Good morning, and thank you for joining us to review the KT-621 phase I-B results in patients with atopic dermatitis. I'm Justine Koenigsberg, Head of Investor Relations. 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 start with an overview of our strategy, how we're advancing oral small molecule degraders in immunology, and the exciting opportunity to see our first-in-class STAT6 degrader, KT-621. Then Jared will take you through the phase I-B trial design and results. After our prepared remarks, we will open the call to questions, and we'll also be joined by Bruce Jacobs, our Chief Financial Officer. If you'd like to ask a question, please use the raise hand icon at the bottom of your meeting window.
To help us move efficiently through the Q&A, we ask that you will be ready to unmute your line when called on. We also ask that you limit yourself to one question and a relevant follow-up so we can make sure to address as many questions as possible this morning. We plan to wrap up the call by 9:30 A.M. We will make the presentation slides available as soon as we complete our prepared remarks this morning in the Investor section of our website, and a replay of today's call will also be available shortly after in the same location. The team will also be available after the call for any follow-up questions. Please note that during today's presentation, you will see references to data from prior dupilumab studies. It is important to note that no head-to-head studies have been conducted comparing KT-621 to dupilumab.
As a result, the KT-621 data presented may not be directly comparable to dupilumab clinical data due to differences in study designs, endpoints, and patient populations, and these data are provided for reference only. 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 the most recent 10-Q filed with the SEC. Any forward-looking statements speak only as of today's date, and we assume no obligation to update any forward-looking statements made on today's call. With that, I'd now like to turn the call over to Nello.
Good morning, and thank you, everybody, for joining us today. This is a truly special moment for Kymera, for the immunology community, and more importantly, we believe, for all the patients who one day may be treated with our innovative medicines. For the first time ever, we're sharing today the profound impact of a STAT6 degrader, KT-621, on patients with Type 2 inflammation. I believe this is a watershed moment and marks the beginning of a new class of transformative medicines targeting STAT6 for more than 100 million patients around the world suffering from Type 2 diseases that have no effective, safe, and convenient oral options.
2025 has been an incredible year of accomplishments for Kymera, and we think of no better way to conclude this year than with these compelling results, which brings KT-621 another important step closer to the promise that is foundational to our drug development strategy: to bring in safe and effective oral medicines with biologics-like activity to areas with significant unmet needs. I'm eager, as you, to get to the data, but before I turn the call to Jared for a full review of the results, I wanted to take a few minutes to provide an overview of our strategy, of how we're working to fulfill our mission to revolutionize the way in which inflammatory diseases are treated. Kymera has established itself as a leader in targeted protein degradation, redefining what's possible in the treatment of immune inflammatory diseases.
From the beginning, we focused our efforts on solving the industry's most difficult problems, challenging ourselves not with what could be done, but with what needed to be done. As a result, our target selection has been focused on going after previously undruggable targets or difficult-to-drug targets, which we believe we could leverage our best-in-industry capabilities in finding optimization of oral degraders into innovative solutions to diseases with significant unmet need. As we've said often, no program is more emblematic of our strategy and capabilities than STAT6. But it's important to note that beyond STAT6, we're advancing a broad pipeline of additional targets. Through this work, we're building one of the most novel and impactful pipelines in immunology that we hope will lead to an entire portfolio of first and best-in-class immunology oral treatments.
We're intentional in our focus in immunology, and we believe we can disrupt the category that needs new innovation by advancing this exciting new modality. We're just scratching the surface of the mass market opportunity. Currently, global sales for advanced therapies are in excess of $100 billion annually. However, while there are approximately 160 million patients diagnosed with 10 of the most common immunological diseases across the U.S., Europe, and Japan, it is estimated that only about 3% are treated with advanced systemic therapies, which are largely made up of biologics. So we have a $100 billion market for only 3% of the patients, mostly dominated by biologics because traditional small molecules have failed to provide comparable efficacy and safety, so here is the real opportunity. Biologics have transformed the treatment of most immunoinflammatory diseases, but they come with many challenges.
These include inconvenience associated with injection or, in some cases, injection-site reactions or pain, stringent storage requirements, the potential risk of immunogenicity, often complex reimbursement or adoption may be hindered by administrative burden, and high costs, which are often not adequately covered by insurance. Additionally, physicians have noted that the top patient concern with injectable drugs is that patients don't like needles, and many patients are not comfortable with self-injecting. As a result, in a recent patient survey, more than 90% of patients on injectable biologics confirmed that they will be willing to switch to a safe and equally effective oral treatment. Clearly, converting many of these patients is undoubtedly a great opportunity for Kymera.
At the same time, even more exciting is that KT-621, an oral drug with potential for biologics-like safety and efficacy, could, in fact, expand the market to the tens of millions of patients that are not on any advanced systemic therapy. The appeal of oral small molecule solutions is clear, but the path to developing compelling small molecule alternatives to biologics has been a challenge, at least we believe, until now. Historically, oral small molecule approaches have focused on inhibition. The key challenges of small molecule inhibitors are driven by their PK/PD profile, which does not allow for full and, importantly, continuous pathway blockade. Degraders, as opposed to small molecule inhibitors, can provide continuous pathway suppression. This is due to the catalytic mechanism of the degraders that allows for repeated elimination of disease-causing proteins to enable deep, durable target knockdown with once-a-day oral dosing, with low doses and low exposures.
As a result, degraders have the potential to deliver biologics-like efficacy with oral treatment. We believe that this will unlock the opportunity to treat a broad range of immunological conditions. With that description of the power of targeted protein degradation and our strategy as background, let's turn to the focus of today's call, KT-621, the first drug targeting STAT6, a transcription factor in the IL-4 and IL-13 pathway. The pathway has been validated clinically by dupilumab across multiple allergic and atopic diseases, from AD to asthma, COPD, and many others, where dupilumab is approved today. STAT6 is the obligate and specific transcription factor in the pathway and is therefore the critical signaling node controlling Type 2 inflammation. By blocking the function of STAT6, we expect to phenocopy IL-4 and IL-13 targeting.
There is also compelling genetics and clinical validation which supports why STAT6 degradation should lead to dupilumab-like efficacy in Type 2 diseases with a favorable safety profile. This includes human gain-of-function mutations, heterozygous partial loss of function, and knockout mice, all of which support the clinical and genetic validation of STAT6. The opportunity for STAT6 degradation is enormous, with more than 140 million potential patients across Type 2 diseases like AD, asthma, COPD, EoE, and others. Yet, less than 2 million patients today receive systemic advanced therapies. As I said earlier, an oral option could unlock access for tens of millions of patients, transforming the treatment of Type 2 diseases. Today's data puts KT-621 one step closer to making this a reality. I wanted to remind everybody that we moved KT-621 into the clinic with confidence, given the compelling preclinical package we have generated. Preclinically, KT-621 demonstrated an exceptional profile.
As we've said in the past, dupilumab-like, in many cases, numerically better than dupilumab in many preclinical studies. Importantly, this profile has translated extremely well into humans. To step back briefly, in preclinical testing, KT-621 has demonstrated several key attributes. It's exquisitely selective and highly potent. In addition, we've shown complete IL-4 and IL-13 pathway inhibition that was comparable or superior to dupilumab. From a safety perspective, it was well- tolerated, even at concentrations up to 40 times above the efficacious dose. And finally, in efficacy models, we see clear reversal of disease, shown here in the goblet cell metaplasia model, with effects that were comparable or superior to the dupilumab arm, highlighting the broad therapeutic potential across Type 2 diseases. Building on this compelling preclinical foundation, we've also generated a strong data set in healthy volunteers.
KT-621 demonstrated robust degradation potency, a safety profile undifferentiated from placebo, and impressive initial effect on Type 2-related biomarkers that were reliant on numerically exceeded published data for dupilumab in healthy volunteers at two weeks. This data validated our thesis and built even more confidence in KT-621's potential as a differentiated treatment option for Type 2 diseases as we advance the program into patient studies. Our clinical plan for KT-621 is designed to be both broad and very efficient. We successfully completed our phase I studies in healthy volunteers, showing robust PK/PD results and favorable safety profile, and today we'll discuss the exciting results in atopic dermatitis patients. Before we get to those results, I wanted to remind everybody that we've already progressed the program into the first phase II-B trial for moderate to severe AD.
We've initiated that trial in October and just recently announced that we dosed our first patient. Additionally, we're preparing to start our phase II-B asthma study next quarter, which remains on track. I should mention briefly that our enthusiasm around asthma is further supported now by some really exciting data that you'll see today in comorbid asthma patients in the phase I-B study. Taken together, we believe these dose-ranging studies, which we refer to as Breadth II and Depth, will enable rapid progression into phase III registrational trials across multiple Type 2-driven indications, including dermatology, respiratory, and GI. Jared will share with you the full trial results next, but I wanted to highlight why we're so excited about the data that we've generated as they demonstrate, for the first time ever in patients, a dupilumab-like profile that strongly supports continued development of KT-621.
Across all study objectives, we have exceeded our expectations. We've shown strong fidelity of translations from healthy volunteers to patients with deep STAT6 degradation in blood and skin. We've observed significant reduction in Type 2 biomarkers across blood and skin lesions, as well as in the lungs using FeNO, which was the primary goal of the study. These results are comparable to and, in some cases, numerically exceed results reported in dupilumab studies at week four. We also achieved robust improvements on all key clinical endpoints, including EASI, pruritus NRS , vIGA-AD patients, and clinically meaningful impact on patients with comorbid asthma and allergic rhinitis. For all of these endpoints, KT-621 data were in line or numerically exceeded published data for dupilumab at week four, further highlighting the exciting potential patient impact.
Importantly, KT-621 was well- tolerated with a favorable safety profile that was similar to the exciting and encouraging healthy volunteer data that we have previously shared. Altogether, this data provides a powerful validation of the enormous opportunity that is in front of us with KT-621 as we advance the program in phase II development in both AD and asthma. With that preview, I'll turn it over to Jared to review these positive results in more details. Jared?
Thanks, Nello. It's a privilege to be able to present these exciting results from the BroADen phase I-B trial in AD on behalf of the exceptional KT-621 team and Kymera. I'll begin with a brief overview of atopic dermatitis and the phase I-B trial design, and then dive into the results, starting with demographics and baseline disease characteristics, and then covering STAT6 degradation, impact on Type 2 inflammation biomarkers, clinical activity, and safety. Atopic dermatitis is a highly prevalent chronic inflammatory skin disease that most often starts in childhood and then stays with patients throughout their adulthood. Skin lesions in AD are disfiguring, intensely pruritic, and painful, impacting quality of life through incessant scratching, sleep loss, depression, missed work or school, and disruption of social activities. Common Type 2 comorbidities include asthma and allergic rhinitis. Many treatment options address symptoms but not the underlying Type 2 inflammation.
Biologics like dupilumab represent a significant advance in the treatment of AD, but only a very small fraction of moderate to severe patients are on dupilumab, and there remains a high unmet need for effective therapies that can reach a much larger segment of the AD population. BroADen is a single-arm, open-label phase I-B trial in patients with moderate to severe atopic dermatitis. The study allowed treatment with prior biologics after washout if the patient had responded, but concurrent medications for AD, including topical therapies, were not permitted. Patients received an oral once-daily dose of KT-621 for 28 days, with an additional 14 days of follow-up after completion of dosing.
Doses of 100 mg and 200 mg were selected based on the results from the phase I healthy volunteer trial and were enrolled sequentially as separate dose groups: 10 patients onto the 100 mg and 12 patients onto the 200 mg dose groups. Endpoints included safety, PK, STAT6 degradation in blood and skin, Type 2 inflammation biomarkers in blood, skin, and lung, and clinical activity using endpoints commonly assessed in AD trials. While the dose groups were enrolled sequentially, and therefore patients were not prospectively stratified by baseline demographics or characteristics, the two arms were generally well- balanced for gender, age, and race. Overall, 54.5% were Black or African American, and 22.7% were Hispanic or Latino. The dose groups were also generally balanced for measures of disease severity, including vIGA-AD, EASI, Peak Pruritus NRS.
In the 100 mg dose groups, 60% were moderate and 40% were severe, with mean baseline EASI and Peak Pruritus NRS scores of 23.5 and 7.4, respectively. In the 200 mg dose group, 50% were moderate and 50% were severe, with mean baseline EASI and Peak Pruritus NRS scores of 26.1 and 7.6. Overall, 54.5% had moderate disease and 45.5% had severe disease, with overall mean baseline EASI and Peak Pruritus NRS scores of 24.9 and 7.5. Approximately 46% of patients had comorbid asthma or allergic rhinitis, and approximately 23% had prior biologics treatment, including four with prior dupilumab, one of whom also had tralokinumab , and one with prior tralokinumab only. The 200 mg group had a higher proportion of patients with comorbid asthma or allergic rhinitis, as well as more patients with prior biologics treatment.
Turning now to the STAT6 degradation results, we measured changes in STAT6 protein levels in blood using flow cytometry. As shown here, deep degradation of 98% was achieved in both KT-621 dose groups by day eight, which was the first time point measured after the start of dosing and reflected steady-state degradation that was maintained through end of dosing, with recovery apparent at the next time point two weeks later. The plasma PK profile at 100 mg and 200 mg was similar to what we observed in the phase I healthy volunteer trial. These results demonstrate high fidelity of PD and PK translation from healthy volunteers to AD patients. In AD skin lesions, STAT6 levels were approximately twofold higher compared to healthy volunteer skin.
Using mass spectrometry to measure changes in STAT6 protein levels in skin, 94% degradation was achieved in both KT-621 dose groups after four weeks of treatment, with multiple patients showing reduction below the LLOQ. We also observed up to 95%- 98% reduction in STAT6 staining by immunohistochemistry in the epidermis and dermis. This confirmed the strong correlation between STAT6 degradation in blood and skin that was observed in healthy volunteers and was consistent with a systemic effect of KT-621 on STAT6 levels. As we will be reviewing the effects of STAT6 degradation across multiple biomarkers and clinical endpoints, it is important to note that degradation in blood and skin were essentially the same in the 100 mg and the 200 mg dose groups.
In order to demonstrate that the STAT6 degradation observed in blood and skin lesions was associated with systemic inhibition of the IL-4/IL-13 pathway, we measured the effect of KT-621 on five different disease-relevant biomarkers of Type 2 inflammation. You are all familiar with the blood biomarkers TARC, Eotaxin-3, and IgE, which we studied in our phase I healthy volunteer trial. In healthy volunteers, baseline levels of all three were low, but we were still able to show a dupilumab-like effect on TARC following 14 days of KT-621 dosing, as well as an even more robust effect on Eotaxin-3. As with dupilumab, we saw a little effect on IgE in healthy volunteers, consistent with the requirement for higher baseline levels and longer treatment duration to see an impact on that biomarker.
Our expectation going into BroADen was that these biomarkers would be significantly elevated in moderate to severe AD patients at baseline, thereby facilitating our ability to show a greater effect with KT-621 dosing in patients compared to healthy volunteers. With today's data set, we are sharing two additional and important biomarkers that were not measured in our healthy volunteer trial. IL-31 is a key cytokine driving itch that is elevated in the blood of AD patients. Notably, a small study of dupilumab in AD patients did not show any impact on blood IL-31 levels. Fractional exhaled nitric oxide, known as FeNO, is produced by airway epithelial cells in response to Type 2 inflammation. In asthma, FeNO is a point-of-care biomarker used to detect Type 2 airway inflammation that has utility in diagnosis and in monitoring response to therapy with biologics like dupilumab targeting the IL-4/IL-13 pathway .
Higher levels have been associated with lower lung function and increased risk for future asthma exacerbations. While FeNO has not been studied in AD patients, we included it in BroADen so we could assess the baseline levels and response to KT-621 in all AD patients and also assess KT-621's effect on any AD patients enrolled who had comorbid asthma. Starting with TARC, I thought I would provide some important context before I share the KT-621 results. As shown here, the published data with dupilumab in AD, eosinophilic esophagitis, asthma, and CRS with NP clearly show that the magnitude of TARC reduction is a function of baseline levels, with higher baselines leading to greater percent reduction in response to dupilumab. In earlier AD trials, where median baseline levels were in the 2,000-4,000 pg/mL range, median TARC reductions at four to 52 weeks were in excess of 70%.
It's important to note that the KRONOS study was a combination of dupilumab plus topical corticosteroids. In contrast, median baseline TARC levels were only approximately 300 pg/mL in the EoE, asthma, and CRS with NP trials, and median TARC reduction at 12-52 weeks was only 25%-39%. In BroADen, median baseline TARC in the KT-621 dose groups was 868 pg/mL at 100 mg and 800 pg/mL at 200 mg, with median TARC reductions at four weeks of 48% and 55%, respectively, consistent with the relationship between baseline TARC and percent TARC reduction established with dupilumab in Type 2 diseases, including AD.
In those BroADen patients with baseline TARC in line with earlier dupilumab AD studies, defined as greater than or equal to 1,600 pg/mL, which is the lower bound of the 95% confidence interval for the median TARC baselines from the dupilumab SOLO 1 and SOLO 2 AD studies, the median TARC reduction at four weeks was 74%, comparable to the dupilumab effect at four weeks in the single-agent phase III studies. Similarly, in the subset of KT-621 patients with lower baseline TARC, defined as less than 1,600 pg/mL , we also observed TARC reduction, in this case, 38%, that was comparable to the dupilumab results in studies with similar lower baseline TARC levels. Here, we summarize our results with KT-621 by showing the time course for TARC reduction stratified by KT-621 dose cohorts on the left, where KT-621 achieves similar levels of TARC reduction across both doses by day 29.
As shown in the previous slide, when we stratified for dupilumab AD studies like baseline levels, including TARC greater than or equal to 1,600 pg/mL versus less than 1,600 pg/mL , KT-621 achieved dupilumab-like inhibition of 74% in the high TARC cohort. We also show the results stratified by median TARC baseline from BroADen, where the median reduction of 71% in patients with baseline TARC greater than or equal to 800 pg/mL is comparable to the effect of dupilumab. For Eotaxin-3, KT-621 achieved strong reduction by day eight, with median reductions of 62% and 73% at day 29 in the 100 mg and 200 mg dose groups, respectively, followed by recovery towards baseline two weeks after the end of dosing. These results at four weeks exceeded the effect of dupilumab on Eotaxin-3 at 52 weeks in patients with asthma and CRS with NP.
While we did not expect to see much of a response in IgE with a relatively short four-week treatment duration, in light of the modest effect reported with dupilumab at four weeks, we did observe a 5%-14% reduction across the two dose groups at day 29 that was in line with the dupilumab results at week four. Strong IL-31 median reduction of 54%-56% was observed across both dose groups at day 29, with recovery to baseline occurring two weeks later. To our knowledge, this is the first demonstration of IL-31 reduction in the blood by a drug targeting the IL-4/IL-13 pathwa y. This is an important data point, as IL-31 is believed to be the most important biomarker of itch response and is known to be downstream of the IL-4/IL-13 pathway.
FeNO, which was noted earlier as an important biomarker of Type 2 airway inflammation, was elevated at baseline in AD patients, including those without comorbid asthma, with median levels of 13-20 ppb across both dose groups. Reduction in FeNO was observed as early as day eight, with median reductions at day 29 of 25% and 33% at 100 mg and 200 mg, respectively, followed by recovery back to baseline two weeks after end of dosing. To our knowledge, this is the first demonstration of FeNO reduction in AD patients and provides initial proof of concept for IL-4 pathway inhibition in the lungs resulting from systemic STAT6 targeting with KT-621. dupilumab has been shown to downregulate Type 2 inflammation and other AD disease-relevant genes in the skin lesions of AD patients as early as four weeks into treatment.
We used paired skin punch biopsies from the same lesion obtained from patients at baseline and on day 29. Given the similar levels of STAT6 degradation and pathway impact across the two doses, we pooled the available samples from all patients to generate a more robust data set. Using a core Type 2 inflammation gene set, KT-621 showed significant reduction at day 29. Specifically, downregulated genes included Eotaxin-3, TARC, PARC, and MCP-4. Results were comparable to dupilumab data at four weeks. Using an AD disease-relevant gene set that includes not just Type 2 cytokines, but also keratin 16, periostin, TSLP, and genes involved in Th17 and Th2 response, among others, KT-621 also achieved significant dupilumab-like reduction at day 29. Taken together, these results demonstrate how deep degradation of STAT6 in AD skin lesions leads to disease-relevant transcriptomic changes reflective of IL-4/IL-13 pathway inhibition.
Moving on to clinical endpoints, we saw strong and generally comparable results across both dose groups and in patients with or without prior biologics treatment. As shown here, KT-621 achieved 62% and 63% mean reductions in EASI by day 29 in the 100 mg and 200 mg dose groups, respectively, and overall 63% mean reduction, with robust impact as early as day eight. The time course shows continuous improvement through day 29 without reaching an apparent plateau, suggesting the potential for further improvement with dosing beyond four weeks. The improvements on EASI, as well as on all the other upcoming additional endpoints, were in line with or numerically exceeded published data for dupilumab at week four in AD trials. An analysis of EASI in patients stratified by baseline TARC or EASI showed that the effect of KT-621 on EASI was comparable in patients with low and high baseline TARC or EASI.
This demonstrated that KT-621 benefited patients with moderate to severe AD to the same extent, regardless of disease severity. The substantial improvement in EASI at four weeks translated to EASI-50 scores of 67% and 83% in the 100 mg and 200 mg cohorts, respectively, and 76% overall. EASI-75 scores were 33% and 25% in the 100 mg and 200 mg cohorts, respectively, and 29% overall. vIGA-AD 0/1 was 22% and 17% in the 100 mg and 200 mg cohorts, respectively, and 19% overall. While categorical endpoints are highly sensitive to and impacted by small Ns, we were encouraged to see robust activity in these measurements. SCORAD is a validated composite measure of AD severity in integrating extent, intensity, and patient-reported impact.
KT-621 achieved 52% and 46% mean reductions in SCORAD by day 29 in the 100 mg and 200 mg dose groups, respectively, and overall 48% mean reduction with robust impact as early as day eight. Pruritus, or itch, is a major clinical manifestation of AD, severely impacting quality of life. KT-621 achieved a rapid and strong impact on two independent measures of itch, including Peak Pruritus NRS and SCORAD itch, a component of SCORAD. As shown here, KT-621 achieved 47% and 35% mean reductions in Peak Pruritus NRS by day 29 in the 100 mg and 200 mg dose groups, respectively, and overall 40% reduction. KT-621 also demonstrated 40% and 47% mean reductions in SCORAD itch in the 100 mg and 200 mg dose groups, respectively, and overall 44% reduction with impact as early as day eight.
The time courses show continuous improvement through day 29 without reaching an apparent plateau, suggesting the potential for further improvement with dosing beyond four weeks. This impact of KT-621 on patient-reported measures of itch is consistent with our observed effect of KT-621 on blood levels of the pruritogenic cytokine IL-31. Just as was demonstrated for EASI reductions, an analysis of Peak Pruritus NRS in patients stratified by baseline TARC or EASI showed that the effect of KT-621 on pruritus was comparable in patients with low and high baseline TARC or EASI. This again demonstrated that KT-621 benefited patients with moderate to severe AD to the same extent, regardless of disease severity. The next three measures were used to capture the effect of KT-621 on various dimensions of patient quality of life in order to further assess the clinical meaningfulness of reducing disease burden and symptoms.
SCORAD sleeplessness is a validated measure of AD severity capturing quality of life impact. KT-621 achieved 72% and 78% mean reduction in SCORAD sleeplessness by day 29 in the 100 mg and 200 mg dose groups, respectively, and overall 76% mean reduction with mean 45% reduction as early as day eight. This is a compelling outcome measure as impact on sleep is one of the most burdensome sequelae of moderate to severe AD. The Patient-Oriented Eczema Measure , or POEM, is a measure evaluating patient experience and impact on quality of life. KT-621 achieved seven point and 11 point mean reductions in POEM by day 29 in the 100 mg and 200 mg dose groups, respectively, and overall nine point mean reduction, which is greater than the minimum clinically important difference of four points. This translated to an overall 73% POEM responder rate.
The Dermatology Life Quality Index, or DLQI, is a quality of life measure validated in AD. KT-621 achieved six point and nine point mean reductions in DLQI by day 29 in the 100 mg and 200 mg dose groups, respectively, and overall eight point mean reduction, which is greater than the minimum clinically important difference of four points. This translated to an overall 61% DLQI responder rate. Here, we show an example of response to KT-621. This patient has severe AD with baseline EASI of approximately 37. She had a history of prior response to dupilumab but came off treatment in 2017 due to lack of insurance. She was treated with KT-621 100 mg once daily on BroADen and demonstrated a rapid response on EASI and itch with 84% EASI reduction and 56% and 63% reductions in Peak Pruritus NRS and SCORAD itch, respectively, by day 29.
This clinical response was associated with 95% STAT6 degradation in blood and 94% degradation in a biopsied skin lesion, which showed deep reduction of STAT6 nuclear and cytoplasmic staining in epidermis and dermis. The patient also had robust biomarker reductions at day 29, including 78% decrease in TARC, 92%- 96% decreases in skin and blood Eotaxin-3, and 93% decrease in skin keratin 16. This exemplifies the internal consistency between STAT6 degradation, biomarker response, and clinical activity in patients treated with KT-621 on BroADen. The reported frequency of asthma and allergic rhinitis comorbidities in AD patients is approximately 25% and 40%, respectively. The enrollment onto BroADen of four patients with comorbid asthma and nine patients with comorbid allergic rhinitis provided us with an opportunity to look beyond AD and perform a focused assessment of biomarker and/or clinical activity relevant to these other two Type 2 allergic diseases.
The four patients with asthma had higher baseline levels of FeNO compared to other AD patients, with a mean baseline of 49 ppb compared to 17 ppb in those without asthma. KT-621 achieved a median FeNO reduction of 56% at day 29 in patients with comorbid asthma compared to 25% in those without asthma. This substantial reduction in FeNO, which exceeded the 31% reduction observed with dupilumab at four weeks in asthma, was associated with a mean 1.2-point reduction in Asthma Control Questionnaire 5 , or ACQ5, and 100% ACQ5 responder rate that represents a clinically meaningful improvement in asthma control. This represents a first demonstration of the potential impact of KT-621 in asthma and is a meaningful result as we approach the initiation of our phase II-B asthma study next quarter.
In those patients with allergic rhinitis who were evaluable for symptoms and quality of life, KT-621 achieved a mean 0.9-point reduction in Total Nasal Symptom Score , or TNSS, and a mean 0.8-point reduction in Rhinoconjunctivitis Quality of Life Questionnaire , or RQLQ, at day 29. These clinically meaningful reductions in TNSS and RQLQ were associated with responder rates of 57% and 33%, respectively. Overall, these results in AD patients with asthma and allergic rhinitis comorbidities highlight the potential for KT-621 in these Type 2 respiratory diseases in addition to AD. This table summarizes the results for AD clinical endpoints by dose group and for all patients. Remarkably, KT-621 treatment led to improvement in all endpoints covering disease burden, symptoms, and quality of life. The robust treatment effect with KT-621 across these endpoints exceeded the upper end of the 95% confidence intervals for historic placebo rates in moderate to severe AD.
Importantly, none of the patients on BroADen required rescue therapy during the four weeks of KT-621 treatment, underscoring the clinical benefit of treatment. This clinical activity was internally consistent with the deep degradation of STAT6 in blood and skin lesions and the strong effect on disease-relevant biomarkers in blood and skin by KT-621. It is also notable that the clinical improvements on disease endpoints with KT-621 were either in line with or numerically exceeded published data for dupilumab at week four derived from the SOLO 1 and SOLO 2 AD trials, added here as reference. KT-621 was well- tolerated with a favorable safety profile across the 100 mg and 200 mg dose groups, consistent with the phase I-A healthy volunteer trial results.
There were no SAEs, no severe AEs, no dose-dependent pattern in the TEAEs, no related TEAEs or TEAEs leading to discontinuation, no AEs of conjunctivitis, herpes infections, or arthralgias, and no clinically relevant changes in vital signs, laboratory tests, or electrocardiograms. In summary, BroADen phase I-B achieved all of its objectives, demonstrating deep degradation in blood and skin with strong translation from the phase I-A healthy volunteer study, profound effect on disease-relevant Type 2 inflammation biomarkers in blood, skin, and lungs, reflecting systemic IL-4/IL-13 pathway inhibition, robust clinical activity in AD with dupilumab-like effect on all measured endpoints, as well as early evidence of activity in comorbid asthma and allergic rhinitis based on improvements in biomarkers and/or patient-reported outcomes, and excellent tolerability with safety profiles similar to what was observed in the phase I-A trial.
These results underscore the significant potential of KT-621 in AD and other Type 2 allergic diseases and support advancement of the program into phase II-B trials in AD and asthma. I'll now turn the presentation back over to Nello for his concluding remarks.
Thank you, Jared. What a presentation. Like we did earlier this year for the healthy volunteer data, I think we have again demonstrated a compelling clinical translation of STAT6 degradation with KT-621. And again, I think we've exceeded our best expectations. As you just heard, we believe these results collectively reinforce the potential for KT-621 to deliver biologics-like profile in patients. And as you've heard me say before, the next few years will be very exciting with what I believe is once-in-a-generation drug development opportunity. As you all know, we take a lot of pride in careful assessment of human genetics and preclinical biology.
We build comprehensive data sets to inform our investment thesis and increase the POS of positive clinical translation for our programs. We started the STAT6 program several years ago with the idea that once-a-day oral STAT6 degrader had the potential to be the first biologics-like oral agent in immunology. And I believe this data set in AD patients completes successfully our initial clinical translation. We started with strong genetics data, compelling preclinical data, a healthy volunteer translation that demonstrated well-tolerated deep degradation that led to dupilumab-like biomarker impact, and finally, the two translations, the one in patients. And here, we have again demonstrated the impeccable translation of the human genetics, the preclinical data that point us to an oral STAT6 degrader to have the potential to transform the treatment of inflammatory diseases with a dupilumab in-a-pill profile.
And I'm sure you'd agree with me that the data we've shared today show that we're well on our way to delivering on this important goal and more. It is worth taking a moment to reflect on what has been an exceptionally encouraging safety profile as we've progressed KT-621 through preclinical and early clinical testing. Throughout all of our preclinical testing up to and including four-month tox studies, we have not observed any safety findings at any dose. And in testing in what has now been over 200 combined healthy volunteers and patients, there have been no reported safety issues of any significance. While this is a small phase I-B study, it seems clear that KT-621 is blocking this pathway as well as an upstream biologic.
It's reducing several disease-relevant Type 2 cytokines in blood, skin, and lung, and in many as well, and in many cases numerically exceeding published dupilumab data. These have resulted in improvements in objective and patient-reported clinical endpoints in AD, comorbid asthma, and comorbid allergic rhinitis. The coherence of all data is, I believe, compelling, and in my view, strongly suggests that we have a potentially transformative drug. Now it's on us to focus on the execution of these critical phase II-B studies in AD and asthma and then build our late-stage capabilities to build a global commercial stage company that will deliver life-changing oral medicines. I want to thank, first of all, the Kymera team for the exceptional work and dedication in driving the KT-621 program forward, and everyone at Kymera should be so proud of what we've delivered today.
I also want to extend our sincere gratitude to the investigators, study site teams, our collaborators and CROs, and most importantly, the patients who participated in the BroADen study. Their partnership and trust has made this progress possible. With that, we look forward to the Q&A discussion.
Thank you. At this time, if you would like to ask a question, please click on the raise hand button, which can be found on the black bar at the bottom of your screen. If you have joined by phone, please dial star nine on your keypad to raise your hand. When it is your turn, you will see a message on your screen inviting you to rejoin as a panelist. Please accept and wait until you are prompted to panelist. Please unmute your audio, turn on your camera, and ask your question.
As a reminder, we are allowing analysts one question and one related follow-up today. We will now pause a moment to assemble the queue. Your first question will come from Judah Frommer with Morgan Stanley. Please go ahead.
Yeah, hi guys. Congrats on the update here, and thanks for taking the questions. I guess first, you know, one of the questions we've been getting over time is just, can you help us with dose selection in the phase I-B? Which dose came first? You know, I guess given the STAT6 degradation you were seeing in TARC reductions, you know, why the need to add the second dose? What do you think you learned from it? And then second, I would just say on itch reduction, you know, that seems to be a real differentiator here.
I guess, how does that make you feel about market opportunity in itch-prevalent conditions, you know, outside of AD and also that rapidity of itch reduction? What does that do in terms of the potential in AD specifically?
Well, thanks, Judah, for both questions. So let's take it one at a time. So the first one, so I don't think at this point it's important that we figure out what dose came first. I think what's important is we wanted to understand really well the translation from healthy volunteer to patients to enable a refinement of our phase II-B doses. So we decided to pick doses that were actually quite similar, I would say almost equal in healthy volunteers, and see whether we would see the same profile in patients.
Obviously, if you do that, you should probably pick in the higher range of the dose because you want to translate a robust degradation profile into patients. So that's where the 100 mg and 200 mg came from. Obviously, you've seen that what we saw in healthy volunteers, we saw in patients, almost equal degradation in blood and skin, and I would say almost equal or comparable downstream effect across the two doses. So much so that it touched and allowed us to look at the overall patient profile of the two doses as we've shown at the end in the summary. One could look at the overall patient to kind of get a more powered number of patients in the study. With regards to the second question, which is a great one, as we know, I'll let Jared actually answer more specifically.
My first reaction is the most, I think, one of the most impactful deliverables of this study has been the impact on patient-reported outcome. Not that it's, you know, superior to others, but because that's what we're treating, right? We're treating patients that have itch, that have trouble sleeping at night, and the fact that we can deliver a drug that has a robust impact on all of these just shows you that this is the type of drug that patients we hope will be looking for. But maybe, Jared, more technically on the other diseases.
Yeah, I mean, I think we're very, you know, gratified to see impact on itch across two different measures, you know, the Peak Pruritus NRS as well as the SCORAD itch. So that concordance, I think, was really important, as well as seeing the relationship between that and the effect we saw on IL-31, which is one of those key pruritogenic cytokines. So fascinating to us and very encouraging to see the impact on that cytokine. And I think all of that together, I think, does potentially lend itself to thinking about, you know, treatment of diseases even outside of AD. Obviously, very important to treat itch and to see rapid kinetics of improvement in itch, which is what we saw, but to be able to treat other diseases like CSU and prurigo nodularis, right? These are other Th2 allergic diseases where itch is a big component. I think it gives us encouragement that we should have activity there as well.
Thanks, guys.
Your next question will come from Derek Archila with Wells Fargo. Derek, feel free to unmute.
Good morning. Yep, thanks. Thanks for taking the questions and congrats on the data here. So this first question for me, I'm not sure if I missed this, but I just wanted to understand maybe the level of efficacy you might be seeing in the dupi and tral experienced patients. That would be interesting. And just as a follow-up, I guess these phenotypes changes that you guys highlight today, you know, they not only look competitive relative to dupi, but some of the other biologics in development are on the market. So I guess, how do you think, you know, oral, you know, STAT6 could kind of reshape the kind of emerging treatment landscape in asthma? Thanks.
Thanks, Derek. Great questions, both of them. Jared mentioned in his conclusion slides that the activity we saw in biologics naive patients and biologics experienced patients was similar, if not the same. You know, I can say that in the four dupi patients, we had 100% EASI 50. Now, I don't want to make a big deal out of it. I think it just tells you that our drug works well and obviously should work well in patients that respond to this pathway drugs. On the second part, again, I'll let Jared maybe comment more on the specifics, but you know, we've been telling everybody for the past two and a half years that STAT6 degradation is going to transform treatment paradigm across all the Type 2 diseases. And I have to thank the team.
I take no credit for it for actually thinking about FeNO even in AD and obviously in comorbid asthma. And it just shows you the drug distributes well to all tissues, including lungs. It degrades the target well. And it tells you if you have a small molecule drug that is very potent, I think we're going to outshine a lot of drugs that are out there. But maybe, Jared, taking us back to earth.
Yeah, no, no, I think you addressed it very well. I mean, I think we were, again, you know, very excited to see this effect on FeNO, you know, both in patients without asthma, which tells us that even in patients with AD, you know, without overt asthma, there is some Th2 tone inflammation probably in the lung leading to upregulation of FeNO.
And then to see an impact on there, I think, was very gratifying in addition to this, you know, profound impact on FeNO in asthma patients. And so I think the fact that, you know, this STAT6 degrader is able to clearly reach the lung, impact Th2 inflammation there, impact lung biomarkers of Th2 inflammation does have important implications for asthma, for our ability to use a once-daily oral drug in asthma and really be as effective as we could be across other Th2 allergic diseases like AD. So I think it just speaks to the enormity of the opportunity for this drug across multiple Th2 allergic diseases where dupi has shown an impact.
Great. Thanks, guys. We'll go back off again.
Thank you.
Your next question will come from Tazeen Ahmad with BofA Securities . Feel free to turn on your camera and ask your question.
Hi guys, can you hear me?
Yes.
Good morning. Congrats on the positive update. I have a couple of quick questions. You didn't see any instances of conjunctivitis. It's a small line of patients, but I think that could be a positive indicator of further differentiation from dupi. Can you talk about what your expectations might be for phase II-B on side effects specific to conjunctivitis? And then does this data be an early indicator that there could be other indications beyond which you've already discussed wanting to go into as potentially available to explore? Thanks.
Thanks, Tazeen. Great question. So just we've been saying this for months. So it looks just empirically that if you target IL-4 and IL-13 in patients with atopic dermatitis, you will see rates of conjunctivitis.
If you look at all drugs in this pathway, you've seen usually rates that are in the 10%, 12%, 15% at week 16. If you look at the data across all those studies, at week four, you see about 5% rates of conjunctivitis. So in a study like ours, we're talking about a patient, one patient roughly. So I think the data tell us that at least we don't have worse rates of conjunctivitis than other drugs in this pathway. Whether we'll have similar or less, I would ask to wait for the phase II-B studies that are ongoing, at least the AD studies ongoing. Jared, do you want to maybe address the second question?
Yeah, in terms of, you know, indications, you know, outside, say, AD and asthma, I mean, I think, again, we feel that all Th2 allergic indications where dupi, you know, is approved and/or shown activity are really fair game, I think, for KT-621. You know, again, the key here is, are we showing systemic inhibition of IL-4/ IL-13 pathway signaling and functional effect? And I think the data, the biomarker data, as well as the clinical data coming out of phase I-B, you know, tells us clearly yes. And so I think that then allows us to think about multiple indications that go beyond AD and asthma, whether that's also, you know, COPD on the respiratory side, you know, CRS with NP, you know, some of the various, you know, other pruritic disorders that we talked about earlier, you know, CSU, PN, etc . I think those are all open.
Maybe I just want to add a quick thing. I know we have many more questions, but I think that what we love about our data is the consistency across all the measurements. So while, you know, obviously it's a very small data set, so we should be careful with overinterpreting them, the fact that we have impact on skin, we have impact on lower airways, we have impact on upper airways, obviously we haven't talked much yet about allergic rhinitis. It just bodes well for all these indications that dupilumab has shown activity when it's chronic rhinosinusitis with nasal polyps, asthma, COPD, AD, pruritus, and all the other indications. So again, small data set, but it speaks so broadly to the potential of this drug, and that's really what we're excited about.
Your next question will come from Alex Thompson with Stifel.
Hey, great. Congrats on the data again. You know, it was interesting to see the data split out by TARC, but I was wondering if you could talk about whether there was any correlation on a patient level between STAT6 degradation and either biomarker or clinical efficacy. I guess, for instance, you know, did patients that got to a lower limit of quantification on STAT6 degradation do better generally? Anything you could say there would be helpful. Thanks.
Yeah, great question, Alex. I think that the data set is too small. I mean, we also have very, very tight data across degradation. So it's really difficult to try and tease out these correlations. I'm sure as we build larger data sets, for example, in this phase II-B study, you know, we'll attempt to look into that, but this was too small for that kind of analysis.
And then maybe as a follow-up, will you include both 100 mg and 200 mg? Are those both doses in the phase II-B?
As promised, we're not going to disclose our phase II-B doses. So we'll know that in 2027, but thanks for asking.
Sounds good. Thanks.
Your next question will come from Brian Cheng with JPMorgan . All right, Brian, you're now a panelist. Feel free to ask your question.
Hey, guys. Just to, thanks for taking our question this morning. Just to touch on the trend in improvement across multiple measures over time, can you speak to the response out to day 43 once patients are off drug at day 28? How does that line up with your understanding of the PK/PD and also target engagement? And then for the second question, you know, as we think through the BroADen phase II setup for atopic derm that will look into efficacy out to 16 weeks, how should we think about the step up in efficacy over time? Thanks.
Great question. So let's start with the first. Maybe just high level. Just if you look at our degradation in blood, you see that at day 43, obviously the target recovers, and that's expected to be after two weeks that you stop dosing. Obviously, we know that the target doesn't recover one day when we stop dosing. It actually takes a few days, if you remember the healthy volunteer studies. And so I think what's important is that when we stop dosing in the following two weeks, there is a recovery of target. There is a recovery of biomarkers.
In the clinical endpoint, I think it's more obvious once you affect this disease morphology in the skin or you affect sensory things like itch, we expect and see that the recovery is lower, right? Because it just takes a while for the disease to come back. So I don't think it's surprising what we see. And I'll let Jared comment. Maybe just quickly on the second, and Jared, maybe you can comment on both. On the second question, I think the most compelling data that we're seeing, and Jared highlighted it, if you look at, for example, if you go to a slide where we have the EASI, we see really robust reduction of EASI right already at day eight. And that kind of slope of curve continues to be steep through day 29.
In a way, this tells us that I believe, we don't know, but I believe that tells us that we're nowhere near the maximal efficacy of our drug. The exciting part of this ongoing study is to actually figure out where we plateau.
Yeah, and just to follow- up on what Nello was saying, I think we do expect to see a step up in efficacy with continued dosing. If you look at dupilumab, what they saw with EASI, for example, they saw 50%, roughly 50% reduction at four weeks and then, you know, 70% reduction out of 16 weeks. And for pruritus, they saw approximately 30% reduction at four weeks and then 50% reduction out of 16 weeks. And so, you know, our results at four weeks, as we showed, numerically exceeded what, you know, dupi showed at four weeks.
I think we're excited at the possibility and expectation that we would see further step up with 16 weeks of dosing.
Great. Congrats on the data.
Thank you.
Our next question will come from Kripa Devarakonda with Truist. Kripa, please go ahead.
Apologies, my Internet is a little bit slow in the hotel here, but congrats on the data. Fantastic data. A couple of questions. One on TARC reduction. Just can you remind me, I might have missed the data, but if the data that you showed was from all patients or if you took a cut of the patients? And also, if you can comment on the dose effect. I know small numbers, but dose effect on EASI- 75, what could be the reason that you saw dose dependence in EASI- 50 but not in EASI- 75? Thank you.
Yeah, so on the TARC, we show all data. So if you look at, I don't think we have to pull up the slide, but I just suggest you look at slide 29 of our deck. You see all patients' data stratified by dose, by TARC at 1600 pg/mL, by TARC at 800 pg/mL baseline. So you'll see that. With regards to dose response, so I want to take kind of a step back. So 100 mg, 200 mg, as we expected, showed exactly the same degradation profile in blood and skin. As expected, this degradation profile leads to impact on biomarkers and clinical endpoints that are comparable. So I'm not sure we should look into any numerical differences between the 100 mg and the 200 mg. Look, it's possible that if you run this study longer, you might see differences.
I think at four weeks, it's a bit hard to say there are differences. Then we go to the next step of, we've said for many months not to focus on these categorical endpoints. They're impacted by, you know, one fraction of a patient, right? We're talking about what you're seeing, the difference between the two is the fact that the 200 mg at 12 patients, the 100 mg at 10 patients. So we really can use the categorical endpoints to even compare. And if you look at the continuous variable endpoints, you look at EASI, especially, they're basically the same. So I think the take-home message for us, two doses behave similarly, and that was what we expected. And in a way, that's what we wanted to see, especially with regards to degradation for us to make the right phase II-B dose selection.
Okay, thank you so much.
Thank you.
Your next question will come from Brad Canino with Guggenheim. Brad, please go ahead.
Okay, perfect. Well, let me add my congratulations as well. And I guess I have a follow-up on one of the previous questions around the deepening of effect. And the question is really, why might you expect EASI change from baseline to deepen further when you've already hit a range of what antibodies deliver at week 16? And I'm also thinking about this in the context of JAK inhibitors, where you really see that effect within the first four weeks play out and then plateau from there. Thank you.
Yeah, I think, Brad, the answer is we don't know, obviously. Our expectation is that generally atopic dermatitis is a disease, especially with regards to skin impact, takes a while to see maximal effect because you're waiting, obviously, for skin cells to regenerate, etc .
We also believe that unlike JAK inhibitors, our biology is very much an IL-4 and IL-13 biology, as you know well. And we know that we expect our biology to be coherent with the general kinetics of what has been seen with other drugs in this pathway. So whether we're slightly faster and better than dupi, I'm not going to say that. I promise I wouldn't say that. I would say we're in the ballpark. We talk about numerically, maybe it's slightly better. Let me not get into this diatribe. But what I will say is, you know, this is a different modality, right? It's a small molecule. It is possible that you're able to engage the pathway a bit faster, but that doesn't mean that you plateau faster. I agree with what Jared said earlier.
I don't have data for it, but I agree with this instinct that I think our effect would deepen with more dosing. Thanks, Brad.
Your next question will come from Brian Abrahams with RBC.
Hey, guys, thanks for taking my question and congratulations on the data. Should we expect the BroADen patients to be representative of the types of patients that you're planning to and expecting to enroll in the phase II-B? And how might any differences, or how much might any of the differences there impact either the rapidity of response or efficacy over longer dosing?
Yeah, thanks for the question. You know, the eligibility criteria, you know, for the phase II-B are going to be very similar to the phase I-B criteria for defining what is moderate to severe. So we expect, you know, that there to be a very similar population.
You know, if you look at our population and our baseline characteristics, you know, we have about, you know, close to 45%-50% of patients on phase I-B had severe disease. You know, the baseline, you know, NRS Pruritus Score , baseline SCORAD, etc. , were very similar to what was seen with dupi. So we are, you know, we did manage to enroll a broad range of moderate to severe patients on phase I-B with those eligibility criteria, and we expect to do the same in phase II-B.
Maybe just to add a small comment, you know, if you look at the early dupilumab studies, our baseline EASI was in the, you know, let's say low 30, 31, 32. The AD trials in the past five years, the mean baseline EASI was around 25. Obviously, we have taken a different approach with the phase II-B in a way that we're very, very focused on, obviously, delivering on these large studies. So this is a global study. We've said it. Majority of our sites would be outside of the U.S. We're very focused on quality of patients, quality of sites, and keeping the expected placebo rates in the, you know, smaller range possible. So again, I think patients are where they are at this day and age, but we are being very proactive on making sure that the patient population delivers, allows us to deliver impeccable data for this drug that has obviously huge potential.
Very helpful. Thanks again and congrats again.
Thank you.
Your next question will come from Andrea Newkirk with Goldman Sachs. Andrea, please feel free to unmute and ask your question.
Good morning, guys. Thanks so much for taking the question and congratulations on the data this morning. Jared, just thinking ahead, I know we're a little ways off from this, but as you think about a potential phase III trial, would you expect to need a head-to-head trial versus dupi, either in order to support approval or physician adoption? And then just one for Nello or Bruce, you've referenced now the potential utility for KT-621 or STAT6 degradation across a range of Type 2 diseases, but how are you thinking strategically about internal versus external development for those programs and prioritization of resources? Thanks so much.
Okay, yeah, thanks for the question, Andrea. So I'll start with your first one, which is, do we need to do a head-to-head phase III with dupi? I think that the short answer is no. You know, if you look at the precedence for registration and approval, whether it's in the U.S. or Europe, you know, in these diseases like AD and asthma, it's not going up against an active comparator. It's going up against placebo. So our anticipation is that we will have a placebo-controlled study, you know, for phase III for initial approval.
Now, whether there might be opportunities, you know, down the road, you know, for doing a head-to-head comparison in order just to see what our activity is like relative to dupi or to support, you know, reimbursement, you know, in some of the European markets, that's always a possibility. But I think our base case is a placebo-controlled phase three for registration and approval.
[audio distortion] On the second question, just high level, we are building the company to take KT-621 all the way. In our current plans, obviously, we have these phase II-B studies. Bruce can tell you more about our runway and cash that we have today. We believe that as we continue to de-risk the program and as our cost of capital decreases, we should be able to continue to fund the program. Now, if we go after seven indications in phase III in parallel, we're talking about 28, 29 phase III studies. I don't think any company in the world can actually do that, not just afford it, but execute. So for us, it's really the priority indications. We have four or five that are the majority of the patients in Type 2 inflammation that we're getting ready to support as a standalone, independent, and wholly owned company and program.
Obviously, you know, post-phase II study, we always are going to be open to discuss potential different win-win opportunities in terms of partnerships, but that's not our base case right now. Maybe Bruce will.
Yeah, I wouldn't add too much, Andrea, other than as Nello said, we're acutely focused on executing on the phase II- Bs right now. We're capitalized to take the company into the second half of 2028, which is at least a year beyond the first readout of those phase II- B studies. So that's where our internal focus is.
Thanks, guys.
Your next question will come from Tom Smith with Leerink. Please go ahead, Tom. Your line is enabled.
Hey, guys. Good morning. Thanks for taking the questions and congrats on the data. Just in the patients who had prior biologic exposure, I appreciate the color on the one patient who responded after prior response to dupi. I was just wondering if you could expand on the background and maybe the narrative for the other four biologic- experienced patients. Were there any non-responders or suboptimal responders that subsequently responded to KT-621, or were these patients all prior responders? And then maybe as a follow-up, you talked about the slope of the EASI and pruritus curves here suggesting we could see some greater benefit of longer dosing. Also appears to be some durability and response on some of these measures out to that two-week follow-up period. Just curious how you're thinking about the potential durability of effect. And for patients that seem to have more of an extended response, are there any common features among those patients?
Jared, do you want to take the first one?
Sure. Yeah, in terms of prior biologic, in order to come on to the study, if patients had prior biologics, they had to have responded to those biologics. If they came off of them, it had to be not because of non-response, but because of maybe they didn't tolerate it or their insurance didn't cover it or they didn't want to take injections anymore. So all of the patients with prior biologics, whether it was dupi or tral , had an actual good response prior, you know, in the past, and then they had an adequate washout period prior to coming on to the study.
And obviously, we saw that they responded well to KT-621. On your second question, you know, it's hard for us. We don't really have enough data to dissect, you know, patients that respond slightly longer than not longer. So those are things we'll continue to keep an eye on. I will say that if you look at the clinical benefits and the clinical effect of drugs in this pathway, obviously, we expect that as you stop dosing, you will eventually have less response. I think what's important that maybe it's underappreciated that if you're able to dose drugs from this pathway, dupilumab, hopefully 621 one day in the early life of patients with Type 2 inflammation, you can actually change their life forever, right? If you're able to stop the atopic march, you actually are able to provide even cures to some of these patients. So that's why for us, pediatric development, it's not maybe a topic for today.
It's an area that we're very focused on as we continue to advance this program.
Super helpful. Thanks for taking the questions. Congrats again.
Your next question will come from Geoff Meacham with Citi. Geoff, you may feel free to turn on your camera and ask your question.
You might be on mute, Geoff.
All right. Here we go. Can you see me? Okay. Good. Awesome. Congrats on the data, guys. Thanks for the call. I wanted to ask you about the speed of onset. The release mentions a pretty rapid onset by day eight and EASI and pruritus. Just curious if you could tie, you know, clinical responses to the mechanism and biomarkers more specifically. That's the first question. And the second one is just another one on FeNO. Really, really impressive data there.
Obviously, just a few patients, but maybe does the baseline in this study in comorbid patients with asthma look like what you want to explore, you know, in phase I-B and future studies? Just wanted to put maybe that in context. Thank you.
Yeah, that's a great question, Geoff, actually. I like it. So the first one is, if you look at degradation of STAT6 at day eight, you see, obviously, we crashed it already. If you look at biomarkers at day eight, in most of them, the ones that we were measuring, we see a really robust effect at day eight. So it's not surprising that we're starting to see this initial impact on disease already at day eight. I mean, we're probably impacting all of these biomarkers as well as STAT6 already on day one.
So again, we reached steady state at four hours in our study. So I think what we have seen is not surprising that this pharmacology happens quickly. On the second question, which I thought was really cool, maybe Jared, you can speak to the baseline of FeNO.
Yeah, I think, you know, those baseline FeNOs that we saw that were sort of in the 50 range in those patients with comorbid asthma, that's very similar to the levels you're going to see in moderate to severe asthma. Now, these patients on our study didn't have moderate to severe asthma. They were having control issues with their asthma, and that's why their ACQ-5s were actually elevated, indicating that they had poor control.
So the fact that we were able to see in these patients who had, you know, FeNO levels that were at least as high as what you'll see in your standard moderate to severe asthma and see such a profound impact on FeNO and also a real impact on improving asthma control by that 100% ACQ-5 responder rate, you know, does give us encouragement. Even though this is a small N, clearly, it does give us encouragement that, you know, in a phase II-B asthma study, that we should be active and potentially as active as dupi, but that remains to be shown in that study.
Awesome.
Thanks, Geoff.
Okay. Thanks, guys.
Your next question will come from Joe Catanzaro with Mizuho.
Thanks for taking my question. Actually, I think a good follow-up, maybe just to the last question in terms of asthma in those four patients, given they're comorbid with AD, is it fair to assume that they had high baseline levels of eosinophils, so eosinophilic asthma? And then, I guess relatedly, thinking about KT-621 and its mechanism and utility in asthma, how should we think about it relative to phenotype, eosinophilic versus non-eosinophilic, whether it will behave like dupi or not? Thanks.
Yeah. I mean, based on our data, based on what we understand about this pathway, this is a Type 2 drug. So we expect that, and in fact, that our patient population will be eosinophilic asthma. Many of our patients had elevated eos. That's both a feature of AD, especially given that it's the more Th2 skewed of the Type 2 diseases.
And obviously, the ones that had, I don't remember exactly, but the ones that had high FeNO likely had also elevated eosinophils at baseline. So again, in terms of placing this drug, we expect it to be, you know, an eosinophilic drug. And I think the important thing about KT-621 in asthma is that I think the opportunity we will have after, obviously, phase III and being approved is to really work with the community here to change how patients are treated with asthma. Right now, patients are treated with steroids for too long without addressing their actual inflammation. And I think this drug can change that paradigm. And that's why we're very passionate about asthma, AD, and the pediatric population for both.
Okay. Great. Thanks for taking my question and congrats on the data.
Thank you.
Thanks, Geoff.
Your next question will come from Mayank Mamtani with B. Riley.
Yes. Good morning, team. Thanks for taking our questions and congrats on the fantastic results. If I could ask one more asthma question, you know, if you could clarify the treatment duration that you might be looking to explore in the phase II-B, you know, dupi had a bunch of different trial designs initially that were conducted. So if you're able to, you know, give any information, what you've learned by FeNO and the eosinophil comment you had earlier. And then on the sort of the safety AE table, I'm sure we'll get at a future medical conference, you know, combining exposure across healthy volunteers. Now I think of 150 subjects. Could you just confirm if you've established the safe, minimally effective dose threshold, or is that going to be a, you know, key phase II-B objective?
I was just curious about the details there.
Yeah. So on the duration, we're not going to, you know, disclose the design of the study yet. So I think it will be early next year when we start the study for CSU. On the safety of our drug, I mean, we have placebo-like safety in the healthy volunteers. We didn't have placebo here, but you could say that it was very similar to that, the safety we saw there. There, we pushed the dose all the way up to 800 pg/mL. So we actually haven't seen any dose-limiting toxicity or any actual toxicity that are relevant of any type. So this is as good of a safety profile as one can hope.
Any AEs that were dose-dependent you can comment on, Nello?
No. There were no dose-dependent AEs either in patients or in the healthy volunteer.
Fantastic. Thank you, guys.
Thanks.
Your next question will come from Andy Chen with Wolfe Research.
Hey.
Oh, he broke up and.
Oh, it appears we have lost Andy.
Okay. Maybe we'll try him back for the next one.
Sure. We'll take our next question from Jeet Mukherjee with BTIG. Jeet will be on in a moment.
Hey, folks, can you hear me?
Yeah.
Great. Pretty momentous day for you folks as a company. So I wanted to extend my congratulations as well. You know, one thing I'm just still quite fascinated by is some of these differences that you're seeing versus DUPIXENT, such as on IL-31 and on FeNO. So just from a biologic and perhaps pharmacologic basis, is there anything you could point to that perhaps might be driving this difference?
Well, it's a great question, Jeet. I would be kind of careful at this stage to claim that we are superior to DUPIXENT. I don't think the message that we want to send today is that. I think the message that we want to send is all the data we've accumulated to date in the past multiple years has shown us that we've blocked the pathway as well as an IL-4 and IL-13 biologics. I think we can safely say that with this data. We will require, you know, larger studies and more analysis to actually get to the specifics of differences. Again, one thing I would say that as we've seen also in preclinical studies, you know, the small molecule is extremely fast at degrading and it's extremely good at getting into tissues. So it's obviously telling us that we have robust effects in the right tissues.
That might be something that, with more studies, would be able to show more and more data that might, you know, share and give rise to some level of differentiation. But again, I would be unscientific to say that we have robust data right now to say we're different. I think we're at least as good as what has been shown with upstream biologics. Let's put it at that.
Fair enough.
Yeah, your question is very good. I'm not dismissing it. You know what I'm trying to do. Go ahead.
Absolutely. Maybe just as a quick follow-up, obviously focusing now turning to your phase II studies, can you just remind us what steps you're taking to mitigate that placebo response?
Yeah. So Jared, maybe you can speak to this.
Yeah. I think, you know, for the phase II-B AD study, for example, I think it's very important that, you know, we have eligibility criteria and trained seasoned physicians to make sure that number one, they're putting on AD patients because sometimes patients who don't have AD are put onto these studies. And number two, to make sure that the patients, you know, if we have an EASI cutoff of 16, for example, for moderate to severe, that they're not putting on patients with lower EASIs who actually really have mild disease, not moderate. This does happen. This is very important for us as we've selected sites, selected investigators, and we ourselves as a sponsor will be providing a lot of close oversight in terms of the screening of patients to make sure the right patients with the right eligibility criteria are enrolled onto the study.
That's going to be critical. Also making sure that we have dermatologists doing the clinical measures and the same person doing the measure of baseline. And then afterwards, that's going to be really important. And again, making sure that we as a sponsor are providing close oversight. It's also very important, you know, to have an array of sites in these global studies. You know, we have both North American sites in the U.S. and Canada, as well as sites ex-U.S. in Europe and in Asia. In fact, you know, our AD study will have a majority of sites outside of North America, although there will still be a substantial number of North American sites.
Great. Thank you.
Thanks, Jeet.
For our next question, we'll return to Andy Chen with Wolfe Research.
Hey, thank you for taking the question. Just one question from my side. I'm curious if your phase I-B here has generated additional confirmatory evidence that degraders are better than inhibitors. And I'm hoping that you can help us quantify how much better a degrader is compared to an inhibitor. Or in other words, if a STAT6 inhibitor were to produce the TARC or IgE data, where do you think they would land? Thank you.
Yeah. No, it's a great question. And I, you know, we've said it for a very long time that for this particular pathway, in order to achieve the biologics-like activity, you have to get really robust blockade. We've said in the past 90%+ , some would argue maybe even more than that. And obviously, I think we've shown that in both healthy volunteers and now in patients.
We believe given how much target is expressed, we believe it's almost impossible with an inhibitor to cover the target 24/7 at this level of inhibition. Again, given the PK/PD reliance of traditional small molecules. With regards to your question, look, IgE is extremely noisy in the first few weeks. So it's really hard to put a number on IgE that one could actually make a comparison with, and on TARC, again, you've seen that it's very dependent on baseline. But assuming you have comparable levels of baseline, I actually don't think that blood biomarkers are the story of differentiation. Even if you look at preclinical models, you can actually change biomarkers even with suboptimal target engagement. When I say suboptimal, I say even 80%-85%. You've seen our preclinical data.
But it's the clinical endpoints and the efficacy endpoints preclinically, which is where you need the robust, deep pathway blockade.
Thank you, Nello.
Thanks, Andy.
Our next question will come from Sudan Loganathan with Stephens.
Hi. Hi, Kymera team. Really appreciate the update here. And I want to convey my congrats again also on the data that you presented for KT-621. So my question, you know, given that BroADen enrolled a substantially higher proportion of African-American patients than dupilumab's earlier AD studies, I think it was about 50% in your study versus dupi's was closer to 70%-80% of actually white Caucasian patients. And considering the known challenges in scoring erythema or skin redness in darker skin, how are you thinking about interpreting the observed EASI- 50 or 75 responses in that context?
And then, did you incorporate any scoring standardization or digital tools to mitigate skin tone-related variability? And will there be any focus on that in the phase II-B in this population or going forward?
I want to just high-level answer, Jared. You can be ready to answer the more technical part. I don't believe that, you know, this is going to be a trend that you'll see in all the other studies. Just to remember, this was a U.S.-only study, 28 days, two required biopsies, the third optional biopsies. So this was really a difficult study to enroll, which, you know, also the site selection was based on, we believe, patients that we would have access to, that would have less access to systemic biologics.
Again, I can't predict what the phase II-B study will look like, but I would be surprised if the percentages would continue to stay the same. But Jared, what do you want to add to the technical question?
Yeah, I think from a technical standpoint, you know, I think all the clinicians and dermatologists that were used in our phase I-B study were all well-trained to be able to assess lesions in both, you know, dark-skinned individuals as well as lighter-skinned individuals. Also important to note that in our African-American patients, you know, we saw concordance across all endpoints. So it wasn't just EASI, it was also pruritus, you know, SCORAD, you know, biomarkers, you know, sleeplessness, all these other endpoints, you know, all sort of came together.
So in addition to the investigators being well-trained to assess extent and severity of skin lesions in a measure like EASI, the fact that all the other measures also, you know, came together, just as you saw in that one example that we gave in the presentation, which was a dark-skinned patient, that really isn't an issue. And I think, you know, if we have those patients in our phase II-B study, again, we'll be using sites with experienced dermatologists who will be well-versed on how to do these measurements across the board.
Thank you.
Thanks for that. I think this was the last question here. So I wanted to thank everybody for tuning in. This is a momentous day for the company. And, you know, we're happy to spend more time with any of you today and the next few days.
And again, I wanted to thank the team here at Kymera for doing an amazing job in the past few years and especially in the past few months. And thanks again, everybody, for joining us today.