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

Good morning. I'd like to welcome everyone to Kymera Therapeutics conference call. [Operator Instructions] The call is being webcast live on the Investor and Media section of Kymera's website at kymeratx.com. This call is the property of Kymera Therapeutics and recording and reproduction or transmission of this call without express written consent of Kymera Therapeutics is strictly prohibited. Please note, the call is being recorded. I would now like to hand the call over to your host today, Bruce Jacobs, Chief Financial Officer. Please begin.

Good morning, everyone, and thank you for joining us today on our call to discuss the new KT-474 Phase I clinical trial data that we released this morning at the TPD Summit. These data are summarized in a press release that we issued this morning. Additionally, the press release and the presentation slides used on this call can be found on the Investors section of our website at kymeratx.com. Starting on Slide 2 of the accompanying presentation. During today's call, we will make forward-looking statements, including statements about our expectations, plans and time lines for clinical development, reporting of clinical trial results and planned regulatory activities, the potential success of our development efforts and product candidates, including the potential for approval and future commercial launch and other projections and expectations regarding our business and other upcoming events. Actual results may differ materially. The risks and other factors that could cause actual results to differ are discussed in today's press release and in the Risk Factors section of our most recent quarterly report on Form 10-Q filed with the Securities and Exchange Commission and other reports filed with the SEC. Any forward-looking statements represent our views as of today only. We may update these statements in the future, but we disclaim any obligation to do so. With me on the call today are Nello Mainolfi, Founder, President and CEO; and Jared Gollob, Chief Medical Officer. We will begin the call with prepared remarks before opening up the call for a Q&A session. I would now like to turn the call over to Nello.

Thanks, Bruce, and thank you, everyone, for joining our call this morning. Another big day for Kymera and for targeted protein degradation. In fact, this morning, at the TPD summit that is actually still ongoing, we presented data from the single-ascending dose portion of the Phase I clinical trial of 474 -- KT-474, demonstrating not only degrade proof of mechanism. But even more importantly, proof of biology, for the first time in targeted protein degradation in a randomized, placebo-controlled, healthy volunteer study. I just want to highlight a few things. So we show that KT-474 has achieved and exceeded the Phase I target degradation of 85%, reaching now up to 96% degradation after just a single dose. Furthermore, we demonstrated that this degradation has a profound effect on downstream relevant biomarkers with up to 97% inhibition of multiple disease-relevant cytokines. Importantly, KT-474 was well tolerated across all dose groups. So the ability to reach such a profound depth of degradation and to achieve biomarker impact after just a single dose goes above and beyond our expectations, these are, we believe, groundbreaking data, and we're really excited today to share them. This is a particularly significant as we expected to be able to reach this level of degradation and downstream biomarker impact only upon multi-day dosing. So as the multiple ascending dose or MAD component of our trial is still ongoing, we look forward to sharing those results before year-end. We believe that the data shared today demonstrate that KT-474 has the potency as we said, up to 96% degradation, the specificity, the PK and safety profile that we believe will allow this drug to potentially be a best-in-class small molecule oral anti-inflammatory agent. KT-474 has the potential to play a very important role in a landscape where there is an acute need for safe and broadly active small-molecule oral drugs. These results are also a key step in derisking KT-474's development as well as a key platform proof of concept, demonstrating that our team and Kymera's platform and discovery engine can generate highly potent orally active, selective and well-tolerated drugs. As a result, we're very excited about our 2 lead oncology programs and the rest of our discovery pipeline with this type of data as a backdrop. I'm also excited for the several opportunities to share Kymera signs at this year's TPD Summit. By the end of the conference, in fact, we would have participated in 5 presentations in which not only are we sharing new data but also our drug development principles and specifically, how one develops degraders in immunology and inflammation as well as in oncology. Titles and times of these presentations can be found in our PR from earlier today. So I want to turn to Slide 3. I just wanted to remind everyone of current Kymera pipeline. We've been focused on key pathways and key targets that will allow us to fully capitalize on the power of the technology to pursue translational hypotheses that cannot be addressed by other modalities. This includes focusing on a drug or not fully drug protein targets, where TPD is the only unlock in technology within disease pathways with a high degree of validation. Our investments in the IL-1R/TLR pathway with our IRAK4 and IRAKIMiD programs and in the JAK/STAT pathway, with our STAT3 program are examples of this target selection strategy. These are all first-in-class targets, each with large franchise potentials in key validated pathways with strong human genetics and human pharmacology data. So we're looking forward to initiating clinical trials in oncology soon and advancing these transformative therapies to patients in need with this novel mechanism. We will be providing updates on this in the upcoming weeks, but our plans remain for both programs to achieve IND clearance by year-end and initiate clinical activities shortly thereafter. We're excited about other pathways and programs consistent with our drug development principles, several of which we have not disclosed, actually, all of which we have not disclosed yet. In fact, I would say that more than 50% of what Kymera is working on is not disclosed in the slide that you're seeing here in front of you. We expect to have more updates on our new programs and initiatives in the coming months, some of which we plan to share when we host our R&D day later this year. I don't want to take any more time from Jared and his presentation of this new and exciting data from our KT-474 Phase I study. So I'll pass it on to Jared.

Great. Thanks, Milla, and thanks for joining us today. I will start on Slide 4 and to remind you why we decided to invest in the IL-1R/TLR pathway and specifically in IRAK4. IRAK4 is a key component of the myddosome complex that mediate signaling through IL-1 receptors and toll-like receptors to stimulate production of multiple pro-inflammatory cytokines and chemokines. Since downstream activation of NF-kappa B as well as MAP kinase is dependent on both the kinase activity and scaffolding function of IRAK4, degraders of IRAK4 have an advantage over kinase inhibitors and being able to more completely block the IL-1R/TLR pathway. Clinical validation for targeting this pathway comes from the clinical activities of antibodies targeting IL-1 family cytokines 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 healthy and do not exhibit susceptibility to infections. Turning IRAK4 forward 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. Some of those opportunities are shown here, including 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 and asthma, which are among the indications that we and Sanofi are initially prioritizing for our IRAK4 program. Compared to an IRAK4 degrader, antibodies targeting cytokines or cytokine receptors are potentially limited in their efficacy by virtue of hitting only 1 or 2 cytokines in conditions where multiple different cytokines or chemokines are driving the inflammation. Furthermore, they cannot be dosed orally. Small-molecule inhibitors like the IRAK4 kinase inhibitors, even though they are showing positive early safety and efficacy in the clinic, have limited impact on the pathway. JAK inhibitors on the other hand, while having a broad anti-inflammatory effect, have safety liabilities that may complicate broad applications. Our orally active IRAK4 degraders can provide a unique solution to all of these challenges. Moving now to Slide #6. IRAK4 expression in autoimmune diseases can provide further insights into its role in disease pathophysiology. In a non-interventional study examining the expression of IRAK4 and inflammatory biomarkers in hidradenitis suppurativa, or HS, we showed that IRAK4 protein measured using immunofluorescence and mass spectrometry with upregulated in active skin lesions and perilesional skin relative to healthy subjects. As shown in the panels in the middle and right part of the slide, immunofluorescence demonstrated IRAK4 upregulation in both the epidermis and dermis of HS skin lesions relative to healthy subjects. Moving to Slide 7. Additionally, as shown here in the heat map on the left, we found that multiple pro-inflammatory gene transcripts were upregulated in HS skin lesions, including MYD88 and toll-like receptors, IL-1 beta, TNF alpha, IL-6, IL-8, interferon gamma and multiple additional drivers of inflammation. Importantly, as shown in the heat map on the right, all of these upregulated genes correlated with IRAK4 protein expression. So I've shown you in these 2 slides that IRAK4 can be overexpressed in sites of inflammation in IL-1R/TLR-driven autoimmune disease and that there is a critical link between IRAK4 and the pleiotropic inflammation seen in HS, suggesting that IRAK4 targeting with a degrader should downregulate expression of these pro-inflammatory genes and thereby impact the severity of disease in HS patients and in other diseases dependent on IL-1R/TLR pathway activation. On Slide 8, here, we want to remind you that KT-474 is a very potent and more importantly, also a very selective compound, which is biologically superior to the clinically active IRAK4 small-molecule inhibitor from Pfizer as shown in this assay, where LPS plus IL-1 beta were used to activate the pathway and where KT-474 was the only agent able to effectively block that type of inflammatory activation. Moving to Slide 9. The anti-inflammatory effect of KT-474, and its superiority to IRAK4 kinase inhibitors was also shown in vivo in various mouse models of inflammation. This slide shows the effect of KT-474 on IRAK4 levels in whole blood and on measures of inflammation in intradermal challenge models using IL-1 family cytokines, including IL-33 and IL-36 and in a model of Th17-mediated multiple sclerosis. In these models, KT-474 outperformed an IRAK4 kinase inhibitor and was comparable to either potent corticosteroids or standard-of-care antiinflammatory drugs at doses achieving greater than equal to 85% IRAK4 knockdown in blood. Similar activity was observed in the mouse MSU gout model driven by TLR4 activation and in the imiquimod psoriasis model, driven by TLR7 and 8 activation. On Slide 10, the effect of daily dosing and the PK/PD relationship for KT-474 in dogs is shown here. Following 7 days of dosing, the extent of IRAK4 knockdown in both PBMC and skin was substantially greater at lower doses compared to knockdown after the day 1 dose, resulting in 85% or greater reduction in the blood and lowering to undetectable levels in skin. PK/PD analysis at the top dose showed that the greater IRAK4 knockdown 24 hours after 7 days of dosing was associated with higher trough levels of KT-474 in blood and skin compared to 24 hours after the first dose. Consistent with the higher steady-state drug levels predicted following multi-dosing based on the half-life in dogs. These results are important to keep in mind when we show the PD effect of single doses of KT-474 in the Phase I SAD portion and anticipate achieving similar effects with substantially lower doses in the MAD portion that uses a once-daily dosing schedule. Moving to Slide 11. Robust systemic knockdown of IRAK4 with daily dosing of KT-474 for 2 to 4 weeks with well tolerated in rats and dogs. Here, we show IRAK4 reduction to undetectable or near undetectable levels in multiple tissues, including PBMC, skin, spleen and lymph nodes, following 14 days of dosing in a dog non-GLP tox study. KT-474 was well tolerated at all doses up to 100 mg per kg and in rats at all doses up to 600 mg per kg. This absence of safety findings in animals with a systemic knockdown of IRAK4 were consistent with the human genetics showing lack of clinical phenotype in IRAK4 all adults. So far, I have shown you our rationale for selecting this pathway in this target with a greater advantage and our preclinical data pointing to specificity, safety and superiority over small-molecule inhibitors. Now I will dive into our clinical data. The ongoing Phase I study of KT-474, represents several important firsts for clinical trials with heterobifunctional degraders, including the first trial to include healthy volunteers, the first trial for a drug in development for inflammation immunology indications that includes a cohort of patients with autoimmune diseases, and the first randomized placebo-controlled study. The use of healthy volunteers in a randomized placebo-controlled design enables us to compile one of the most robust human safety and PK/PD data sets in the TBD field. The randomized placebo-controlled portion of the study in healthy volunteers with 6 to 2 randomization of active drug to placebo are comprised of an SAD portion, which is now completed dose escalation after enrolling 7 cohorts as well as a parallel staggered MAD portion consisting of 14 daily doses of drug that is continuing to enroll. Following completion of the MAD portion, the recommended Phase II dose will be tested in an open-label MAD cohort of patients with hidradenitis suppurativa or atopic dermatitis and to confirm PK and PD and show impact on inflammatory disease biomarkers in vivo. In addition to safety and PK, the key endpoints in the SAD include IRAK4 knockdown and PBMC and ex vivo response of whole blood to TLR agonists, while in the MAD portion, additional PBMC points include IRAK4 knockdown and skin as well as effects on scan and/or blood biomarkers of inflammation. I'll now turn to presentation of the results from the SAD portion of the trial. As shown on Slide 13, we enrolled a total of 57 subjects across 7 cohorts at single oral doses ranging from 25 to 1,600 milligrams. The median age was 38, and approximately half of the subjects were female. We are pleased to demonstrate as others have done before us, that our heterobifunctional degraders, in this case, KT-474, exhibit PK profiles very much in line with traditional small molecules. Plasma PK showed a half-life of 25 to 40 hours, a Tmax of 7 to 24 hours and dose-dependent increases in exposure, which plateaued after 1,000 milligrams. This PK is consistent with our plan to administer KT-474 on a once-daily dosing schedule. On Slide 14, profound dose-dependent IRAK4 degradation was observed in PBMC using mass spectrometry establishing proof of mechanism for KT-474. This slide shows absolute IRAK4 protein levels over time as low as percent reduction from baseline. IRAK4 reduction was seen as early as 8 hours following dosing on day 1 and with maximum degradation occurring by 48 to 72 hours, shown here at day 3 to 4. At the top 3 dose levels, absolute IRAK4 protein levels approached or exceeded the lower limit of quantitation or LLOQ for the highly sensitive mass-spec assay. In fact, because we have so many subjects who exceeded the LLOQ with the mass spec, IRAK4 peptide used to report results last June, which posed challenges to our ability to accurately assess the percent knockdown of IRAK4, we transitioned to an alternate peptide that further increased sensitivity of the assay with a lower LLOQ. IRAK4 degradation following a single dose was maintained for at least 6 days with recovery to our baseline occurring between day 7 and 14. Intrasubject variability was quite low, especially at the higher-dose levels. Going to Slide 15. Here, we show the mean and median percent reduction from baseline for IRAK4 at the nadir 48 hours post dose across each of the dose levels. The placebo group includes placebo subjects pooled for each of the 7 cohorts. A steep dose response is apparent with the largest change seen at 75 milligrams followed by smaller but significant incremental increases in knockdown in subsequent cohorts, plateauing after the 600-milligram dose. Remarkably, at doses of 600 to 1,600 milligrams, mean IRAK4 knockdown was 93% to 96%. As mentioned before, because of the PK of this drug, we expect to achieve these profound levels of degradation at much lower doses in the MAD portion of the study. On Slide 16, IRAK4 reduction in PBMC was also shown by flow cytometry with results for absolute mean fluorescence intensity change over time and percent change from baseline, mirroring what was seen using mass spec. With flow cytometry, we observed a similar percent reduction of IRAK4 in circulating monocytes and lymphocytes shown here for the SAD 7 cohort. While baseline levels of IRAK4 were higher in monocytes compared to lymphocytes, KT-474 treatment resulted in reduction approaching the LLOQ of the assay for both cell subsets. Turning to Slide 17, in ex vivo, cytokine stimulation assay was used to establish proof of biology in the most direct manner by demonstrating the impact of IRAK4 lowering in PBMC in vivo on the ability of TLR agonists to stimulate myddosome dependent pro-inflammatory cytokine and chemokine production in whole blood ex vivo. Whole blood samples were drawn predose and at various time points post dose into true culture tubes containing either LPS at TLR4 agonist or R848, a TLR7 and 8 agonist. After overnight incubation, supernatants were separated from cells and then analyzed for multiple disease relevant cytokines and chemokines as shown in the figure. As shown on Slide 18, inhibition of ex vivo cytokine stimulation was associated with IRAK4 knockdown in PBMC of greater than or equal to 85% at 24 to 48 hours post dose. Results for LPS and R848-induced cytokines in the top 2 dose levels are shown here as mean maximum inhibition at 24 to 48 hours compared to pre-dose baseline. These 2 cohorts were the only dose levels where we obtained samples for cytokine analysis at both 24 hours and at the 48-hour nadir. Broad inhibition of multiple cytokines and chemokines, including IL-1 beta, IL-6 and TNF alpha, IL-8, IL-12 and IL-17, among others, was seen for both LPS and R848, with maximum inhibition of up to 97%. It is noteworthy here that this profound impact on cytokines was seen after just a single dose of KT-474. These findings with both TLR4 and TLR7 and 8 agonists were consistent with the robust in vivo activity of KT-474, associated with greater than or equal to 85% IRAK4 knockdown in preclinical models of gout in psoriasis that are driven by TLR4 and TLR7 and 8 agonists, respectively. On the next slide, blinded safety analysis showed that single oral doses of KT-474 from 25 milligrams up to 1,600 milligrams leading to substantial IRAK4 knockdown for at least 6 days post dose were safe and well tolerated with no serious adverse events. The most common treatment-related adverse events deemed possible or probably related by investigators were mild to moderate headache and GI symptoms that were self-limited. In summary, we have completed SAD dose escalation in the KT-474 Phase I trial and shown that we can safely achieve plasma exposures leading to marked sustained IRAK4 reduction in PBMC that translates into broad and potent inhibition of TLR-stimulated cytokines and chemokines, including those involved in Th1, Th2 and Th17 inflammation as well as neutrophil chemotaxis and activation. This represents the first proof of mechanism and proof of biology for a heterobifunctional degrader in a placebo-controlled study. These findings support the potential for KT-474 to become a well-tolerated, best-in-class oral anti-inflammatory drug with broad activity across multiple autoimmune inflammatory diseases and continue to provide strong validation of Kymera's platform and discovery engine. As shown on Slide 21, dose escalation is ongoing in the healthy volunteer MAD portion of the trial, where we anticipate maximizing IRAK4 knockdown at substantially lower doses on a once-daily dosing schedule as shown in preclinical models. We plan to present MAD results later this year and are on track to complete the healthy volunteer MAD by year-end. The MAD patient cohort will begin enrolling early next year, and we currently plan to share those data around mid-2022. Thank you for your attention, and we are now happy to take any questions.

[Operator Instructions] And our first quesiton coming from the line of Brad Canino with Stifel.

Great presentation here. Jared, if the thesis for degradation being better than the inhibitor is that you remove the myddosome complex and its ability to activate NF-Kappa-B even when that IRAK4 kinase domain is inactivated, then I guess which of these cytokines is most closely related to NF-Kappa-B? Because I'm just trying to get a sense for if we can learn anything about the differential biology of the degrader with these cytokines or if this is more confirmatory of what we already know about the IRAK4 activity?

Yes, thanks for the question. In our in vitro work, the impact that we've seen of a degrader compared to a kinase inhibitor is really across multiple different cytokines. So when we show that the greater advantage when we're taking PBMC and we're stimulating them with TLR agonist in IL-1 beta in vitro, when looking at readouts which might be IL-6, there might be TNF. They might be IL-1 beta et cetera, really across the board, we really see a greater impact on multiple different cytokines when we're using the degrader compared to when we're using the kinase inhibitor. I think it's because NF-kappa-B really is the dominant signaling pathway here, downstream of the myddosome along with MAP kinase. I mean IRAK4, 5, 7 does have some impact. But really, the two dominant pathways are the others, which is why I think you have the sort of context independent impact of a degrader across multiple different sort of inflammatory stimuli and affecting multiple different cytokines, whereas when you use a kinase inhibitor, across maybe a few cytokines and it's much more context dependent. You see the effect more with weaker inflammatory stimuli and less so with stronger stimuli.

Okay. That's helpful. So I guess for a follow-up, can you also explain why these cytokine responses are based only on TLR agonist? Does it have something to do with the cell type that you used? And are you going to be looking at agonizing the IL-1 receptor and potentially the combo both when you do the MAD and the other cell types?

Yes. Yes. So in the SAD, we focused on the TLR agonist just because it gives us a very broad look at the effect we're having on this myddosome pathway by looking at essentially 2 different TLR agonists that are going through different TLR pathways, TLR4 and TLR7/8. And we were very happy to see this very broad effect across multiple different cytokines in response to both of those stimuli. We have added IL-1 beta as another stimulus in the MAD for the ex vivo cytokine response. We actually didn't have that assay validated in time for the SAD, so we added it into the MAD. So for the MAD, you'll see the data both for these 2 TLR agonists as well as for IL-1 beta. But again, our expectation is that these are all going through the same pathway. They're all going through the myddosome pathways. So impact on TLR4 signaling impact on TLR7 signaling that tells us that we should see robust effect on IL-1 beta. And in fact, we have seen that in our in vitro studies.

I think -- this is Nello here. I just want to add one point. This is actually the first time that anybody has shown ex-vivo cytokine stimulation inhibition with an IRAK4-targeting agent in a Phase I study. And I think while -- I mean, your question, we're very, very actually interesting and insightful. But I do want to make the point that seems such a breadth of activity with 2 different stimuli that actually organize the pattern in very different way with a dose that is really well tolerated. I think it's really telling us that we have some great potential here. But obviously, the MAD data would be quite relevant.

Yes. One other thing I want to add also is when you're stimulating with toll-like receptor agonists, you are actually inducing the production of cytokines like IL-1 beta and IL-6 and others. So in the system where we're activating with the TLR agonist, we're actually also essentially looking at the response to IL-1 beta as well because IL-1 beta is being produced in that system. And so you have -- essentially, yet you're stimulating with LPS or R848, but you've also -- because you're doing that, you've also got IL-1 beta being produced, and that's been activating to the IL-1 receptor. So all that's happening at the same time in these TLR agonist systems. And so you shouldn't think of this as well, we only looked at TLR agonist, and we really don't know what happens with signaling through the IL-1 receptor. I think that this reflects, in many ways, signaling through both of those receptors.

Our next question coming from the line of Eliana with UBS.

Just in terms of the Phase II dose selection, can you elaborate a bit in terms of what your bar for tolerability will be for the go-forward dose? And I guess, how you're thinking about defining maximum degradation given you're seeing protein degradation, multiple days after the single dose? And yes, how you're thinking about tolerability as well as defining I guess, MAD degradation?

Thanks, Andy. So I'll start and then I'll pass it to Jared. This is Nello here. So the way that we're going to select the Phase II dose is based on our MAD study in which we will do this molecule for 14 days once a day and look at degradation of IRAK4 in blood and skin impact on downstream biomarkers. Again, we've seen some of them already, and we'll see more data before the end of the year. So we -- what we expect to see is a degradation of IRAK4, there is at least 85% or more as the data shown today that has a downstream impact on relevant cytokines. We don't expect, although we will see once we generate data, that safety will be something that will be dose limiting. I mean everything that we've seen so far as you saw reported by Jared in our slides are pretty mild findings that are possibly are probably treatment-related because this is still a blinded study. And if you know this, they were not even seen on the top dose and only on 2 of the cohorts. So based on this benign profile that actually reached 7 days of degradation, not just 1 day, as you know, from our regulation profile, we expect that we'll be able to pick our dose based on PK/PD and downstream cytokine and not be limited by tolerability at least at our expectation going into our MAD study. Jared, do you want to add anything?

No, no, I mean I agree with everything you said, Nello. I mean I think ultimately, it boils down to that, that we truly believe that in the MAD portion, we'll find out that we need a substantially lower dose of drug given daily to optimize the PD that we want in blood and skin, and that will ultimately be the dose that we'll take into the final patient portion of the Phase I study.

Yes. Maybe it's fair to say that the range that we're exploring in the MAD is much tighter than the range that we've seen here, and our top dose is much lower than the top dose of the SAD. And we know when we take our data that we've generated in humans from the SAD, the PK, the PD and we put that into our modeling. Our modeling tells us that we should be able to achieve these sorts of levels of degradation which then should translate into these effects on cytokine induction with substantially lower doses given daily in the MAD.

Our next question coming from the line of Michael Schmidt with Guggenheim.

Just one more on cytokines. Just could you help us contextualize the ex vivo data that was reported today and to what degree does that correlate with potential in vivo changes. And then again, how will those changes derisk the various applications for the drug?

Yes. Yes, great question. I mean I think importantly, what we've seen is that 85% or greater degradation of IRAK4 in peripheral blood mononuclear cells is what we need to see this sort of impressive impact on the ability of toll receptors to induce all of these various cytokines. I mean, for us, what's really important here is the fact that we're using 2 different TLR stimulus LPS and R848, and looking at not just 1 or 2 cytokines, but we're looking at 8, 9 different cytokines. And these are all very disease-relevant cytokines that are driving Th1, Th2, Th17 diseases, which often have sort of mixed sort of pleiotropic cytokines involved in the pathogenesis. And so seeing this broad effect across all of these different cytokines, including very deep inhibition of these cytokines following a single dose of drug associated with 85% or greater degradation, that's much -- very much in line also with our mechanistic models of inflammation in animals where we've also shown that 85% or greater degradation has an impact on these modules of IL-33 and IL-36-driven inflammation or these models of TLR4 or TLR-7 inflammation. And so I think we have this very nice connection between the amount of degradation we need in vivo in these healthy volunteers that translates into a real ex vivo effect on cytokine induction and the same level of degradation that we need in these mechanistic models of inflammation in animals that translates into anti-inflammatory effects in those models.

Yes. And I think it's important to note that many of the cytokines that we have in the table here have drugs that have big impact on diseases going from psoriasis to array to us and many other indications. So the fact that we're able to impact a broad set of these, really sets this molecule up for going in multiple diseases and hopefully having the deep impact that we want to see in a broad variety of diseases. And so both the preclinical data showing that the impact on some of these cytokines has impact on disease-relevant models and now this early clinical data through ex vivo activation confirming that this pathway, it does have a profound effect on these kind of pleiotropic inflammation really makes us quite confident that going into a disease setting next year, we should be able to see substantial effects.

That makes sense. And then the follow-up, I guess, how do you think about selection of a potential recommended Phase II dose down the road in terms of balancing perhaps on one side, maximizing target degradation and perhaps on the other side, choosing a dose that perhaps meet your threshold but maximizes the safety of the therapy.

Well, I think as Nello mentioned before, fortunately, we haven't really seen any sort of safety hurdles here. Again, the human genetic is telling us that we can essentially get rid of IRAK4 in adults without there being safety consequences. -- the fact that in our preclinical GLP tox studies and animals, we essentially eliminate IRAK4 for multiple different tissues, and we don't see any safety signals. And the fact that here, with 7-plus days of deep knockdown of IRAK4, we're not seeing any safety signals. We don't think safety is going to be sort of a rate limiting here. And so really, for us, the most important thing is to knockdown IRAK4 enough to maximize the effect on the signaling pathway. And this sort of a readout, the cytokine readout, which is the most direct way to really understand whether the IRAK4 knockdown we're achieving in vivo is having the optimal or maximal effect on this pathway is through this sort of an assay where we do this ex vivo cytokine induction. And so I think the dose we want to take into Phase II is a dose that is achieving levels of IRAK4 reduction that are going to be maximizing inhibition of this pathway as shown by the sort of a readout where you're looking at the various cytokines and chemokines that are really driving the diseases that we want to treat. Ultimately, in Phase I, once we finish the MAD portion and have a recommended Phase II dose, we then plan on bringing that into an open-label cohort of patients with HS and AD, so we can really then confirm that whatever that dose is, yes, we're seeing the same level of IRAK4 degradation in blood and skin, we're impacting inflammatory biomarkers in the skin and blood, and we have confidence that, that dose is the dose that we need to see clinical impact when we go into Phase II studies in these patients.

And our next question coming from the line of Geoff Meacham with Bank of America.

You have Alex on for Geoff Meacham. Thank you for taking my question and congrats on the data. So just a couple of questions from me. Why didn't you guys see a dose-dependent response for IRAK4 change? Do you think that's just because you've hit the maximum level of degradation -- And next, where are you guys expecting to release the MAD data? Is it going to be at a medical conference or a Science R&D Day?

Yes. So I'm not sure I followed the first question well. So I'll try and answer, and if I didn't get it well, you can -- you have the chance to ask it again. So we do see a nice dose responsive effect of degradation of IRAK4 in circulating PBMCs. In reality, once we reach 600 mg, we reached the lower limit of quantitation of our assay, which is highly sensitive, as Jared said, when we shared the data in June, we were using a different peptide with a bit less of a tighter window. We had to actually go back and use a peptide that had even a lower limit of quantitation. And so then what you see between 600 and 1,600 , you have to almost look at that as complete IRAK4 degradation that we can measure up to 96%, 95%, 94%. So we don't expect that there is anything less -- actually less there to degrade. That's why it seems that it's plateaued. On the -- on your second question, we will be announcing in the next few weeks, the venue in which we will share the MAD data. So stay tuned.

Our next question coming from the line of Marc Frahm with Cowen.

Congrats on the data. Maybe just to follow up a little bit on the dose response. When you did the whole blood assay, did you test lower doses than just blood from patients with dose level 6, particularly maybe the 75-milligram dose that's reaching levels of inhibition that's more into the small molecule IRAK4 inhibitors. And what's the dose response seen?

Yes. So we've taken blood and then the ex vivo experiment for the activation of cytokines with those agonists and the nadir only at the last 2 cohorts. That's because at the nadir of 48 hours. And that's mainly because what we did in the early time points where in the early doses were early time points in which we weren't able to capture the high level of degradation. And then in fact, we actually had to switch time points of detection once we understood that this molecule behaved with the later near that we initially had anticipated -- And to be honest, we didn't even expect to reach this level of such a deep degradation. So for us, this ex vivo cytokine, we didn't have really high expectation in the SAD. And then once we started seeing that we were reaching this really deep may 48 hours, we shifted the time of collection. We started collecting at 48 hours and 24 hours. And then we saw this the side of an impact. So then when we go into the MAD study, obviously, there, we will reach steady state. So we wouldn't have this problem of time of detection, but it will be at the -- I believe, day 7 and day 14, Jared, that we will look at. So we would have reached steady state of degradation at that point.

Okay. That's very helpful. And then maybe just as a follow-up, either for Jared or Nello. Can you put this cytokine activation assay data kind of in the broader context, not just of what's been seen with other IRAK4 molecules but other pathway, other things like IL-4 inhibition JAK inhibition that are clearly very active once we've gotten to patients?

Yes. Yes. It's a good question. I think this is probably, at least someone that I've seen probably one of the most comprehensive sort of ex vivo sort of cytokine inhibition sort of experiments performed, where we're looking at multiple different stimuli, and we're looking at multiple different cytokines. I'm not aware, for example, with the Pfizer compound, they really haven't shared for the IRAK4 kinase inhibitor from their Phase I study, any data showing any ex vivo cytokine inhibition. So we don't even know if they ran it or whether they ran it and they just didn't see anything, but we haven't seen those data. And I'm not aware of there being those sort of data for JAK inhibitors. We have seen some data for there's a novel MK2 inhibitor, which presented some data that also did show some ex-vivo cytokine inhibition, that's affecting the P38 Mount kinase pathway. But even in there, the number of different cytokines and chemokines that they looked at, we're less than what we're looking at here. So I think it's probably fair to say this is probably the most sort of robust data set. With regard to all of these different cytokines that are disease relevant and the multiple stimuli looking at it ex vivo. I don't think you'll find this sort of a comprehensive data set with other compounds.

Operator, I think we just have time for 2 more questions, if you would.

Our next question coming from the line of Vikram Purohit with Morgan Stanley.

So just one, quick one from our side. So on Slide 5, you've laid out a few more indications as potential disease areas to explore with 474 then I think you've alluded to previously. So I wanted to see, just based on the data you're seeing coming out of the Phase I study here. If you have a sense at this point about whether any of these indications are more appealing to prioritize versus others when you look beyond HS and AD?

Yes. Thanks, Vikram. That's actually a great question. Thanks for picking that up. So actually, based on the Phase I data, we've had. As you know, this is a program that we will codevelop with Sanofi from Phase II and beyond. And I'm not speaking for them today. I just want to be clear. But I can tell you that we've had further conversations with our partner. And clearly, there is a expanded excitement to explore this mechanism even beyond the early indications that we've disclosed. But I think it's realistic to expect that this will be done in a stepwise approach. I think already the initial investment is substantial going into these large indications in a parallel or probably slightly staggered manner. So it's probably unrealistic to expect that we're going to go with 6 indications from the get-go. -- but it's likely impossible that in probable, I should say, that we will expand quite quickly, assuming that the molecule continues to behave well in later stages of still early development.

Now last question coming from the line of Ted Tenthoff with Piper Sandler.

And really comprehensive data set. And Jared, great job of the actual Summit presentation earlier this morning. I thought there were some great questions associated with that. Most questions have been asked and answered, but I wanted to get a sense if from any of your modeling you can start to correlate these knockdowns and the cytokine activity to potential clinical scores, appreciating, a, this is novel biology; b, we're still very early here? But just as you're starting to do modeling, where do you think this puts you in comparison to some of the other programs in the disease areas you're thinking about?

I think the key thing, Ted, is really coming back to this broad effect that we're having across all of these different Th1, Th2, Th17 cytokine but just selectively degrading IRAK4. We talk about having an oral anti-inflammatory drug with a broad effect. And so I think here, when we sort of compare it to sort of other approaches, now when we look at our mechanistic in vivo models of inflammation, we also see the sort of broad effect across multiple different models, in diseases that are IL-1 receptor TLR driven many, many diseases, including the ones that are on Slide 5 that we've talked about. And so I think that this tells us is that having this sort of a broad anti-inflammatory effect across all these different cytokines should allow us to really have an impact clinically on diseases that are known to be driven by these cytokines, including diseases where monoclonal antibodies picking on individual cytokines have shown to have activity and clinically validated this pathway. Well now saying, okay, well that's been clinically validated. But now we're able to pick off not just 1 or 2 cytokines, but multiple cytokines. And many of these diseases are really never driven by just 1 or 2 cytokines. And so I think that combination of the in vitro data, the in vivo data and that overall arching approach tells us that we should that overall that this does derisk, we think the probability of success in the clinic in these sorts of diseases.

Thanks, Ted. Maybe as in closing, I'll just like to just maybe close with a few thoughts. And I apologize for everybody that didn't get to ask questions. As you guys all know, we're available off-line obviously, anytime you know us where we make ourselves available. So feel free to reach out to us for any follow-up. I just want to say a few things. First of all, I want to thank the team here at Kymera for continuing to execute flawlessly I think it's not -- obviously, we're still a young company. And this Phase I study is one of the most comprehensive, and I would say, sophisticated study that I've seen, maybe I should just say recently in direct development, the type of assets that we've developed, again, you guys have not seen us presenting Western blot data ever because we like to show you quantitative measurement of proteins for which -- which we do through all sorts of more quantitative as you've seen us report on ex vivo and you see us in the MAD study report on many more even, I would say, nuanced assays to continue to expand our understanding and derisking this program. So I want to thank Jared's team, especially I know the preclinical group for doing what they do every day. I also want to just capture what I think we've learned today, I think what we've learned is this mechanism and this molecule has the potential to be the best-in-class anti-inflammatory drug. The ability to knock down the protein to a lower limit of quantitation, the ability of this knockdown to have such a pleiotropic effect. The ability to do so in a very well-tolerated manner and also our ability to project that in a multi-day dosing paradigm, which you will see before the end of the year, we are confident that we should be able to do this at much lower doses. I think really the -- we have really high expectations from this drug. And I know you do too. And so we're really excited to continue this discourse with all of you as the year progresses towards even more transformative data with our MAD data set. So I want to thank you again for the time, the questions again, we're available throughout the day and in the next few days.

Ladies and gentlemen, that does conclude our conference for today. Thank you for your participation. You may now disconnect.