Good morning, and welcome back to H.C. Wainwright's Second Annual Autoimmune and Inflammatory Virtual Conference. My name is Andres Maldonado, and I'm a biotech analyst here at the firm, and it's my pleasure to welcome you to our next fireside chat with Kymera Therapeutics. Today, we're joined by Chief Medical Officer, Dr. Jared Gollob of Kymera. Jared, welcome. It's a pleasure to have you here.
Thanks so much, Andres. Appreciate the invitation.
Great! So, you know, for those investors who are not familiar with the Kymera story, could you give us a brief overview of the company's pipeline and its overall positioning in the dermatology space and beyond?
Yeah, maybe just to try to address it succinctly, you know, we were founded in 2016. We're currently based in Watertown. You know, we are a platform-based company, where our platform is targeted protein degradation, which can include heterobifunctional degraders as well as molecular glues and other means of degrading targets of interest. You know, we are a clinical stage company, so we have a very active research and clinical arm of the company. We've actually moved four programs into the clinic since 2021, including one immunology program, IRAK4, which is currently partnered with Sanofi, as well as three oncology programs. You know, the technology that we're using is disease-agnostic, but I think we've had to date a mix of both oncology and immunology programs.
But a recent, you know, pivot, I think, to even greater emphasis on immunology, you know, based in part on, you know, what we've learned and the success that we've had with Sanofi on the IRAK4 program. You know, in terms of our overall sort of philosophy around sort of approaches in the immunology space and dermatology in particular, I think, you know, we view within immunology, you know, there being a very attractive development space for degraders. Because, you know, within immunology, you have a number of very successful drugs, largely injectable biologics, that have clinically validated a number of key pathways in inflammation, whether it be Dupixent and validation of IL-4/IL-13 pathway, or drugs validating, you know, IL-17 or TNF in diseases like HS.
But I think it's also clear that even though these are very successful drugs in these spaces, they're probably only accessing about 10%-12% of patients with moderate to severe disease, and not even accessing patients with milder disease. So there's still a huge opportunity for more patients to benefit from these treatments, with part of the restriction being either the fact that these are injectables, or for those oral drugs that are out there, some of the safety issues or activity issues.
And we view oral degraders as really a unique approach, or really the only approach, you know, from an oral drug, oral small molecule standpoint, that can actually fully block, you know, these key clinically validated pathways and result in the same sort of activity as injectable biologics, but with the convenience of oral drugs, and hopefully with the same sort of safety profile. So I think there's a real potential for these oral degraders going after the right targets, to really open up a much larger segment of these patients who could benefit from these drugs. Not just moderate to severe patients, but even patients with milder disease. Also open up to more pediatric patients, especially in diseases like AD or EoE, in the Th2 disease space.
And ultimately, even open up more indications that have not yet really been explored or taken advantage of by drugs like Dupixent. So again, I think this, we see a very good match, in particular for the degrader technology in the immunology space for all of the above reasons. And that's why we are very excited about this particular area, and why there's been a pivot in our pipeline to somewhat greater emphasis on the immunology opportunities right now, while still maintaining interest in oncology. And of course, because we're disease-agnostic, continuing to be very aware of other opportunities outside of immunology and oncology, where we can apply the degrader advantage.
Great. Thank you so much for that, overview. So maybe moving on to individual pipeline programs, starting with KT-474, your IRAK4 program. You know, can you discuss some of the limitations with the current standard of treatments for both indications, hidradenitis suppurativa and atopic dermatitis, and how you see KT-474 filling the gap for the current, unmet medical need?
Well, you know, I think, you know, for both HS and AD, there have definitely been really significant advances in the therapeutics being developed, you know, for both of those indications. You know, for HS, you know, the IL-17 drugs have been a great advance. You know, even the JAK inhibitors, though not yet approved, have also been a significant advance in terms of activity. And then in AD, of course, you know, you have, Dupixent-
Mm-hmm.
... you have IL-13-targeted agents and even other oral drugs. I think one of the key limitations here has been the fact that, you know, the dominant drugs are, you know, injectable biologics, which for the most part, are going after individual cytokines rather than having a broader anti-inflammatory effect. I think some of the oral drugs like JAK inhibitors in HS and AD, while they do have a broader anti-inflammatory effect and are quite active, there's significant safety issues, I think. You know, black box warnings associated with JAK inhibitors. And so I think there still is a real sort of unmet need for oral drugs that have a broad anti-inflammatory effect, but with a safety profile that's as clean as some of the most effective injectable biologics to be able to bring into the space.
And as I mentioned earlier, to be able to then open up, you know, the opportunity to be treated with active drugs, with biologics-like activity, to a much larger proportion of patients, a much larger swath of, of indications, and to be able to go even earlier in either milder disease or in pediatric patients. And I think that this is something that we believe that, you know, oral degraders, you know, have the potential to do, and that a drug like KT-474, you know, has the potential to do. It could therefore be a real advantage over, you know, either the IL-17 or TNF biologics, or over drugs like the JAK inhibitors, where again, I think there are safety issues that have to be overcome.
Great, very helpful. So I guess in that same context, for KT-474's, you know, as we start to think about the market, specifically for hidradenitis suppurativa, you know, we're aware that diagnosis, you know, has been an issue in this indication. Could you maybe talk about some of the barriers to accurate diagnosis for HS?
Yeah, I think, I think that this is a really important subject, because HS is one of those diseases that can mimic other diseases or other benign conditions. You know, it's a very, you know, painful, morbid disease, but, you know, people may come in with the disease, and they may be diagnosed with a skin infection or with an abscess, and, and the clinicians may not necessarily be thinking about HS, for this particular patient. And I think, so I think part of this is a physician awareness of the diagnosis. And what usually happens is, is that, you know, the fewer treatments you have that are believed to be transformative, the less the word gets out in terms of awareness and how these patients should be diagnosed.
So you end up having a lot of patients, you know, who just aren't recognized, or they're diagnosed later in their disease than is really necessary. So now by the time they come to clinicians, they've got moderate to severe disease. And if you look at the prevalence, you know, in a disease like HS, I think it's believed to be about or the estimates currently are about, you know, maybe 0.3% of the population in the U.S. and the EU. But if you ask most key opinion leaders in the space, they thoroughly believe that the true prevalence is probably 2%-3% of the population in the U.S. and EU. The problem is just that it's under-recognized.
So I think what will happen, as happens in a number of different diseases, when you start to have more and more effective treatments that are capable of being given to a broader and broader population of patients, the push to increase awareness and to diagnose early is gonna get stronger and stronger. And so we do believe that if we're able to develop, you know, an effective drug like KT-474 for a disease like HS, where you now have an oral drug that can be given to a broader population, if it's highly effective, I think you'll find that awareness, and therefore diagnosis, and therefore prevalence, will continue to increase over time.
Great. So then the next question would be, you know, given the... You know, it would be great for you to talk about the rationale behind the trial design in the context of Sanofi's studies in HS and also in AD, and how they've informed your kind of decision-making, you know, relative to the other competitors in the landscape for the trial design.
So, you know, just as a reminder, for the KT-474 program, you know, Kymera drove the phase I development, you know, with Sanofi's assistance, and now Sanofi really holds the reins and is driving phase II development. You know, a lot of effort went into the phase I program in terms of not just looking at safety and efficacy in healthy volunteers and in patients, but also looking at pharmacodynamic markers to really understand what doses are needed to give us the desired knockdown to maximize the impact on the pathways of interest.
So we really had a very, I think, comprehensive understanding from over 150 subjects on phase I as to what doses would give the desired level of knockdown, which for us is in, you know, in the vicinity of 85%-90% or greater knockdown to maximize impact on the pathway. And so I think when Sanofi then designed these randomized placebo-controlled phase II studies in HS and AD, you know, they had that information available, so they could be more selective in terms of the doses that they brought into those studies. These both of these studies are powered to be able to show an impact of drug over placebo.
You know, both of these are 16-week studies in HS and AD, with the appropriate endpoints to look at, lesion burden and symptoms in particular, you know, pain for HS, and pruritus for AD. So we think that these designs, you know, are, you know, quite good designs to enable in a very straightforward way to understand in these first proof of concept phase II studies, is there activity of our drug in HS and AD relative to placebo? And importantly, with these 16-week studies, you know, what is the safety and tolerability of the drug? And I think both of these studies will be able to answer that question and then provide an important springboard to the next stage of development.
Great, very helpful. I think you touched about it, you know, before, but can you maybe go a little bit more in detail on, you know, the history of, you know, elucidating some of these crucial biomarkers in either AD or HS, and, you know, how they, you know, influence, you know, key decisions on selection of primary endpoints?
Well, you know, I, I think ultimately, you know, in phase II studies and beyond, the proof of the pudding will be in the clinical endpoints. And so I think a lot now is riding on impact on those endpoints. With that being said, I think still one of the crucial biomarkers is just really understanding the impact of the drug on IRAK4 itself. And we've learned that measuring IRAK4 in blood, we can also measure it in skin, but measuring IRAK4 in blood in particular, you know, is a very good biomarker for the pharmacologic effect of our drug and really tells us, you know, are we- do we have the right dose, and are we persistently keeping, you know, IRAK4 down to the level we, we wanna keep it down?
So I think from a biomarker standpoint, showing that our critical PD marker is letting us understand that with the doses we're choosing, we're knocking the target down the way we wanna knock the target down. That information, in conjunction with safety and efficacy from the clinical endpoints, I think really is key. Now, there may be some other things that we do look at within these studies. We may look at, you know, circulating, you know, cytokines, for example, pro-inflammatory cytokines, to see what the impact of our drug is, you know, on those parameters. But I think ultimately, for this current stage of development in phase II, the most important things are the clinical endpoints, the safety, and then confirming PK and PD, you know, that we saw in our phase I program, and showing that we're achieving levels of target knockdown that should translate into strong activity.
Great, very informative. So in the interest of time, let's shift gears to KT-621, Kymera's STAT6 program. So really would be great to get some insight on, given the success of dupilumab, you know, what prompted Kymera to look into the STAT6 pathway?
Well, I think that success was certainly central. I mean, looking at how transformative a drug like Dupixent has been, which is targeting IL-4/ IL-13 receptor upstream, and looking just how it's transformed the treatment of AD, asthma, in the near future, COPD, EoE, and other diseases, it's clear that this has been an incredibly important drug and will continue to be an important drug in treating Th2 diseases. One of the real issues here has been just access to drug. And I mentioned this earlier, the fact that maybe at most 10%-12% of patients eligible to get a drug like this are getting it, because of the restrictions or the problems or just the aversion to injections.
Our desire has been to say, well, if there's a way to open up drugging this pathway to a much larger proportion of patients with moderate to severe disease, and to open it up to milder patients, to pediatric patients, and to other indications, this would be really important way for us to be able to help, you know, the, you know, tens of millions of people who suffer from these diseases. And so that was our interest in STAT6, because STAT6 is a transcription factor, which uniquely only serves the IL-4/ IL-13 pathway. So if we were able to develop a way to selectively degrade only STAT6, we knew we could then selectively only hit that IL-4, the IL-13 pathway, in the same way that, you know, a drug like Dupixent does, but now with an oral drug.
One of the key problems has been that, you know, oral small molecules, it's very difficult for these oral small molecules, you know, where you're targeting key signaling components within pathways like this, it's very difficult for those small molecules to ever match the efficacy of the biologics, you know, where you wanna shut down that pathway completely. And what we've learned from our IRAK4 program, pre-clinically and clinically, and now we're learning pre-clinically for STAT6 and even our TYK2 program, is that a degrader is the one approach that can do that. This is the one small molecule, by degrading a transcription factor like STAT6, that can shut down that pathway to the same extent as an injectable biologic, like Dupixent.
So this has been our great interest, therefore, in targeting STAT6, is that here now we have an opportunity to develop an oral small molecule with the activity of an injectable biologic, like dupilumab, with, we believe, the same safety profile, but now with the convenience of oral administration that could open this up to such a larger universe of patients that can now benefit from this treatment.
Great, that makes a lot of sense. And maybe for some of the investors on the call, can you maybe highlight historically what some of the challenges have been, in the field of, you know, developing a STAT6 inhibitor? It seems like it's a pretty high bar, you know, to really get something that's efficacious and really hits the target properly.
Well, you know, I think when we think about targeted protein degradation and the advantage of the degrader technology, one of the advantages is being able to go after undruggable targets or very difficult to drug targets. I think transcription factors have been traditionally very difficult to drug. These are proteins that rely on protein-protein interactions, protein-DNA interactions. They have phosphorylation-dependent and phosphorylation-independent effects. You know, they're complicated proteins that are difficult to drug with small molecules. So number one, just developing a ligand to a transcription factor is difficult. And then you're developing a ligand to a transcription factor that is highly selective, only for that transcription factor is difficult.
And then being able to drug that transcription factor in a way that is complete enough to be able to shut down the pathway that that transcription factor is serving, is also quite difficult. But we believe that our technology was capable of doing this, and we have developed now a very potent degrader of STAT6. This is a small molecule that degrades STAT6 with picomolar potency, which is almost unheard of in the small molecule field. It is highly selective for STAT6. If we look at 11,000 different proteins in the proteome-
Mm.
... we are only degrading STAT6. We know that STAT6 is very selective for the IL-4/IL-13 pathway, and we know in our hands, when we compare our degrader to an inhibitor of STAT6, only the degrader can fully block the IL-4/IL-13 pathway the same extent as Dupixent. So we really feel that this is an approach that requires a degrader, and that being able to develop a degrader against STAT6, you know, was not an easy task, but now we have, you know, a very beautiful drug in terms of its potency and selectivity, that we think now can really unlock this pathway, in a way that an inhibitor of STAT6 just is not going to be able to do, to give us that biologics-like activity, and a safety profile that is, you know, similar to Dupixent.
'Cause I think in the immunology space, it's incredibly important that one have a very clean safety profile.
Great, very helpful. And then I guess, again, moving on in the interest of time, let's move on to Kymera's KT-294 program, your TYK2 inhibitor program. So, even though, you know, TYK2 remains a critical regulator, considering inflammation, you know, what do a lot of the loss-of-function experiments tell you about, the target safety and tolerability profile?
Yeah, I think this is an important question, because these, you know, human loss-of-function, you know, mutants, so to speak, you know, are very informative in terms of the tolerability of being able to hit a target. This has been the case for IRAK4, for example. So we know that there are IRAK4 patients who have mutations leading to complete loss of IRAK4, and we know that in early childhood, they are susceptible to getting certain bacterial infections, but by adolescence and young adulthood, they no longer have that susceptibility to infections. That gives us a lot of confidence that we can knock that target down hard, without there being, infection liabilities.
In TYK2, we know that the loss-of-function variants in TYK2 result in near full, but not complete abrogation of signaling through the IL-12, IL-23, and type one interferon pathways, which is important, because that near full blockade, you know, is able to very effectively, you know, block inflammation that's being mediated through those pathways. But by not 100% blocking those pathways, one is not at risk for clinically significant or severe infections. So we know that these loss-of-function humans can have some infections. They can have, you know, relatively mild, atypical mycobacterial infections, or they could have herpes simplex infections. So there is some susceptibility to intracellular and viral infections, but these are usually mild in severity and readily treated, or they just readily resolve on their own.
So we do think that that is very helpful in our understanding that we can hit this target hard, engage this target with a degrader, degrade it by 90%-95%, 24/7, essentially, and maybe have some risk of mild infections, just as you see with TYK2 small molecule inhibitors. But we believe that we will have superior activity in diseases, because our ability to fully engage or near fully engage those critical IL-12, IL-23, and interferon pathways is superior to what other drugs can do. And what's also very important is that we spare the IL-10 pathway.
So drugs like SOTYKTU, because they, in reality, are not really selective for TYK2, they also hit the JAKs, they end up blocking the IL-10 pathway, and that can be detrimental when it comes to treating diseases like inflammatory bowel disease, where you need IL-10 for mucosal healing. So really, only a TYK2 degrader can truly recapitulate loss of function, where we're, you know, hitting the 12, 23 interferon pathways, but we're sparing the IL-10 pathway.
Great. That was very helpful. So, you know, maybe to dive a little deeper into some of the advantages of degradation for TYK2, curious if you could highlight... Obviously, specifically, you know, you're hitting the target, you're degrading it, you're getting it out of the pathway's ability to signal, but are there advantages in terms of maybe dosing or, you know, the safety-efficacy ratio that you plan on to leverage in later clinical studies? If you can highlight those, that would be helpful for us.
Yeah, you know, I think, I think there's a similar sort of approach here, as I just described, you know, for STAT6, which is that, you know, in order to achieve biologics like activity, so if we think about TYK2, if we think about a disease like psoriasis, and we think about the IL-23 injectable biologics, you know, the sort of PASI 75s and PASI 90s that you see with SKYRIZI, it's been really impossible for any of the oral TYK2 inhibitors to reach that level of biologic activity. And that, I think, you know, has consequences, not just for being able to match that activity in psoriasis, but it also appears to be a predictor for whether one is gonna be active in diseases like inflammatory bowel disease, and maybe even potentially lupus, maybe to a lesser extent.
And so I think what's important, again, you know, when we think about a TYK2 degrader, is, you know, we want to be able to hit these pathways as hard, essentially, as an injectable biologic, like an IL-23 antibody. And it's only by having that degree of blockade of the pathway do we think that we can achieve that level of activity in a disease like psoriasis, for example. And so for us, you know, for us, a daily dosing paradigm, where we're able to degrade TYK2 by greater than 90%, you know, our preclinical data tell us that we should have activity that is comparable to the injectable anti-IL-23 biologics, for example.
That level of pharmacologic engagement, where you're keeping the target down to that extent 24/7, so even in between doses, you're still blocking that pathway by 90% or greater, that's the only way we believe you're gonna have biologics like activity. And if we're able, for example, to establish that level of activity, you know, in psoriasis, number one, we would be very competitive with the injectable biologic, but now we have an oral drug, that should have a comparable safety profile.
But it also, I think, bodes well for our being able to move into other areas like IBD, where, you know, again, you know, there could be a real advantage to having this IL-10 sparing, while still having this very potent and complete effect against these other pathways that would allow us to be, you know, highly active and still safe in these other disease areas that include, IBD, but also the interferonopathies, which include lupus and other interferon-driven diseases.
Great. No, that's very helpful. Maybe touching upon something you just mentioned, you know, obviously, for psoriasis, the standard endpoint has, you know, shifted from PASI 50 to 75 to even a 100. So, you know, as, you know, investors are looking to, you know, understand market dynamics, you know, in a very crowded environment here, you know, where should they be focused on key points of differentiation for your TYK2 program, you know, positioning it in a defensive or offensive position, you know, in the overall landscape, which has been very crowded over the past couple of years?
Yeah, I think that's a, that's a great question, and I think... Look, I think ultimately we want our TYK2 degrader to be active across multiple different key indications that are driven by IL-12, IL-23, interferon, which includes, as I mentioned earlier, psoriasis, IBD, lupus, and others. I think it's very important, you know, if you're gonna develop an oral drug in this space, that you need to be as active or close to as active as biologics. Now, one could argue that if you have an oral drug that maybe is not quite reaching the level of activity of biologics, but is still safe and well-tolerated, that could still be a very impactful, transformative drug for patients. And I think that's true, whether it be STAT6 or TYK2.
But I think, you know, given our current expectations, you know, having an oral drug that is as active as biologics would clearly differentiate this from the other TYK2 small molecules. And then also having additional biologic differentiation, so sparing IL-10 would differentiate it from the BMS TYK2. I think having strong activity against the interferon pathway would distinguish it from the Takeda TAK allosteric inhibitor, which is more selective for TYK2 against the JAKs, but because it still has scaffolding function, is also not as strong against the interferon pathway as, say, TYK2.
I think here we have a drug that could encompass all of those key features you'd want to see in a small molecule degrader, biologic differentiation when it comes to diseases like IBD and lupus, and pharmacologic, strong pharmacologic engagement, where we should at least be as active as the, you know, best injectable biologics. I think if all of that is realized, I think this drug, you know, will, could be very transformative and should be, you know, best in class when it comes to TYK2 targeted, oral small molecules.
Great. You know, very helpful again. And, you know, my last question, I would be remiss if we didn't ask, you know, on a macro level, you know, where do you see... You know, as you look across autoimmune and dermatology indications, where do you see the biggest surprises coming from the targeted degrader space over the next five years? Whether that be inroads in biomarker analysis, inroads in more, potential indications, or maybe some kind of novel engineering that you see for the field that might open the world of degraders up more. Just curious on your broad, thoughts there.
Yeah, it's a great question. It probably requires a longer time to fully answer it. But what I will say is that I think, and maybe this shouldn't come as a surprise, but it might, I think the versatility of degraders is gonna be key over the next five years. Because, you know, degraders are not just so-called PROTACs or heterobifunctional molecules, they're obviously, they're molecular glues. Now they're extending to, you know, so-called extracellular TPD, you know, LYTACs, you know, being able to degrade extracellular proteins. Or also being able to develop degraders that are tissue-specific, tissue-restricted, you know, targets that are of great interest in immunology, but you only want to hit that target in a B cell, you don't want to hit it in T cells or in other types.
Being able to restrict the cell types where you're having your effect, being able to degrade extracellular proteins like IgG or IgE or IgA. You know, being able to use molecular glues that may now allow you to go after targets that, despite your best efforts, still remain unliganded, so you can't apply heterobifunctionals. But now molecular glues give you a handle on getting other into other undrugged targets that now open up more opportunities. I think this is going to be the future, you know, both in the autoimmune, autoinflammatory space, but in the multiple other sort of therapeutic areas where I think, you know, degraders are gonna be touching and hopefully, you know, establishing new standards.
Great. Well, that's all the time we have. I'd like to thank Dr. Gollob and Kymera Therapeutics, you know, for participating in our conference. Congratulations really on all the progress you've made over the course of the year, and we look forward to future updates. Thank you very much.
Yeah. Thank you, Andres. Thank you for all the great questions.