I would like to thank everyone for joining us this morning at this busy time as we approach the holidays. We very much appreciate you taking the time to be here for this update, which we're excited to share with you all. As you have noticed by now, we're using a different format for this call, making use of the video cameras to which you all have been accustomed. I'm here in one of the conference rooms in the Kymera offices in Watertown, and Nello and Jared are in their respective offices here at Kymera as well. After some prepared remarks from Nello and Jared, they will join me here in this room, and we'll turn the call over to questions from our covering analysts. We will be sharing a slide deck on this call.
We plan to post that to our website after we wrap our presentation, which we plan to conclude by around 9:30. The three of us will also be available throughout the day for follow-up. At this time before we get started, I'd like to just remind everyone of our forward-looking statement language. The comments that management may make on this call include forward-looking statements as outlined in the press release. Actual events and results could differ materially from those expressed or implied by any forward-looking statements, or results of various risks, uncertainties and other factors, including those set forth in Kymera's most recent filing with the SEC, any other future filings that the company may make with the SEC. You are cautioned not to place any undue reliance on these forward-looking statements. Kymera disclaims any obligation to update such statements except as required by law.
With that said, before I turn the call over to Nello, I wanted to briefly outline the agenda today. Nello will make some introductory remarks before handing the call over to Jared. Jared will cover, first a brief update on our two oncology programs before the KT-474 update, and then we'll conclude with some closing remarks from Nello. After which we will take questions, and our goal, as I said, is to finish the call around 9:30. With that said, I will turn the call over to Kymera's Founder, President, and CEO, Nello Mainolfi.
Thank you, Bruce, and thank you everybody for joining us today. This is a period of time for Kymera, and I believe this extends to the whole field of targeted protein degradation. We founded this company six years ago to harness the potential of this exciting new modality to bring more effective treatments to patients. With our KT-253 IND cleared, we now have four clinical stage programs across a variety of indications in oncology and inflammation. We have built a company that has differentiated itself on target selection strategy, disease area focus, platform and strategy. The underpinning principle has been to focus on areas that would allow us to scale to a fully integrated global biotech using TPD to unlock novel biology and high value therapies for patients. Today is a key step towards that goal.
We're validating our molecular design and our platform capabilities by demonstrating fidelity of translation of PK, PD, and safety from preclinical models into patients. With three programs supporting our approach in patients with cancer and immune inflammatory diseases. We're also validating our target selection strategy going after previously undrugged targets in validated pathways where we believe TPD is either the only or the best way to unlock the full biology of the target. You've heard me and us say that IRAK4 degradation is the only way to fully block the IL-1R and TLR-driven inflammation, and that small molecule inhibitors or upstream blockers are insufficient to do so. Data that we're sharing today, while early, are for the first time validating our thesis and more broadly demonstrating that when applied to the right molecular target, targeted protein degradation has the potential to be a truly transformative technology.
I also wanna point out that KT-474 was the first heterobifunctional degrader to have been dosed to healthy volunteers and then to HS and AD patients, and is also the first to show what seems to be profound clinical impact in such complex diseases. Again, because we're degrading and not inhibiting a key protein in inflammation. While all of the individual datasets that we're sharing today are impressive in their own right, it is critical to step back and assess the totality of the data, namely the degradation in blood and skin, the impact on disease relevant biomarkers in blood and skin, which we believe are then linked to the observed clinical responses that are meaningful even just with four weeks of dosing.
When everything like, lines up this way, it strongly supports our confidence in this drug and in its mechanism in HS, in AD, and I'm confident beyond these diseases. I hope you will share our and Sanofi's excitement around the potential clinical and commercial opportunity that KT-474 offers in large indications, most of which don't currently have a well-tolerated oral option. With this level of validation, proprietary insights in target selection, discovery and clinical translation, combined with a very strong cash position, we believe we're uniquely positioned to accelerate our growth in areas of large commercial and clinical opportunities. We're excited to share more with you about this later and probably even more next year. Going to the next slide. As you can see from our pipeline, we've made tremendous amount of progress this year, we have exciting potential for next year.
For KT-474, we're excited to now support Sanofi as they advance the drug into phase II. Our initial indications will be HS and AD, with the first study initiating in 2023. More details will be shared on this topic as plans are refined with our partner. Our two clinical oncology programs, KT-413 and KT-333, will move into further clinical trials, providing the opportunity to determine if the degradation we've observed with these molecules results in clinical activity, particularly at higher doses, and in our target patient population. With the recent IND clearance from FDA in hand, we plan to initiate our phase I trial for our MDM2 degrader, KT-253, also early next year. Going to slide six, just back to the data. Very briefly, I'll give you a summary of what you will see today.
You read from the press release this morning, our two clinical stage oncology programs, KT-333 and KT-413, are progressing through dose escalation in their phase I trials. These early data from these trials are very encouraging, as both molecules are demonstrating fidelity of PK/PD translation from preclinical models to patients. We know dose-limiting toxicity observed in the completed cohorts. Our question with these molecules was if dosing weekly or once every three weeks, depending on the programs, will translate in humans with same kinetics of degradation and safety that we've seen in preclinical species. The early data are telling us that we were right in our choices and give us the confidence that in 2023 we will be able to answer the question of the program's ability to demonstrate clinical impact in patients.
We talked about KT-253's IND clearance. I'm excited that we have another program where we have a clear degrader rationale to explore clinically, which hopefully will follow the path we have paved with ARID 4 and KT-474, with biological superiority over a small molecule inhibitor. As we said in the PR, KT-474 HS and AD data have exceeded even the most optimistic expectations we had for this relatively small trial. Not only have we achieved our study objectives in terms of PK, PD, and safety, but KT-474 has clearly gone above and beyond our expectations in what we have seen on biomarkers and especially on clinical endpoints. Even using the most stringent analysis of response data, for example, using HiSCR 75 in HS, we see responses even after just 4 weeks.
Responses I should note last beyond the last dose, which speaks to the power of the mechanism. As I said earlier, it is the line that you can draw between degradation, biomarker changes, and clinical endpoint, all following the same time and kinetics that make this small data set even more compelling. In addition, we've seen that even the modest non-adverse QT effect we first observed in healthy volunteer resolved itself with continued dosing, which we believe further de-risk an observation that we already had determined to be manageable. Jared will share all the specifics around the data, but we believe we have in KT-474 a drug that has best-in-class potential, not only in HS and AD, but potentially in a broader variety of immune inflammatory indications.
Of course, we're very excited that our partner, Sanofi, will be taking KT-474 into phase II studies in HS and in AD initially, starting the first trial in 2023. We look forward to continuing our collaborative partnership, and we appreciate their enthusiasm for the molecule and for making a timely decision so that we could share it with you this morning. On this aspect, I would like to thank the whole Sanofi team for being great partners along the way, and especially John Reed and Paul Hudson for enabling the rapid decision-making process of late. I'll now turn it over to Jared to take you through the data. We will reconvene after that.
Great. Thank you, Nello. Starting with our oncology programs, as shown on slide eight, STAT3 is a traditionally undrugged transcription factor implicated in the malignant phenotype of various tumor types through both tumor cell-intrinsic mechanisms, where STAT3 pathway activation drives tumor cell proliferation and resistance to cell death, as well as through tumor cell-extrinsic mechanisms, where STAT3 mediates development of an immunosuppressive tumor microenvironment. KT-333 is a potent, highly selective degrader of STAT3 in development for the treatment of hematological malignancies, including STAT3-dependent T-cell malignancies such as peripheral T-cell lymphoma, cutaneous T-cell lymphoma, and LGL leukemia, as well as solid tumors. Slide nine shows that KT-333 dosed IV weekly drove complete and durable tumor regressions in mouse xenograft models of STAT3-dependent ALK-positive ALCL.
The tumor PD that achieved this robust response was greater than 90% STAT3 knockdown for 48-72 hours, which is the target PD for the clinic that we expect will achieve anti-tumor responses in the target patient populations. The KT-333 Phase 1 trial design is shown on slide 10. The study is comprised of a Phase Ia dose escalation component in liquid and solid tumors, which is ongoing, followed by Phase 1b expansions in STAT3-dependent T-cell malignancies and solid tumors. Patients are dosed weekly with an IV infusion of KT-333 on days one, eight, and 15 of 28-day cycles. The study is currently enrolling patients into dose level two, with dose level three-four and beyond predicted to be the efficacious dose range.
As shown on slide 11, dose level one has been completed with four patients enrolled, including three with solid tumors and one with CTCL, all of whom were heavily pre-treated. There were no DLTs, treatment-related SAEs, or treatment-related AEs leading to discontinuation. Week one plasma PK for DL 1 is shown on slide 12. The half-life was approximately six hours. While not shown here, there was no evidence of drug accumulation following the week 2 dose. As shown on slide 13, STAT3 degradation in PBMC was demonstrated by mass spectrometry in all four patients in DL 1 following the first and second doses, with mean maximum degradation averaging 66% for the cohort and ranging from 50%-80%. The nadir was observed between 24-96 hours post-infusion, with recovery of STAT3 levels between doses.
This level of STAT3 knockdown was in the range of what was predicted for tumor based on preclinical mouse xenograft PK/PD data. The kinetics of degradation with rapid knockdown, maintenance for up to 96 hours, and then recovery to baseline before next dose is what we wanted to see translated in the clinic to predict robust clinical activity and safety in the target patient populations once we reach 90% target knockdown, which we expect should happen in the next couple of cohorts. These results are summarized on slide 14. The first dose level has been completed, showing initial proof of mechanism for STAT3 degradation in PBMC and no safety signals, with good translation of PK/PD from preclinical models to patients.
DLT is currently enrolling patients. Based on the PK/PD, which we have shown today with robust target knockdown for 72 hours followed by recovery, we expect to be at efficacious doses by DL 3 to 4. IRAKIMiDs are heterobifunctional compounds targeting degradation of IRAK4 as well as the IMiD substrates, Ikaros and Aiolos, in development for the treatment of MYD88 mutant B-cell malignancies, including DLBCL, Waldenström's macroglobulinemia, and primary CNS lymphoma. As shown on slide 16, oncogenic mutations in MYD88 lead to activation of the IRAK4 and NF-κB pathway, as well as upregulation of IRF4 and inhibition of the type 1 interferon response. Simultaneous inhibition of both pathways through degradation of IRAK4, as well as Ikaros and Aiolos, is required for antitumor activity in models of MYD88 mutant DLBCL. KT-413 is Kymera's lead IRAKIMiD in development for MYD88 mutant B-cell malignancies.
As shown on slide 17, KT413 dosed IV intermittently every three weeks achieved durable complete tumor regressions in mouse models of MYD88 mutant DLBCL, whereas potent IMiDs alone, such as CC220, only achieved tumor growth inhibition. The tumor PD that achieved this robust response was 80%-90% Ikaros knockdown and 50%-70% IRAK4 knockdown for approximately 72 hours, which is the target PD for both nadir and shape of the curve for the clinic that we expect will achieve antitumor responses in the target patient populations. The KT413 phase 1 trial design is shown on slide 18. The study is comprised of a phase Ia dose escalation component in B-cell lymphomas, which is ongoing, followed by phase 1b expansions in MYD88 mutant and MYD88 wild-type DLBCL. Patients are dosed every three weeks with an IV infusion of KT413.
The study is currently enrolling patients into dose level three, with DL 3 or 4 and beyond predicted to be the efficacious dose range. As shown on slide 19, DL 1 and DL 2 have been completed with patients enrolled, including follicular lymphoma and DLBCL, both of whom were wild type MYD88 and heavily pre-treated. There were no DLTs, treatment-related SAEs, AEs leading to discontinuation, or neutropenia observed in these cohorts. Cycle one plasma PK for DL 1 and DL 2 is shown on slide 20. There was a dose proportional increase in exposure with half-life of 30 to 59 hours. While not shown, no accumulation was seen during cycle two.
As shown on slide 21, dose-dependent degradation of all three targets for at least 72 hours was demonstrated in PBMC by flow cytometry, with up to 40% knockdown of IRAK4 and 95%-100% knockdown of Ikaros and Aiolos, respectively, with recovery between doses. Serial tumor biopsies obtained in DL 1 at baseline and cycle three, day four, showed 27% reduction of IRAK4 and 41%-66% reduction of Ikaros and Aiolos by mass spec.
The kinetics of degradation with rapid knockdown, maintenance for up to 96 hours, and then recovery to baseline before next dose is what we wanted to see translated in the clinic to predict robust clinical activity and safety in the target patient populations once we reach 50%-70% IRAK4 knockdown, along with 80%-90% Ikaros/Aiolos knockdown, which we expect should happen in the next couple of cohorts. These results are summarized on slide 22. The first two dose levels have been completed, showing initial proof of mechanism for IRAK4, Ikaros, and Aiolos degradation in PBMC and tumor, and no safety signals, with good translation of PK/PD from preclinical models to patients.
DL 3 is currently enrolling patients, and based on the PK/PD we have shown today, with robust target knockdown for 72 hours followed by recovery, we expect to be at efficacious doses by DL 3 or 4. I'm now going to turn to the IRAK4 KT-474 program and present the new results from the phase 1 part C patient cohort. As shown on slide 24, IRAK4 is a key component of the midzone complex that mediates signaling through IL-1 receptors and toll-like receptors to stimulate production of multiple pro-inflammatory cytokines and chemokines. Since downstream activation of NF-κB as well as MAP kinases is dependent on both the kinase activity and scaffolding function of IRAK4, degraders of IRAK4 have an advantage over kinase inhibitors in being able to more completely block the IL-1R TLR pathway.
Clinical validation for targeting this pathway comes from the clinical activity of antibodies targeting IL and family cytokines across a wide variety of diseases, as well as from the activity of an IRAK4 small molecule kinase inhibitor in rheumatoid arthritis. Human genetics indicate that IRAK4 knockdown should be well-tolerated, as adults with mutations leading to complete loss of IRAK4 are generally healthy and do not exhibit susceptibility to infections. We believe targeting IRAK4 with a degrader therefore has the potential to achieve a broad, well-tolerated anti-inflammatory effect that provides multiple development opportunities in TLR, IL-1R-driven autoimmune diseases. Slide 25 provides several lines of evidence highlighting the advantage of IRAK4 degradation over kinase inhibition. Others you can find on our November deck on our website.
Importantly, the scaffolding function of IRAK4 has been shown to be critical for the proper formation of MyD88 oligomers that then mediate the recruitment of other midzone components necessary for TLR, IL-1R signaling. Furthermore, proinflammatory cytokine induction in B cells activated through TLR9 and in PBMC activated through combined TLR4 and IL-1R stimulation is blocked by IRAK4 degradation, but not by kinase inhibition. Again, showing the greater dependency of the TLR, IL-1R pathway on the scaffolding function of IRAK4 compared to its kinase activity. Collectively, these results suggest that IRAK4 degradation should outperform kinase inhibition in the clinic, especially in diseases with intense pleiotropic inflammation. Today we are excited to share initial clinical data that we believe is validating our thesis in patients.
Some of the potential development opportunities for an IRAK4 degrader are shown on slide 26. These include diseases characterized by Th1 and Th17 inflammation and neutrophils, such as hidradenitis suppurativa and rheumatoid arthritis, or by Th2 inflammation and eosinophils, such as atopic dermatitis. Compared to an IRAK4 degrader, antibodies targeting cytokines or cytokine receptors are potentially limited in their efficacy by virtue of hitting only one or two cytokines in conditions where multiple different cytokines or chemokines are driving the inflammation. They cannot be dosed orally. IRAK4 kinase inhibitors, while showing positive early safety and efficacy in RA, had little activity in HS, underscoring the limited context-dependent effect of kinase inhibition on the pathway. JAK inhibitors, on the other hand, while having a broad anti-inflammatory effect, have safety liability that may complicate broad applications.
We believe our orally active IRAK4 degraders can provide a unique solution to all these challenges. KT-474 is a potent and highly selective degrader of IRAK4 in development for the treatment of TLR, IL-1R-driven autoimmune diseases. Slide 27 shows the design of a phase I trial which enrolled over 150 subjects. Parts A and B were in healthy volunteers and consisted of randomized, placebo-controlled, single and multiple ascending dose studies that we have reported on previously. In the 4 MAD cohorts where KT-474 was dosed daily for 14 days, we demonstrated robust IRAK4 degradation in blood and skin, as well as broad inhibition ex vivo in whole blood of multiple TLR-stimulated disease-relevant cytokines and chemokines. KT-474 was generally well-tolerated at doses up to 200 milligrams.
Non-adverse, self-limiting mean QTCF prolongation of 10-20 milliseconds was observed that was neither dose nor exposure-dependent. The part C patient cohort, completed on October 20th, was an open-label study in moderate to severe HS and AD, where patients were dosed daily for 28 days with 75 milligrams in the fed state. Patients were required to be off any therapies for their disease at the time of enrollment with appropriate washout periods. The main objective of part C was to show safety, PK, and PD in patients that were comparable to what we observed in healthy volunteers. In addition, extending the dosing interval from 14-28 days provided an opportunity to demonstrate an impact on inflammatory biomarkers in blood and skin and explore clinical activity. Patient demographics are shown on slide 29.
A total of 21 patients were enrolled, including 13 HS and 8 AD, with median ages of 40 and 31 years respectively. As shown on slide 30, most HS patients had moderate disease severity, with one severe and two very severe by HSPGA. three patients had prior adalimumab. These included the two patients with very severe disease, one of whom also had additional biologic therapies. Most AD patients also had moderate disease severity, with two severe and one mild. None of the AD patients had received prior biologics, including dupilumab. Patient disposition is shown on slide 31. Among the 21 enrolled patients, 1 HS and 1 AD patient withdrew from treatment early after 45 doses for personal reasons and not because of any AE, leaving 12 HS and 7 AD patients evaluable for PD and clinical endpoints through day 42.
We brought one dose into part C, selecting 75 milligrams in the fed state, predicted to give an equivalent plasma exposure and PD effect to 100 milligrams in the fasted state administered in MAD 3. The primary objective of part C was in fact to demonstrate that KT-474 would have the same PK/PD relationship in patients in part C as we saw in healthy subjects in the MAD cohorts. As shown on slide 33, steady-state plasma mean Cmax and Ctrough levels and mean half-life for 75 milligram dose daily in the fed state were comparable to 100 milligrams dose daily to healthy volunteers in the fasted state, validating our choice of 75 milligrams fed for part C to achieve the 100 milligram fasted exposures. Steady-state plasma exposures were maintained through the completion of dosing on day 28.
Importantly, we observed, using flow cytometry, the same blood PK/PD relationship in patients that we saw in healthy volunteers, with the degree of IRAK4 knockdown in PBMC tracking with plasma Ctrough levels of KT-474. Specifically, in both patients and healthy volunteers, plasma concentrations of greater than 3 nanograms per mil achieve IRAK4 degradation of greater than 80%, and in many cases, more than 90%, even with a less quantitative method such as flow, which generally underestimates degradation by roughly 10% compared to mass spec. This three nanogram per mil threshold was substantially lower than the steady-state mean Ctrough of approximately nine mics per mil seen in patients.
While we had limited mass spec IRAK4 PBMC data on part C due to some technical challenges, given we had multiple study sites, we did see robust IRAK4 knockdown close to the lower limit of quantitation in the patients whose samples were evaluable on day 28. Serial biopsies of skin lesions for measurement of KT-474 levels and IRAK4 were performed at baseline at the completion of treatment on day 28 and two weeks post-treatment on day 42. As shown on slide 34, concentrations of KT-474 in skin lesions of patients after four weeks of dosing were high, approximately threefold above that in healthy subjects after two weeks of dosing, confirming that skin exposure was not at steady state after just two weeks in the previous healthy volunteer MAD study.
Slide 35 shows that baseline IRAK4 protein levels in skin, as measured by mass spec, were approximately twofold higher in both HS and AD skin lesions compared to the skin of healthy subjects from the MAD cohorts. These findings in HS were in line with what we previously reported in our HS non-interventional study. Following 28 days of treatment with KT-474, mean IRAK4 levels in AD and HS skin lesions were reduced to at least the same level as healthy subjects. KT-474 was generally safe and well-tolerated. As shown on slide 37, adverse events occurring in more than one patient included headache, fatigue, and diarrhea, most of which were mild and resolved spontaneously without any intervention. There were no serious adverse events, no drug-related infections, and no adverse events leading to interruption of dosing or treatment discontinuation.
As shown on slide 38, modest QTCF prolongation in the range observed in healthy volunteers at 100 milligrams in MAD 3 was also seen in patients at day 7 to 14, spontaneously declined to baseline with continued dosing and sustained plasma exposure through day 28. Upon cessation of dosing after day 28, the QTC interval remained stable in the normal range through day 42. There were no QTC-related AEs. As shown on slide 40, a whole blood ex vivo stimulation assay using the TLR ligands LPS or R848 showed broad inhibition of multiple disease-relevant cytokines and chemokines of up to 84%-98% in HS and AD patients from days 14 to 28, comparable or superior to what was observed in the healthy volunteer MAD 3 cohort.
While not shown here, the inhibition was generally greater at day 28 compared to day 14, raising the possibility that not only the extent of IRAK4 knockdown but also the duration of that knockdown has an impact on TLR IL-1R pathway activation. To determine whether KT-474 had a systemic anti-inflammatory effect in HS and AD patients, we measured plasma levels of IL-6, CRP, SAA, and IL-1β at baseline and at various times during and after the 28-day treatment period. IL-6, CRP, and SAA were more frequently elevated at baseline in HS compared to AD, consistent with what has been reported in the literature.
The analysis of change from baseline was restricted to those patients whose levels were greater than the upper limit of normal. IL-1β baseline levels were low in most HS and AD patients, and since the normal range is broad and not well-defined, all patients with evaluable samples were analyzed for change from baseline. As shown on slide 41, the evaluable HS patients showed suppression of all four analytes, with mean maximum reductions through day 42 ranging from 41%-63%. While CRP was not elevated in any of the AD patients, the evaluable AD patients showed 36%-56% suppression of the other three analytes. It was not uncommon for HS and AD patients to show peak inhibition one to two weeks after the completion of dosing.
We believe this is the first demonstration that IRAK4 degradation in patients has a systemic effect on inflammation in both HS and AD patients. This is meaningful not only because it shows that we can inhibit systemic inflammation, but also because these data demonstrate for the first time that this pathway is activated in both HS and AD, and that it contributes substantially to the inflammatory burden of both diseases. To be clear, if this pathway was not activated, degradation of IRAK4 would not lead to inhibition of downstream markers. We previously showed strong upregulation of multiple disease-relevant pro-inflammatory gene transcripts in HS skin lesions compared to healthy subjects and established a correlation between IRAK4 protein expression and the upregulation of those genes.
We therefore applied RNA-seq to serial biopsies of skin lesions to determine how systemic IRAK4 degradation in blood and skin would affect the expression of pro-inflammatory genes known to be relevant to either AD or HS. Slide 42 shows select disease-relevant genes downregulated in skin lesions of at least 50% of AD or HS patients at day 28 compared to baseline. The response of individual evaluable AD or HS patients is shown in each plot. In AD, affected genes included the Th2 cytokine IL-5, the inflammasome NLRP3, as well as CXCL1 and IL-2RB. Genes affected in HS included IL-1 family cytokines IL-1 beta and IL-36α, mediators of Th1 inflammation such as interferon gamma and granzyme B, the Th17 cytokine IL-17A, and drivers of innate immunity such as IL-8 and CSF3. The downregulation was substantial, with many genes inhibited more than 90% in both diseases.
This demonstrated for the first time that IRAK4 degradation can have a broad impact on the pleiotropic inflammation that characterizes diseases like HS and AD. We believe these are very meaningful data with strong downregulation of inflammatory biomarkers in the skin, again demonstrating the high level of relevance of this pathway to the manifestations of these diseases. Turning now to the assessment of clinical efficacy, the exploratory clinical endpoints used for HS and AD, as well as the timing of those measures, are shown on slide 44. These endpoints were chosen so we could assess the impact of KT-474 treatment on the burden of skin disease as well as on symptoms such as pain and pruritus that impact quality of life for these patients.
Beginning with AD, as shown on slide 46, there was a mean 37% reduction in skin lesions as measured using the EASI score, with reductions in individual patients of up to 76%. Maximum reduction was seen by day 28 and was maintained at day 42. As shown on slide 47, peak pruritus over the past week or past 24 hours was reduced by an average of 52% and 63% respectively, with maximum reductions occurring by day 42. Peak pruritus responders, defined as greater than or equal to 4-unit reduction in peak pruritus over the past week or past 24 hours, were seen in 57% and 71% of patients respectively, with the responses sustained after day 28. As shown on slide 48, the investigator's global assessment of disease severity improved in 2 of 7 patients and remained stable in the others out to day 42.
Recall that this assessment tends to be a lagging indicator of activity. Slide 49 shows a representative AD patient with severe disease who had a dramatic improvement on KT-474, with 67% reduction in EASI score, 75% reduction in pruritus, and reduction in IAGA disease severity score to mild. Notably, the improvement in skin lesions continued for 2 weeks following the completion of dosing on day 28. This clinical improvement was accompanied by evidence for a systemic anti-inflammatory response, including reduction of circulating IL-6 and IL-1β levels and reduction of multiple inflammatory biomarkers in the skin, including IL-1β, TNF, CXCL8, COX-2, NLRP3, and IL-5. These promising signs of clinical activity in AD are summarized on slide 50.
The impact on clinical endpoints measuring disease burden and symptoms, including mean 36% reduction in EASI score with maximal reductions of up to 76%, mean 52%-63% reduction in peak pruritus NRS, and 57%-71% peak pruritus NRS responder rate is beyond what has been observed in placebo arms at 4 weeks from multiple randomized trials of active biologics in AD and is competitive with reported dupilumab activity at 4 weeks. The demonstration of this clinical impact in conjunction with robust IRAK4 reduction in blood and skin, as well as evidence for a systemic anti-inflammatory effect involving downregulation of multiple disease-relevant inflammatory biomarkers, including IL-5, IL-6, IL-1 beta and NLRP3 provides confidence that IRAK4 is a key driver of inflammation in AD and that targeting IRAK4 has the potential for clinical benefit in AD.
We are very excited to be the first to demonstrate the strong biological and clinical early validation for IRAK4 degradation in AD. Moving on to HS, the efficacy analyses were performed in all patients, which included 2 patients with very severe disease. In addition, we also performed the same analyses in a subset of patients that only had moderate to severe disease, which was the target population for this study, where dosing was limited to only 4 weeks. The mean AN count at baseline was 8, with a range of 5-18. As shown on slide 52, the AN count was reduced by an average of 46% in all patients and by 51% in the moderate to severe subset, with reductions in individual patients of up to 100% and with maximum reduction occurring by day 42.
The proportion of patients achieving an AN count of 0, 1 or 2 at day 28 was 42% in all patients and 50% in those with moderate to severe disease. HiSCR50 response is defined as a 50% or greater reduction in AN count and no increase in abscesses or draining fistulas. Shown on slide 53, the proportion of HiSCR50 responders was 42% in all patients and 50% in those with moderate to severe disease. As you will see in the summary table at the end, HiSCR75 response, defined as 75% or greater reduction in AN count, was seen in 25% of all patients and 30% of those with moderate to severe disease. Symptoms of pain and pruritus were significantly impacted by KT-474.
As shown on slide 54, there was a 49%-55% average reduction in pain in all patients and in those with moderate to severe disease, respectively, with maximum reduction occurring between days 28 and 42. Pain NRS 30 response is defined as at least a 30% reduction and at least 1 unit reduction from baseline in pain NRS. As shown on slide 54, the pain NRS responder rate was 50% in all patients and 60% in those with moderate to severe disease, plateauing after day 28. Pruritus is a major problem in HS patients, along with pain, but has been rarely measured in prior interventional trials of active agents in HS.
Slide 55 shows that KT-474 reduced peak pruritus by an average of 62% in all patients and by 68% in those with moderate to severe disease, with maximum reduction by day 42 in all patients and by day 28 in those with moderate to severe disease. As shown on slide 56, the physician's global assessment of disease severity improved in five patients, including clearing of disease in one patient with moderate disease at baseline and remained stable in the other evaluable patients out to day 42. Again, recalling that this measure tends to be a lagging indicator of activity. Slide 57 shows a representative HS patient with moderate disease who had complete clearing of her skin lesions by day 28 and full resolution of pain and pruritus, with maintenance of her response two weeks after completion of dosing.
Serial skin biopsies showed marked reduction of multiple inflammatory biomarkers in the skin, including IL-1β, IL-36α, IL-17A, CXCL1, interferon gamma, granzyme B, COX-2, and IL-5. Slide 58 shows a second HS patient with 80% reduction in AN count and 90%-100% reduction in pain and pruritus by day 42, accompanied by reductions in circulating IL-1β and SAA levels. These strong signs of clinical activity in HS are summarized on slide 59.
The impact on clinical endpoints measuring disease burden and symptoms, including HiSCR50 and HiSCR75 responder rates of up to 50% and 30% respectively, pain NRS responder rate of up to 60%, mean reduction of pruritus of up to 68%, and disease severity improvement in up to 50% of patients is well beyond what has been observed in placebo arms at 4 weeks from multiple randomized trials of active biologics in HS and is comparable or superior to adalimumab activity at 4 weeks. The impact on pruritus is notable as to our knowledge, this has only been rarely assessed in prior HS clinical trials with other biological agents.
The demonstration of this clinical impact, in conjunction with robust IRAK4 reduction in blood and skin, as well as evidence for a systemic anti-inflammatory effect involving downregulation of multiple disease-relevant inflammatory biomarkers, including IL-6, IL-1β, IL-36α, IL-17A, and IL-8, provides confidence that IRAK4 is a key driver of inflammation in HS and that targeting IRAK4 has the potential for clinical benefit in HS. We believe these data clearly differentiate this mechanism from IRAK4 inhibition as well as from the mechanisms of other drugs in clinical development in HS. Conclusions are shown on slide 61.
We have demonstrated that KT-474 administered to HS and AD patients has safety, PK, and PD similar to healthy volunteers, is associated with modest non-adverse QTC prolongation that spontaneously resolves back to baseline during the final two weeks of dosing, achieve robust IRAK4 degradation in blood and skin associated with a systemic anti-inflammatory effect, and shows promising clinical activity in HS and AD that exceeds benchmark placebo rates and compares favorably to standard of care biologics.Overall, the patient cohort results exceeded our expectations for a study with only four weeks of dosing. We believe KT-474 exhibited activity that is clearly differentiated from IRAK4 small molecule kinase inhibitors and appears competitive with standard of care biologics or other agents in development in both HS and AD, and importantly, has the potential to improve the lives of patients with HS and AD.
These data support advancing KT-474 into phase 2 clinical trials, and we are excited Sanofi has committed to initiating trials in HS and AD. I'll now turn it back over to Nello for his concluding remarks.
I'm not sure there is anything I can or should say on top of what you've seen in the past 30, 40 minutes. Maybe it's worth focusing on what the data mean for Kymera today and tomorrow. As I said earlier, today marks a pivotal time for the company. You have seen comprehensive validation of our platform, discovery and clinical efforts, and more importantly, of our target selection strategy and disease focus. With KT-474 positioned as a drug that has the potential to really disrupt the I&I space in diseases with large commercial opportunities and higher met needs such as HS and AD, but also related diseases like RA, IBD, lupus and others. We look forward to collaborating with our partner, Sanofi, to continue the development of this program with the vision of it becoming the best in class oral medicine in this space.
Just to reflect on what you've seen from Jared, the safety, the strong relationship we have built between degradation, downstream markers, impact in blood and skin, and impactful clinical responses well beyond placebo rates are impressive. I have not seen such a total package for a drug in early development. This is what TPD can do for us and for patients. With KT-474 in Sanofi's hands, Kymera can focus on seizing the moment and capitalizing on the knowledge, the insights, and the choices we've made, and expand and accelerate our efforts in additional areas of innovation where we know we can generate true value by degrading undrugged or poorly drugged targets.
This starts with our oncology pipeline, STAT3, IRAK4, and MDM2, and extends to our underexposed preclinical pipeline, where we're doubling down on targets that are similar to IRAK4, where a clear degraded rationale has the potential to bring best-in-class drug to large clinical and commercial areas. We encourage everybody to digest the data from today. We're available to follow up if there are questions. Hopefully there'll be an appreciation of what Kymera has done this year and more importantly, of what this sets up to being able to do going forward. Our trajectory to becoming a fully integrated global biotech has clearly been accelerated, we believe, by what we're sharing here today. We look forward to continuing this path with many of you. I would like first to thank the Kymera team.
We were recently named the best place to work by The Boston Globe. This is a testament to the amazing team that we have here of committed, data-driven, courageous individuals that every day go above and beyond what others think it's possible to push the envelope on a new technology that will transform patients' lives around the world. I also wanna thank our board for their support, our partners, collaborators and investors for allowing us to execute, and the patients in our studies that are willing to collaborate with us to advance innovative therapies for the broader patient populations. Finally, all of you for attending today. We will be happy to answer any questions in the Q&A session. Before doing so, I wanna wish everybody a great holiday season. We'll now take a short break. We'll meet you again for the Q&A.
Great. Thanks everyone for joining us. Thanks for that brief pause there while we assembled here in the conference room. We're gonna open up the call for questions now. The analysts know the system for doing that. Just a reminder, we will post these slides shortly. They should be up in the next before the market open at least. With that, operator, we'll turn it to the first question.
Great. Thank you. Our first question comes from Marc Frahm from TD Cowen. Please unmute your audio and video and ask your question.
Hi, thanks for taking my questions and congrats on the data today and the update from your partner. Maybe just on KT-474, can you speak to maybe the dynamics of the resynthesis rate that you see with IRAK4 and kind of the timing of when the pathway might be coming on relative to what you're seeing on this kind of longer term effect on the clinical endpoints kind of beyond the dosing?
Thanks. Thanks, Mark. Thanks everybody for participating today. I'll let Jared answer. I just wanna maybe provide a bit of context. What we've seen, we've shown in the past that when we degrade the target, we obviously see extended duration of degradation beyond the last dose. Today we kind of focus the degradation on the conservation of PK/PD because that was the key question for us and Sanofi going into the study. Obviously we had data from this study and from previous study that if you stop dosing, we conserve PD for at least a week. That is an important aspect of the technology, being able to see the degradation to maintain beyond the last dose.
That obviously, as you see today, I'll let Jared comment on the impact on cytokines and chemokines and on clinical efficacy. Maybe, Jared, you can comment on how we read that part.
I mean, we thought it was very interesting and encouraging that we see this sort of continued effect even beyond 28 days, both when we looked at plasma cytokines in vivo, where you see continued reduction even beyond 28 days, and of course, for some of the clinical endpoints, the same phenomenon. In some ways it makes sense in part because as Melo said, you know, knockdown is not just going away when dosing stops. You know, it persists at maximal levels for at least a week, and then you're starting to get some recovery, but you're not getting full recovery even by day 42. What it also tells us, we think importantly, is that this is having a real disease modifying effect.
It's really impacting the inflammatory cascade in a way where we wouldn't expect it just to snap back right after dosing is stopped. In fact, if you look back at different, you know, biologics such as monoclonal antibodies like anti-TNF drugs, you see a similar phenomenon, you know, even when the dosing is stopped or after single doses, where the drug has been cleared after X number of half-lives, you still see an impact on the disease and on clinical endpoints. I think what this is telling us is that this is having a disease modifying effect that is persisting beyond, you know, the end of dosing.
Maybe I just wanna add one thing. I know we'll have plenty of questions, so I don't wanna take too much time, but maybe actually the first questions allows me, allows me to say one thing that probably applies to a lot of questions that will be coming. I think it's hard for a small study to focus on one particular data point. I think we are focused on the totality of the data. If you look at the kinetics of degradation of cytokines and chemokines impact in blood and skin, which again, went above our expectations. We weren't, to be honest, expecting to see this broad anti-inflammatory effect both in blood and skin with such a deep, profound inhibition. If you look at the chemokines transcripts in the skin, most of those are at more than 90% inhibition of gene transcripts.
Those are profound PD effect. That translates into these early clinical activities. We've said for nine months, you know, we shouldn't overread the clinical activity, so I'm not gonna start today to overinterpret it. I think if you put it all together and you see the kinetics of responses, hopefully you guys on the other side appreciate that we're showing how even clinical scores change from day 0 to day 42. You see that there is a clear path of increased activity as the dose continues and as there is accumulated both degradation and impact on cytokines. That to us is the key take-home point. The pathway is activated in HS and AD, otherwise we wouldn't see impact on biomarkers.
This drug, which to be honest continues to be amazing, even in just four weeks of dosing, is showing activity that is hard to say there is a placebo-related activity. Like, there is clear signal. That's really what we take home from this data, and that's why we're excited about going into phase II with Sanofi, because there we will know the true clinical activity of this drug, which personally I believe will be way more impactful than what we're seeing today after four weeks of dosing. We just don't know the kinetic. As I've said in the past few months, we don't know the kinetics of degradation. Before we start comparing this drug, let's keep in mind that we don't know whether we are at 50%, at 100% or at 20% of maximal effect that this drug can have.
I'll pause here. Just get out of my system some of these comments and happy to take more questions.
Great. Thank you. That was very helpful.
Thanks. Maybe we can get the next question. Thanks, Marc.
Our next question comes from Vikram Purohit from Morgan Stanley.
Hey, Vikram, can you hear us?
Hi, good morning.
Hey, good morning.
Yes, I can. Good morning. Thanks for taking my question. Hi, good morning. Just one housekeeping question that I wanted to clarify. We received some questions on how to best interpret the tables in the press release. I think, there's some questions around a footnote about the results representing deepest reduction from days 28 to 42. If you could just first clarify exactly how those measurements were made and how we should tie some of that data back into the slides that you presented on the measurements through 28 days. Question one.
Thanks, Vikram. Why don't I let Jared answer? I just wanna say, obviously, in the press release, we try to be as succinct as possible. I would refer everybody to the slide we're showing from day one to day 42, so you can see where the numbers are. Jared, maybe you can explain how we did.
Yeah. I think, you know, we were careful in the presentation to describe not just the numbers we were seeing, but also the kinetics, where we were seeing maximum response, where we were seeing plateau. And that's why we refer to, you know, day 28 or day 42. The reason for having maximum effect between day 28 and day 42 is that because, you know, in many instances, the response continued to evolve even beyond day 28. I think when people think about, well, you're dosing for 28 days, you know, why isn't it just a day 28 time point? The reason is because as you can see from those response curves, in many cases, the response continued even beyond day 28.
We wanted to make sure that we were capturing in those tables the maximum response we were seeing during that day 28 to day 42 period.
Just to add one thing, we've shared all the data, so obviously everybody can go and analyze and interpret, as they wish.
Great. Appreciate the clarification. If I could ask a quick follow on then.
Sure.
When it comes to the partnership with Sanofi, is there the scope for development beyond AD and HS? At what point do you think decisions around more indications could be made? Is it possible to hear kind of updates in the near term, or do you think it's more likely that we see updates from the first set of phase 2 programs and then there's new indications nominated beyond that?
That's a great question, Vikram. First, I'll take an opportunity again to thank the Sanofi team for really making this decision very, very quickly. I'm not gonna go into the days, but very quickly. It speaks to the quality of the data and probably less to us. With regards to indication, I think what we were able to say today is that clearly HS and AD, and obviously you've seen the data, are the priority indications. I believe that this data are only telling us that this pathway is clearly relevant in potentially a wide variety of diseases, given that even in this very complex one, we have such a rapid effect.
I will say that obviously I can't speak for Sanofi, and we haven't addressed the broader prioritization yet, but I would say that these continue to be the top two and, you know, and we've officially communicated that. I would confirm that the first study will start in 23. Again, we're being vague about 23 because we're still working on the transition. I am confident that with early traction we will continue to expand, but those are conversations we'll have to have with Sanofi and officially communicate.
Okay. Understood. Thank you for taking my questions.
Thanks.
Thanks, Vikram. Operator, can we have the next question, please?
Yes, sir. The next question comes from Eric Joseph from J.P. Morgan.
Hi. Good morning. Congrats on these data. Yeah, a couple questions from us. On safety, Excuse me, with KT-474 and QTC, can you just sort of talk about the percentage of patients that experienced some degree of prolonged gradation and whether there are any noteworthy trends by either baseline health or concomitant med use? I guess, do you anticipate either down the road the need for a thorough QTC study at all or, you know, potential contraindications?
Just looking forward, is there much you can share today in terms of how broadly within AD, HS, Sanofi might look to further understand the activity profile, whether it's both in sort of biologic naive or perhaps also biologic experienced patients, they might look to understand the activity profile of KT-474? Thanks.
Thanks, Eric. Maybe I'll take the second question first, and then I'll let Jared answer the first one. On the second question, you know, I have a strong view on that, but we haven't had that discussion with Sanofi yet. Just bear with us. We will discuss more details of the phase II design once we have discussed and aligned, and then we will officially communicate both on how we design the study and then how we position it on the market. The only thing I will say that we are looking at this drug as a potential best-in-class oral option. I would imagine that this will be developed with that idea in mind.
With regards to the first one, the only thing I wanna clarify before I pass it to Jared, you know, we have seen this very unique phenotype with QT that seemed to kind of appear and peak at day seven, and then now we've learned that kind of slowly then eventually naturally goes back to baseline with continued dosing. This is something that before we learned this, we already thought it was something that we could manage and was de-risked. Now with this data, it's even more de-risked. We're thinking less about, you know, the impact of this now we can say transient QT effect. I wanna kind of the medical kind of opinion from Jared on this.
Yeah. Maybe, you know, Eric, you know, the QTC prolongation that we saw was really sort of a group effect. You know, it's not occurring in just one or it selects subjects based on their baseline characteristics. That's very similar to what we saw in the healthy volunteers. In fact, you know, the magnitude of the effect also was quite similar, and really no relation to sort of baseline, you know, characteristics. Overall, you know, quite comparable, in terms of this sort of group effect when you see this delayed prolongation that's sort of modest and peaks at around day seven. Also now with part C, you know, for the group, seeing the spontaneous resolution with continued dosing beyond day 14, and then what appears to be resolution down to baseline, you know, by day 28.
You know, in terms of your question around, you know, ThoroQT, we don't think that there would be a need for a ThoroQT study. We've discussed this with various cardiology consultants. The fact that we identified, you know, this somewhat atypical sort of QT prolongation in phase I in healthy volunteers in a study that, you know, fairly extensively now would really probably, you know, obviate the need to have a ThoroQT study. I think what will be important, you know, over time in phase II, is to continue sort of monitoring this on an outpatient basis with regular ECGs, hopefully to show that this spontaneous resolution, you know, to baseline at day 28 persists when we go into 12 and 16 week phase II studies with longer term dosing.
Thanks, Eric.
Operator, next question, please. Thank you.
Sure. Next question comes from Bradley Canino from Stifel.
Great. Thanks, great to see all the multipronged progress today. I guess for KT-474, I'm curious about the HS patients that received prior biologics. Did that impact the results on KT-474? Just overall, there was a bit of variability in the gene transcription data and in the cytokine levels. Did that correlate at all to skin measurement outcomes for patients?
Jared, do you wanna take this one? Thanks, Brad.
Yeah. Yeah. Yeah. Thank you. Brad, your first question before the skin question, just repeat that again just so I make sure I understand what you wanted to have answered.
There were four patients in HS that had received prior biologics, and I'm wondering.
Right. Right. Got it.
If that impacted their results versus the others.
Got it. Yeah. I mean, overall, you know, it was interesting. There were only a very small number of patients actually who did have prior biologics. In AD, there weren't any. Then in HS, there were three patients. You know, interestingly, the two very severe patients that came on the study both had had, you know, prior adalimumab, which is an anti-TNF. One of them had also, after progressing on anti-TNF, had also then had anti-IL-17 and another, a 2nd anti-TNF. I think what we saw that in those patients with very severe disease who had, you know, proven somewhat refractory to prior biologics, the responses in those patients were not the same sorts of good responses we saw in the other patients.
That might reflect the fact that with a much greater inflammatory disease burden, that it might have required a longer period of dosing with KT-474 to be able to see an impact with the drug. I think that's something that will have to be explored, you know, in future trials where there probably will be more patients perhaps who might have had, you know, prior therapies, and we can further understand that.
The other question was about, the t-gene transcripts and cytokine.
Oh, yeah, the gene transcripts. Well, I think, you know, we were very pleased in skin. I mean, we're recalling that, you know, we were using RNA-seq to look at a variety of different gene transcripts in skin, comparing baseline levels to day 28 levels. We were not expecting that every patient would sort of have the same sort of response. You know, what we showed was that in the majority of patients, you know, genes, you know, in 50% or greater of patients, we actually saw, you know, had this sort of a response. We are seeing a fairly consistent effect across the patients in these particular genes that were of great interest to us because they were disease relevant genes. We do expect to see some variability in these sorts of biomarkers.
To us, what was consistent was the fact that you're seeing multiple disease relevant genes in AD and HS being impacted. You see a majority of patients within AD and HS, you know, showing an impact for each of these individual genes. For an initial small study with a relatively small data set to be able to show that sort of a consistent effect on inflammatory biomarkers in the skin, and for that to then be seen in conjunction with these impressive clinical responses in the skin, both in reduction in skin lesions, but also very importantly, reduction in symptoms like pain and itching, you know, further to us provides the internal consistency that provides that connection between the biomarker effects that we're seeing and then the translation of that into clinical activity.
Yeah. I mean, I just wanna add a small part. I think the fact that we see an impact on these gene transcripts versus baseline is telling us that in both HS and AD, again, as Jared said earlier, the pathway is activated, this has never been shown in this way. I think maybe this is the least kind of maybe the least the data set that we're paying less attention, but I actually feel is the one that should warrant more attention because this is actually saying that the pathway is activated in HS and AD in blood and skin, which nobody has shown before, that this drug can impact with more than 90% inhibition of those inflammatory genes in the skin.
It's not surprising that we have an impact in both scores and symptoms. That's the point of today's presentation.
Hey, thanks, Brad. We probably got to move to the next question. Operator?
Sure. Our next question comes from Chris Shibutani from Goldman Sachs.
Thank you very much. Appreciate you taking the question. How do you think the data that you've seen so far informs potential dose selection strategies across the two indications? I'd be curious to know what data points you think in particular might be guiding as we think about the next stage of studies. Secondly, perhaps one for Bruce. With the Sanofi decision coming here in December, congratulations. Can you just help us from a housekeeping modeling standpoint, how we should think about a potential milestone, the payment timing, when you would record that? Maybe to extend that further, what implications does this have on your thinking about further business development opportunities across the platform? Thank you.
Thanks, Chris. Just on the, on your first question, it's a great question, actually. I think what we learned from this study, from that plot with all those dots that we tried to kind of summarize it quickly in 1 slide, was that the PK/PD relationships between basically compound concentration in blood and degradation in blood, is conserved between healthy volunteer and patients. Now we have a 25, a 50, a 75, a 100, and 200 mg dose. 4 of them are, you know, fast and 1 is fed, to model phase 2 doses. That's how we're basically looking at the data.
The phase 2 dose or doses, more likely, will be refined as we look at the analysis. I can tell you in my head I have numbers, but obviously we need to align with Sanofi on what those numbers are and then disclose them publicly. Maybe Bruce, on your second question.
Chris, on the milestone, we've been somewhat apologetically a little vague in the past about the specific triggers. We did disclose this morning that there will be a milestone on the first patient dose in the first phase 2, and then those milestones would scale based on the number of indications they pursue up to a certain number. We just haven't said, and probably won't yet say, what that number is, but you can assume that the first patient dose will trigger that first milestone. I know he asked about BD. I don't know.
Yeah. How does that impact? How does today impact Kymera's trajectory? If I can paraphrase your questions, Chris. I think a lot, but not so much driven by the milestone from Sanofi. I mean, that would be meaningful, and it would be great when it happens. I think what I'm most happy about today, as somebody that, you know, founded this company six years ago, is that the validation of our platform, our target selection strategy, of our discovery team, of our translational team, and of our clinical development team on actually pulling together what protein degradation can do, and validating it, allows us to dream probably bigger than we had done before.
I think the validation that you can go after these targets that are not drugged or drugged well, like IRAK4, and showing that you can see... I mean, I don't wanna debate numbers today on the clinical endpoints because to me, that's not the numbers we should debate. If you look at the totality of the data, as I said earlier, it's clear that we see a clinical effect across these indications. This is already showing that our target selection strategy that we've been talking about for 5 years on IRAK4 was the right one, and probably this will become a huge drug. This allows us to do more. We have our oncology programs that, you know, STAT3, IRAKIMiD, MDM2, there is small molecules. We have a biological hypothesis that we're superior.
I think I feel a lot bolder, that, you know, we know what we're doing here on differentiating targets. Our preclinical pipeline, we have programs like IRAK4, maybe even bigger than IRAK4, and we feel bolder than we felt, you know, a few months ago. That's the reality of it. BD is part of the tools that we'll use to build a fully integrated global commercial stage biotech company. I'm sure we will do that at some point, I'm not sure that today's data changes that aspect. It changes on how we're kind of thinking about where this company can go.
Thanks, Chris.
Great. Thank you. Appreciate it.
Our next question comes from Ellie Merle of UBS.
Hey, guys. Congrats on the data. Thanks so much for taking the question. Just in terms of, like, the different patients, and I know it's a small numbers, but were there any predictors of response, I guess, of the patients who showed greater EV reduction in AD or in HS who, say, achieved, you know, the HiSCR75 or had a greater AN count reduction? And then in terms of thinking about the study designs, in HS and AD going forward, if there's any color you can provide maybe in terms of the patient baselines and anything you're thinking about in terms of patient selection. Thanks.
Yeah. Do you wanna take the first one?
Yeah. I think, you know, because it's a small study, Ellie, it's hard to really look at or really sort of come up with predictors of response. I think we were very actually pleased to see that the majority of patients with either HS or AD were responding. Yes, there might have been some differences in magnitude of response, but overall, there's a very consistent effect.
On multiple clinical endpoints in almost all the patients in HS and AD, that corresponded with the impact we were seeing on IRAK4 levels and the impact on inflammatory biomarkers. Again, I think it's encouraging that we see that sort of a global, consistent effect, really not a large enough study for us to sort of retrospectively go back and look at precise predictors of response. As I mentioned, you know, majority of AD patients had not had prior biologics. The same case with the HS patients, with just a small handful having prior biologics. In terms of study design for phase 2, I mean, Sanofi obviously will be driving those study designs, you know, with certainly some input from us as well.
You know, there are different things one can think about when thinking about the patient populations. I think certainly there will be moderate to severe patients. Some of the subtleties come down to how much prior therapy do you permit on your study, or which prior therapies do you allow? Those will be things that have to be sort of worked out. Ultimately, you know, on these studies, you wanna have a somewhat real-world population and not be too overly selective, in order to really see what sort of activity the drug is capable of with longer-term 12 and 16 week studies.
Yeah, I mean, maybe just one quick thing to add. you know, in AD every patient responded, and in HS, almost every patient responded. I think that's another important thing to keep in mind. I think it's fair to say, Jared, correct me if I'm wrong, but where we saw most activity, you could definitely see this broad anti-inflammatory effect in the skin or in blood that correlated with, you know, good degradation. There was that. It's just that we can do analysis on such a small number of-.
Yeah. I mean, fortunately, almost all the patients had that profile, which is great. That's sort of a nice problem to have, you know, everybody's showing a nice response, you know, in terms of the target degradation, the inflammatory biomarker response, and then clinical response. Yes, there are always going to be some gradations of clinical response. I think the clinical response, it's also important to look at it in its totality. I mean, I can't emphasize more of the importance, not just of the impact on skin lesions, but on symptoms. You know, in HS, pain is overwhelmingly what impacts quality of life. In AD, itching is what overwhelmingly impact quality of life.
To be able to really have the sort of fairly substantial large impact we had on those symptoms in addition to skin lesions, I think is something that we really wanna highlight because it is so important, not just to us and to patients, ultimately, it's also important to regulators because they wanna see with drugs that they want to approve in the future, are you affecting how patients feel and function? If you're gonna do that, you got to affect those sort of symptoms that are driving quality of life for those patients.
Just a quick follow-up.
Go ahead, Ellie, if you have a quick one.
Just a quick one on the kinetics. I mean, you've alluded to you're still understanding them and maybe just your thoughts on your current hypothesis on if you expect the responses to deepen from here. I guess any learnings from the cohort where you're exploring dosing, I think it's a couple times a week or every other day, in terms of what you're thinking about dose frequency and the kinetics. Thanks.
Yeah. I think on the kinetics of responses, obviously, we dose only for four weeks. It's hard to imagine that if you dose longer, you won't see more responses. I mean, it's really hard for us to imagine that. What I said, and I think we can stand by it, we don't know where we are on that response curve. You know, some biologics, they or some therapy, at four weeks are relatively close to their maximal activity. Some other drugs are far away. In reality, we don't know where KT-474 is. The fact that we see, if you see the curve, which I think I encourage everybody to look at, the curve of responses is a clear, it's clearly telling you, look at the steepness of that curve.
You know, we look forward to seeing where the curves end up at week 12 or week 16. With regards to infrequent dosing, as we said, you know, we never discussed that study design. It was brought to us from, you know, people that obviously pay attention to ClinicalTrials.gov. We said that we would share if there was any meaningful learning. There's nothing to report today. There's nothing on either PD or safety that we feel like needs to be shared at this point. At some point, we'll probably have it. I know the team is writing a publication. Maybe it will be in there. At some point, we will share. Today we wanna focus on the patient cohort and understand all the totality of data we're sharing today.
Thanks, Ellie. Operator, next question.
Great. Our next question comes from Michael Schmidt from Guggenheim.
Hey, guys. Congrats on the data, and thanks for taking my question. I actually wanted to switch gears and ask a question about KT-333. You know, on this phase I study, just remind us what tumor types you're enrolling and talk about your expectations for potentially seeing single agent activity at dose level three and four next year. Also, you know, how should you think about the potential of this drug in fibrosis? You know, what level of knockdown, for example, would be necessary in that, in that application, and what are your plans there? Thanks so much.
Jared, do you wanna take that first one?
Yeah, sure. In terms of tumor types, Michael, we're enrolling essentially, you know, solid tumors and lymphomas, you know, for phase I dose escalation. As you saw in our slide, you know, we've enrolled of those four in that 1st dose level, there were three solid tumor patients and one with cutaneous T-cell lymphoma, cutaneous T-cell lymphoma being one of the target patient populations. You know, we're encouraged by the fact that we're seeing levels of knockdown and persistence of knockdown that suggests we're starting to get closer to target levels of knockdown and persistence that in our preclinical models translated into efficacy in STAT3-dependent malignancies.
You know, now that we have more sites up and running and activated, especially sites that have cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and LGL leukemia, we're now starting to pivot to make more of an effort to find those patients, to start to bring those patients on, you know, to the next dose level, dose level two and dose level three, where we expect we might start to see the level of degradation needed for activity. We wanna really start exploring, at least preliminarily, in our target patient populations.
Your other question about outside of oncology, I think maybe the easier way to answer that is, you know, we will give a maybe we'll do a real R&D day next year. This is more of a development day. We will talk about some of the other programs that we're advancing, and that particular question might be answered there.
Great. We're gonna try to pick up a little speed here and go to the next question. Thanks, Michael.
All right, our next question comes from Geoff Meacham from BofA Securities.
Hey, guys. Morning, thanks for the question. Congrats on the data. You guys evolved from mechanism to phase 2. Do you think the clinical effect could be more pronounced, in the more severe, you know, HS or AD patients? Is there a threshold level of IRAK4 degradation that you think you need to achieve, you know, that would sort of suggest a clinical effect? A follow-up on QT. I mean, would you guys characterize it maybe at a high level, you and your experts, this as kind of a non-issue now going forward? Or, you know, I just wasn't sure of the level of kind of a monitoring that you'd have to do in future studies. Thank you.
Thanks, Geoff. Those are great questions. Actually, maybe I'll touch on the second one, and then maybe Jared can take the first one. I think what we said before the study when we just had a 2-week study where we saw this self-limiting plateau, the fact that because it was in a very subclinical range and did not seem to be dose or concentration dependent, we thought that was a manageable profile that would allow us to develop and commercialize the drug. I think now with the fact that it resolves and it's basically a transient effect, I feel that, you know, your characterization, at least maybe it's the way I feel, but obviously we have to continue to monitor it to make sure, as Jared said, that this resolution is maintained.
We have no reason to believe that that would not be the case, but, you know, there'll be some more, you know, due diligence to do before we can, you know, put it behind us. Maybe Jared, on the first one.
Sure. Yeah, on the phase 2 population, you know, I think, you know, almost certainly it will continue to be moderate to severe. What the breakdown between moderate and severe will be sometimes depends on how you set up the study and the sites that you're using. I think we do wanna continue to get experience in patients with, you know, severe as well as moderate disease, where we think we should be impactful based on what we've seen so far in phase 1. You know, in terms of threshold levels of knockdown, that's always a good question. It's always somewhat hard to answer.
You know, in terms of level of knockdown in the blood, what's encouraging to us is that if we look at that sort of 3 nanogram per mil threshold that we showed to give us at least 80% knockdown or greater, we know we're at, you know, sort of trough levels, at least with the dose that we brought into part C that's well above, you know, those levels that give us at least 80% knockdown. I think that we'll probably wanna be at a dose that's giving us at least that amount of knockdown, if not more, hopefully in the 90% range, somewhere in that range, you know, in phase II.
In the skin, we are very pleased to see, you know, that knockdown to healthy levels or even below healthy levels, given the fact that levels are even higher, twofold or more higher in HS and AD skin lesions, tells us that knocking it down to at least healthy levels or below is giving us a real impact on inflammatory biomarkers and importantly, an impact on clinical endpoints. I think we know that in skin, we wanna be able to see that sort of, that same level of knockdown in order to sort of see clinical efficacy. I think we have some, a pretty decent sense, you know, from what we've learned in part C in terms of the type of knockdown that we need.
Now it's just a matter of phase II of maintaining that, sustaining that now, not just for four weeks, but out to 12 and 16 weeks, and to see, you know, what the kinetics and response looks like and just how deep those responses can be.
Thanks, Geoff.
Fantastic.
We can go to the next question. Thank you.
Sure. Our next question comes from Timur Ayvazov of Raymond James.
Yeah. Thanks very much for taking the question. Just maybe just a few quick housekeeping questions in the HS. Can you just talk about the type of care patients receive from day 28 to day 42? A second part of the question, just more of a general question. In terms of your positioning for KT-474, are you intending the drug to be positioned before biologic use or after biologic use, or, you know, in combination biologics? Thank you. Thank you.
I want to take the second one. Thanks, Timur. These are both great questions. Jared can maybe get ready on the first one. It's too early for us to say positioning, right? I think that the goal is to go into phase 2 studies to look at broader patient population. Again, as I say, personally, I feel that this drug has the potential to be first-line therapy, based on the safety and the activity profile. I don't see a reason why it wouldn't be. It's early. My statement hopefully will continue to be correct in the next few years. That's just my personal view today. That's to be honest, what we hope to get to.
You know, these markets are so large that even positioning in a different context will still result in multibillion-dollar drug. I think right now, from what we know today, I think there's no reason to believe that this drug couldn't be a first drug that people take in those indications.
Your question on day 28 to day 42, even though dosing has stopped, those patients are still on study. They're still being followed, you know, for clinical endpoints, for PD biomarker endpoints, even for PK. And essentially, those patients, you know, remain on just, you know, our drug alone. In order to be valuable, you know, they're not able to go on to any other therapies during that continued observation period.
Thanks, Timur. Next, operator, can we go to the next question, please?
Our next question comes from Mike Kratky of SVB.
Yeah, hi, everyone. Thanks for taking our questions. Congrats on the data. I guess on efficacy in atopic dermatitis, you know, did you assess any other metrics such as EASI-50, 75, 90? Curious how those compared. Just one housekeeping one. Can you confirm that patients were not allowed any rescue therapy or topical corticosteroids here?
Yes. I think in terms of your question around the EASI score, we really did sort of the straightforward % reduction in EASI, but we did note that we had patients whose EASI scores changed or reduced as much as 67%-76%. Recalling that, you know, we're talking about an N of 7, which makes it harder, you know, to do multiple different sort of EASI permutations.
On the second question about rescue therapy.
Oh yeah, on the rescue therapy. Really similar to what I just answered previously, you know, for HS, patients were not allowed to go onto concurrent medications throughout that 40-day period. You know, if they were to go on anything, they would then not be evaluable anymore.
Great. Thanks, Mike. We're gonna.
Thanks.
Thank you. We're gonna try to get through as many of these as we can in the next five or so minutes. Operator?
Our next question comes from Kelly Shi of Jefferies.
Congrats on the great progress and thanks for taking the question. Just curious, we saw greater cytokine reduction in the patients in the healthy volunteer cohort. Have you observed any impacts on the level of the cytokine reduction in the patients who actually experienced the prior biologics? Also, just quickly for KT-333, are you planning to screen patients on the hyperactive STAT3 signaling pathway? Thank you.
The first question was... Sorry, the... It was not clear...
When patients experienced the prior biologics, have you observed any impact on the level of cytokine reduction?
Cytokine reduction.
Yeah. In those patients who received prior biologics, we actually haven't broken down the response looking at those patients specifically because it was just a small number. That's something that we can go back and do. I do recall that in terms of effect on gene expression in the skin, we did see a very profound effect on gene expression in the skin on at least one of those patients who'd had prior biologic therapy.
Yeah. The other question was, are we doing pre-screening for KT-333 to look at where the pathway is activated in the clinical trial? I guess the answer is no.
Yeah, no, we're not doing any pre-screening of that sort.
Great. Thanks.
Our next question comes from Zisheng Chu of Baron.
Great. Thank you very much. Two quick questions from me. First, on the, on the headache as a SAE, I wonder if you can provide a bit of color there. I think the signal was also observed in, you know, healthy volunteers study as well. Secondly, on your two oncology programs, I know it's early, but both of them show some the recovery of target engagement. I guess, would that be a positive in terms of safety, or would that be read as a you need more dosing, more dose there to further?
Yes. The oncology first, then Jared can comment on the safety. I just wanna correct, it was not an SAE, it was just an Adverse Event, the headache. Jared will correct it. I couldn't help myself. On the oncology, the important thing that we wanted to see was the profile of degradation was considered between preclinical and clinical. For KT-333, we need to see degradation of STAT3 for at least 48 hours and then recovery to baseline between 48 and next dose. For IRAKIMiD, reduction of Ikaros and Aiolos in IRAKIMiD for about 72 hours and then return to baseline.
The most impressive thing about those two studies is that we are seeing exactly that, which allows us to believe in those drugs, that once we get to the degradation profiles that are slightly better than these, we're very, very close, we should be expecting clinical responses. The fact that we're degrading Ikaros and Aiolos at 100% with KT-413 and we're seeing recovery as predicted, and we're not seeing neutropenia in those two cohorts, are telling us that all the work that we've done in coming up with the drug, with the dosing paradigm, with the frequency, was all work that actually ended up translating in the clinic. That's, I think, the most impressive data for the oncology that probably today will be not discussed as much as KT-474. Jared, on the headache.
Yeah. On the headache side, as Nello said, you know, there was no headache SAE. We did have headache adverse events. The large majority of them were just mild and self-limiting, not requiring any intervention. There was one subject who had several episodes of severe headaches, that was responded as quickly to, you know, single doses of Tylenol, did not result in any dosing interruptions or discontinuations.
Great. We wanted to get everyone out of here. There's a couple few questions we're not gonna get to, so we'll reach out to you folks after the call. Just wanna thank everyone for joining and turn it over to Nello just for some quick closing remarks.
Yeah. Thanks again for attending today. As I said earlier, I think this data will transform how we think about protein degradation. I think if you look at the totality of KT-474 data, it's telling us it's an active drug in HS and AD. Phase II studies will tell us how active it will be. That's what I would like for you to take home. I think it also tells us that we can select the right target, build the right molecules and build drugs that have huge potential. It also tells us we can do that over and over again. We can do it for 413, we can do it for 333. We should expect that we'll do it for 253 and any other program that is coming from our preclinical pipeline.
We're excited about where we are. We couldn't dream for a better outcome today. I want to thank Sanofi again for allowing us to share their decision today. You know, we're happy to follow up with anybody that unfortunately we couldn't take questions today on the call, today, tomorrow, on whenever is possible. Have a great day and thank you.