Autoimmune and Inflammatory Disease Virtual Conference. Very pleased to have with us Dr. Jared Gollob, the Chief Medical Officer of Kymera Therapeutics. Jared, good morning and welcome. Maybe we can start with a brief introduction of Kymera before we delve into the pipeline questions.
Sure, absolutely. Kymera, we were established back in 2016. We are a targeted protein degradation company. We have now moved 5 programs into the clinic over the last 4 years in both oncology and inflammation. We think we've been very successful in showing the translation of PK and PD and efficacy from our preclinical programs into the clinic across the first 4 programs where we have data, including IRAK4 and our oncology programs. We have pivoted now toward a focus that's largely on inflammation and immunology.
That focus, which is exemplified by the STAT6 and TYK2 programs, for example, comes in part from our early success with IRAK4, but also comes from how we've evolved our TPD platform over time to the point now where we can access these high-value targets like STAT6 and TYK2, which are really critical signaling nodes within highly validated pathways within immunology and inflammation diseases, be it Th2 diseases for STAT6 or IL-17 interferon-driven diseases for TYK2. The unique pharmacology of our degraders now enables us not just to access these targets, but to degrade these targets in a way that can allow for full pathway blockade with oral degraders.
Now we're in the, I think, incredible position of having oral degraders that can block pathways to the same extent as upstream injectable biologics and achieve the same sort of activity, potentially in safety, with oral drugs, which really can be transformative now, we believe, across multiple different indications within immunology and inflammation. STAT6 and TYK2 are sort of the tip of the iceberg. Two programs we're incredibly excited by. We're going to be announcing another program in May and more to come after that, again, focused on going after these highly validated, high-priority pathways in inflammation and immunology and being in the unique position of being able to access these signaling nodes with the unique pharmacology of degraders that can give us that biologics-like activity.
Great. Thanks. Maybe since 2025 is all about STAT6 and TYK2, can you tell us what got Kymera into these 2 programs and why are these of high interest for the company?
Look, I think STAT6 has been of high interest not just to Kymera, but to the big pharma and biotech in general for a decade. Ever since it was clear that targeting the IL-4, IL-13 pathway with drugs like dupilumab were highly successful and really transformative for patients with Th2 diseases, there's always been a great desire to try to find other ways of targeting those pathways, especially with oral drugs, to try to make it more accessible to a much larger fraction of patients.
Once we got our technology to the point where we were able to actually develop degraders to a target like STAT6, that really represented, I think, a real sea change in the ability to target STAT6 and to be able to target it in a way with potency and selectivity and with the degrader pharmacology that would allow us to fully block that IL-4, IL-13 pathway to the same extent as biologics. We see that as a tremendous opportunity, not just to transform the space to patients, but also a very tremendous commercial opportunity. Likewise for TYK2, I think a real aim with TYK2 targeting has been to try to recapitulate the TYK2 loss of function phenotype where patients are protected from multiple autoimmune diseases. TYK2 small molecules have tried to do that, but they really have come up short.
We believe that the degrader technology, our degrader against TYK2, is the way to be able to sort of phenocopy TYK2 loss of function and realize the full potential of hitting the TYK2 pathway to treat autoimmune diseases that can really differentiate substantially from what's been achieved so far with TYK2 small molecule inhibitors. I think these 2 targets really exemplify Kymera's approach in the immunology and inflammation space and how we're trying to take advantage of our degrader technology to really push the envelope and develop transformative drugs.
Great. Maybe that might be a segue for historically, what were the challenges with respect to developing a STAT6 inhibitor? What differentiation approach does degrader bring to the STAT6 program?
I think when we think about proteins that are particularly amenable to the degrader technology to find the right solution, I think we think about transcription factors, which are notoriously difficult to drug potently and selectively. We think about multifunctional proteins with scaffolding function. TYK2 is an example of the latter, STAT6 of the former. I think one of the real challenges in drugging STAT6 was to try to come up with novel ligands that could enable one to develop degraders that would be potent and highly selective for STAT6. I think it's taken a while to develop that technology and evolve that capability. At Kymera, we have been in the forefront of developing degraders against these difficult targets and evolved our platform in a way that now allows us to do this quite effectively.
I think for STAT6, I think that's been the main challenge. What you need to do for STAT6 is not just sort of temporarily or partially inhibit it, but you want to be able to sort of fully block STAT6 sort of 24/7 if you're going to try to match the efficacy of biologics. STAT6 inhibitors can have problems sometimes with selectivity and potency and usually are not able to sort of fully block and inhibit STAT6 24/7. It will probably be very difficult for those sorts of drugs to obtain biologics-like activity. Whereas with degraders, we've shown preclinically we can degrade STAT6 95% plus 24/7 and result in full blockade of the pathway that's comparable to what Dupilumab can do, but with greater potency.
I think that's what's going to be needed to be able to develop an effective STAT6 targeted approach to treating these sorts of Th2 diseases.
Got it. Let's dig into some data. The preclinical data showing comparable efficacy with Dupilumab were perhaps the most important data apart from the picomolar degradation efficiency. Can you tell us the major takeaways from the preclinical data sets and also how good are the atopic dermatitis models with respect to translation in human clinical trials?
Yeah, I think it's a great question. I think that the models for which we've shared data include the house dust mite asthma model, which is really sort of a gold standard Th2 inflammation model that dupilumab has used and shown efficacy in. That's probably one of the best Th2 models out there for showing proof of concept in a Th2 disease. Within that so-called HDM model, we've been able to show that when we give our degrader at a dose that leads to at least 90% knockdown of STAT6, we're able to show activity that's comparable, if not even superior, to what is achieved with dupilumab, which we compare head-to-head within those experiments. For us, that is extremely encouraging.
That is why we sort of set the bar at at least 90% for the sort of degradation we want to be able to achieve in the clinic in order to potentially enable us to match the activity of dupilumab. Now, in terms of atopic dermatitis, there are not really very good models of atopic dermatitis that really reflect what happens in humans. There are various AD models that one uses. We use an AD model that is similar to one that Dupi has used. We went head-to-head with Dupi in that model. Looking at, for example, impact on IgE in that model, we showed again that we have activity that is at least comparable to Dupi.
I think those models, whereas they're not absolutely predictive of what you're going to see in the clinic, they give us a very powerful way of showing what sort of knockdown we need to have activity in those models and also allow us to compare our activity to Dupi to give us a setting to where that bar needs to be in the clinic for the degree of knockdown, the sort of pharmacology we need to be able to reach Dupi-like activity.
Got it. Given the upcoming data, let's talk about some of the biomarker aspects. Historically, IgE and TARC have been used for Dupi trials, but have only seen modest changes in both the biomarkers for healthy volunteers. What are your expectations with respect to these biomarkers? Can baseline biomarker levels predict treatment response? Finally, what are the expectations from the HV trial data?
Yeah, look, I think it's important to understand what the limitations are for various biomarkers that you're looking at in healthy volunteers versus patients. I think for us, from the very beginning, even before we started enrolling onto the phase 1A healthy volunteer study, we were very clear that for us, the number one biomarker is STAT6. And for us, it's to show that we can degrade STAT6 by at least 90% or greater in blood and skin at doses that are safe and well tolerated. Given our preclinical data showing that 90% is where we see activity comparable to Dupi, we believe that if we can show in healthy volunteers that we can achieve that level of degradation at doses that are safe and well tolerated, that greatly de-risks the program and should predict for our success once we move into patients. Now, you mentioned TARC and IgE.
Yes, those are biomarkers that have been looked at in healthy volunteers. They tend to be at normal levels in healthy volunteers. Regeneron, in their paper looking at Dupilumab in healthies and looking at those biomarkers, was able to show some clear signal from noise within those assays for TARC and IgE. They were able to show for TARC, for example, that you could see anywhere from 15%-35% reduction within the first, say, week after dosing, but with no clear dose response. I think that was important. No clear dose response, but you could see a signal. For IgE, in that same sort of timeframe, 7-14 days, they were not able to see much of an effect on IgE, maybe 5% at best or even less, really because there is a longer half-life for IgE.
When we look at those data, from the beginning, we've guided that we do expect to see, hopefully, a Dupi-like effect on those biomarkers, something comparable to Dupi, in addition to showing the hopefully profound, hopefully, impact on STAT6 in blood and skin. I think patients, when we move into phase 1B in AD patients with moderate to severe disease, that will be a much better platform for showing, we believe, more robust effects on Th2 biomarkers in blood as well as in skin. When Dupi has looked at that, they've seen very robust effects on those biomarkers that can then potentially predict for or correlate with clinical outcomes. That is why I think that phase 1B study, which is a single-arm open-label study, is going to be very heavily focused on those biomarkers because these biomarkers rarely move much in placebo groups in randomized studies.
We do not really need a placebo arm to be able to show a robust effect or Dupi-like effect on biomarkers in that phase 1B study, where we will also be looking at clinical endpoints at 4 weeks because that study is only going to be with 28 days of dosing in phase 1B. Again, we think that will allow us an even more robust opportunity to show Dupi-like effect on biomarkers.
Got it. Given several indications planned for the STAT6 program, how are you thinking of running those trials post-POC trial in patients?
I think, as I mentioned, for us, what's most important is accelerating development for the STAT6 621 program, ultimately to get to phase 3 as soon as we can because we believe we have a drug that's going to be transformative in the space. Our phase 1A data is going to allow us to choose the doses that we need for these critical phase 2B studies in AD and in asthma, the AD phase 2B starting in Q4 of this year, the asthma study in Q1 of next year. We think of these as sentinel phase 2B studies, meaning these are going to be the critical dose range finding studies that will allow us to pick the doses that are going to go into phase 3.
For example, you can think of the AD study, the dose that comes out of that phase 2B will enable parallel phase 3 studies, not just in AD, but in other skin diseases where Dupi has gone before, as well as in a disease like EoE, a GI disease. Whereas the asthma phase 2B will allow us to select the dose not just for asthma phase 3, but also for COPD and maybe CRS with NP and other diseases of that sort. In terms of how we prioritize indications, there are many places we can go where Dupi has gone, right, in various Th2 diseases in the derm, GI, and respiratory space. We are prioritizing the larger indications first. That's why these 2 phase 2B studies, which we think are the only phase 2B studies we'll need to do, are going to be in AD and in asthma.
We also anticipate having phase 3 programs, not just in AD and in asthma, but also in COPD to start. Really focusing on the largest indications first and then being able to also move into somewhat smaller, but still very important indications, either in parallel with those or staggered. We haven't decided on the exact approach there. I think that gives you an idea of how we're thinking about prioritizing indications.
Got it. Let's switch gears to the TYK2 program. Even though TYK2 remains a critical regulator considering inflammation, what do loss of function TYK2 experiments tell us about the safety and tolerability profile?
Yeah, I think, I mean, we're fortunate to have human genetics to guide us here. And TYK2 loss of function, complete loss of TYK2 in humans, not only protects from a variety of different autoimmune diseases, especially Th17 and interferon-driven diseases, but these patients also have a fairly minimal phenotype when it comes to risk of infections. You may see some mild viral infections or some mild intracellular infections that are readily treated with antibiotics. These patients don't come down with life-threatening infections. That's probably because even with TYK2 loss of function, there's still some small residual amount of signaling through IL-12 and IL-23 and even interferon receptors that's been shown in various publications that probably does protect against severe life-threatening infections or even moderate infections. We're expecting, again, from the human genetics and from that experience that deep TYK2 degradation over time should be well tolerated.
Got it. Again, similarly, what advantage do degraders have over the current approaches prevalent in the TYK2 landscape?
Yeah, I think that's a really important question, right, because I think there has been some sort of TYK2 fatigue in the sense that small molecule inhibitors have clearly been active and have clearly provided proof of concept and validation for the pathway. They sort of all come up short, these various TYK2 small molecule inhibitors, when it comes to trying to reach biologics-like activity. We think the reason for that is that they lack the depth and breadth of inhibition that one is trying for if you're trying to phenocopy TYK2 loss of function. For example, inhibitors are only able to inhibit the pathway maybe 60%-70%. They're not able to get sort of 24/7 inhibition even at that level. It's more cyclical inhibition that you get with typical small molecule inhibitors.
That's translated into these inhibitors all sort of coming up short with regard to reaching biologics-like activity in diseases like psoriasis. We think the real advantage of our TYK2 degrader 295 is that we've shown preclinically in rodents and in monkeys that we can knock this target down 95% or greater round the clock, so 24/7. No let-up, 95% degradation, and it's kept there. We believe that that should enable us to phenocopy TYK2 loss of function and to do that in a way that is hopefully safe and well tolerated. Importantly, we believe it's that level of degradation and pathway inhibition that will be needed in order to achieve biologics-like activity. Our plan for the TYK2 program is we're going to be starting phase I in healthy volunteers in the second quarter of this year.
We will have a readout by the end of the year. That readout should be able to tell us, can we achieve 95% degradation of the targets sort of round the clock? If we can, that's telling us we're getting pharmacology that should sort of phenocopy potentially TYK2 loss of function. I think the next important step after that would be next year then to have probably a placebo-controlled phase 2 study, probably in a disease like psoriasis, where one can readily assess activity relative to placebo in a reasonable timeframe. There, we would want to see that we have biologics-like activity, IL-23 injectable biologics-like activity in psoriasis to really say, okay, we've got a drug that really is differentiated from small molecule inhibitors, potentially even differentiated from the Johnson & Johnson IL-23 peptide inhibitor.
If we're able to reach that biologics-like activity, which even the J&J compound has not been able to attain, that for us would tell us we want to then move forward probably a multiple phase 3 campaign. It's not necessarily in psoriasis. I mean, maybe psoriasis, but I think we're thinking also about IBD and lupus and other Th17 and Type I interferon-driven indications.
Got it. You mentioned psoriasis. For psoriasis, the standard endpoint has shifted from, I think, PASI 50 to 75 to even 100, raising the efficacy bar for these therapies. Plus, there are 10 other drugs which are approved. Where do you see TYK2 program being a value add to the landscape?
Yeah, I think that's a fair question. I think, as I just alluded to, essentially, for this drug, I think, to add value, we believe we need to be able to show biologics-like activity. Again, I think even the J&J compound, which is a highly active drug and has shown activity recently, not just in psoriasis, but also in IBD, is perhaps a new sort of gold standard for oral drugs. I think it's still falling short. If you look at a disease like psoriasis, you look at PASI 90 levels, it's not quite achieving what you can with, say, anti-IL-23 injectable biologics. I think if we end up wanting to sort of be in that psoriasis space, I think we're going to have to be an oral drug that is able to achieve biologics-like activity.
This is something which has still not been achieved yet, even with the best small molecules. As I mentioned earlier, even though it's possible that our proof of concept phase 2 study might be in psoriasis, we're not necessarily committed to developing first in psoriasis. We might then want to take the drug, and maybe it's possible we could prioritize inflammatory bowel disease or lupus or other indications. We haven't decided yet how we're going to prioritize development beyond initial phase 2 proof of concept. It may or may not include psoriasis initially.
Got it. Going back to KT-621 and IRAK4 program, biological variability has been cited to be one of the biggest limiting factors in AD. With respect to your 621 and IRAK4 program, how have you kind of thought about tackling the variability in the trial design?
Yeah, I think if by biologic variability, you're alluding to the sort of placebo effect that you can see within these AD studies, which maybe attests to that, right? I think it's all about how important it is to select the right patients for your study, to select the right sites and the right investigators to be running your studies, and to have, again, the right eligibility criteria for your studies to try to do all you can to minimize placebo effect. Having very milder patients, you're more likely to see a higher placebo effect than with more severe patients. I think for us, it's going to be important, again, the eligibility criteria that are already out there for the KT-474 phase 2B study in AD. Again, for phase 2B with KT-621, that's still a work in progress.
When we think about approaches that can try to minimize that variability or try to minimize that placebo effect, it is going to be about making sure that we bring patients who really have AD onto the study because AD is a clinical diagnosis. It's not a histopathologic diagnosis.
You really need clinicians who know how to diagnose AD to make sure we have the right eligibility criteria, to make sure we get moderate to severe patients, and to make sure we have clinicians and research teams at the sites who are able to stringently apply those criteria to make sure we are only getting moderate to severe patients on the study, and to make sure we have clinicians and investigators at these sites who are very adept at doing the clinical endpoint measures, whether it be EASI or pruritus NRS, whatever it is that we're looking at, to make sure they're adept at doing those measures and doing them consistently and having an investigator consistently seeing the same patient over time.
All of these, I think, can be important factors that one needs to pay very important attention to in order to try to get the best study possible and try to minimize the sort of placebo effect you're going to see within the study.
Got it. Very helpful. Maybe we can kind of go back to the IRAK4 program. If you can briefly talk about the ZEN and ADVANTA in terms of trial design, endpoint selection, and dosing. Also, what are the key learnings from the historical trials in AD and HS with respect to the 474 program?
Yeah, I mean, both of these studies, these are ongoing phase 2B studies that Sanofi is running. These studies, following an interim analysis, a blinded interim analysis of safety and efficacy last June, were converted from smaller phase 2A proof of concept studies to more expansive phase 2B dose range finding studies to get us more quickly, ultimately, to phase 3 for both HS and AD. Both of these studies were expanded. The patient numbers were almost doubled across both studies. Additional dose levels were added to make sure that these were full dose range finding studies. Both of these studies have all of the classic standard primary and secondary endpoints for HS and AD and the appropriate eligibility criteria to make sure we're getting moderate to severe patients. These studies, the current guidance is for these to read out sometime in the middle of 2026.
I think in terms of other elements of design, just going back to your prior question, right, in terms of how do you try to minimize biologic variability to try to make sure the placebo rate, whether it's for HS or AD, isn't too high, it sort of comes back to those same principles that I just spoke to earlier that Sanofi is also following as they not just in the design of these studies, but also how they operationalize the study.
Got it. That kind of brings us to the last question for today's fireside. With the promise of one target a year, how do you prioritize where to put the focus on as the company expands and the pipeline expands?
Yeah. Yeah, look, I think we're fortunate that we have a platform technology that we've spent a lot of time and money and have brought in amazing people to really evolve that platform into something that we think is sort of unprecedented in the field, which gives us an incredible multiplicity of opportunities to go after high-priority targets with our focus now being on inflammation and immunology. You mentioned one new program a year. I think we say at least 1 new program a year. I think we have the ability to go beyond even program a year. If we stick to that for now, I think the sort of targets and pathways that we're going to go after are going to maintain the sort of approach and philosophy that we've taken for STAT6, for example.
We do not want to take a lot of biologic risk in the pathways we are going after. We want pathways that are highly clinically validated and/or genetically validated within inflammation and immunology so that we are not taking on biologic risk. We then want to take full advantage of the degrader technology and pharmacology to go after key signaling nodes within those pathways where we are confident that if we fully degrade those targets, we can fully block these pathways to the same degree that upstream injectable biologics can block these pathways. We are very confident we can develop oral small molecule degraders that will have the activity and safety of injectable biologics. By doing that across multiple pathways and multiple indications, it can truly be transformative. I mean, we truly believe that at Kymera, we have the potential to have the best oral immunology pipeline in industry.
We have to obviously work for that. I think where we are now with IRAK4, STAT6, and TYK2, and a new program we'll be announcing in May, I think this gives you an idea of our sort of our ambition and our philosophy and our approach and where we expect to go in the future.
Got it. Very helpful, Jared. As usual, great speaking with you. Thanks for giving us time. Good luck with the STAT6 program readout.
Yeah, thanks so much, Edmund. I appreciate the opportunity and all the great questions.