All right, welcome to the B of A second day of the healthcare conference. My name is Geoff Meacham. I'm the Senior Biopharma Analyst here at B of A. We're thrilled today to have Kymera Therapeutics, and with me on stage is Nello Mainolfi, who's President and CEO. Nello, good to see you.
Thanks, Geoff.
Yeah.
Thanks for having us here. Great conference.
Yeah. So, give us maybe, like, the five-minute, you know, or a couple-minute high-level, focus for this year and going forward, and then we'll get right to some questions.
Yeah. So, you know, we're—Kymera is a company focused on taking targeted protein degradation and use it for creating a new generation of medicines, mostly focused in immunology and oncology. We have a lot going on, and we have a lot of upcoming data readouts in the next 6-12 months. So, maybe starting with, we have two oncology programs that are really about to conclude our phase 1 dose escalation study. We have an update at EHA with our STAT3 degrader, KT-333, which, you know, I'm sure we'll discuss. Some exciting data in heme that we're seeing. We have an update for our MDM2 degrader at ASCO. We haven't... The abstract has not been released yet. You know, exciting data there in both heme and solid tumors.
And then, you know, next year, we'll be really focused heavily in immunology. We have our KT-474 program in partnership with Sanofi, an IRAK4 degrader. We expect to have phase 2 data in both HS and AD in the first half of 2025. Then we have our STAT6 wholly owned degrader. We're starting phase 1 in the second half of the year. We expect to have phase 1 data in the first half of 2025. We have our TYK2 degrader that, we're starting phase 1 in the first half of the year, with hopefully data in the second half of next year. And, you know, we have a lot going on under the hood, as they say. We might be able to share some new programs or new exciting research that we're doing at Kymera.
Maybe we'll share something in the first half of next year, too. We'll just have to see, depending on how busy we get with all the clinical readouts. So maybe I'll pause here and go from there.
Yeah, that's perfect. Yeah. So I guess, Nello, you know, when you guys, you know, IPO'd, there were a number of TPD companies out there, and I think investors kind of threw them all together with the idea that, you know, one company's technology sort of has read through to another's. And as it turns out, that's not really true, you know. And so you guys have avoided a lot of the, you know, pitfalls from some of your competitors. Give us a perspective on kind of how you view the Kymera platform and what you think is unique about it relative to other TPD companies.
Yeah. So, yeah, so going back, we IPO'd in 2020, August. You know, since then, we took four programs in the clinic. We've seen high fidelity of translation of PK/PD safety and early efficacy. You know, not much that surprised us in the translation, mostly positive. I actually bring it back to, we have been very focused on, as a platform-based therapeutics company, I like to say, instead of a platform company, we've been focused on what is the platform going to do for patients? And how do we marry the benefit of the platform with the unmet need and the opportunity? And so we've been much more, I would say, therapeutic focused than, you know, kind of trying to identify proof of concept for the platform.
You know, I can't say that we got everything 100% right, but we focused on targets that had not been drugged or drugged well, where protein degradation is the best way or the only way to tackle them, and the targets that we believe were in areas where, you know, patients were looking for new opportunities. You know, while we're, you know, I would say between early and mid-stage development, I can say that if I go through the programs, if I start with IRAK4, I think IRAK4 degrader has a profile that is not seen in immunology. This is a Th1, Th17, even partially Th2 broad anti-inflammatory agent with a de-risked safety profile based on human genetics that could be applicable in a wide variety of indications.
We're starting in HS and in AD, but we can go way beyond, and we've seen some really early exciting data there. STAT3, we're seeing some exciting data in some indication in heme oncology for a mechanism that hasn't really been explored before, without any dose-limiting toxicity. Same can be said about MDM2 in terms of potential. You know, if you think about STAT6, it's, you know, probably the perfect target for protein degradation, a Dupi-like in a pill. TYK2, again, lots of promise for the mechanism, but I think the small molecules haven't delivered, and I think we have a great opportunity there.
I don't like to speak about other companies, but I think for Kymera, we've been focused on first becoming master of the technology, and then importantly, applying it for the right targets, where we know and we expect the biology to marry the technology well.
Is there a number of patients for, you know, across the board in I&I and oncology, once you hit a certain threshold, you'd feel pretty comfortable in sort of the target, like a platform risk?
Yeah
so to speak, right? Like a tipping point, you know, of, okay, now we can move forward more aggressively to focus more on efficacy now that we have treated patients for a certain length of time.
Yeah, that's actually a great question. So there is different ways probably to answer that question. I would say that we've actually dosed our drugs. I was just doing the math while you were asking the question, to probably north of 200 patients now, across our programs, probably even more than that. So I think there is two aspect. There is, you know, how many patients you've dosed, and then how long you've dosed your patients. You know, for our immunology franchise so far, we've dosed a lot of patients, and but only recently we've started to dose, you know, 16 weeks, you know, in our phase 2 study. And so that data is maturing and is evolving.
We don't. You know, we expect, given that we've dosed that drug to 150 patients already, we feel pretty good about the profile. In oncology, maybe less patients, but for longer. You know, our STAT3 degrader has been dosed, you know, to probably, as of the abstract, around 40 patients now, but in many cases for, you know, multiple months. I think we have patients with 10 cycles, so we're talking about close to a year. MDM2, kind of similar. So... And then we have extensive preclinical safety. I think what I can say about safety, if I look across the industry, is that there is no protein degradation-specific safety concern. I think that has been already de-risked by, you know, Revlimid and the E3 degraders, small molecules that have been on the market for years.
I think what we learned that, depending on the target biology, you might see target-specific safety issues, and that's true whether you use degraders or you use small molecules. I think or biologics or RNAi. I think it's important, though, if you pick a degrader target, there is two paramount things that we at Kymera care about. First, specificity. It is critical that you're very specific for your target because this is a very powerful technology, and you don't want to degrade other proteins. And then that you know very well what is the biology of your target. And when you do have the biology of the target, it can be so powerful that it can go beyond the expected pharmacology. For example, think about MDM2 degradation. We know that MDM2 complete degradation 24/7 is non-compatible with a beneficial therapeutic effect.
And so there, you know, you have to get creative with maximizing your therapeutic potential of the mechanism with the beauty of the technology. So for example, for MDM2, we know that if we give a degrader to a sensitive cancer cell, that cancer cell is going to die in a matter of hours, at least committed to apoptosis in a matter of hours. So what we have devised for mechanism like this, we have this pulsatile dosing. We dose once every three weeks with an MDM2 degrader, and we can see robust activity in the absence of any, for example, thrombocytopenia, neutropenia, things that are known to plague the MDM2 mechanism.
So I think you also have to optimize and really think about how the technology works, and then optimize how you dose this molecule when you work in mechanisms that are fundamental to biology.
Is the conversation different, are the markets different between I and I and oncology, I think from a risk-benefit perspective, right? I mean, I and I indications can be obviously not, you know, not lethal, but pretty severe and devastating, right? But-
Yeah. So I mean, look, I think our goal at Kymera as part of building, you know, a global player in immunology and other diseases as we continue to grow the company, our goal has always been if we build molecules like our... You know, if you look at our immunology franchise, these are meant to be oral degraders with biologics-like activity. So our dream is that we can dose, we can treat as many patients as possible. So when I think about, for example, STAT6, which is a program that we wholly own, and, you know, is in the IL-4/IL-13 biology, you know, there is about 150 million patients that suffer from Th2-driven inflammation. Now, a subset of those have mild-- they have moderate to severe.
A large percentage of those have mild disease. A drug that could, that has the potential to have Dupixent activity and safety, potentially, with the convenience of an oral drug, our dream is that we can put the drugs in the hands of as many patients as possible. If you think about Th2 inflammation, that is a very severe disease, when, especially when it impacts small children.
Yep.
You just have to do a Google search to see 4-, 3-, 4-, 2-year-old children with severe atopic dermatitis, children with severe EoE. These are life-changing experience, and I think we want to serve those patients with a convenient, effective, and safe therapy, and that's the value proposition there.
Yep. Well, let's get into some of the programs. So, KT-474, help us with kind of the, how you view the target profile relative to, you know, there's obviously a pretty competitive landscape, you know, across, you know, many I and I indications, but, you have good proof of concept.
...Yeah, you know, I like to tell the story that when we started our IRAK4 program around, you know, 2017, we started talking more broadly, I would say 2019. And we were saying, you know, our first indication, at least at that time, was HS. We were met with a lot of skepticism. You know, I think at the time, there was only one drug in HS that was active. It was Humira, that has some activity. And then the, as I'm sure you recall, Geoff, we as a drug development industry, had been facing lots of failures in HS.
It was thought to be an intractable disease, and now it's great to see, you know, many drugs, you know, more drugs approved, many drugs that are active, and now the fact that the notion that almost now HS is a, you know, is a competitive space, which obviously is good for patients. So what I would say, sorry, long story, but to get to the short part of it, the immunology landscape has been changed by biologics. Biologics have served two things. They've validated the biology. If you think about TNF, IL-17, IL-4, IL-13, IL-23, IL-12, these are all huge mega blockbuster drugs that have told us these cytokine, these particular cytokines and mechanisms are responsible for diseases. They've done that, but they've also changed the treatment landscape.
Ten years ago, if you had RA, you wouldn't have almost any reasonable therapy. If you have psoriasis, you would have topical creams and some general anti-inflammatory agent. I think now we have targeted therapies that have changed the landscape. The future of immunology, I believe, is having oral therapies that will have much broader application. And so IRAK4, going back to your question, is a typical example of a drug that has a broad anti-inflammatory profile. You know, IL-1, IL-1, IL-18, IL-33, IL-36, TLR7, TLR8, TLR4, these are all agonists of this pathway that have shown to have activity in a wide variety of diseases. The goal here with an IRAK4 is to have an oral drug that can have a broad anti-inflammatory effect.
You know, our goal is not that we need to be better than an IL-17 drug in HS, or we need to be better than Dupixent in AD. Our TPP is we want to have an active drug that is well-tolerated, that can be one of the key tools, ideally, the first-line tool for patients that, as you know, go through so many treatment paradigms to manage their disease over their lifetime. And so our goal is an active drug with a good safety profile that is convenient and accessible.
Right. And when you have a derm indication, obviously, you sort of visually... there, you-- in theory, you could move faster, you could de-risk faster, you could kill drugs faster. When you shift gears to, to, let's say, STAT6, you know, STAT6, looking at, you know, either pulmonology or GI diseases, like how, you know, how do you think about, you know, that in the, in the context of the potency that you could achieve with a, with a degrader?
Yeah. So we've shown in derm the beauty of... So the beauty of protein degradation, you can monitor target engagement over time. So you almost know in real time the level of degradation, for example, in the case of our experience with IRAK4 in blood and skin, after one dose, after 14 doses, after 28 doses. And that tells you, you know, how you are impacting both the target and the downstream biology. And we've built a lot of knowledge and expertise around the correlation between the central compartment and the skin or other non-central biomarkers.
I think we have built enough knowledge, both in the clinic and pre-clinically, to being able to be quite comfortable to generate data that can speak to other tissues. I mean, in our pre-clinical species, we've shown robust degradation in lungs with STAT6 in both non-human primates and rodents at concentrations that are similar to the ones that we see in blood at the same doses. So we know that we can see a one-to-one correlation between, you know, lungs and central compartment. We've done the same for GI, for spleen. So I think we understand enough about the compounds, both potency and distribution, that we believe venturing outside of our initial foray in derm should be something that we can do comfortably.
Right. When you look at HS, I mean, you brought that up, you know, there's it's been recently a more competitive space. You see a lot of major pharmas, big biotechs, go after more orphan, you know, indications right across I and I. Is that, you know, is that still, in your view, a faster path strategy? I feel like now FDA may not, you know, give you speed concessions, right? They still may require the same, you know, kind of work, you know, de-risking. Is that so is that something that, you know, you think over time you could go after more rare indications and with some speed?
So, it's an important question. So I want to start by saying that going after—you know, rare disease, orphan diseases is important as an industry because patients suffer, and we don't want to build an incentive structure where we're no more incentivized to go after smaller indications. This is the risk of some decisions have been made by outside of, let's say, the biopharma industry. Having said that, I think as a growing biotech that is aspiring to be a global player, and understanding how pricing pressure and regulatory environment is evolving, we believe that going in large indications first is the priority.
Right.
I think in order to build compelling medicines, and in order to pay for the development of those drugs, you need to prioritize larger indications. So for example, I mean, we've already done with IRAK4, with HS and AD, which are important, you know, common diseases. For STAT6, we believe that it's important to prioritize AD, asthma, COPD. We will go after the smaller indications, too, but in a more staggered manner. And that is because, right now, and I believe in the future, volume will be important, with regards to value creation for our medicines. And the pricing, will not be, what decides, you know, how much valuable some of these medicines are.
The IRA obviously plays a pretty big role into that. Go after the big indications first.
Yeah. I mean, you know, I think, you know, IRA, depending on the indications you're after, might have limited impact. Nonetheless, you know, if you think about AD, asthma, EoE, PN, I mean, some of these diseases in TH2 inflammation, these are 80% non-Medicare covered. I think COPD is the only one that probably has 80% Medicare impact, and that's probably the most impacted by IRA. But regardless of that, I believe that IRA or not, the way we have to think about pricing our medicines will have to come from a place of responsibility. And so if we do that, then you imagine that volume will be important, and regardless of how IRA will evolve, right? No matter what, there will be probably new regulations by the time some of our drugs are approved.
And so I think thinking about addressing large patient population and getting our drugs to as many patients as possible is how we're thinking about developing our medicines.
Right. Well, let's switch gears to oncology. But I think one of the sort of platform kind of question that I would have is, when you look at a lot of, you know, novel mechanisms in oncology, the goal here is to limit resistance. And so, I guess the question for, you know, for you, Nello, and Kymera is how much of a role does genetics play into, you know, into the discovery process, target selection, just given, because I, I'm not sure. I don't know if, you know, E3 ligases or components of the ubiquitin proteasome tend to pop up a lot in some of these, you know, liquid tumors that are very refractory, right?
Yeah. I mean, that's a great question. So obviously, one of the most unfortunate aspects of how cancer progresses is resistance mechanism, right? We see in every tumor types, whether it's resistance mechanism against that particular target through mutation or through other mechanisms. And unfortunately, that's the reason why we haven't been able to conquer such a complex disease or multiple diseases, multitude of those diseases. With regards to how you think about protein degradation in oncology, so you have one big plus, which is we're actually removing the protein, and we're allowing less evolutionary pressure to that particular cancer cells, because most of these mechanisms, at least in our hands, are driving cell death and cell apoptosis through removal of target.
Now, because you're using E3 ligases, in a way, you can imagine that cancer has now two protein they can play with to create resistance mechanism. You have your own target you're going after, let's say it's MDM2 in this case, just for using my own example. And then you have the E3 ligase that we're using to drive degradation. And in fact, it's known that in multiple myeloma with Revlimid, one of the escape mechanism, resistance mechanism, is regulation of cereblon, which is the E3 ligase responsible for the action. I think where the space is going in oncology, and for sure at Kymera. So first, we're not seeing the level of resistance, at least preclinically, and so far clinically, that small molecules have seen, and maybe it's because we removed the protein.
Additionally, I think responsible drug developers with protein degraders are thinking about using E3 ligases that have, that are essential to the cell. So if you do that, and you know there are companies, you know, we are working on novel E3s that are essential, that allow you, the cancer, not to obviously downregulate that particular E3 gene, because that will have an impact on actually its own survival. I think that's kind of maybe 3D chess level of players that we're thinking about for degraders in oncology, but there is an area that I think you have to think about. Yeah.
... Yeah, and I guess on a as a follow-up to that, when you think about the, you know, the protein degradation, you know, pathways, it's very foundational to a cell, and if you look at other, you know, drugs, for example, like Velcade, it does show some activity in solid tumors, but obviously myeloma is the-
Yeah.
You know, is the core. Is there an idea that, you know, you could use, you know, E3 or whatever target you have in the degradation pathway that could work equally well in liquid and solid tumors?
Yeah. I mean, I don't think that's, that comes down to using degraders or not. I think this comes down to the target you choose.
You just don't see too many drugs that work in both.
Yes.
Yeah.
But that's because... I mean, I think what I would say is that it's, you know, the bar in to be really active in solid tumor is really high, and that's true for every type of mechanism. And I think a lot of novel mechanism tend to have, you know, more activity in heme, because it's just... I think the bar for having activity in heme oncology is generally being determined to be lower. I think there are drugs that work in both, but they're, you know, less.
I would say that, you know, a mechanism that is fundamental to tumor biology, again, for example, MDM2, I think we, you know, at, at our ASCO update, you know, our goal is to share that, you know, we can see activity in both solid and, and liquid tumors, given that we have two arms in AML and solid tumor lymphoma. I think there are other mechanisms that can show the same, but I agree with you. I think it's, it's just not been shown often.
Right. And I know you haven't talked about the data, but for MDM2 or for STAT3, can you... I guess, what does, you know, what would you view as a success from a, you know, from a data disclosure-
Yeah
-in oncology?
I mean, for KT-333, STAT3, we, you know, the abstract for EHA is out since yesterday, so I can speak a bit more. You know, for that mechanism, again, going back to the solid tumor, liquid tumor, preclinically, we've seen as a single agent, robust activity in T-cell lymphomas and leukemias. Really no activity as a single agent in solid tumor, but intriguing activity in combination with PD-1 and actually other agents. In what we have shown up at ASH last year confirmed activity in CTCL and some early activity in other tumor types. I think here at EHA, at least in the abstract, we're showing some more activity in CTCL in terms of PRs. And I think we're seeing a really intriguing signal in Hodgkin's lymphoma.
In classical Hodgkin's lymphoma, we have two, the first two patients on the study, we saw two complete responses. These are patients that are coming after standards and after PD-1s. And we saw refractory to both mechanisms, we're seeing both complete responses there. We might have more data by the time we present the poster. This is an intriguing, a kind of novel mechanism. We expect that this is driven by immunomodulatory mechanism of STAT3, which actually bodes well with the fact that we're expecting this mechanism to work well in combination with PD-1 in solid tumors. So that's gonna be an interesting discussion, EHA for STAT3. And then MDM2, I mentioned, we don't have the abstract out.
All I can say, we'll have more patients in heme and solid, and hopefully, we are able to show activity in the absence of the typical dose-limiting toxicity, which has been mostly thrombocytopenia and neutropenia, which we've shared preclinically. We're able to create a therapeutic index that thanks to our degrader mechanism and the fact that we can dose less frequently, and hopefully, we'll be able to continue to show that.
What do you think the likely next step is? And either is it a registration phase 2, or do you want to, you know, sort of go methodically, you know, into a dose-finding phase 2 and then a larger phase 3?
I think it depends. It's a great question. It depends on the type of activity and the indication. I think it, maybe it's too early to tell, but I can say that we're thinking about, depending on the mechanism of indication, we might have different options across both programs.
Okay. Makes sense. Thank you very much.
Thanks, Geoff.
All right.
It's been great.