Good morning. I'd like to welcome Kymera to this fireside chat.
This one.
at the Guggenheim Conference here. My name is Michael Schmidt. I'm one of the biotech analysts, and I'm really pleased to welcome Nello Mainolfi, their CEO. Nello, welcome. Thanks for joining us.
Thanks, Michael.
So Nello, I'll just jump right into questions. You recently highlighted your IND pipeline at an R&D Day earlier in January, including your first-in-class degrader program targeting STAT6. Just remind us real quick, what excites you about this target, and why do you think protein degradation is the right approach for addressing STAT6 in inflammatory diseases?
Yeah, maybe. So thanks again for having us. So I will start with why degraders in immunology. So I think we spent some time on January 4th, and even on our JPM presentation later the following week, talking about why we've made this increased investment in the space. And this goes back to the work we've done with IRAK4, and then also from a further interest in and deep dive into key pathways, key modes, key targets that can allow us to continue to build on our expertise. So what I would say is, if you look at the space in immunology, you know, in the past 15, 20 years, biologics have done two key things: validating targets and pathways, and more importantly, impacted the lives of millions of patients.
And, you know, you can think about, you know, the anti-TNF, the anti-IL-17, the anti-IL-4 receptor, with the IL-4/13 pathway. These are all multi-billion-dollar drugs that have changed patients' lives. But it also taught us that if you block some of these cytokines or receptors, you can impact a wide variety of diseases, going from skin conditions, to respiratory, to GI, to traditional rheumatology. But so the space, the immunology space, is now, you know, up to $200 billion-plus market, which is dominated by biologics. What we feel very committed to is to provide a different way to help patients, which is using oral degraders in these key validated pathways.
The reason why we believe that all degraders can be really meaningful is because we've shown with KT-474, both preclinically or in the clinic, and now with these other programs, so far preclinically, that you can block these pathways fully with a degrader molecule. And so you can have a biologics-like pathway blockade with the flexibility of an oral small molecule. So when it comes to... Sorry, long prelude to the STAT6 question. If you think about all the key pathways that have been validated out there and have a meaningful impact on patients, the IL-1 pathway, we continue to see validation. Recently, AbbVie had a really exciting data with the IL-1 alpha antibody in HS. So in there, we have KT-474, which is the best way with an oral drug to block that pathway, that can be similar or superior to upstream biologics.
Another important pathway that probably is one of the most well-validated pathway in the past 10 years, it's the IL-4/IL-13 pathway, where it's been shown that it's a key regulator of Th2 inflammation. Th2 inflammation, you know, atopic diseases are all this family of diseases that are characterized by this, again, biology that drives allergic type of inflammation. And so these are atopic derm eosinophilic asthma, COPD, and many other diseases, eosinophilic esophagitis and other, let's say, smaller diseases. That pathway signal, so the IL-4 receptor that, for example, is blocked by Dupixent, signals through a key specific and selective transcription factor, which is STAT6. And we believe that if you can combine pathway validation, human genetics, and the technology's capabilities, you can find these, I think, once-in-a-generation targets, and we believe that's what STAT6 is.
It's the selective transcription factor of the IL-4/IL-13 pathway. It's a transcription factor difficult to drug with other modalities, and we believe that with an oral degrader, as we've shown preclinically, we can mimic biologics like pathway blockade, and we have the opportunity to access much broader patient population, given that we'll have, hopefully, an oral drug that can mimic that type of activity.
All right. Great, thanks. Then, you know, looking ahead, I think the IND, pre-IND enabling activities are underway. You do have a clear roadmap in terms of development opportunity, essentially based on the Dupixent, you know, activity. But maybe talk about how you think about prioritizing indications and sort of early studies for the molecule.
Yeah, I mean, I, I think what we said early in January is that, you know, as we enter clinical development, which, which will be in the second half of this year, of 2024, we'll be able to share more about our, our plan- our clinical development plans. But what we can say is that in, in the current environment, for us, it's important to prioritize indications where we can-- we believe we have-- we will have meaningful patient impact in the... worldwide. And so I think indications that have potentially millions of patients, are the indications what would be prioritized, both in early as well as in late development.
That doesn't mean they will not develop also in the smaller indications, but I think the priority will be to the ones that have been well-characterized, that impacted by this pathway where we have a clear line of sight to value creation.
Do you think targeting STAT6 might be particularly differentiated in any of those indications, perhaps relative to some of the biologics which target the interleukins?
Well, you know, I think what we've shown with our data preclinically is that if you use an IL-4 or IL-13 antibody, like dupilumab, you can block that pathway fully, and you can measure the inhibition of the pathway, looking at downstream effector molecules, like IgE, TARC, periostin, another type of translatable biomarker. What we've shown is that if you block STAT6 in vitro and in vivo, you can block the pathway to the same similar extent. So while we didn't go into this program with, you know, we need to be a molecule that behaves like dupilumab and has that type of activity, I think we're just looking at our data.
Our data shows that in every context that we've looked at, again, preclinically, we've been able to show that we're at least as potent, actually, in many cases, more potent than an antibody. In vivo, we're able to block these effector molecules that have been shown to be clinically relevant, at least as well, if not better than the upstream biologics. So, we're just looking at data when we make our conclusions.
Okay. Great. So maybe switching gear, talk about, KT-294, which is your TYK2 inhibitor. And then, you know, similar question, I mean, to what, to what degree do you believe the sort of kinase-independent scaffolding function of TYK2 contributes to its, signaling activity? And where do you see, or how much opportunity is there to differentiate, essentially from Sotyktu, which is approved now?
Yeah, so, you know, I think TYK2 is an extremely interesting biological problem. It's, it's why I think, you know, the BMS has done an elegant work, you know, going from human genetics... You know, again, let's not forget, TYK2 is human genetics validation, pathway validation, and then they show that you can develop a drug that blocks the pathway, blocks the target, and is approved in indications that can help again, also, in this case, millions of patients around the world. The, the TYK2 biology is actually way more complicated than I think what's maybe understood by, let's say, the general population. So first, the scaffolding function of TYK2 is well characterized. It actually is important for receptor functioning.
And so I will start with kinase ATP blocker of TYK2 are actually mostly not being developed in these indications where, you know, the allosteric TYK2 inhibitors are being developed. And that's for two reasons: One, for selectivity, it's really difficult to get ATP binding selectivity across all the JAK classes of kinases and even beyond, but also because of the biology. So if you actually use this allosteric inhibitor, like Sotyktu, for example, and you know, the Takeda molecule, not only you block the signaling function of TYK2, but you actually partially block the scaffolding function of TYK2 because you change the protein in a way that actually blocks some of the scaffolding function.
That's the reason why if you have a selective TYK2 inhibitor, you're able to not only block IL-23, which is-- which you will see even if you just block the kinase function, but you also can block, to some extent, type I interferon pathway, because, again, you're blocking some of its scaffolding function with the allosteric inhibitor. So first, you know, the molecule that is approved, Sotyktu, is not highly selective for TYK2. It actually hits JAK1, and this is why, because it hits JAK1 and hits IL-10 biology, we believe this is the reason why it's not been active in IBD, because IL-10 is important for intestinal homeostasis. And so it's very easy to differentiate from that molecule. It's a selectivity angle.
But generally, what we've shown is that if you remove the protein altogether, we're able to mimic the loss-of-function genetics profile, which means that you'll block IL-23, IL-12, and Type I interferon fully. There is no small molecule that can do that because they're not able to block all the functions of TYK2 with this allosteric inhibition mode. And so we expect that not only so we remove the protein fully, but we've shown also in vivo, non-human primates, that we're able to remove the target fully. So we combine target pharmacology with full biological loss of function and profile, and we believe that will translate in meaningful differences in psoriasis, in IBD, in lupus, and in other indications that these pathways are very relevant into.
Great. Then similar question, you know, any thoughts on, sort of early thoughts on a possible development strategy? You know, how do you prioritize, opportunities for this molecule?
So I think, actually, what I maybe forgot to mention, STAT6, maybe I can cover for both. I mean, this, the phase 1 study for both of these programs will be, in our view, extremely important. If we think about STAT6, if you look at even the healthy volunteer or early patient data with dupilumab, you can see that you can look at, biomarkers, whether in blood and skin, that demonstrate full pathway, blockade. And so having us an ability to replicate that type of dataset should be able to de-risk our development in a major way. For TYK2, I think it's the same. There are no small molecules of TYK2 that block the pathway fully, for 2 reasons, I've said it already.
One is because they do not hit the target fully, because they're kind of stoichiometric small molecule inhibitors, and because they don't remove all scaffolding functions of TYK2, because they are small molecule inhibitors. So in our phase 1 study, even in healthy volunteers, we should be able to show full pathway engagement, meaning we'd be able to show that we're degrading the target 95% plus. And that when you look at what is the phenotype of basically absence of TYK2 in even healthy volunteer, we believe that would be differentiated from the phenotype of the small molecule inhibitors. Then, you know, we'll do patient studies as we've always done, and I think talking about what is the first indication, I think it's too early to tell now.
Okay. And maybe just a quick platform question. How do you approach E3 selection for your, you know, immunology pipeline, and how much is informed by your experience with KT-474, where I think you believe you use a cereblon binder, or do you have--have you evaluated any other options that might be optimized for those applications?
Yeah, that's a great question. So I'm not gonna be able to go into the specifics, but high level, what I will say, there is two things. For every program, whether it's immunology, oncology, or any other areas that we're doing early outside of these, we always look at what is the, the expression, biology, and localization of the E3 ligase versus the target of interest for that program, and then that's how we select the E3 ligase. And I think we've said the structure might even be public, but, you know, in some, in some of our... You, you've said about cereblon for IRAK4, if you look at our other oncology pipeline, we, we use also E3 ligases that are not cereblon. And again, that was purely based on biology, and following the principles that I just outlined.
So for immunology, there are two concepts. One, what is the E3 ligase that is expressed in all relevant cell types that are important for the biology we're going after? If you look at our STAT6 presentation on our—you can go on our corporate deck or R&D Day, you see we've characterized that biology in all human relevant cell types. I don't even remember the list of all the cells that we looked at. That's because we wanted to make sure that the degradation was consistent across all these systems, and so our selection is always driven by that first. Then what I will say, you know, we have taken the first degrader into immunology. There are lots of considerations with regard to regulatory safety and how one plans the development of these drugs outside of oncology.
So we have a wealth of knowledge and relationships that we've built and de-risking works that we've done, which obviously I'm not sharing today, that is very informative for any other program that we want to develop in immunology.
Okay. Then, maybe a good segue to talk about KT-474, the IRAK4 degrader program. Just, you know, as we look ahead into next year when we'll get data from the two phase two studies in HS and AD, you know, it's a bit early here, but remind us, you know, what's the right way to look at clinical benchmarks, perhaps, set here by injectable biologics when we look at some of those data?
Yeah.
coming out next year?
I mean, what I would say is that what's exciting for the IRAK4 program is that, the pathway upstream, continues to show strong validation. I mentioned before, IL-1, there is strong data with IL-18, for example, in AD recently, or at least early data, I believe, from GSK. There is data with IL-33 in asthma. So the beauty of an IRAK4 degrader is that with a single oral small molecule, you should be able to block all the upstream IL-1 cytokines. So you should actually have the combined activity of these upstream biologics. Obviously, that's a really high bar, but that's really what we're trying to do. But in reality, it's really difficult to compare a drug going after the IL-1 TLR pathway against a drug that is going after TNF on IL-17. Those are, in a way, different pathways.
So our target product profile for this drug, and I believe that Sanofi in their R&D Day, I believe in early December, have touched on, you know, what, what is the expectation, what is the, even the commercial expectation for this drug? What is the profile of the drug? So I always recommend everybody to listen also to their, to their R&D Day. And so the profile is having an oral drug that has robust activity to help patients that are even pre or post biologics, that, you know, will benefit from a convenient, safe, and active options. And so from where I stand, I'm not so fixated on showing that we're superior to an IL-17 biologics. I wanna just make sure that patients have access to an active drug that is convenient and accessible.
I think that profile will deliver a multibillion-dollar drug across all these possible indications.
Okay, great. And then switching gears, let's talk about your 2 oncology assets, starting with KT-333, the STAT3 degrader, where we've seen some phase 1 data recently at ASH, and there were several monotherapy responses and certain lymphoma subtypes. Yeah, just remind us the key takeaways from that data set and how you think about next steps for the program.
Yeah, you know, we've shown in preclinical studies that if you degrade STAT3 in a subset of T-cell lymphoma leukemia, you can really block proliferation, and actually, you drive to apoptosis. We've also shown that in this syngeneic model, again, preclinical, and you give a STAT3 degrader, you actually change the tumor microenvironment in a way that will synergize with immunotherapy. We've also shown and not shared yet, that there are some subset of solid tumors that are actually sensitive to STAT3 degradation, even as a single agent and even better as combo. So our phase 1 study has really been built to validate our preclinical package. So in T-cell lymphoma, and actually, we saw some activity also in Hodgkin's lymphoma, which we had not explored preclinically.
And so, we've confirmed anyway that in some heme indications that are sensitive to this pathway, we can see robust activity. We've also shown that through a tumor biopsy that we were able to have from one patient, that that signature that we'd seen preclinically is replicated in the clinic. So for this year, we'd like to be able to show, hopefully, the totality of the phase 1 escalation data and the confirmation of both the opportunities in heme as well as the potential path in solid tumors. As we said, often, for us, you know, these programs, it's really about the totality of the opportunities, and we believe that one small opportunity in one subset of heme might not be good enough for us to continue to invest in this program.
So that's what we're trying to do, build the dataset to continue to create excitement for us to continue to invest in the program.
Right. So talk about sort of expectations for the next clinical update on the program, and sort of how do you think about the bar, specifically in T-cell lymphomas or in general in lymphomas?
Yeah.
to pursue next steps?
I mean, I think, you know, we've shown a small subset of patients. I think if we continue to see multiple tumor types with robust responses where we see, you know, lots of majority of patients benefiting from the drug, I think that's an interesting profile.
Okay.
Obviously, in solid tumor, again, we don't expect single-agent activity, at least broadly, and so there it's more of a combo. But we need to generate data both clinically and preclinically to support the potential exploration as a combo therapy.
Right. And maybe real quick, yeah, on a solid tumor front, what are sort of the, you know, the gating factor to advancing this? Just remind us what you're doing in phase 1 here, and how should investors get confidence in the opportunity in solid tumor?
Yeah, I mean, it's a bit tricky when, you know, preclinically, you haven't seen robust solid tumor activity. Again, we have some more recent data that actually has shown some early activity. We'll share that, hopefully this year. But generally, let's say, here, the opportunity is sensitizing patients to a PD-1 drug, and so it's really difficult to do that in a phase one single-agent dose-escalation study. So there, we're thinking about, can we generate enough, again, biopsy data, early phase one data, together with our preclinical data, does that totality influence positively our decision to continue in that space? So I think that's gonna be more looking at the totality of the data, while in heme, it's gonna be based on actual patient data.
Right. Okay, great. And then maybe just closing with KT-253, MDM2 degrader, which addresses a obviously very attractive target. But, you know, there's been some data generated with some small molecules historically, that, you know, have impacted normal hematopoiesis. You know, just remind us why you believe a degrader approach is here, value added, and, and how differentiated the program could be.
Yeah, I mean, I think one thing that we've done really well at Kymera is translating these programs in the clinic. The profile that we had preclinically has always translated into the clinic, PK, PD, safety, and early efficacy. So hopefully, there is some level of appreciation that if we've said that preclinically, we can circumvent the heme tox because of a degrader mechanism, where we can maximize efficacy and safety by overcoming the feedback loop and dosing infrequently. Hopefully, there is an understanding that that there is high probability that that profile will translate. And in fact, in our early patient data, I know we only shared, I don't know, maybe three patients in November of 2023. Our first patient on the study had a prolonged response without any signs of the typical heme tox. That, for us, is paramount.
This phase 1 data, go, no go, it's really go, no go. We'll see... It will depend on can we see efficacy, so robust antitumor activity in a variety of tumor types. We have AML, ALL, we have Merkel cell, we have - this is not about selecting the indications, but this is about proving that you can see clinical activity in the absence of the heme tox that has plagued the whole space. I think with that in our hands, we are building these, I would say, really elegant biomarker selection strategy, which we will share this year, that will inform clinical development. So this year, expect, hopefully, confirmation that our thesis was right on efficacy and safety, and also what the development path is gonna look like.
I can assure you, based on the data we already have, the development path is gonna look very different for any other small molecule inhibitors that has been developed in the past 15 years.
Maybe just lastly, just I know you did say you had sort of this dose of one data disclosure last year. How far in into the phase one are you at this point? You know, how many patients' worth of data will we get this year?
Yeah, you know, I mean, you know as well, like, we can't really give this, you know, middle-of-the-study patient updates. But what I will say is we hope to be able to complete the escalation study this year based on our expectations on doses and when we hit our DLTs or our, our maximum tolerated doses. And so, you know, whether it's gonna be 1 or 2 disclosures, we hope that this year we'll be able to share, you know, close to or the totality of the data.
Right. All right, great. Well, with that, it's time to close. So Nello, thank you so much. I really appreciate it.
Thank you!