Kymera Therapeutics, Inc. (KYMR) Earnings Call Transcript & Summary

Good morning. Welcome to the third day of the Bank of America Healthcare Conference. My name is Geoff Meacham, I'm the Senior Biopharma Analyst here. And we're really excited today to have Kymera Therapeutics. Speaking on behalf of Kymera is the CEO, Nello Mainolfi. And we're going to do like a 5-minute or so presentation and then we'll do a Q&A afterwards. Nello?

Thanks, Geoff. Thanks for the invite and the opportunity to present. We just have a few slides of introduction, just to set the stage for the Q&A that we'll have in a few minutes. Just to remind everybody, Kymera was founded now almost 6 years ago with the goal of building a fully integrated biotech that will be able to take targeted protein degradation from an early technology into a commercial stage reality. The platform is obviously disease agnostic. The platform is also target type agnostic. We had decided early on to focus in oncology and immunology for our internal pipeline, but also thanks to our partnerships, especially with Vertex, we're able to work on 7 different diseases, 5 outside of oncology and immunology. We can say we're already a disease-agnostic platform. As we've done from the early days, while our goal is to continue to fully integrate the company, it is important to also synergize with the biopharma industry. We found opportunities of real win-win collaborations with companies out there that can provide us with the opportunities again to build new capabilities. We have, as I mentioned already, collaboration with Vertex that is focused on diseases and targets outside of oncology and immunology, and one with Sanofi where we're collaborating on our IRAK4 program as a clinical and commercial collaboration as well as another earlier program that we haven't disclosed. You'll see this in a minute. While we were not the first company in protein degradation, we were focused on really advancing the technology and being really thoughtful about the targets that we've chosen as well as the technology evolution that we've invested in. And so that allowed us to deliver some firsts for the TPD space. We were the first company to execute on a placebo-controlled randomized Phase I study in healthy volunteer. First company to take a heterobifunctional degrader into immunology and inflammation. First company to take a degrader against a transcription factor in the clinic with STAT3. We believe that obviously there is a high level of focus on execution, but there has to be a high level of focus on innovation as we advance the company. We continue to invest in our discovery pipeline, and we have a commitment to have at least one new IND clinical program per year. And we closed the first quarter with about $523 million, which allows us to plan thoughtfully our investments in the next few years and have cash into 2025. Obviously for the 5 minutes, I don't want to go too long or too deep on details, but I think it's important to highlight where Kymera stands out in the space of TPD. And I don't refer the TPD space as only the other 2, 3, 10 other companies out there that are focused on TPD. I just would like to characterize it as a general space, including large companies that are investing in this. And even if you take the totality of TPD investment, I think Kymera stands out on a few things. The first one is our target selection strategy. If you followed us, or maybe in the next 2 minutes you'll see from our pipeline, we work on pathways with high degree of validation, but we work on undrugged targets, targets that have not been drugged or fully drugged before where protein degradation is the only way to elicit that type of biological and eventually clinical response. These are first-in-class targets that we pursue. Our platform is very differentiated. We've invested in novel E3 ligases from the early days, and so we have been able to now develop programs where we can selectively degrade proteins in the human volume. We have a program going in development that is sparing degradation from one particular tissue type for example. I think for our clinical data, we take a very thorough approach about how one designs clinical studies with degraders, which is not the same as small molecules, and I think the field is probably learning that. We've talked about the firsts. We've talked about innovation. Maybe I'll -- I know I have a couple of more slides, but maybe I'll stop on this pipeline slide. Actually, maybe just go over one more. But on the pipeline, just to level set, this is our publicly disclosed pipeline. The program there is more advanced. We have 3 programs in Phase I and one that is going into Phase I soon. KT-474, is an IRAK4 degrader. We believe this mechanism has the potential to be best-in-class anti-inflammatory oral small molecule drug based on human genetics, preclinical validation and clinical validation of other agents in this pathway. We've demonstrated some really profound Phase I healthy volunteer degradation data in blood and skin as well as a really solid safety profile. I'm sure we'll talk about it in the Q&A. And this program is now going in patients of HS and AD in a Phase I we call it Part C. You can imagine almost a Phase Ib study. Then our second program, IRAKIMiD, we degrade both direct for Ikaros and Aiolos. This is a dual degrader that is being designed to address MYD88 mutant lymphomas. That program is in patients in a Phase I study. KT-333 is our first molecule in our STAT3 franchise. You see these are large franchises, the IL-1R/TLR, oncology, immunology, JAK/STAT, so STAT3 oncology/immunology. And that's kind of the theme of how we think about target selection as well. STAT3, our first molecule, KT-333 designed for oncology indications, now in Phase I in liquid and solid tumors. And we have also other efforts that are a bit earlier in immunology and fibrosis with the same mechanism. And then our p53 stabilizer, we believe this is the first time that we can biologically replicate cancer genetics data with a MDM2 degrader that addresses p53 wild-type tumors that actually are more than 50% of tumors out there. And this program is going -- we're filing an IND in the second half of the year and going in the clinic shortly thereafter. We will have clinical data across the top 3 programs in the second half of the year. Patients' data across our pipeline, HS and AD lymphoma, leukemias and solid tumors. For KT-474, will be degradation will be -- so PK/PD impact on disease-relevant biomarkers as well as exploratory clinical endpoint. For the 2 oncology programs, 413 and 333, we will be sharing PK/PD safety and the understanding of where we are in terms of those and expectation of eventual clinical efficacy. This would be the first kind of de-risking event for those programs. I'll actually stop here, Geoff, and we can go into some Q&A. Thank you. Let me know where I should sit. Right here? Okay, perfect. And we've got Jared, our CMO as well here.

Let's talk a little bit about the TPD space. I mean there's a lot of companies in the space, there's a lot of unique skills that you guys have with respect to target identification, chemistry, etc. What would you say is the top sort of differentiation between you and some of the other companies? Everyone tends to lump them all together. But obviously, it depends on the platform independent of drugs.

Yes. No, it's a great question. I think I tried to address that in the previous slide. Generally, I think there is a philosophical approach to how one builds a company with a new technology. And our approach has always been we want to be here for the long term. We made investments on target selection, on platform, on capabilities that to be honest, we haven't seen yet fully bear out, and that's because some of them will have medium to long-term impact. We have decided to build capabilities that, again, will continue to allow us to grow in the long term. I think importantly, how we think about target selection is very differentiated. I think our targets are biologically differentiated from others' efforts in the same biological areas. And I think those opportunities, sorry, my phone is ringing, will provide us to generate data that are not just incremental over let's say small molecules, but data that will be hopefully transformative for patients. And I think maybe practically, one thing that I think we're very proud of, besides the capabilities and the technical skills, is the approach that we took in expanding the capabilities of our platform with regards to novel E3 ligases. The ability to do selective pharmacology is something that the industry has been trying to do for 50 years. And I think protein degradation is set up perfectly to use the expression of E3 ligases as a way to then selectively degrade proteins in tissues or in cell types of interest. By no means it's easy, and we spent 3 years already on this, but we believe that that will be a huge value-creating event as these programs get into the clinic.

And along those lines, Nello, when you think about the therapeutic areas, it makes sense, the I&I and oncology, hematology. But as you de-risk these indications further in the molecules, what other -- what does the science tell you to describe the role of E3 ligases? Is there maybe other indications as well?

Yes. No, it's a great question. It's actually a very topical question because those are discussions that we've been having with our team internally. Also, with some new board members that have joined recently that have built companies like we want to. And the discussion is, at which point we transition from a disease-focused company into a disease-agnostic company and actually let both the E3 ligase, but let's say the signs drive the target selection? I think initially, we wanted to stay focused, but I think we're at a critical time where we believe that that transition will probably start to happen. And that doesn't mean that we're going to be wildly going in 20 different diseases, but think about our hypothesis has always been pathway with a high degree of validation, targets that have not been drugged. And clinical and commercial opportunities there are really large. If you think of it that way, it doesn't have to be just oncology and immunology.

Right. Perfect. Well, just on the pipeline, on 474 you guys have had discussions with FDA to extend dosing from 14 to 28 days. Just talk to that and talk to the dose titration and the decision to stick with the 100 mg dose. Then we can get into some of the more specifics.

Yes. First of all, I think it's a great opportunity to clarify also a couple of things. The goal of the Part C, again, some people might want to call it the Phase Ib, but we've always called it Part C of the Phase I study. The AMB were set not healthy volunteer, Part C is disease, it is patients. The goal has always been, for a new technology in a new area, can we confirm that a degrader operates in patients with the same level of activity? It was really a simple PK/PD question that we had discussed with Sanofi 2 years ago when we signed our collaboration. Can we confirm that with different level of targets in the skin as we've seen, do we have the same level of degradation? That was the reason for this study, relatively simple de-risking event for Phase II selection. And once we completed our Phase I healthy volunteer study, we were very impressed by how the molecule behaves. And we felt that running another 2-week study was not going to add a lot of value. We thought, what can we learn more? We decided, not Sanofi, not the FDA, we decided to say, let's extend the study, measure degradation in skin, which is a relevant tissue, that we believe will take longer than 14 days to reach steady state. In fact, in a 2-week study in the skin, we had not reached steady state of degradation. Can we take it to 28 days and being able to measure PK/PD and impact on biomarkers in the skin and also add these exploratory clinical endpoints not to say that we're going to have a proof of concept in patients, but to say that we might be able to correlate patient-by-patient the PK/PD, the biomarker or any trend that we might see in terms of clinical endpoint measurements. The 100 mg dose very quickly was we thought was the right active dose. It was saturated degradation in blood, close to maximum degradation in skin, but clearly, that slope was going down drastically. With more doses, we expect that we would saturate barren skin as well. We've seen really strong cytokine ex-vivo with that dose, so we felt it was let's call it the minimal/maximal efficacious cohort.

Can you speak to -- so far, this is obviously a pretty novel mechanism across the board and so you've had a lot of comprehensive safety data. Talk to sort of your experience thus far with 474 and the totality of the data, things like liver, cardiac, kind of safety.

Yes. What I would say first of all is, I've been in small molecule directly my whole career. It's really difficult to find small molecules that have the safety profile that 474 has had that will address everything. The molecule has gone through preclinical safety going from 2 weeks to 4 weeks. We recently completed a 4-month tox study as well. Obviously in tox you do super pharmacological doses. We've always had a very, very pristine safety profile. Which again, I think it's a rarity in small molecules. What we've learned in the clinic in our Phase I, that the molecule is very well behaved. We had no serious adverse events. Some mild adverse events that were mostly headaches, nausea and palpitations, mostly nonobjective kind of findings. What we have disclosed last week, though, I will address that because obviously it's an opportunity to clarify a few things. We decided to disclose that we had also observed a non-dose responsive, non-adverse QTC prolongation that was between 10 and 20 milliseconds. To clarify, the QT interval never went above 450, so this was non-adverse. We stayed within actually the so-called normal range. The QTC delta was, again, the mean was between 10 and 20, so just above noise. And never, no subjects ever reached more than 30, so never reached 60 and above which is where the risk of arrythmia is increased. So much so that when we presented the data to the FDA to extend the duration of the study, we included this data and the feedback was very constructive, continue the study. I do want to clarify one thing about this QT that we disclosed. We didn't have to disclose, but we decided to disclose externally. This was non-dose responses, so at 25 mg or 200 mg, we saw the same effect. With nonconcentration responses, there was sevenfold difference of exposure, six or sevenfold between 25 and 200. We did not see an increase of these effects. It's self-limiting, plateaus at day 7, so between day 7 and day 14, we saw the same effect. The fact that we see the self-limited plateaued effect bodes really well in terms of clinical development. Our consultant, former FDA consultants as well as others, including the FDA feedback, was again, supportive. And we don't believe, based on all the work that we've done, that this finding as it is today will have any impact on the clinical development of these drug plans. I only want to add one more thing because there is some report about potential tie to IRAK4. I want to have the opportunity to clarify this in this venue. Based on our knowledge, our understanding and our science, there is no relationship between these very modest QT findings and IRAK4. And that's based on multiple data points. The first and most important one, IRAK4 null individuals, people that are actually born without IRAK4, do not have any phenotype. And that is much more important than some obscure paper that claims otherwise. But internally, I think we have the most definite data. And the data is what I'm going to share now. We have taken -- we have developed a preclinical cardiomyocyte assay to kind of being able to measure this finding because, I didn't say it before, we never saw any QT in any study that we've done preclinically in dogs. Maybe because it's so modest we couldn't detect it, or dogs are not as sensitive, but we've looked out to 4 months and never saw it. We wanted to replicate this preclinically, and we built this cardiomyocyte, human cardiomyocyte assay. And in that assay, we've been able to demonstrate that as you go in high concentrations, you actually can see this change of current in cardiomyocytes. That shape of the curve that points to what could be seen as a QT finding in humans in the full body. And actually, even there is time dependent. Like in humans, we didn't see it on day 1, also in the cardiomyocyte assay, it took us a few days to see it for the first time. This was KT-474. We took another degrader that we have in the company that had, very similar to 474, same E3 ligase, the same scaffold, dosed it, and we did not see any effect on current cardiomyocyte. The only difference between those 2 molecules was that KT-474, as a measurable IC50 for an ion channel at high concentration, this analog has no measurable IC50 for ion channel at those concentrations. We believe that the signal that is defining there is self-limited because I think there's only so much concentration you can get into that particular tissue. It's driven by not IRAK4, but by a very minor off-target effect of the drug.

That's really helpful context. As we move from sort of the safety studies to the proof-of-concept in patients, your next study is 28 days, I think. How much differentiation in this time period could you really see in biomarkers or anything sort of clinically predictive?

Yes, let maybe Jared answer this question.

We think that as Nello said earlier, the sort of key objective of that 28-day study is to really demonstrate that we've reached steady-state degradation in the skin, that we're able to impact inflammatory biomarkers in the skin. These are now in biopsies of active inflamed lesions in HS and AD patients. And to potentially connect those findings with clinical endpoints. Our decision to include clinical endpoints wasn't because we thought we would be able to definitively show proof of concept. As you know, these endpoints usually require 12 to 16-week studies. This is 4 weeks. But if you do look at the literature, especially at randomized placebo-controlled studies of HUMIRA in HS or DUPIXENT in AD, you can actually see by 28-day, separation between placebo and drug. I think that told us -- and you can see the same thing in some of the JAK inhibitors. This told us that we probably could potentially see some signal of clinical activity if we look at 28 days. Definitely not with 14 days, but now extending to 28 days, we think there is a possibility. The aim here is not to look at sort of a group change or impacted endpoints, but look at individual patients and to look within patients at a potential connection between IRAK4 knockdown, impact on inflammatory biomarkers in the skin in blood, and these select clinical endpoints. I think that will be a very useful exercise for us to now do as part of this Phase Ib.

Right. Okay, that makes sense. To the other programs, so 333 and 413, you guys will have your proof of mechanism this year. Give us a sense for what we should expect with respect to that data? Is it similar to what you've done with 474 in terms of just the safety and tolerability kind of disclosures?

I would just to say that our plan is, this year we'll be in dose escalation in Phase Ia across both of the programs, the 413 and the 333 programs. And I think our expectation is that as we get into the latter part of the year, we will have escalated far enough to be able to start to understand not just PK and safety, but also pharmacodynamic activity. I think one of our goals is to be able to show proof of mechanism which we define as being able to show impact on the target. For STAT3, to be able to show STAT3 knockdown in blood as well as potentially in tumors if we can get serial tumor biopsies. And for 413, being able to knocked down for IRAK4, but also the IMiD substrates, Ikaros and Aiolos, again in blood as we've done with 474, but also potentially in tumor tissue as well. And for us, what will be important is to be able to show that we can start to see sufficient knockdown of these targets with acceptable safety that would then bode well for being able to then before the dose escalate start to see clinical antitumor activity. Which we anticipate maybe seeing by the end of the year, but more likely next year when we're starting to enrich for the target patient populations within these 2 studies at doses that are active enough to potentially induce antitumor responses.

Right. Perfect. Okay. And from looking at your chart, I mean, obviously, Sanofi is your collaboration partner for 474, but your other assets are unpartnered for the most part. Nello, to what degree do you look at partnership potentially as a source of nondilutive capital. I mean a lot of your partners, they'll offer capital, but they really offer a lot of expertise. In TPD, probably not, right? What are you looking for potentially from some sort of a potential partnership?

Yes, I think it's a great question. As a company that has more ideas and opportunities than money, and that's always been our case even though we have $500 million plus, but the opportunities for these technologies are, I think endless is a bit of a cliche, but are many and vast. And the platform that we've built allows us to do a lot. There is always the discussion that we have internally always and also with others, what is the win-win for us? And I don't believe that there is any particular capabilities that we would benefit preclinically, as you pointed out, but some areas where we would be creating potential win-win opportunities could be as we've done with Sanofi for 474, other indications where there is particular knowledge, both clinically and commercially, that can allow us to forward integrate. For example, with 474, we get to co-develop and co-commercialize in the U.S. 50/50, if we choose to do it later on. That's an opportunity for us to build capabilities in the U.S. in a de-risked manner. Are there other programs, whether it's in immunology or in oncology, where they require large investments in potential large, randomized studies that we could benefit doing it in a partnership given that we have so many other activities going on? There's clearly opportunities for commercial partnerships as most companies of our size would do. And then I think there is -- there will be probably a lot of opportunities with our E3 ligase platform. To be honest, we've kept if I may use this word companies that pay on that side because there is so much competitive knowledge and intelligence that we want to keep. But we're not going to be able to prosecute the opportunities with these novel E3 ligases. I'll just give an example. We have E3 ligases that spare for example the bone marrow, the cardiomyocytes and GI. You can come up with 20 programs that we know are active clinically that have dose-limiting toxicity in 1 or more of those tissues. Probably Kymera would be not generating as much value as possible if we say we're not, we're going to do everything on our own. there might be opportunities there in the medium term that we might want to explore in partnerships.

Right. And last question, and I know you talked a little bit about the safety tolerability for 474 for your assets, but in the TPD space, there have been other companies that have had some safety issues. Talk a little bit about kind of your thoughts on tolerability from other companies in the space, including say the Curises of the world.

Yes. Obviously, let me separate. There was some data from an IRAK4 plus 33 plus other kinase inhibitors from Curis that had some safety issues. We can confidently say that those safety issues had nothing to do with IRAK4. We've never seen them preclinically. We've never seen them clinically. We believe they're actually driven by some other kinase than they inhibit. I would continue to say that we believe our safety profile with 474 is very robust and that this finding, this QT is, as we said, self-limited and not an adverse event. Again, we're talking about a non-adverse event that we choose to disclose. We have, I think we might be the only company that has run chronic tox with a degrader and in a non-oncology indication. And we've seen, as I said, I'm just going to characterize qualitatively a very good profile. We actually feel really good about the safety of our compounds, so much so that our nondisclosed pipeline right now is equally split between oncology and immunology in large disease potential because we actually feel like we've de-risked the safety, including learning through our experience with this early program. We feel even more bullish about where we can go.

Awesome. Nello, Jared, thank you very much. Thanks for having the conversation.

Thank you.