All right. Good afternoon, everyone. Thanks for joining us here at the Leerink Partners Global Biopharma Conference. My name's Tom Smith. I'm one of the senior biotech analysts here at Leerink. It's my pleasure to welcome our next company to the stage, Kymera Therapeutics, and happy to be joined by President and CEO Nello Mainolfi. Nello, thanks for joining us.
Thanks, Tom, for having us.
So, Nello, why don't you go ahead and kick us off here with, maybe a brief overview of the company, some of the key upcoming milestones, and, sort of the setup here over the next 12 months?
Yeah. So just a brief intro. Kymera is a company focused on targeted protein degradation. It was founded about eight years ago with the mission of building a fully integrated company that will take this really potentially transformative modality into a commercial stage reality, I would say generally in a disease-agnostic manner. We have focused for the first few, you know, eight years now mostly in immunology and oncology. And we, you know, our philosophy has been around working in pathways with high degree of validation, going against targets that have not been drugged or drugged fully by any existing modality, where we believe protein degraders can provide a really outsized value creation opportunity. So we have a pipeline of programs that are in the clinic or about to go in the clinic. So we have an IRAK4 degrader program that is in phase 2 studies.
This is actually in partnership with Sanofi. It's in phase 2 in HS, hidradenitis suppurativa, and in AD, atopic dermatitis, with data phase 2 data projected to be disclosed in the first half of 2025. This is a program that we've run, both obviously discovery and early development at Kymera, and we've showed in a phase 1 study, that we could degrade the target fully and have meaningful impact on skin symptoms of HS and AD in a small patient cohort. We have 2 programs that are currently in phase 1 studies in immuno-oncology. We have a STAT3 program, KT-333. We've shown some early proof of concept last year at ASH, showing activity in T-cell lymphoma and leukemias.
This year we're really looking forward to disclosing the totality of the phase 1 data, phase 1A dose escalation data, and really talk about what is the development plan going forward for this first-in-class STAT3 degrader in oncology. We have another degrader program in the clinic against MDM2. This is KT-253. We've shown really early data last year, with, you know, the first few patients where we started to see impact on the pharmacology, actually anti-tumor effect without the typical heme tox of MDM2 agents, which really speaks to the value proposition with that program. This year also here we expect to share the majority, if not the totality of the phase 1 data, and really point into, what's ahead for this program in phase 1, expansion, phase 2, and beyond. Then we have two immunology programs that are about to enter the clinic.
We have a TYK6 degrader. This is a program we're really excited about, potential to mimic biologics-like activity in a normal small molecule. This is entering the clinic in the second half of this year with phase 1 data in the first half of 2025. Then we have a TYK2 program, degrader program, where we expect it to have best-in-class TYK2 biology and, and hopefully also clinical outcome, that is entering the clinic in the first half of next year with data in 2025. You know, recently we've talked about our, deeper focus in immunology driven by what we believe are these best-in-class programs with biologics-like activity in a normal molecule. And we expect this program to be, where Kymera will have spent a lot of time and focus.
I would say generally, I wanna make sure that everybody understands we're a company that will have the same bar across all disease types and disease areas with regards to what we invest and the type of investments that are based on how meaningful these drugs can be, the clinical and commercial impact of our mechanisms.
Got it. Great overview. I think, I wanna take a step back and just talk somewhat high level about how you think about the benefits and challenges of protein degradation overall, and then specifically with respect to the immunology and the shift and prioritization of the immunology side of your platform.
Yeah. So, you know, protein degradation is, you know, at high level, very simple concept. You can use the small molecules to have a genetics-like knockdown effect or even knockout effect if you have a really good molecule. So it's the opportunity to go beyond what's attainable with other technologies. Remember, only 20% of the genome has been addressed by existing modalities. Most of the undrugged proteome is within the cell wall, so cannot really be addressed by either antibodies or I would say also these genetic therapies that are still limited by delivery to particular target class in the liver. And so what protein degradation can do, it allows you to go beyond what's been done with other modalities, with a small molecule, potentially oral approach. And the reason why we can do it is because unlike, again, antibodies, we can go in the cell.
Unlike small molecules, we don't need to inhibit the function of the protein, but we only need to elicit a binding event and then drive these protein that we're bound to, to the natural machinery that is in each one of our cells of removal and disposal and degradation. We're co-opting an existing, natural machinery and targeted against disease-causing protein. I think it's only obvious that this technology has huge potential. I think it's our responsibility as a company in the space, and I and I hope every other company feels the same way, to make sure we use it for the right target, for the right diseases, for the right patients. Because I think if as we continue to do that and do more, the real power of this technology can be visible beyond the people that are familiar with it.
Yep. That makes sense. Okay. I wanna start by talking about your IRAK4 degrader program, KT-474. You mentioned you have the partnership with Sanofi running the phase 2 ZEN study and the phase 2 ADVANTA study. Those are ongoing, enrolling. Maybe just talk a little bit about the data that led to the Sanofi opt-in, and then I guess what drives your confidence that as you see the results from the phase 2, you're gonna see clinically meaningful efficacy with a nice balance of safety.
Yeah. So, I mean, what we've shared, what we were able to build at Kymera and this is actually, you know, part of the reason why we have increased our investment in immunology. We've been able to show that you can build an oral degrader that can preclinically degrade this target in a variety of cell types that are relevant to immune-inflammatory diseases. We've shown that this could be really well tolerated in short-term as well as long-term preclinical tox studies. Then we went into the clinic and demonstrated that we were able to replicate the preclinical package, which speaks to degradation impact on disease models, into both healthy volunteers and patients. We show that we can degrade the target fully in blood. We can degrade the target meaningfully in skin and bring the target level to what it is for healthy volunteers.
We can show that we can impact cytokines and chemokines in blood and in skin of HS and AD patients in a robust way. Some of these transcripts that we were looking, in the skin of HS and AD patients post 28 days of dosing, we were downregulating some of these transcripts in the 80%, 90%, 95% plus. So a meaningful impact on biomarkers of inflammation. And then, as we were saying, we ran a, let's call it phase 1b study in HS and AD. We showed impact on signs and symptoms of HS and AD measured by AN count, HiSCR, pain in HS, or EASI scores and pruritus in AD, to levels that are on par, if not even more meaningful than standard of care.
Now, what we caveat is that that was a small study, 28 days without placebo, was really a PKPD study. But I think the fact that the totality of the data demonstrated a really meaningful impact on, on patients and also on patients' quality of life gave us and Sanofi the confidence that these can be a really meaningful mechanisms in these diseases and actually beyond these. And so that's really what gives us the confidence that, you know, hopefully early next year in the first half of next year we'll be able to demonstrate unequivocally in a placebo-controlled randomized study that IRAK4 degradation can meaningfully change the lives of patients with these, with these diseases.
Got it. Obviously, Sanofi is executing these studies.
Yeah.
But can you speak to, I guess, the level of visibility you have into recruitment rate, I guess, like when you expect to be in a place, mainly driven by Sanofi, but to kinda narrow down timing for when we could see data from either study?
Yeah. So, what, what I, I wanna clarify. So Kymera was responsible for running the studies all the way through the end of phase 1. And Sanofi is now responsible going forward, for running and, and also paying for all the, phase 2 studies and beyond. And so, you know, we, we are fortunate that the way our partnership in-is constructed that we get, updates on the programs, a-again, in, in, in obviously in a, we-we just get an update on how operationally the program is, is being executed on. We are unfortunately not in the position to disclose updates. The communication for these programs is on Sanofi first and foremost.
But what I can say is that as far as we understand, the program is still on track to deliver on the timelines of data, as we said, first half of 2025, as it's been disclosed recently by both companies and as it's depicted on the ClinicalTrials.gov website.
Yep. Okay. That makes sense. Quite a bit of data at AAD over the weekend focused on HS. I mean, more so than any other AAD historically, I think speaks to the level of interest and obviously the level of development and investment that's going into novel therapies in HS. Anything, I guess, catch your eye in terms of small molecule development? We saw data from Novartis's remibrutinib in, in HS. Is BTK degradation something you guys are considering, or is that something that's come onto the radar?
Yeah. So first I'll start with, you know, I'm really we're really excited about the level of investment in HS. When we started IRAK4 program in 2017 and we start talking to investors about this program, at least to publicly faced investors in, I would say, maybe 2019, you know, I, I would say we were met with a lot of skepticism around, you know, is HS a tractable disease? Lots of drugs have failed. And we had a, we had a compelling case for both the biology of IRAK4, the relevance of the pathway in this disease, and the fact that we believed this was actually one of the most important unmet needs in dermatology. Full stop. And I think we feel a bit vindicated that, lots you know, there are many mechanisms that have been explored.
I think what we've seen, we've seen clear activity with IL-17 directed biologics. And I think it's nice to see that there are other small molecule mechanisms that are being taken into that space. I have seen the BTK data. It's obviously early. There was a relatively small set of patients. I personally believe that the value proposition with IRAK4 is the fact that you're blocking a pathway through which several cytokines signal and that actually impacts a wide variety of downstream cytokines. You know, we'll see, you know, what happens with the BTK class as there are several agents there. Obviously that class has had several issues with, you know, the safety profile in general. So I will wanna see how these molecules outside of oncology look.
you know, I think it's great news for patients that more and more mechanisms are being explored.
Yep. Okay. You've also talked about potential indication expansion opportunities for 474. I guess just broadly, like, what's the criteria or framework that you're using to consider these additional indications, and then how does Sanofi factor into this?
Yeah. I mean, you know, I think there are considerations that one makes with regards to an IRAK4 degrader, where is it best applicable? And you can do that regardless of any clinical data that you've generated. If you just look at the pathway biology and the pathway validation in the clinic and when I say the pathway, I mostly refer to upstream cytokines that must signal through the IRAK4 node. I think you would expect to see activity in respiratory, in GI inflammation, in rheumatological inflammation. So it's actually not a leap of faith to have confidence into thinking about an IRAK4 degrader in a broad variety of other disease types and disease areas and, and, and patient types.
I think, you know, we're glad that Sanofi is taking a pretty aggressive approach right now with running two parallel basically two parallel phase 2 studies, with a molecule that hasn't had any previous phase 2 study. I believe that Sanofi will be the one disclosing which and when new indications, you know, what they will be and when we will start studies. But I think my sense is, you know, seeing data from these phase 2 study will be part of that decision-making process of expansions into others.
Got it.
That doesn't mean just the efficacy data, but just, you know, seeing the drug being tested to more than 23 patients.
Right. Over a longer period of time.
Yeah.
No, that makes sense. Okay. I wanna switch gears and talk about the STAT6 degrader. Quite a bit of investor interest in this program since you, you unveiled it, earlier this year. Maybe if you could just talk about some of the advantages you see of degrading STAT6 compared to more directly targeting some of the individual cytokines and then maybe just high-level some of the preclinical data that you've generated on the, the STAT6 compound.
Yeah. So I will start by saying that while we disclose our STAT6 program in January, we have been working in this pathway for years. So hopefully it, it doesn't come across that we're just found ourselves with the STAT6 program a few months ago. And so what we say about STAT6 is informed by years of work that we've put into this pathway and into this particular mechanism. And so, where is that coming from? You know, it comes from our philosophy of investment and, and programs. We believe that degraders have to come in when there is a strong validation of the pathway, but there is a better way to impact that pathway. And that better way needs to be, enabled by a degrader program.
So when you think about all the pathway in immunology that we wanted to invest in, it was obvious for us to think about the pathway that has probably the biggest drug in immunology today and in the next five years, which is the Dupixent, dupilumab. IL-4 receptor alpha targeting has transformed Th2 inflammation and has the potential to impact 150 million patients around the world. What we totally believed that, targeting this pathway with an oral drug will allow us and generally the biopharma industry to access and to have many more patients access a very powerful mechanism, in a more efficient and in a more compelling way. And so us targeting STAT6 was driven by the fact that we thought that this particular target is a selective and specific transcription factor downstream of that receptor.
By targeting it with an oral small molecule is the only way, by an oral small molecule degrader is the only way to block the pathway the same way as the upstream biologics and have the convenience of an oral small molecule. That's really where the program is coming from. The reason why we believe a degrader is the best way to target STAT6 is because, as you know, the reason why biologics work so well is because through the way that they're dosed and through the high level of affinity that they have for their intended target, they can saturate the target, in this case IL-4 receptor alpha, in a way that blocks the signaling of the pathway completely. And as we know, traditional small molecules have a really hard time because they're occupancy-based, they're stoichiometric, and they're driven by their PK.
It's extremely difficult for a small oral small molecule to block a target the same way as a biologics. And because a degrader is a catalytic mechanism has a catalytic mechanism and in our case has biologics like potency, as you've seen, we are a picomolar degrader of STAT6. Now we have everything we need to being able to saturate fully the pathway. And in fact, we've shown in our preclinical species that we're able to block this pathway and we look at downstream TH2 biomarker in the same way, if not better, than a saturating dose of an upstream biologic like dupilumab.
Got it. Okay. And you plan to start dosing healthy volunteers in the second half of this year, data possible in 2025. I guess what are you looking for with that sort of first readout?
Yeah. You know, I think, you know, as I said at the R&D day, we're on this particular concept, we're sitting on the shoulders of giants. You know, we've seen the work that Regeneron and Sanofi have done on this particular target and pathway. We know that there are several indications starting from AD going to asthma, more recently COPD, chronic rhinosinusitis, EOE. These are diseases that don't really have other options, that have been now addressed by this drug. And actually we know what is the phenotype of blocking this pathway. For example, in healthy volunteers, obviously we need to degrade the target well, and we have full confidence we'll be able to do that. We hope that we'll be able to replicate our preclinical safety profile, which is very really pristine, so demonstrating that the drug is also safe.
And then even in healthy volunteers, we can demonstrate that some of these biomarkers of TH2 inflammation can be modulated. For example, you can reduce total IgE as well as TARC in healthy volunteers by, you know, 20%-25%, with it's been shown with dupilumab. So showing degradation of target safety and impact on these biomarkers will be already a huge win after healthy volunteers. And then in patients, we know exactly what it looks like in a broader set of biomarkers, both in blood and skin, what is the signature needed that demonstrate a full blockade of this pathway. And so we look forward after our phase 1 healthy volunteers to go in patients ASAP and show that signature. And then obviously we'll have all the downstream development.
I think with that signature in hand of full IL-4/13 blockade, degradation, and safety, I think you'll have a package of knowing that you, you know, probably have a drug in your hand. And then it's obviously going through the motion of developing all this indication, building the safety package that you need, to go later in registration.
Yep. Okay. I wanna shift gears and talk about the TYK2 degrader, which you also unveiled earlier this year. Not to say that it just appeared out of nowhere. I'm sure this is another degrader program that you've been working on for quite some time. TYK2, I mean, this as a target, again, at AAD we saw some interesting.
Yeah.
Interesting data in psoriasis that maybe suggests there's still room to go on the small molecule inhibition side. I guess how do you think about TYK2 degradation relative to small molecule inhibition and what more you can get out of degradation that you can't necessarily with the small molecule inhibitor?
Yeah. I mean, what I wanna say about TYK2 I've actually not quite probably said it that way. This is a program that we've spent more time than many other programs in our pipeline. I don't wanna say all other programs 'cause it might not be true, but for sure many other programs. And the reason for that is because, it's a program that it's a target that has, you know, one of the most elegant human genetics data out there. It's a program and a target that has been fully validated by pharmacology. And it's a program that we felt we must have a clear differentiation story. Unlike IRAK4 where there is really no good small molecule, we have an approved agent. Unlike STAT6 where there is no other agent, we have an approved agent. So we don't invest in programs just because we can.
We invest in programs because we know that we can build a really differentiated value-creating medicine. And so with TYK2, we've done a huge amount of work to characterize inhibitors. And by that I mean inhibitor, in any mode of action that you can imagine. And we wanted to understand what is the biology of inhibiting TYK2. And what I will say is that that is way more complicated than what's, I think, the general public understanding of inhibiting TYK2. Inhibiting TYK2 is very molecule-specific. These are all allosteric inhibitors that all modulate that protein in a different way from each other. And so it's not surprising that each molecule has actually a very different outcome. If you look at all these molecules in the clinic, they're all kinda look different, but they're all in the same bucket.
Unless you fail, they're all in the same bucket of, you know, you can do 10, 20, 10% plus and minus in, let's say, PASI-75 score in psoriasis. They're all gonna look the same, ±10, 10%. The reason is because they're going after a subset of the functions of TYK2, which is a catalytic function and some aspect of its scaffolding function. But if you look at, actually, loss of function phenotype is very different than what these small molecules can do. Loss of function phenotype looks like an IL-23 and a type I Interferon saturating biologics. That's what that phenotype looks like. There is no small molecule that can reach that phenotype just because the biology and the opportunities of these small molecules to block these targets.
So sorry, long story short here, to say that we have confidence that degrading STAT6 will be biologically and clinically differentiated. And while, you know, psoriasis study will be important to characterize, I'm sure, you know, we'll disclose this later. But let's assume that there'll be a psoriasis study to show how it impacts this, you know, this very relevant disease for this mechanism. What I think will be important for a STAT6 degrader is to demonstrate the differences across a plethora of diseases. And that it goes beyond IL-23 only. And this is where I think small molecules are gonna have a hard time showing a profile that can be compared to biologics. You know, we're looking forward to seeing data in GI inflammation. We wanna see data in rheumatology. I think the package will be very important to compare with.
Yep. Got it. Just in the last couple minutes that we have, I wanna shift gears again to oncology. You have a couple of data readouts, both for 333 and for the MDM2 degrader program. Just sorta help set expectations, what we should be looking for out of those early but important readouts.
Yeah. I mean, for 253, as I said, our value proposition is I mean, I think nobody can argue that p53 is not a super relevant node in oncology. This is, p53 wild-type tumors represent more than 50% of all human cancers. And this pathway is relevant in many of them. I think what we learned, the small molecule inhibition of MDM2 p53 interaction is insufficient to create a profile where you maximize efficacy and safety. And so our goal in a phase 1 dose escalation will be to show everybody that we can have strong anti-tumor activity in a subset of tumor types, let's assume more than one, without the typical dose-limiting toxicity. I think if we can show that, this program could be a huge development program across a variety of tumor types.
For 333 and STAT and so that's the goal of this year. For 333 STAT3, we've shown that we have early activity in T-cell lymphoma, in CTCL we've shown. We've shown some intriguing early activity in Hodgkin's lymphoma. I think for that program, it's important for us to disclose the clinical and preclinical data and make the case for Kymera investing in late development. And that case needs to be a clear line of sight to value creation in multiple tumor types. What I will say is that having activity in CTCL, for example, will not be enough for us to say this is a big development program. It has to be multiple tumor types, ideally where we have a clear line of sight to activity in solid tumor in combination.
and we know that we'll be able to share both clinical and preclinical data to be able to make the case that, again, this program clears the bar for investment, across the whole pipeline. And so the data, both clinical and preclinical, is what we plan to share between mid and end of the year in 2024, for STAT3 and for MDM2.
Got it. All right. Unfortunately, we're up against time. Nello, thank you so much for joining us and for sharing the updates and the insights. We'll stay tuned to the Kymera story.
Thank you, Tom. Thanks everybody for listening in.