I'm Ellie Merle, one of the biotech analysts here at UBS. Thank you for joining us in a very sunny Miami for the UBS Biopharma Conference. Very happy to have Kymera Therapeutics here with us today for a fireside chat. Joining us from Kymera is Nello Mainolfi, President and Chief Executive Officer. With that, Nello, thank you so much for joining us.
Thanks, Ellie, for having us.
Of course, and, listen, there's a lot of talk around targeted protein degradation, what this could mean as a modality. I think, you know, investor feedback recently has been, you know, come back in terms of excitement, say, relative to two years ago. In your view, what do you think people are missing? What have we learned about this modality in the last couple of years from all the clinical data, and what do you see as the value of this modality relative to, say, traditional modalities, like traditional small molecule inhibitors and antibodies?
Yeah. So first, thanks for having us. You have comfortable chairs up here, I would say.
Yeah.
To your question, what's the promise? What's the opportunity with targeted protein degradation? The opportunity is to have a small molecule-based modality that can remove disease-causing proteins. And so you can have a knockdown-like phenotype with the flexibility of an oral or a small molecule, oral or otherwise. And in a nutshell, there is no other technology out there that can be disease agnostic, tissue agnostic, organ agnostic, target agnostic in the way that protein degradation can be. The promise is, to us, more exciting than it was seven years ago when we founded the company, and the reason why I say that is because the premise is the same, but we've learned a huge amount in the past few years, at least we at Kymera have. We feel we're in the position now to fully realize that value.
I mean, I fully appreciate that, and I agree, that to fully realize value of a novel modality, you have to have an impact on patients. And I think where maybe, you know, I think that the sentiment versus the reality is being a bit caught in the middle, you know, many of the companies in this space are still relatively early in their clinical development stage. So data set has been extremely exciting, at least our data I can speak for, but still early in clinical development. And so I think the next 2 to 3 to 5 years will generate a series of medicines that will change treatment paradigms across many disease areas, and I think the full appreciation of the space will happen.
The only one other comment I will make on protein degradation and in general on any modality, that you know, your platform, your technology, your discovery engine, whatever you wanna call it, is always as good as your product. And I think if we all focused on the products that we're generating and less so on the degradation modality that we're using, we would advance the conversation much more productively. We are a company that loves our platform, but we're focused on making drugs. So we wanna talk about the drugs, what they're doing in the clinic, and the opportunities in front of us.
Great. Let's talk about 474. You recently moved into phase 2s in atopic derm and HS. Can you tell us a little bit about the value of IRAK4? There's a lot going on in the I&I space. What's so promising about IRAK4 relative to the many other targets? And, you know, walk us through some of the early data we've seen so far.
Yeah. So, you know, I go back to target selection that we believe as being quite unique at Kymera. We've been focused on what can the technology do? What can protein degradation do to provide a very meaningful, differential solution to patients? And the approach that we've taken has been to focus on pathways that have been validated, going after targets that have been undrugged or poorly drugged, and where protein degradation is a unique unlocking solution, and then importantly, in areas where there is a meaningful clinical and commercial opportunity. And so if you apply that concept to immunology, and I know we'll talk more about this, you know, either later, but for sure in January, in our R&D Day. You know, we've learned that biologics have helped us validate novel pathways.
If you think about TNF, you think about the IL-1 family, you think about IL-17, you think about IL-4/13. These biologics have showed us that these key fundamental pathways are driver of many of these immune inflammatory diseases. What we believe we can do at Kymera is go into those pathways and provide a solution that is competitive with the biologics, in many ways, superior, and have the convenience of small molecules. So for IRAK4, we know there are two drugs or biologics that block cytokines upstream of IRAK4, IL-1, IL-18, IL-36. Some have approved, some have shown clinical activity, but only by degrading IRAK4 you can actually capitalize on the full clinical potential of all those single cytokine blockers with a single oral small molecule.
That's the promise of protein degradation, pathway blockade that is superior to small molecules because we're removing the protein, and it's competitive with biologics because we can fully block a pathway that is activated by several cytokines and has the convenience of an all small molecules. We've shown, you know, in all of our pipeline, we've shown exciting early data. For IRAK4, we've shown that we can degrade the target fully in blood. We can degrade the target extensively in skin. We can demonstrate that the signature in healthy volunteers and in patients is of a broad signaling. And then we've also shown benefits to patients with both HS and AD by degrading IRAK4.
And we've shown, although not in a head-to-head, that our profile is meaningfully differentiated from an IRAK4 small molecule inhibitor that others have developed. So we're going now, where we initiated two phase studies, our partner Sanofi has. But, you know, we're following the studies very closely, and we're excited to being able to, you know, fully demonstrate the clinical activity of this mechanism in a couple of, you know, really meaningful indications and then continue to develop this drug.
Mm-hmm. Absolutely. And it seems like you have phase 2 data coming from both of those programs in the first half of 2025. That's a very important catalyst for you guys and thinking about the proof of concept for, you know, degraders, as you mentioned. How should we think about what's clinically meaningful in these indications? And tell us a little bit more about the designs here.
Yeah. So both studies have been powered to evaluate clinical benefits. So I think the goal is to hopefully the goal is to execute a flawless study. The ambition is to demonstrate through the study that the drug has impact on patients, and that's really what we hope to get out of this study. They're powered, so the HS study has a placebo and one dose. The AD study has placebo and two doses. They're both recruiting between 100 and 115-120 patients. And they're powered to demonstrate hopefully differential activity from placebo. We have all the endpoints that people have used in this type of indications, HS, all you know AN counts counts and all the different high scores and pain measures.
In AD, EASI scores and pruritus and all the categorical scores that we look at. And you know, I think we have a unique opportunity to have a profile that shows meaningful clinical activity that is statistically significant from placebo, and a profile that would be competitive by being an oral small molecule with hopefully a good safety profile.
Mm-hmm. Absolutely. And, a common question I get from investors is how to think about the safety, both because we're using a novel modality, but also, because of some of the QT Prolongation effects that we're seeing in some of the very early data. Maybe walk us through what was seen there and what gives you confidence in the safety of your IRAK4 degrader.
Yeah, I mean, so far, the safety profile has been quite benign. I think the most common adverse event, if I remember correctly, was headache and some nausea. We had a transient subclinical QT prolongation in the study that actually resolved on its own while patients were still continuing to be dosed and never reached levels that were considered adverse. So, it's obviously something that we've uncovered. We believe that we demonstrated the signal resolved spontaneously while patients are on therapy, so it's a transient, again, subclinical effect. And, you know, we'll continue to monitor and make sure that that profile stays the same.
Otherwise, you know, with that and outside of that, we believe the safety profile is consistent with a, you know, a potential meaningful drug in immunology, given what the adverse event profile looks like so far.
Mm-hmm. Well, certainly very excited to see the data in the first half of 2025.
Yeah, so are we.
Turning to oncology, you recently had a pretty meaningful update where you showed initial, clinical efficacy data from your STAT3 and MDM2 degrader. Maybe starting with STAT3, can you tell us a little bit about the mechanism behind this target in oncology and where you see the potential role for this in future development?
Yeah, I mean, I'd like to maybe take a step back, hopefully not too far. You know, the one of the reasons that keeps us extremely excited and motivated at Kymera is, you know, we built these degraders, and we built a very, let's call it, simple translational hypothesis. For example, for IRAK4, we believe we can block the pathway fully better than a small molecule inhibitor, and we believe we've shown that already, and now we want to show further clinical activity. For STAT3, we believe there is no other way that you can block fully, let's say, activity of STAT3 than with a degrader. And we believe we have the first agent that selectively, specifically acts on that particular target.
And we've shown already in the first few patients that we're able to impact tumor size of patients with, in this case, we've shown a partial response in the CTCL patients. That effect is dose level 2. We believe the clinically active doses will be dose level 3 and 4. So the thesis going into these programs in terms of clinical activity, pre-clinically, we've seen strong antitumor activity in T-cell lymphoma and leukemias, a single agent. And we've seen some exciting activity in solid tumors, especially in combination with PD-1 and other agents that we haven't disclosed yet. And so in this dose escalation study, we went into the study with expecting antitumor activity in Heme and to be honest, not much in solid tumor.
We're seeing some intriguing stable diseases, even as you'll see from the poster, for a relatively prolonged amount of time. So, we're trying to tease out, you know, what's happening also in solid tumor. Hopefully, we'll have some biopsies, and we'll look at the signature in tumors as it relates to the potential impact on the tumor microenvironment. So, I think the ASH will be an exciting update, later in the year.
Mm-hmm. Yeah, certainly looking at the number of patients that you've dosed, but we haven't yet seen efficacy for. It's too early. Maybe what should we expect at this update at ASH?
I mean, the cutoff date of the abstract that I believe was July tenth, had 21 patients on study, 12 of which were evaluable for a disease assessment. So, I think all I can say is we will have more than 12 patients worth of data in December. Unfortunately, I think we want to wait for the poster to talk about what we'll see in the poster.
Mm-hmm, um-
But we'll see. All I can say, we'll see both more patients in the, let's say, targeted heme population and also more patients in the solid tumor population.
Mm-hmm. And help us think about the potential opportunity in these T-cell lymphomas, the unmet need. And then also from a biology perspective, why do you think we're seeing efficacy in these particular lymphomas?
Yeah. I mean, many of these lymphoma, CTCL, PTCL, have either STAT3 mutations, STAT3 activation, pathway activation. In fact, if you take a biopsy of some of these tumor types, you'll see there is extremely high level of phospho-STAT3, which is telling us that the pathway is highly activated. And so we expect, again, based on also preclinical data, that many of these patients could respond to a STAT3 degrader. And, you know, many of these have, you know, the treatment paradigm is, I guess it's not optimal for patient outcome. There are some active therapies, especially in CTCL, with CD30, CD30-positive patients with an ADC, but otherwise, I think there's still an unmet need for many of these subpopulations.
I will say that, you know, as we continue to evaluate opportunities, for us to be excited about this program, we'd love to see opportunities in heme as well as opportunities in solid tumors to be really excited about, advancing this program into Phase 1 B and beyond.
Mm-hmm. Absolutely. As you do cohort expansion and continue to dose escalate, how should we think about the degree of data in terms of... that we could get next year and the timeline from here?
Yeah. So I would say at ASH, we will have, you know, a robust data set across several dose levels. I believe that based on our understanding of, you know, trial execution, we should be able to complete the phase 1a in the first half of next year. And I think at that point, we'll be able to provide an update on the totality of the data as well as on next steps.
Mm-hmm. That'll be interesting. Turning to the MDM2 degrader, walk us through the rationale there, particularly relative to inhibitors and what we've seen from the early data.
Yeah. So for MDM2, again, I think high fidelity with what our target philosophy has been and will continue to be is, this is, you know, p53 is one of the most well-characterized tumor suppressor as being the target of many programs in the whole industry, both small and large companies. The challenge has been that stabilizing p53, which will lead to cancer cell death, if p53 is wild type, has been met with challenges. Because as you stabilize and increase p53, by, let's say, inhibiting MDM2 p53 interface, you create a feedback loop that increases the expression of MDM2. So small molecules have had a hard time to stoichiometrically and effectively block this feedback loop. And I think what's happened is that the line between efficacy and on-target toxicity has been crossed several times.
And it's not surprising based on the biologist was trying to explain. If you use a degrader, what we see is that we overcome the feedback loop, because, as you know, this is a catalytic mechanism, and in the first four hours, we see commitment to cell death of these cancer cells. And basically, there is a commitment to death that is now independent of our compound being on board. So we can actually, dosing frequently, allow cancer cells to die, while normal cells do not have this prolonged exposure to p53 elevation. And we believe that that creates this therapeutic index that allows us to maximize efficacy and safety.
What we're excited about for this very small data set that we shared last week is that what we expected to happen happened probably better than we ever expected. But even on the first couple of patients, I would say the first patient on study has been on study for now 6-7 months, I believe, with continued response, without the typical heme tox that you see with MDM2 inhibitors, which are thrombocytopenia or neutropenia. And again, continues to do well on therapy. So that shows, at least based on, you know, the early patients that our hypothesis about degradation versus inhibition and the separation of the therapeutic index is playing out. So that's very exciting, but it's still early. We plan to have an update next year.
As you know, we just started dosing in the arm B, it's called, which is the AML-ALL study, which is a parallel staggered dose escalation study, so with that, we don't confuse the profile between solid tumors and AML. And so we hope to be able to provide a meaningful update next year, ideally together with a patient stratification sensitivity profile that we're developing internally, which I believe will be the last piece of the puzzle to allow this program to really take off in terms of thinking about late development.
Mm-hmm. And the update for MDM2, would that include both from arm A and arm B?
I think it's too early to say, but that's our feeling right now, that it should be a comprehensive update. But we'll see how things evolve and, as data come in, we'll decide what's the best way to do it.
Mm-hmm. And in terms of indication selection, both particularly in, in solid tumors, where you're exploring that as well as in heme, can you talk about the rationale, particularly in, you know, the cohort B for the indication selection, but then also in solid tumors, where you think the biology might make the most sense?
Yeah. So I mean, as I was trying to say earlier, so you have to have p53 wild type to be sensitive to an MDM2 p53 agent, but that is clearly not sufficient. I think we can say that clearly. Now, several companies in the space using small molecule inhibitors have chased or pursued different hypotheses, whether it's upregulation, amplification of MDM2 and others. What we have seen preclinically a very different sensitivity signature, and we haven't disclosed yet. As I said, we probably will disclose it next year together with the clinical data.
So we know that there are some set, some subset of heme, especially in the AML-ALL space, that share this signature, probably the majority of patients which will have this signature or a large, let's say, a large number of patients will share this signature. Maybe not the majority, but a large. So we don't believe we need to have a signature to select patients in AML-ALL. And then in solid tumors, where, as you know, it's obviously a different context, we know that there are some subset of tumor types that are sensitive, but we're also learning that actually the sensitivity signature that is evolving and still evolving might actually be across several tumor types and not specific to just some tumor types.
That's really what we're trying to tease out from the work that we're doing, both pre-clinically and clinically. It's an exciting time, and hopefully we'll be able to have something that we can pursue, and to accelerate development, which that will allow us to do, instead of going one by one in all the different tumor types.
Mm-hmm. Will be interesting to get more data next year on that, at a mid-year update?
We'll see. I think that's, looks like that might be a good time, but we'll update you on that maybe early next year on what they expect... you know, more refined expectations.
Mm-hmm. Understood. Well, heading into your R&D day in early January, what can we expect there?
So, you know, as we said on the call the other day, we've learned a lot about what it takes to make meaningful drugs. Obviously, as I said, we're still early, but we've had some exciting times at Kymera, demonstrating what a degrader can do for patients with complex autoinflammatory diseases. And we've also learned a lot about what type of targets are best suited for protein degradation. And then we also said we're committed to go after larger opportunities. And you'll see, once you think about all of those, you'll see that our focus in immunology is, you know, hitting all these pillars that we want to focus on. And I think in January, what we'd love to be able to share with all of you is new, new programs that will be approaching the clinic.
Again, target types that we're very familiar with, the transcription factors, scaffolding proteins, in pathways that have validations by either biologics or small molecules, where we believe we would have an extremely competitive profile in markets that are, you know, $10 billion, $20 billion plus. And so that, you know, without giving away too much, that hopefully will be enough of a teaser to tune in on January fourth. And then, you know, we'll have time to follow up during the following weeks with everybody.
Mm-hmm. Mm-hmm. Absolutely. You started out at the beginning by saying that the most important part, you know, will be ultimately seeing the clinical impact-
Yes.
... in the specific drugs. How do you prioritize, indication selection and therapeutic areas? You have oncology. You seem very excited about the emerging immunology portfolio. What's your priority in terms of the strategic focus?
Well, I would say that, you know, we set a very clear bar from the start. I would say maybe we've refined that bar, maybe for everybody a bit, or we've communicated a more refined bar last year about what are the things that we really care about. And as I mentioned, you know, part of that decision was discontinuation of one of our programs that didn't quite fit the criteria that I just talked about. So we're excited about all the programs that cleared that bar, meaning, meaningful drug, best-in-class mechanism, broad indications, clinical and commercial opportunities. And whether they're in immunology or oncology, they have to clear that bar.
We believe right now that there is higher probability of having more programs that fit that profile in immunology than in oncology, just if you look at how the space is evolving. But, you know, as I said, we're very excited about the existing oncology programs, and as long as they continue to fulfill these criteria, we'll be continuing to be excited about advancing them. I mean, you know, we will be going in large areas, so you know, at some point there'll be discussions about what Kymera does alone and what Kymera does in partnerships. But I think now is not the time to have to define those conversations.
Mm-hmm. Absolutely. Well, with that, Nello, thank you so much for joining us, and we look forward to all the updates.
Thank you. Thanks for having us.