sorry, I went off topic. The point is, we've shown extensive data preclinically of how potent and effective KT-621 is. Now we've shown early clinical data that probably reinforces even more. I would say, as we're saying, this exceeded our expectation, also in terms of potency.
Obviously, as I said earlier, there are two named degrader programs from two companies, but we have not seen any actual data. It is really on them to show what they have versus KT-621. I am not sure we have to do the opposite besides, obviously, the press releases. What we would like to say is that we have a molecule that has been proven also clinically. We are going to move quickly. It is on others to prove that they have something that can compete with this. I have never seen—we have been working in the degrader space for nine years since I founded this company. This is by far the most compelling data set we have shown clinically, and I think by every company in the space. I think I can say that easily.
It shows how much we've learned over the years versus the first-generation degraders, for example, like KT-474 versus KT-621. I would call it 2nd generation degrader. Lots of learnings along the way. It's going to be hard to beat. Next question.
Our next question will come from Alex Thompson with Stifel. Please go ahead.
Hey, great. Thanks for taking my question and congrats on the data. Sorry, I'm in a cab, so not on video. Anyway.
No problem.
Just sort of to triangulate around your preclinical data and the PD data you're seeing in healthy volunteers, could you talk a little bit about your expectations for STAT6 degradation beyond the blood and skin? You alluded to some of the data in the mouse asthma models, etc. What should we expect in some of these other organs that you're going to be thinking about testing in long term? Thanks.
Yeah, great question, actually. The most compelling data set that we've shown preclinically was in non-human primates. I believe that data still exists in our version of the corporate deck, which should go live at 9:30 A.M. this morning, which will contain the rest of the pipeline and the data from today. There, we show that we can degrade the target in skin, obviously in blood, in spleen, as well as in lungs. Really speaking to the fact that the beauty about KT-621, without, again, sharing too much information, is that it has a very even distribution profile across different tissues. We've actually designed that. This was not a discovery. We have designed it.
It took us a few iterations, I would say, as a company, not on this program, to figure out what are the molecular properties that a degrader needs to have to have consistent degradation across all tissues. Kudos to my chemistry team and obviously others, DNPK, etc., for designing a molecule that has this distribution profile. As we go into our asthma study, hopefully early next year and in other indications, our expectation is what you are seeing in blood and skin is going to be seen in other tissues. I always like to think of skin as the highest bar, not only because historically it has been hard for us to degrade it clinically, but because it is the outermost outer layer in the human body, has not a lot of, obviously, blood supply, at least the outer layer.
For example, the levels of the targets are quite low. As Jared pointed out, it is 1/5 of the blood. You have to have an exceptionally potent degrader to kind of take that level and put it down to baseline. That is the confidence we have also for other tissues that actually might be easier to get to. Next question.
Our next question comes from Kripa Devarakonda from Truist.
Hey, guys. Thank you so much for taking my question and congratulations. Great data. Given the breadth of the programs that you can now do with 621, what dupilumab has shown, should we expect any kind of change in how you're thinking about the rest of the pipeline, how you prioritize capital allocation now that you're going to go full force forward with 621? Maybe a question on 621 itself. Do you see any risk of compensatory mechanisms resulting from chronic STAT6 degradation? I know you have to wait to see it in patients, but mechanism.
Yeah, great question. Yeah. On the first one, I mean, you have seen recent changes that we made as recent as our past quarterly call, where we made the decision to, at least for this time, pause our KT-295 clinical development, our TYK2 degrader. We said part of the reason, if not the majority of the reason, was to have our team and our resources focused on KT-621. Obviously, at that time, we were privy to most of this data, probably not all, but most of it. We had the punchline already. Hopefully now that everybody's seen the data, you can appreciate that we have, I think, a molecule that rarely, an opportunity that rarely has happened in the industry, right?
If you think about the history of this industry, very rarely you have this very disruptive technology that finds the right target and has huge potential. Obviously, we're still early. But so very rarely this happens. We're excited about that. We're very thoughtful about resource allocation, as you all know. With regards to your second question, we've dosed KT-621 in preclinical species for efficacy studies, in challenged animals for multiple months. We've never seen any compensatory mechanism. We're highly confident that that should not happen.
Okay. Great. Thank you so much.
Our next question comes from Sudan Logananthan with Stephens.
Hi. Thank you, Nello and the primary team for the update here. Congrats on the exceptional data. In light of this very encouraging outcome for KT-621, how do you view it potentially, if you view it any differently now, how it kind of fits in the treatment paradigm for treatment of some of these INI indications? In recruiting for the upcoming trials, have you thought about taking on patients that have failed on DUPI or patients that have failed on other developing biologics in these INI spaces? How the degrader mechanism of STAT6 degrader, STAT6 mechanism for KT-621, may differentiate on that aspect of things where it could provide some better outcomes for patients that are failing on current therapies?
Okay. Thank you for the question. I'll take some of it. I want to let Jared maybe speak to what kind of patients we're recruiting to the phase I- B study. We can all level set about expectations there too. At a high level, I tried to do it earlier today. There are, let's say, tens of millions of patients, hundreds of million patients with Th2 diseases that are diagnosed with Th2 diseases. Biologics penetration, even in AD, is quite low. I think companies in the space quote 10%-15%. I think if you call it biologically eligible, if you actually just look at all moderate to severe, it's much less than 10%. I think the problem we have is, obviously, we have effective drugs, again. I think we have a problem of patients accessing advanced systemic therapy easily.
That is what 6 2 1 is there for. We want to make sure that we can treat as many patients as possible. Sure, scientifically and even from a drug development point of view, you can get really creative on where you differentiate what subset of patients. I always tell my team, and the team always thinks about that. We have some really sophisticated views and all of that. I always tell my team, why do we not start with the patients that are actually not getting the drugs? That is tens of billions of dollars of value before we try and solve problems that are still there. Maybe Jared, can you at least speak to what we are doing right now? We level set on the patients we are recruiting to the I-B study.
Sure. In our phase I-B study, we are allowing patients who are both biologics or DUPI naive as well as patients before. If patients have been on dupilumab previously, they cannot have come off of it for disease progression. If they did not tolerate DUPI or they came off for other reasons, they would be eligible. Essentially, even though we have not discussed what we are going to be doing for II-B trial in AD, you can imagine that we would be taking a similar approach. In reality, actually, there are not many patients who actually fail or progress on DUPI therapy. That gets back to one of the prior questions about compensatory mechanisms, is that when you are blocking the IL-4/IL-13 pathway successfully, there usually are not resistance mechanisms that emerge. This is not like oncology. We can have mutations and then have resistance mechanisms that are compensatory here.
It seems as though these diseases, if they were going to respond to IL-4/ IL- 13 blockade, they maintain that response. If you look at DUPI studies that go out over one, two, and even more years on therapy, those patients maintain their treatment. I think that will give you an idea of the kind of patients we're thinking about for phase I-B and phase II-B, patients who are either biologics naive or if they've been on biologics, just to be safe and to make it a cleaner study, not including those small number of patients who may have progressed after prior DUPI therapy.
Okay. Next question. Thanks, Jared. Next question.
Our next question comes from Ellie Merle with UBS Securities. Please go ahead.
Hi. This is Jasmine for Ellie. Thank you, guys, for taking our question. Just a specific one in terms of the biomarker data you showed is really interesting. To dig a little deeper into TARC and Eotaxin-3, so even looking in the healthies, can you talk a little bit more about the clinical relevance of the level of reductions that you see so far? To follow up on some earlier questions, specifically for these biomarkers, can you talk about how these reductions you see in healthies, you think, can be expected to translate into patients? Do you expect these to be different in AD versus asthma? Thanks.
Thank you. Thanks for the question. I've actually addressed it. Jared, do you want to take this one?
Yeah. I think the question around clinical relevance is always a tricky one. I think looking at these biomarkers in healthies, the main purpose there is to be able to demonstrate that we're achieving functional blockade of the IL-4, IL-13 pathway. Even in healthy volunteers, where it can be challenging to show an impact on biomarkers that are essentially at normal levels because these pathways are not really activated to a significant extent. The fact that we were able to see these robust changes in TARC up to 37% and then Eotaxin up to 63% is really telling us that we're achieving significant blockade of the IL-4, IL-13 pathway. At least for TARC, when we can compare healthies to healthies, at a level comparable, at least comparable to dupilumab.
For Eotaxin, when we compare what we're seeing in healthies to what dupilumab saw in patients with asthma, for example, we're seeing effects that appear to be even superior. In terms of translation to patients, we have to always be careful in trying to claim that impact we're seeing on biomarkers in healthies is going to inform what we're going to see in patients. We still think that the most important thing that we've shown in the healthies is our ability to fully degrade STAT6 in blood and skin. That ultimately is what hopefully will translate into clinical efficacy and positive clinical outcomes in patients. These impacts on biomarkers give us a lot of confidence that we are blocking the IL-4/ IL- 13 pathway in a dupilumab-like manner.
Ultimately, the true test in patients will be to see impact on these biomarkers with a DUPI-like effect on those biomarkers in both blood and skin in patients in our phase I-B study.
Cool. Thanks, Jared. Next question.
Our next question comes from Kalpit Patel with B. Riley.
Yeah. Hey, Nello. Hey, Jared. Good morning. And congrats on the update today. Maybe just one quick question for Jared. I know there's some noise in the biomarker data. But if we look at the IgE reduction in the placebo arm with your degrader, it seems to be comparable to some of the active arms or most of the active arms. But then when we go back to the dupilumab data, historically, there is sort of a separation by day 14, day 28. And then the separation continues up to day 84. So I'm just curious if Jared had any thoughts.
Yeah. Kalpit does not want to hear my thoughts. Jared, I am joking. Jared, you answer first because I have my own as well.
Hopefully, Nello and I have power. That'll come out soon. No, I think that for IgE, I think the important thing, if we go back to the DUPI data, if you look at the day 7 data, right, there's essentially little to no separation from placebo at day 7. They actually didn't look at day 14. You have to interpolate if you want to sort of try to come up with what they saw at day 14. At day 29, you're seeing maybe a 5%-10% change. If you look at actually the DUPI data in patients and you look at IgE, you don't see much of any effect within the first two to four weeks. In fact, it takes months, many months, before you actually start to see an impact on IgE, even in patients with Th2 allergic diseases.
I think that just comes back to what we were saying, that in order to impact IgE with an IL-4/ IL- 13 pathway inhibitor, you really have to impact not just IgE production, but you have to impact class switching, B-cell class switching. Because IL-4 drives B-cell class switching. That class switching leads to then IgE production. When you're treating with an IL-4/ IL- 13 pathway blockade, the impact on class switching for those B cells that have not yet switched is going to be delayed. That is going to take longer before you see the impact on both B cell and along with plasma cell production of IgE. That is why we really should not expect to see changes in IgE probably for months.
I think overall, again, if you look at our data, if you look at the DUPI data, and you look at placebo, and you look at the various dose levels, I think they're very comparable results where in a similar time frame, 7-14 days, you're seeing minimal movement relative to placebo. I think that's expected.
Thanks, Kalpit. Next question. Thanks again.
Thank you.
Our next question comes from Jeet Mukherjee with BTIG. Please go ahead.
Hey, folks. Thanks for taking the question. Maybe just coming back to that IgE data at the 28-day mark. Just in terms of that DUPI healthy volunteer study, it seems like they were able to get closer to that maybe 20%-30% reduction by 28 days. Just given that you had mentioned the IgE levels at baseline were similar between that DUPI study and yourselves, just any reason why there may be a smaller effect for you folks? Maybe as a second question, Nello, you had mentioned the potential for different doses between dermatological and respiratory indications. Just given the robust effect we're seeing, is that a scenario you still see unfolding? Thanks.
Okay. Jared, I'm going to take the first one because you basically answered the previous one. I get to get it out of my system. I think Kymera is really, really good at what we do. What we cannot do is change the biology. We just cannot change the biology of IgE. IgE reduction takes a long time because, again, IL-4 promotes B-cell class switching. Then these long-lived plasma cells produce IgE. You have to wait for them to go away. Yes, it's true that 29 days, you see, I don't think 20, you see 15%- 16% reduction with some doses. I actually look at, there is another publication I'm looking at in front of me where there is IgE reduction in a phase II study in AD where week four, there actually is no IgE reduction.
I think what we're saying is that what we're all seeing in the first few weeks is really noise. We had a placebo, let's call it after form. If the placebo didn't show so much noise, we could have even claimed 15%. As we discussed it within the team, we decided to call it that we had no meaningful activity because that's the reality of the biology. On your second question, which was around so what I want to maybe clarify a bit better, what I said is we're likely going to take the same doses in the phase II-B studies in AD and in asthma. What I said, it's possible that the phase III dose could be the same. It could be different.
We do not expect it to be different because for the reason that I mentioned, there is no differential exposure of our compounds, at least in our preclinical species across tissues. We believe it is unlikely that in asthma, we are going to see different exposure in the lungs than we will see in the skin in AD that leads to different pharmacology. I guess that is why we are going to run the study. I think from this phase I study, what we can determine is that we can degrade the target as well in blood, as well in skin. We can centrally move biomarkers that are sensitive. I mean, if you look at Eotaxin, given that we are almost done, I want to give a shout-out to the team. Nobody had looked at Eotaxin in healthy volunteers. I promise you, we did not look at 20 and pick Eotaxin.
The team said, let's look at Eotaxin because out of all three, Eotaxin is the only specific biomarker of IL-4 and IL- 13. That's why if you look at the error bars on that slide, they're so tight because that's really all driven by that pathway. The baseline level is extremely low, but that is so sensitive. You can reduce it so well. All these biomarkers are telling us we're hitting the pathway really, really well. Now it's all coming down to patients and efficacy and biomarkers. I think we're fortunate to be here. I think we're pinching ourselves here. Thank you. Jared, anything you want to add?
I was just going to add one last thing really quickly on the day 28 point that was made. You have to remember that our dosing only goes through day 14. And as we showed, we get recovery of target starting within three to four days after end of dosing. So by day 28, you're really not having much of an effect on the pathway anymore. Whereas with DUPI, these long-lived monoclonal antibodies are staying around for a longer time, which is why you might start to see an effect at day 28 with DUPI, whereas for our drug, the kinetics are going to be different.
Yeah. That's fair. All right. Thanks. Any other question? I think we're in time almost.
There are no more questions at this time. I'll turn the call back to Nello Mainolfi for closing remarks.
Thank you. This is really a momentous day for Kymera. I mean, we really feel both the excitement but also the responsibility of holding these potentially really amazing drugs here in our hand. I want to thank the team first for doing an amazing job to generate this data. We're so glad the data are out there because we've been just dying to release this data for now a bit. I want to thank everybody for also I know this is ASCO Monday. I know many people are busy, but I appreciate the attendance to the call. We continue to remain available the rest of the day and the next few days to take more questions.