Today, we're gonna get started with our next presenting company, Kymera. My name is Ted Tenthoff. I'm a senior biotech analyst at Piper. And before I begin, I'm required to point out certain disclosures regarding the relationship between Piper and Kymera that are posted both at the back of the room and also at the registration desk. So as you may know, Kymera is a leading targeted protein degradation company focused on undruggable targets. Partner Sanofi is conducting phase II studies of KT-474 in atopic dermatitis and also hidradenitis suppurativa. And Kymera will report phase I data on their STAT3 degrader, KT-333, at ASH in just a couple of weeks, and also host an R&D day in early January, I think maybe on the 4th-
Fourth, yeah.
Regarding the company's efforts in immunology. Here with us today from Kymera is Founder, President, and CEO, Nello Mainolfi. Nello, always a pleasure to see you, sir.
Good to see you, Ted.
So the entire protein degradation field has suffered some major pullback during the recent biotech downturn. And we really see this as with all of the different technologies, where there's first this period of unbridled excitement, and then the reality of development sets in. And now it's really up to the leaders in the field to report data that provides promise of the underlying technology. This is exactly the point where I think we are with protein degradation. So Nello, let's start with 474. Why is IRAK4 such a good target to degrade, and walk us through some of the safety and efficacy data you've reported so far.
Yeah, thanks, Ted. Thanks for the invite. If you don't mind, I just want to comment on your comment about protein degradation-
Sure.
- and the space. I mean, I think with any new modality, there is an aspect of early validation of the technology, and then there is an aspect of validation of the product-
Yes
... of the assets that you build. We at Kymera, I can't comment on the space, I think it would be inelegant, but at least I just address the Kymera story. We are focused on building products, and we, to be honest, took for granted that a targeted protein degradation can, is a technology that can give rise to meaningful drugs. And so our target selection, our execution, our strategy has been focused on building meaningful assets that would bring outsized value to patients first and then to all shareholders. And I cannot imagine... I mean, if I go back several years ago when we founded the company, everything that we said we were going to do, every program that we've taken into the clinic, we've seen the right level of translation.
With KT-474, that we'll touch in a minute, we've seen translation of PK, PD, safety, and early signs of efficacy with limited number of patients, as you know. For KT-333, our oncology programs, we've seen the same translation. I'm sure we'll talk about it, of key safety, PK, PD, and early signs of efficacy. MDM2, we've seen the same. Even for KT-413 that we've decided to discontinue, that was not because of lack of efficacy or dose-limiting toxicity. So, I think if you select the right targets and you execute embracing the fact that you're developing a novel modality, I think you can do well. Now, we can't comment on the broader market dynamics that probably plays into it, but we feel really good about where we are.
And, you know, to your point, though, you're absolutely right. A lot of the other companies sort of said, "Okay, novel technology, you know, let's take known targets." But I love how you guys have gone after novel targets and frankly, built the broadest pipeline in the clinic of really any protein degrader-
I agree.
degrader place, so.
More is to come, as you know.
Yeah.
But let's start with KT-474. So why is it such a good target? So, our philosophy for target selection is based on four key pillars. We like to work in pathways that have had clinical validation, where there is ideally human genetics data on the actual target, where protein degradation is the, or that target, that particular target has not been drugged or fully drugged by other technologies, where protein degradation is the unlocking technology, and then importantly, a target that we believe has meaningful clinical and commercial opportunity. And so IRAK4, actually being the first target of our pipeline, I think is able to represent all of these pillars at the fullest. So the pathway's been validated by biologics. We have an...
So the pathway, the IL-1 TLR pathway, sees signaling of cytokines through the receptor, that signal through the myddosome complex, of which IRAK4 is a key node, and IL-1 beta has a drug approved, IL-18 has a drug that actually GSK is taking into AD with some early interesting data. IL-33 has shown activity in several other immune indications. IL-36 has shown activity in several other immune indications. So we know the pathway is relevant in immunology. IRAK4, as a scaffolding kinase, has been drugged with small molecule inhibitors, I would say, with limited impact because the function of IRAK4 goes beyond the kinase function. So with a degrader, for the first time, we're able to show both preclinically and clinically, that we can block the pathway fully.
So now you have an oral degrader that can have the clinical impact of the whole family of IL-1 family cytokine blockers, again, in a single oral molecule. So that's really the unique biological and clinical opportunities. And then in terms of indication, as you know, HS and AD are the first indications that Sanofi and Kymera are moving forward. But this, I would say, is the, is really the tip of the iceberg. We have plenty of other opportunities that make both clinical and commercial sense that, we hopefully will be able to prosecute as the molecule continues its clinical development.
Now, Sanofi exercised their option last year, maybe around the time, I think, you had an R&D day, and it was lined up perfectly. You know, tell us about the phase II studies that they're conducting now, and remind us of what your retained economics are-
Yeah.
-on 474.
Yeah, let's start maybe with the economics, to remind. So we signed this deal in 2020. Seems like 20 years ago. Only three years ago, everybody. And so we had the program was at that time in nine enabling studies that came with a $150 million upfront, $1.4 billion of milestone just for this program. About a $1 billion-dollar around clinical and regulatory milestones. And more importantly, we have milestones at initiation of every phase of development across multiple indications. As you know, we've disclosed recently that the first patient dose in HS triggered a $40 million dollar milestones. We expect to have a first patient dose in the AD study quickly, soon, and that will also trigger another milestone.
And more importantly, besides, you know, this healthy and rich milestones, is the opportunity that Kymera has now that Sanofi is in charge of the program, to go back in and co-develop and co-commercialize the drug in the US, splitting 50/50 costs and profits, while at the same time having, some, relatively, rich royalties in the rest of the world, double-digit, high teens royalties. So that's on the economics. With regard to the trial, just to summarize the data we've shown, in the phase I study that was conducted by Kymera, we've shown full degradation of target in blood. We've shown robust degradation of the target in skin. We've shown a good safety in healthy volunteers, and importantly, in patients, we've seen strong anti-inflammatory effect, both systemically and in the skin.
We recently published a Nature Medicine paper that actually goes even in more details about what we've seen in blood and skin. And we've seen impact on signs and symptoms of HS and AD. Again, this was a small study, so hard to know how the signal will evolve, but if you look at the totality of the data, there is clearly a strong signal of activity. And so we look forward now that Sanofi is in charge of the program, again, initiated both HS and AD studies. These are placebo-controlled randomized studies, where we expect, based on clinicaltrials.gov information, to complete recruitment by the end of 2024, to complete the actual study in January, February of 2025, and having data in the first half of 2025.
We believe that the studies are powered to evaluate the clinical activity of the drug-
Yeah.
versus placebo.
It's gonna be exciting. Just in the interest of time, I wanna kinda transfer to some of the other ones.
Yeah.
But obviously, broad opportunity with Sanofi, with KT-474. So now your lead wholly-owned program is STAT3 degrader, KT-333. I love this program. I love this target.
I'm aware of that.
I tell you every time. So walk us through the biology. Why is STAT3 such an, such an interesting target?
Yeah, I mean, STAT3 is, you know, one of those, undrugged transcription factors that, you know, if you look in the literature, you do a PubMed search, you'll find probably 30,000 publications. The role of STAT3 in human biology, as it's been studied, goes from modulation of inflammation to, oncogenic driver of many type of tumors to a fibrotic, signaling molecule. Clearly is a key, driver of regulation of the systems across many indications. The challenge with targeting STAT3 is that, you know, this is a DNA-binding transcription factor that actually resides in the nucleus. In the cytoplasm and then is, moves into the nucleus as it's activated in its, phosphorylated form. And, you know, it's been challenging to track with small molecules.
There are some, there have been, you know, for a while-
Yeah
... small molecule SH2 binders that have limited ability to fully block its role, and so we felt that by degrading the target, we will have the only full context independent agent to target STAT3. And so what we know, for example, in oncology, that STAT3 has a cell-intrinsic role in driving cell proliferation of many T-cell malignancies, but also has an immune modulation role, especially with regards to maintaining a tumor supportive microenvironment. So the removal thereof will allow to have a high inflammatory burden around the tumor that will allow activity, especially in combination with PD-1.
So in our phase I studies, we're evaluating the drug as a single agent in dose escalation for now, and, you know, the expectation going into the study was to being able to hopefully replicate the single agent activity in the T-cell malignancies, and when it with regard to solid tumors, trying to tease out this immune signaling phenotype hopefully by a tumor biopsies that would allow us to build further confidence to explore combination therapies beyond phase IA.
You reported some data earlier this year at the International Malignant Lymphoma Conference. This was just on the PTL side. Maybe walk us through there and what we should expect at ASH.
Yeah. So what we've shown so far, and again, I think we're a company that's been able to show the translation over four programs now. We've shown that what with the profile that we had developed pre-clinically translates really well clinically, degradation, dose-dependent degradation, all the way to close to 90%. We've seen also translation of PD. We see impact on downstream biomarkers like even CRP or SOCS3 that are downstream of STAT3, so showing that we're able to impact genes downstream of STAT3 in a dose-responsive manner. We've also shown really robust safety. I mean, the drug is seen, at least as of the latest disclosure, be well tolerated in patients that have had it even after multiple months of therapy. So there was an initial kind of validation.
We call it proof of mechanism.
Sure.
What we look forward to demonstrating in the upcoming readouts is an early proof of concept. Basically saying, now that we degrade the target well, does that have an anti-tumor effect in patients that are sensitive to this mechanism? So again, the sensitive tumors that we've seen pre-clinically, CTCL, the LGL, the PTCL, and so those are patients that hopefully we would recruit to this study and demonstrate that the degradation leads to an anti-tumor effect.
Great. Well, we're looking forward to that. You mentioned the broad mechanism here. How ultimately do you envision developing this drug even beyond, T-cell lymphomas?
Yeah. So I would say if we stay for a second in oncology, as I mentioned, beyond the T-cell malignancies that are interesting opportunities, but obviously limited to a relatively well-defined subset. I think the bigger opportunities are the ones in solid tumors. And I think if you look at the literature, there are examples of the role of STAT3 in non-small cell lung cancer, in head and neck cancer, in colorectal cancer, mostly in our experience, potentially in combination with other agents. And so I think generating supportive PD and safety and target engagement data in phase I, combined with preclinical data that we're still building, will allow us to invest further into expansion in solid tumors.
Looking forward to that. So MDM2 may not be a target that people are familiar with, but people certainly know about p53. So walk us through about how MDM2 works to regulate p53, and tell us about your degrader KT-253.
Yeah. So p53 is the most common tumor suppressor gene. It is wild type in 50%+ of tumors. And what does it mean to be a tumor suppressor gene? It means that elevating a tumor suppressor gene, suppress tumors, and so the industry has gone after p53 elevation. There's also another mutation aspect that I'm not gonna touch on, but the largest opportunity is in wild type p53, potentially millions of patients. And the idea is, if you upregulate p53, tumor cells will die, again, because it's a tumor suppressor. So, MDM2 is the E3 ligase that is responsible for regulating p53. So if you remove the E3 ligase, p53 should go up, and in fact, it does go up.
With small molecule inhibitors, we've seen the inhibition of p53 MDM2, and that has had challenges because the way the cancer cells function, that as they see elevation of p53, they naturally increase levels of MDM2, again, to regulate p53. And so small molecules have had challenges overcoming this feedback loop. With the degrader mechanism that you know well, Ted, we can catalytically remove MDM2. So we actually do not allow the feedback loop to get in the way of the biology, and so we're able to degrade MDM2 fully, and in a few hours, have cancer cells commit to apoptosis. So inherently, we're creating a therapeutic index. Cancer cells die, healthy cells do not commit to apoptosis. We dose once every three weeks, and so our thesis is we maximize efficacy while we retain good safety.
I don't believe there's been a good example of a small molecule MDM2 inhibitor that has be able to decouple safety from efficacy, so much so that most of those studies have had dose reduction issues. In our study, first patient, we've seen a very profound response without any signs of thrombocytopenia, neutropenia, which are the typical bone marrow toxicities of this mechanism. So it's very exciting. It's early data. Next year, we'll plan to report on a broader set of data, hopefully validating that this is still true, that we're creating a therapeutic index, and together with that, we're spending a lot of time building a sensitivity signature that will go beyond p53 wild type.
Okay.
We would love to be the p53 status to be the only sensitive biomarker, but unfortunately, that's not true. So we have to go one step deeper. But we believe, and we'll disclose this next year, probably together with the clinical data, that our signature of sensitivity will allow us to go broadly in both liquid and solid tumors.
Very cool, and a really interesting program and cool approach. Now, you've hinted at an IL-4, IL-13 degrader, by which hinted, I mean, it's on your pipeline slide on the website.
It's on our website, yes.
So-
But we didn't say what the target was.
Right.
Although we're hearing a lot of good guesses, so.
This is obviously the pathway of blockbuster, blockbuster Dupixent. You know, what can we expect from the R&D Day early next year?
Yeah, no, it's. I mean, it's very simple. I know it feels like Kymera is doubling down in immunology today, but in reality, we were the first company in immunology. And once we saw the clinical data, and all it took for us to learn how to design and discover and develop a degrader in immunology, you know, 2, 2.5, 3 years ago, that we saw that translation, that validation and the opportunity that immunology gives, we decided to really double down on immunology. And for us, it's very simple. Immunology is a field that is dominated by biologics. Biologics have validated pathways. If you think about TNF, IL-17, IL-4, IL-13, IL-23, these are all mega blockbuster drugs, right? That are validated pathways. For us, it's really simple.
We believe that protein degraders is the only class of drugs that can be compared in terms of specificity and efficacy to biologics, but have the convenience of small molecules. Unlike traditional small molecule based on inhibition, that are never able to mimic the biologic because they're not able to block the pathway to the same extent, we believe degraders can do. So we started this work several years ago, and now that we're at the cusp of, you know, entering IND-enabling studies in the clinic, you know, we want to be able to share where these new clinical programs are. And again, these are in this mega blockbuster space, where we believe we'll have a potentially best-in-pathway differentiated drug.
So with so much going on, you've already had the partnership with Sanofi, obviously, for KT-474. You had an earlier stage discovery deal with Vertex. How is partnering going to fit into Kymera's long-term strategy?
I mean, look, if we want to build a global commercial stage, large biotech, we have to continue to think about how to do that organically.
Yeah.
It's silly to think that Kymera is going to develop all of our drugs on our own.
Mm.
You know, there are synergies to find. I think, you know, if you look at Sanofi partnership at the stage in which we signed that partnership, made a lot of sense.
Yep.
You know, today, maybe we wouldn't do that type of partnerships, but at the time, it made a lot of sense. And so how do we continue to think about forward integrating the company, and maximizing value? I think it's hard for us, especially in immunology, to partner before we have meaningful proof of concept data. Because first, we believe we're the best at doing that, we believe we'll be the fastest at doing that, and we believe that's where we want to invest our money.
Right.
There might be other areas, or there might be opportunities where, you know, synergies can be built. So I think Kymera continues to explore those BD opportunities, but, they will have to really make sense.
Yeah. And also, that's a point where you really see that kick up in valuation-
Exactly
... too, that can be recognized.
Yeah.
So, um-
At some point, they'll have to have that.
Yeah. So with, with all that said, you know, resources are finite-
Yes
... in this, in this environment. How much cash do you guys currently have, and how long does this fund the company?
So we have about $440 million.
Maybe another milestone coming, right?
Yes. So actually, the 435, I believe the number is-
Yeah
... does not include the $40 million that we just got or the next one. But the runway that we're seeing into the first half of 2026 includes those two milestones.
Yeah.
So I think, so it's important that we have a long cash runway, first half of 2026. More importantly, what are we going to see between now and then? We're going to see the ASH data.
Yep.
We're going to see the R&D Day. We're going to see a meaningful data set on MDM2 next year. We're going to see the complete phase IA data of STAT3 next year. And we're going to see the phase II data for 474.
Yeah.
We'll see more, just wait for the R&D Day in January to share more about the timelines of the new programs.
Cool. Well, I'm looking forward to it. I think it's virtual, so everybody can attend.
Everybody should attend.
Everyone should attend. All right. No, thank you, as always.
As always. Thank you.
Thanks, everybody.